Targeting property and toxicity of a novel ultrasound contrast agent microbubble carrying the targeting and drug-loaded complex FA-CNTs-PTX on MCF7 cells.

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Zhang, Jie; Zhang, Yu; Liu, Junxi; Li, Guozhong; Wen, Zhaohui; Zhao, Yue; Zhang, Xiangyu; Liu, Fenghua

2017-10-01

The application of ultrasound contrast agents not only is confined to the enhancement of ultrasound imaging but also has started to be used as a drug system for diagnosis and treatment. In this paper, Span60 and PEG1500 were used as membrane materials, and a new targeting and drug-loading multifunctional ultrasound contrast agent microbubble enveloping the FA-CNTs-PTX complex was successfully prepared by acoustic cavitation. With the breast cancer cell line MCF7 as the research target, the effects of the microbubble with FA-CNTs-PTX on the proliferation and toxicity of MCF7 cells were studied using a CCK-8 and AO/EB double-staining method. The influences of the microbubbles with FA-CNTs-PTX on the cellular morphology and apoptosis period of the MCF7 cells were detected using an inverted fluorescence microscope. The apoptosis of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was investigated with flow cytometry and an annexin and PI double staining fluorescence quantitative analysis. The results indicated that the ultrasound contrast agent microbubble with FA-CNTs-PTX remarkably inhibited the proliferation of MCF7 cells, which was mainly controlled by the drug loading rate and the nanometer size of the microbubbles. Moreover, the proliferative inhibition rate of the microbubbles with FA-CNTs-PTX was related to the cell apoptosis period of MCF7 cells. Its inhibition degree on the proliferation of MCF7 cells was higher than that of the hepatoma HepG2 cells. The apoptosis rate of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was higher than that of normal human umbilical vein endothelial cells (HUVECs), and the microbubbles with FA-CNTs-PTX could target the MCF7 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation.

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Belcik, J Todd; Mott, Brian H; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J; Ammi, Azzdine; Linden, Joel M; Lindner, Jonathan R

2015-04-01

Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×10(8) IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (Pultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; Pultrasound and microbubbles by 70% (Pultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase. © 2015 American Heart Association, Inc.

Ablation of benign prostatic hyperplasia using microbubble-mediated ultrasound cavitation.

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Li, Tao; Liu, Zheng

2010-04-01

Benign prostatic hyperplasia (BPH) is a world-wide common disease in elderly male patients. A number of invasive physiotherapies have been used to replace prostatectomy. In this article we report our hypothesis of using microbubbles-mediated ultrasound cavitation effects to ablate prostatic tissues. Microbubble ultrasound contrast agent is widely used contrast media in ultrasonography, yet it is also found to act as cavitation nuclei or enhancer. Once excited by a high peak pressure ultrasound pulse, the mechanical effects, like shock wave and microstream, released from cavitation could produce a series of bioeffects, contributing to sonoporation, microvascular rupture and hematoma. BPH is known to have hyperplastic neovasculature and this make it possible to be disrupted by the physical effects of cavitation under existing microbubbles in circulation. Mechanical ablation of prostatic capillary or small vessels could result in pathological alterations such as thrombosis, micro-circulation blockage, prostatic necrosis and atrophia. Thereupon it could effectively treat BPH by nontraumatic ways. (c) 2009 Elsevier Ltd. All rights reserved.

Quantitative evaluation of contrast-enhanced ultrasound after intravenous administration of a microbubble contrast agent for differentiation of benign and malignant thyroid nodules: assessment of diagnostic accuracy.

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Nemec, Ursula; Nemec, Stefan F; Novotny, Clemens; Weber, Michael; Czerny, Christian; Krestan, Christian R

2012-06-01

To investigate the diagnostic accuracy, through quantitative analysis, of contrast-enhanced ultrasound (CEUS), using a microbubble contrast agent, in the differentiation of thyroid nodules. This prospective study enrolled 46 patients with solitary, scintigraphically non-functional thyroid nodules. These patients were scheduled for surgery and underwent preoperative CEUS with pulse-inversion harmonic imaging after intravenous microbubble contrast medium administration. Using histology as a standard of reference, time-intensity curves of benign and malignant nodules were compared by means of peak enhancement and wash-out enhancement relative to the baseline intensity using a mixed model ANOVA. ROC analysis was performed to assess the diagnostic accuracy in the differentiation of benign and malignant nodules on CEUS. The complete CEUS data of 42 patients (31/42 [73.8%] benign and 11/42 [26.2%] malignant nodules) revealed a significant difference (P benign and malignant nodules. Furthermore, based on ROC analysis, CEUS demonstrated sensitivity of 76.9%, specificity of 84.8% and accuracy of 82.6%. Quantitative analysis of CEUS using a microbubble contrast agent allows the differentiation of benign and malignant thyroid nodules and may potentially serve, in addition to grey-scale and Doppler ultrasound, as an adjunctive tool in the assessment of patients with thyroid nodules. • Contrast-enhanced ultrasound (CEUS) helps differentiate between benign and malignant thyroid nodules. • Quantitative CEUS analysis yields sensitivity of 76.9% and specificity of 84.8%. • CEUS may be a potentially useful adjunct in assessing thyroid nodules.

Splenic abnormalities: a comparative review of ultrasound, microbubble-enhanced ultrasound and computed tomography

Energy Technology Data Exchange (ETDEWEB)

Peddu, P.; Shah, M.; Sidhu, P.S. E-mail: paul.sidhu@kingsch.nhs.uk

2004-09-01

The ultrasound appearances of abnormalities of the spleen are reviewed and images compared with computed tomography. Focal lesions, both benign and malignant, trauma, infarction and congenital abnormalities are presented. The use of microbubble ultrasound contrast media as an aid to identifying and characterizing abnormalities is discussed.

Counter-propagating wave interaction for contrast-enhanced ultrasound imaging

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Renaud, G.; Bosch, J. G.; ten Kate, G. L.; Shamdasani, V.; Entrekin, R.; de Jong, N.; van der Steen, A. F. W.

2012-11-01

Most techniques for contrast-enhanced ultrasound imaging require linear propagation to detect nonlinear scattering of contrast agent microbubbles. Waveform distortion due to nonlinear propagation impairs their ability to distinguish microbubbles from tissue. As a result, tissue can be misclassified as microbubbles, and contrast agent concentration can be overestimated; therefore, these artifacts can significantly impair the quality of medical diagnoses. Contrary to biological tissue, lipid-coated gas microbubbles used as a contrast agent allow the interaction of two acoustic waves propagating in opposite directions (counter-propagation). Based on that principle, we describe a strategy to detect microbubbles that is free from nonlinear propagation artifacts. In vitro images were acquired with an ultrasound scanner in a phantom of tissue-mimicking material with a cavity containing a contrast agent. Unlike the default mode of the scanner using amplitude modulation to detect microbubbles, the pulse sequence exploiting counter-propagating wave interaction creates no pseudoenhancement behind the cavity in the contrast image.

Counter-propagating wave interaction for contrast-enhanced ultrasound imaging

International Nuclear Information System (INIS)

Renaud, G; Bosch, J G; Ten Kate, G L; De Jong, N; Van der Steen, A F W; Shamdasani, V; Entrekin, R

2012-01-01

Most techniques for contrast-enhanced ultrasound imaging require linear propagation to detect nonlinear scattering of contrast agent microbubbles. Waveform distortion due to nonlinear propagation impairs their ability to distinguish microbubbles from tissue. As a result, tissue can be misclassified as microbubbles, and contrast agent concentration can be overestimated; therefore, these artifacts can significantly impair the quality of medical diagnoses. Contrary to biological tissue, lipid-coated gas microbubbles used as a contrast agent allow the interaction of two acoustic waves propagating in opposite directions (counter-propagation). Based on that principle, we describe a strategy to detect microbubbles that is free from nonlinear propagation artifacts. In vitro images were acquired with an ultrasound scanner in a phantom of tissue-mimicking material with a cavity containing a contrast agent. Unlike the default mode of the scanner using amplitude modulation to detect microbubbles, the pulse sequence exploiting counter-propagating wave interaction creates no pseudoenhancement behind the cavity in the contrast image. (fast track communication)

Ultrasound imaging of the mouse pancreatic duct using lipid microbubbles

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Banerjee, B.; McKeown, K. R.; Skovan, B.; Ogram, E.; Ingram, P.; Ignatenko, N.; Paine-Murrieta, G.; Witte, R.; Matsunaga, T. O.

2012-03-01

Research requiring the murine pancreatic duct to be imaged is often challenging due to the difficulty in selectively cannulating the pancreatic duct. We have successfully catheterized the pancreatic duct through the common bile duct in severe combined immune deficient (SCID) mice and imaged the pancreatic duct with gas filled lipid microbubbles that increase ultrasound imaging sensitivity due to exquisite scattering at the gas/liquid interface. A SCID mouse was euthanized by CO2, a midline abdominal incision made, the common bile duct cut at its midpoint, a 2 cm, 32 gauge tip catheter was inserted about 1 mm into the duct and tied with suture. The duodenum and pancreas were excised, removed in toto, embedded in agar and an infusion pump was used to instill normal saline or lipid-coated microbubbles (10 million / ml) into the duct. B-mode images before and after infusion of the duct with microbubbles imaged the entire pancreatic duct (~ 1 cm) with high contrast. The microbubbles were cavitated by high mechanical index (HMI) ultrasound for imaging to be repeated. Our technique of catheterization and using lipid microbubbles as a contrast agent may provide an effective, affordable technique of imaging the murine pancreatic duct; cavitation with HMI ultrasound would enable repeated imaging to be performed and clustering of targeted microbubbles to receptors on ductal cells would allow pathology to be localized accurately. This research was supported by the Experimental Mouse Shared Service of the AZ Cancer Center (Grant Number P30CA023074, NIH/NCI and the GI SPORE (NIH/NCI P50 CA95060).

Acoustic Characterization and Enhanced Ultrasound Imaging of Long-Circulating Lipid-Coated Microbubbles.

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Li, Hongbo; Yang, Yanye; Zhang, Meimei; Yin, Liping; Tu, Juan; Guo, Xiasheng; Zhang, Dong

2018-05-01

A long-circulating lipid-coated ultrasound (US) contrast agent was fabricated to achieve a longer wash-out time and gain more resistance against higher-mechanical index sonication. Systemic physical, acoustic, and in vivo imaging experiments were performed to better understand the underlying mechanism enabling the improvement of contrast agent performance by adjusting the physical and acoustic properties of contrast agent microbubbles. By simply altering the gas core, a kind of US contrast agent microbubble was synthesized with a similar lipid-coating shell as SonoVue microbubbles (Bracco SpA, Milan, Italy) to achieve a longer wash-out time and higher inertial cavitation threshold. To bridge the structure-performance relationship of the synthesized microbubbles, the imaging performance of the microbubbles was assessed in vivo with SonoVue as a control group. The size distribution and inertial cavitation threshold of the synthesized microbubbles were characterized, and the shell parameters of the microbubbles were determined by acoustic attenuation measurements. All of the measurements were compared with SonoVue microbubbles. The synthesized microbubbles had a spherical shape, a smooth, consistent membrane, and a uniform distribution, with an average diameter of 1.484 μm. According to the measured attenuation curve, the synthesized microbubbles resonated at around 2.8 MHz. Although the bubble's shell elasticity (0.2 ± 0.09 N/m) was comparable with SonoVue, it had relatively greater viscosity and inertial cavitation because of the different gas core. Imaging studies showed that the synthesized microbubbles had a longer circulation time and a better chance of fighting against rapid collapse than SonoVue. Nano/micrometer long-circulating lipid-coated microbubbles could be fabricated by simply altering the core composition of SonoVue microbubbles with a higher-molecular weight gas. The smaller diameter and higher inertial cavitation threshold of the

Lung surfactant microbubbles increase lipophilic drug payload for ultrasound-targeted delivery.

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Sirsi, Shashank R; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y; Mountford, Paul A; Borden, Mark A

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta(®), Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload.

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

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Donghee Park

Full Text Available Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

Science.gov (United States)

Park, Donghee; Song, Gillsoo; Jo, Yongjun; Won, Jongho; Son, Taeyoon; Cha, Ohrum; Kim, Jinho; Jung, Byungjo; Park, Hyunjin; Kim, Chul-Woo; Seo, Jongbum

2016-01-01

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the

Microfluidics-based microbubbles in methylene blue solution for photoacoustic and ultrasound imaging

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Das, Dhiman; Sivasubramanian, Kathyayini; Yang, Chun; Pramanik, Manojit

2018-02-01

Contrast agents which can be used for more than one bio-imaging technique has gained a lot of attention from researchers in recent years. In this work, a microfluidic device employing a flow-focusing junction, is used for the continuous generation of monodisperse nitrogen microbubbles in methylene blue, an optically absorbing organic dye, for dual-modal photoacoustic and ultrasound imaging. Using an external phase of polyoxyethylene glycol 40 stearate (PEG 40), a non-ionic surfactant, and 50% glycerol solution at a flow rate of 1 ml/hr and gas pressure at 1.75 bar, monodisperse nitrogen microbubbles of diameter 7 microns were obtained. The external phase also contained methylene blue hydrate at a concentration of 1 gm/litre. The monodisperse microbubbles produced a strong ultrasound signal as expected. It was observed that the signal-to-noise (SNR) ratio of the photoacoustic signal for the methylene blue solution in the presence of the monodisperse microbubbles was 68.6% lower than that of methylene blue solution in the absence of microbubbles. This work is of significance because using microfluidics, we can precisely control the bubbles' production rate and bubble size which increases ultrasound imaging efficiency. A uniform size distribution of the bubbles will have narrower resonance frequency bandwidth which will respond well to specific ultrasound frequencies.

Theragnostic ultrasound using microbubbles in the treatment of prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Lee, Hak Jong; Yoon, Young Il; Bae, Yun Jung [Dept. of Radiology, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of)

2016-08-15

The use of gas-filled microbubbles in perfusion monitoring as intravascular ultrasound contrast agents has recently become more common. Additionally, microbubbles are employed as carriers of pharmaceutical substances or genes. Microbubbles have great potential to improve the delivery of therapeutic materials into cells and to modify vascular permeability, causing increased extravasation of drugs and drug carriers. Prostate cancer is the most common neoplasm in Europe and America, with an incidence twice to three times that of lung and colorectal cancer. Its incidence is still rising in Asian countries, including Japan and Korea. In this review, we present current strategies regarding the synthesis of microbubbles with targeted ligands on their surfaces, with a focus on prostate cancer.

Ultrasound contrast agents: An overview

International Nuclear Information System (INIS)

Cosgrove, David

2006-01-01

With the introduction of microbubble contrast agents, diagnostic ultrasound has entered a new era that allows the dynamic detection of tissue flow of both the macro and microvasculature. Underpinning this development is the fact that gases are compressible, and thus the microbubbles expand and contract in the alternating pressure waves of the ultrasound beam, while tissue is almost incompressible. Special software using multiple pulse sequences separates these signals from those of tissue and displays them as an overlay or on a split screen. This can be done at low acoustic pressures (MI < 0.3) so that the microbubbles are not destroyed and scanning can continue in real time. The clinical roles of contrast enhanced ultrasound scanning are expanding rapidly. They are established in echocardiography to improve endocardial border detection and are being developed for myocardial perfusion. In radiology, the most important application is the liver, especially for focal disease. The approach parallels that of dynamic CT or MRI but ultrasound has the advantages of high spatial and temporal resolution. Thus, small lesions that can be indeterminate on CT can often be studied with ultrasound, and situations where the flow is very rapid (e.g., focal nodular hyperplasia where the first few seconds of arterial perfusion may be critical to making the diagnosis) are readily studied. Microbubbles linger in the extensive sinusoidal space of normal liver for several minutes whereas they wash out rapidly from metastases, which have a low vascular volume and thus appear as filling defects. The method has been shown to be as sensitive as three-phase CT. Microbubbles have clinical uses in many other applications where knowledge of the microcirculation is important (the macrocirculation can usually be assessed adequately using conventional Doppler though there are a few important situations where the signal boost given by microbubbles is useful, e.g., transcranial Doppler for evaluating

Ultrasound contrast agents: an overview.

Science.gov (United States)

Cosgrove, David

2006-12-01

With the introduction of microbubble contrast agents, diagnostic ultrasound has entered a new era that allows the dynamic detection of tissue flow of both the macro and microvasculature. Underpinning this development is the fact that gases are compressible, and thus the microbubbles expand and contract in the alternating pressure waves of the ultrasound beam, while tissue is almost incompressible. Special software using multiple pulse sequences separates these signals from those of tissue and displays them as an overlay or on a split screen. This can be done at low acoustic pressures (MIdeveloped for myocardial perfusion. In radiology, the most important application is the liver, especially for focal disease. The approach parallels that of dynamic CT or MRI but ultrasound has the advantages of high spatial and temporal resolution. Thus, small lesions that can be indeterminate on CT can often be studied with ultrasound, and situations where the flow is very rapid (e.g., focal nodular hyperplasia where the first few seconds of arterial perfusion may be critical to making the diagnosis) are readily studied. Microbubbles linger in the extensive sinusoidal space of normal liver for several minutes whereas they wash out rapidly from metastases, which have a low vascular volume and thus appear as filling defects. The method has been shown to be as sensitive as three-phase CT. Microbubbles have clinical uses in many other applications where knowledge of the microcirculation is important (the macrocirculation can usually be assessed adequately using conventional Doppler though there are a few important situations where the signal boost given by microbubbles is useful, e.g., transcranial Doppler for evaluating vasospasm after subarachnoid haemorrhage). An important situation where demonstrating tissue devitalisation is important is in interstitial ablation of focal liver lesions: using microbubble contrast agents at the end of a procedure allows immediate evaluation of the

Acoustic bubble sorting for ultrasound contrast agent enrichment.

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Segers, Tim; Versluis, Michel

2014-05-21

An ultrasound contrast agent (UCA) suspension contains encapsulated microbubbles with a wide size distribution, with radii ranging from 1 to 10 μm. Medical transducers typically operate at a single frequency, therefore only a small selection of bubbles will resonate to the driving ultrasound pulse. Thus, the sensitivity can be improved by narrowing down the size distribution. Here, we present a simple lab-on-a-chip method to sort the population of microbubbles on-chip using a traveling ultrasound wave. First, we explore the physical parameter space of acoustic bubble sorting using well-defined bubble sizes formed in a flow-focusing device, then we demonstrate successful acoustic sorting of a commercial UCA. This novel sorting strategy may lead to an overall improvement of the sensitivity of contrast ultrasound by more than 10 dB.

The 'humble' bubble: Contrast-enhanced ultrasound

International Nuclear Information System (INIS)

Marshall, Gill; Sykes, Anne; Berry, Jonathan; Jonker, Leon

2011-01-01

The use of contrast-enhanced ultrasound (CEUS) is increasing within the field of medical imaging. Ultrasonic contrast agent (UCA) contain gas microbubbles similar in size to red corpuscles which provide highly reflective interfaces, enabling dynamic demonstration of echogenic streams of the contrast within the anatomical area of interest on real-time grey scale ultrasound. Longevity of the microbubbles has been improved by changing their composition. The application of CEUS in the UK continues to grow, bringing it into territories historically occupied by computerised tomography (CT) scanning and magnetic resonance imaging (MRI). Hence, the role of CEUS may be of interest to all diagnostic imaging practitioners. Here we summarise the mode of action and use of CEUS, and its role within a range of applications. The potential risks of CEUS are compared to other contrast-enhanced imaging techniques. The benefits of CEUS and its implications for diagnostic imaging practice are also covered.

Computer-assisted quantitative assessment of power Doppler US: effects of microbubble contrast agent in the differentiation of breast tumors

International Nuclear Information System (INIS)

Kettenbach, Joachim; Helbich, Thomas H.; Huber, Sabine; Zuna, Ivan; Dock, Wolfgang

2005-01-01

Rationale and objectives: To objectively quantify the effects of a microbubble contrast agent to differentiate breast tumors with power doppler ultrasound and to compare these results with color doppler ultrasound (CD US). Methods: In 47 patients a microbubble contrast agent was injected intravenously. Computer-assisted quantitative assessment of the color pixel density was performed to evaluate the increase in Doppler signals. Results were compared to previously published results of a color Doppler ultrasound study. Results: Peak color pixel density at contrast-enhanced power Doppler ultrasound was higher for carcinomas than for benign tumors (P < 0.03). Time to peak enhancement was shorter in carcinomas than in benign tumors (P < 0.01). For both parameters, diagnostic accuracy of power Doppler ultrasound was 69 and 78%, and for color Doppler ultrasound 62 and 76%, respectively. Conclusions: Quantitative assessment of contrast-enhanced power Doppler ultrasound showed significant differences in malignant and benign breast tumors. Diagnostic accuracy of contrast-enhanced power Doppler ultrasound was higher compared to color Doppler ultrasound

Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis.

Science.gov (United States)

Kim, Jinwook; Lindsey, Brooks D; Chang, Wei-Yi; Dai, Xuming; Stavas, Joseph M; Dayton, Paul A; Jiang, Xiaoning

2017-06-14

Effective removal or dissolution of large blood clots remains a challenge in clinical treatment of acute thrombo-occlusive diseases. Here we report the development of an intravascular microbubble-mediated sonothrombolysis device for improving thrombolytic rate and thus minimizing the required dose of thrombolytic drugs. We hypothesize that a sub-megahertz, forward-looking ultrasound transducer with an integrated microbubble injection tube is more advantageous for efficient thrombolysis by enhancing cavitation-induced microstreaming than the conventional high-frequency, side-looking, catheter-mounted transducers. We developed custom miniaturized transducers and demonstrated that these transducers are able to generate sufficient pressure to induce cavitation of lipid-shelled microbubble contrast agents. Our technology demonstrates a thrombolysis rate of 0.7 ± 0.15 percent mass loss/min in vitro without any use of thrombolytic drugs.

Effect of microbubble contrast agent during high intensity focused ultrasound ablation on rabbit liver in vivo

International Nuclear Information System (INIS)

Chung, Dong Jin; Cho, Se Hyun; Lee, Jae Mun; Hahn, Seong-Tae

2012-01-01

Objective: To evaluate the effect of a microbubble contrast agent (SonoVue) during HIFU ablation of a rabbit liver. Materials and methods: HIFU ablations (intensity of 400 W/cm 2 for 4 s, six times, with a 5 s interval between exposures) were performed upon 16 in vivo rabbit livers before and after intravenous injection of a microbubble contrast agent (0.8 ml). A Wilcoxon signed rank test was used to compare mean ablation volume and time required to tissue ablation on real-time US. Shape of ablation and pattern of coagulative necrosis were analyzed by Fisher's exact test. Results: The volume of coagulative necrosis was significantly larger in the combination microbubble and HIFU group than in the HIFU alone group (P < 0.05). Also, time to reach ablation was shorter in the combination microbubble and HIFU group than in the HIFU alone group (P < 0.05). When analyzing the shape of tissue ablation, a pyramidal shape was more prevalently in the HIFU alone group compared to the combination microbubble and HIFU group (P < 0.05). Following an analysis of the pattern of coagulative necrosis, non-cavitary necrosis was found in ten and cavitary necrosis in six of the samples in the combination microbubble and HIFU group. Conversely, non-cavitary necrosis occurred in all 16 samples in the HIFU alone group (P < 0.05). Conclusion: HIFU of in vivo rabbit livers with a microbubble contrast agent produced larger zones of ablation and more cavitary tissue necrosis than without the use of a microbubble contrast agent. Microbubble contrast agents may be useful in tissue ablation by enhancing the treatment effect of HIFU.

Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound.

Directory of Open Access Journals (Sweden)

Jonathan A Kopechek

Full Text Available RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14. Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9 or control RNA (n = 8 during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3 confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively. Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease.

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles

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Fan, Z.; Chen, D.; Deng, C.X.

2013-01-01

Ultrasound application in the presence of microbubbles has shown great potential for non-viral gene transfection via transient disruption of cell membrane (sonoporation). However, improvement of its efficiency has largely relied on empirical approaches without consistent and translatable results. The goal of this study is to develop a rational strategy based on new results obtained using novel experimental techniques and analysis to improve sonoporation gene transfection. We conducted experiments using targeted microbubbles that were attached to cell membrane to facilitate sonoporation. We quantified the dynamic activities of microbubbles exposed to pulsed ultrasound and the resulting sonoporation outcome and identified distinct regimes of characteristic microbubble behaviors: stable cavitation, coalescence and translation, and inertial cavitation. We found that inertial cavitation generated the highest rate of membrane poration. By establishing direct correlation of ultrasound-induced bubble activities with intracellular uptake and pore size, we designed a ramped pulse exposure scheme for optimizing microbubble excitation to improve sonoporation gene transfection. We implemented a novel sonoporation gene transfection system using an aqueous two phase system (ATPS) for efficient use of reagents and high throughput operation. Using plasmid coding for the green fluorescence protein (GFP), we achieved a sonoporation transfection efficiency in rate aortic smooth muscle cells (RASMCs) of 6.9% ± 2.2% (n = 9), comparable with lipofection (7.5% ± 0.8%, n = 9). Our results reveal characteristic microbubble behaviors responsible for sonoporation and demonstrated a rational strategy to improve sonoporation gene transfection. PMID:23770009

Ultrasound-induced Gas Release from Contrast Agent Microbubbles

NARCIS (Netherlands)

Postema, M.A.B.; Postema, Michiel; Bouakaz, Ayache; Versluis, Michel; de Jong, N.

2005-01-01

We investigated gas release from two hard-shelled ultrasound contrast agents by subjecting them to high-mechanical index (MI) ultrasound and simultaneously capturing high-speed photographs. At an insonifying frequency of 1.7 MHz, a larger percentage of contrast bubbles is seen to crack than at 0.5

Acoustic bubble sorting for ultrasound contrast agent enrichment

NARCIS (Netherlands)

Segers, T.J.; Versluis, Michel

2014-01-01

An ultrasound contrast agent (UCA) suspension contains encapsulated microbubbles with a wide size distribution, with radii ranging from 1 to 10 μm. Medical transducers typically operate at a single frequency, therefore only a small selection of bubbles will resonate to the driving ultrasound pulse.

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles.

Science.gov (United States)

Fan, Z; Chen, D; Deng, C X

2013-09-28

Ultrasound application in the presence of microbubbles has shown great potential for non-viral gene transfection via transient disruption of cell membrane (sonoporation). However, improvement of its efficiency has largely relied on empirical approaches without consistent and translatable results. The goal of this study is to develop a rational strategy based on new results obtained using novel experimental techniques and analysis to improve sonoporation gene transfection. In this study, we conducted experiments using targeted microbubbles that were attached to cell membrane to facilitate sonoporation. We quantified the dynamic activities of microbubbles exposed to pulsed ultrasound and the resulting sonoporation outcome, and identified distinct regimes of characteristic microbubble behaviors: stable cavitation, coalescence and translation, and inertial cavitation. We found that inertial cavitation generated the highest rate of membrane poration. By establishing direct correlation of ultrasound-induced bubble activities with intracellular uptake and pore size, we designed a ramped pulse exposure scheme for optimizing microbubble excitation to improve sonoporation gene transfection. We implemented a novel sonoporation gene transfection system using an aqueous two phase system (ATPS) for efficient use of reagents and high throughput operation. Using plasmids coding for the green fluorescence protein (GFP), we achieved a sonoporation transfection efficiency in rate aortic smooth muscle cells (RASMCs) of 6.9%±2.2% (n=9), comparable with lipofection (7.5%±0.8%, n=9). Our results reveal characteristic microbubble behaviors responsible for sonoporation and demonstrated a rational strategy to improve sonoporation gene transfection. Copyright © 2013 Elsevier B.V. All rights reserved.

Synthesis of Laboratory Ultrasound Contrast Agents

Directory of Open Access Journals (Sweden)

Jaemin Oh

2013-10-01

Full Text Available Ultrasound Contrast Agents (UCAs were developed to maximize reflection contrast so that organs can be seen clearly in ultrasound imaging. UCAs increase the signal to noise ratio (SNR by linear and non-linear mechanisms and thus help more accurately visualize the internal organs and blood vessels. However, the UCAs on the market are not only expensive, but are also not optimized for use in various therapeutic research applications such as ultrasound-aided drug delivery. The UCAs fabricated in this study utilize conventional lipid and albumin for shell formation and perfluorobutane as the internal gas. The shape and density of the UCA bubbles were verified by optical microscopy and Cryo SEM, and compared to those of the commercially available UCAs, Definity® and Sonovue®. The size distribution and characteristics of the reflected signal were also analyzed using a particle size analyzer and ultrasound imaging equipment. Our experiments indicate that UCAs composed of spherical microbubbles, the majority of which were smaller than 1 um, were successfully synthesized. Microbubbles 10 um or larger were also identified when different shell characteristics and filters were used. These laboratory UCAs can be used for research in both diagnoses and therapies.

Evaluation of high frequency ultrasound methods and contrast agents for characterising tumor response to anti-angiogenic treatment

Energy Technology Data Exchange (ETDEWEB)

Rix, Anne, E-mail: arix@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Lederle, Wiltrud, E-mail: wlederle@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Siepmann, Monica, E-mail: monica.siepmann@rub.de [Department of Medical Engineering, Universitätstraße 150, 44780 Bochum, Ruhr-University Bochum, Bochum (Germany); Fokong, Stanley, E-mail: sfokong@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Behrendt, Florian F., E-mail: fbehrendt@ukaachen.de [Department of Nuclear Medicine, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Bzyl, Jessica, E-mail: jbzyl@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Grouls, Christoph, E-mail: cgrouls@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Kiessling, Fabian, E-mail: fkiessling@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Palmowski, Moritz, E-mail: mpalmowski@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Department of Nuclear Medicine, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany)

2012-10-15

Purpose: To compare non-enhanced and contrast-enhanced high-frequency 3D Doppler ultrasound with contrast-enhanced 2D and 3D B-mode imaging for assessing tumor vascularity during antiangiogenic treatment using soft-shell and hard-shell microbubbles. Materials and methods: Antiangiogenic therapy effects (SU11248) on vascularity of subcutaneous epidermoid-carcinoma xenografts (A431) in female CD1 nude mice were investigated longitudinally using non-enhanced and contrast-enhanced 3D Doppler at 25 MHz. Additionally, contrast-enhanced 2D and 3D B-mode scans were performed by injecting hard-shell (poly-butyl-cyanoacrylate-based) and soft-shell (phospholipid-based) microbubbles. Suitability of both contrast agents for high frequency imaging and the sensitivity of the different ultrasound methods to assess early antiangiogenic therapy effects were investigated. Ultrasound data were validated by immunohistology. Results: Hard-shell microbubbles induced higher signal intensity changes in tumors than soft-shell microbubbles in 2D B-mode measurements (424 ± 7 vs. 169 ± 8 A.U.; p < 0.01). In 3D measurements, signals of soft-shell microbubbles were hardly above the background (5.48 ± 4.57 vs. 3.86 ± 2.92 A.U.), while signals from hard-shell microbubbles were sufficiently high (30.5 ± 8.06 A.U). Using hard-shell microbubbles 2D and 3D B-mode imaging depicted a significant decrease in tumor vascularity during antiangiogenic therapy from day 1 on. Using soft-shell microbubbles significant therapy effects were observed at day 4 after therapy in 2D B-mode imaging but could not be detected in the 3D mode. With non-enhanced and contrast-enhanced Doppler imaging significant differences between treated and untreated tumors were found from day 2 on. Conclusion: Hard-shell microbubble-enhanced 2D and 3D B-mode ultrasound achieved highest sensitivity for assessing therapy effects on tumor vascularisation and were superior to B-mode ultrasound with soft-shell microbubbles and to Doppler

Ultrasound-microbubble mediated cavitation of plant cells: effects on morphology and viability.

Science.gov (United States)

Qin, Peng; Xu, Lin; Zhong, Wenjing; Yu, Alfred C H

2012-06-01

The interaction between ultrasound pulses and microbubbles is known to generate acoustic cavitation that may puncture biological cells. This work presents new experimental findings on the bioeffects of ultrasound-microbubble mediated cavitation in plant cells with emphasis on direct observations of morphological impact and analysis of viability trends in tobacco BY-2 cells that are widely studied in higher plant physiology. The tobacco cell suspensions were exposed to 1 MHz ultrasound pulses in the presence of 1% v/v microbubbles (10% duty cycle; 1 kHz pulse repetition frequency; 70 mm between probe and cells; 1-min exposure time). Few bioeffects were observed at low peak negative pressures (cavitation presumably occurred. In contrast, at 0.9 MPa peak negative pressure (with more inertial cavitation activities according to our passive cavitation detection results), random pores were found on tobacco cell wall (observed via scanning electron microscopy) and enhanced exogenous uptake into the cytoplasm was evident (noted in our fluorescein isothiocyanate dextran uptake analysis). Also, instant lysis was observed in 23.4% of cells (found using trypan blue staining) and programmed cell death was seen in 23.3% of population after 12 h (determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling [TUNEL]). These bioeffects generally correspond in trend with those for mammalian cells. This raises the possibility of developing ultrasound-microbubble mediated cavitation into a targeted gene transfection paradigm for plant cells and, conversely, adopting plant cells as experimental test-beds for sonoporation-based gene therapy in mammalian cells. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis.

Science.gov (United States)

Huang, Cuiyuan; Zhang, Hong; Bai, Ruidan

2017-07-01

Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble-mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

Hemostatic mechanism underlying microbubble-enhanced non-focused ultrasound in the treatment of a rabbit liver trauma model

Science.gov (United States)

Zhao, Da-wei; Tian, Meng; Yang, Jian-zheng; Du, Peng; Bi, Jie; Zhu, Xinjian

2016-01-01

The aim of our study was to investigate the hemostatic mechanism underlying microbubble-enhanced non-focused ultrasound treatment of liver trauma. Thirty rabbits with liver trauma were randomly divided into three groups—the microbubble-enhanced ultrasound (MEUS; further subdivided based on exposure intensity into MEUS1 [0.11 W/cm2], MEUS2 [0.55 W/cm2], and MEUS3 [1.1 W/cm2]), ultrasound without microbubbles (US), and microbubbles without ultrasound (MB) groups. The pre- and post-treatment bleeding weight and visual bleeding scores were evaluated. The serum liver enzyme concentrations as well as the blood perfusion level represented by mean peak contrast intensity (PI) ratio in the treatment area were analyzed. The hemostatic mechanism was evaluated by histological and transmission electron microscopic examination of liver tissue samples. The MEUS subgroups 1–3 (grade 0–1, grade 0–2, and grade 1–2, respectively) exhibited significantly lower post-treatment visual bleeding scores than the US and MB groups (both, grade 3–4; all, P hepatic cells became edematous and compressed the hepatic sinus and associated blood vessels. However, the serum liver enzyme levels were not significantly altered. Microbubble-enhanced non-focused ultrasound does not significantly affect blood perfusion and liver function and can be used to induce rapid hemostasis in case of liver trauma. PMID:27633577

Facilitating Intracellular Drug Delivery by Ultrasound-Activated Microbubbles

NARCIS (Netherlands)

Lammertink, BHA

2017-01-01

The goal of this thesis was to investigate the combination of ultrasound and microbubbles (USMB) for intracellular delivery of (model) drugs in vitro. We have focused on clinically approved drugs, i.e. cisplatin, and microbubbles, i.e. SonoVue™, to facilitate clinical translation. In addition, model

Microbubbles as contrast agent for in-line x-ray phase-contrast imaging

International Nuclear Information System (INIS)

Xi Yan; Zhao Jun; Tang Rongbiao; Wang Yujie

2011-01-01

In the present study, we investigated the potential of gas-filled microbubbles as contrast agents for in-line x-ray phase-contrast imaging (PCI) in biomedical applications. When imaging parameters are optimized, the microbubbles function as microlenses that focus the incoming x-rays to form bright spots, which can significantly enhance the image contrast. Since microbubbles have been shown to be safe contrast agents in clinical ultrasonography, this contrast-enhancement procedure for PCI may have promising utility in biomedical applications, especially when the dose of radiation is a serious concern. In this study, we performed both numerical simulations and ex vivo experiments to investigate the formation of the contrast and the effectiveness of microbubbles as contrast agents in PCI.

Real-time contrast ultrasound muscle perfusion imaging with intermediate-power imaging coupled with acoustically durable microbubbles.

Science.gov (United States)

Seol, Sang-Hoon; Davidson, Brian P; Belcik, J Todd; Mott, Brian H; Goodman, Reid M; Ammi, Azzdine; Lindner, Jonathan R

2015-06-01

There is growing interest in limb contrast-enhanced ultrasound (CEU) perfusion imaging for the evaluation of peripheral artery disease. Because of low resting microvascular blood flow in skeletal muscle, signal enhancement during limb CEU is prohibitively low for real-time imaging. The aim of this study was to test the hypothesis that this obstacle can be overcome by intermediate- rather than low-power CEU when performed with an acoustically resilient microbubble agent. Viscoelastic properties of Definity and Sonazoid were assessed by measuring bulk modulus during incremental increases in ambient pressure to 200 mm Hg. Comparison of in vivo microbubble destruction and signal enhancement at a mechanical index (MI) of 0.1 to 0.4 was performed by sequential reduction in pulsing interval from 10 to 0.05 sec during limb CEU at 7 MHz in mice and 1.8 MHz in dogs. Destruction was also assessed by broadband signal generation during passive cavitation detection. Real-time CEU perfusion imaging with destruction-replenishment was then performed at 1.8 MHz in dogs using an MI of 0.1, 0.2, or 0.3. Sonazoid had a higher bulk modulus than Definity (66 ± 12 vs 29 ± 2 kPa, P = .02) and exhibited less inertial cavitation (destruction) at MIs ≥ 0.2. On in vivo CEU, maximal signal intensity increased incrementally with MI for both agents and was equivalent between agents except at an MI of 0.1 (60% and 85% lower for Sonazoid at 7 and 1.8 MHz, respectively, P power imaging coupled with a durable microbubble contrast agent. Copyright © 2015 American Society of Echocardiography. All rights reserved.

Effect of microbubble ligation to cells on ultrasound signal enhancement: implications for targeted imaging.

Science.gov (United States)

Lankford, Miles; Behm, Carolyn Z; Yeh, James; Klibanov, Alexander L; Robinson, Peter; Lindner, Jonathan R

2006-10-01

Molecular imaging with contrast-enhanced ultrasound (CEU) relies on the detection of microbubbles retained in regions of disease. The aim of this study was to determine whether microbubble attachment to cells influences their acoustic signal generation and stability. Biotinylated microbubbles were attached to streptavidin-coated plates to derive density versus intensity relations during low- and high-power imaging. To assess damping from microbubble attachment to solid or cell surfaces, in vitro imaging was performed for microbubbles charge-coupled to methacrylate spheres and for vascular cell adhesion molecule-1-targeted microbubbles attached to endothelial cells. Signal enhancement on plates increased according to acoustic power and microbubble site density up to 300 mm. Microbubble signal was reduced by attachment to solid spheres during high- and low-power imaging but was minimally reduced by attachment to endothelial cells and only at low power. Attachment of targeted microbubbles to rigid surfaces results in damping and a reduction of their acoustic signal, which is not seen when microbubbles are attached to cells. A reliable concentration versus intensity relationship can be expected from microbubble attachment to 2-dimensional surfaces until a very high site density is reached.

Cavitation and contrast: the use of bubbles in ultrasound imaging and therapy.

Science.gov (United States)

Stride, E P; Coussios, C C

2010-01-01

Microbubbles and cavitation are playing an increasingly significant role in both diagnostic and therapeutic applications of ultrasound. Microbubble ultrasound contrast agents have been in clinical use now for more than two decades, stimulating the development of a range of new contrast-specific imaging techniques which offer substantial benefits in echocardiography, microcirculatory imaging, and more recently, quantitative and molecular imaging. In drug delivery and gene therapy, microbubbles are being investigated/developed as vehicles which can be loaded with the required therapeutic agent, traced to the target site using diagnostic ultrasound, and then destroyed with ultrasound of higher intensity energy burst to release the material locally, thus avoiding side effects associated with systemic administration, e.g. of toxic chemotherapy. It has moreover been shown that the motion of the microbubbles increases the permeability of both individual cell membranes and the endothelium, thus enhancing therapeutic uptake, and can locally increase the activity of drugs by enhancing their transport across biologically inaccessible interfaces such as blood clots or solid tumours. In high-intensity focused ultrasound (HIFU) surgery and lithotripsy, controlled cavitation is being investigated as a means of increasing the speed and efficacy of the treatment. The aim of this paper is both to describe the key features of the physical behaviour of acoustically driven bubbles which underlie their effectiveness in biomedical applications and to review the current state of the art.

Detection of an occult hepatocellular carcinoma using ultrasound with liver-specific microbubbles

International Nuclear Information System (INIS)

Harvey, Christopher J.; Lim, Adrian K.P.; Blomley, Martin J.K.; Cosgrove, David O.; Taylor-Robinson, Simon D.; Gedroyc, Wladyslaw M.W.

2002-01-01

The radiological surveillance of cirrhosis to detect the development of hepatocellular carcinoma (HCC) is problematic because no highly sensitive and specific imaging investigation is available. Ultrasound is typically the first modality used but is less accurate than other imaging modalities. We report the first case of a patient with cirrhosis in whom US imaging with liver-specific microbubbles detected an HCC prior to its detection by MR. The use of liver-specific microbubble US contrast agents is an exciting development in the detection of HCC in chronic liver disease and may help to rectify some of the shortcomings of US. (orig.)

Collapse dynamics of ultrasound contrast agent microbubbles

Science.gov (United States)

King, Daniel Alan

Ultrasound contrast agents (UCAs) are micron-sized gas bubbles encapsulated with thin shells on the order of nanometers thick. The damping effects of these viscoelastic coatings are widely known to significantly alter the bubble dynamics for linear and low-amplitude behavior; however, their effects on strongly nonlinear and destruction responses are much less studied. This dissertation examines the behaviors of single collapsing shelled microbubbles using experimental and theoretical methods. The study of their dynamics is particularly relevant for emerging experimental uses of UCAs which seek to leverage localized mechanical forces to create or avoid specialized biomedical effects. The central component in this work is the study of postexcitation rebound and collapse, observed acoustically to identify shell rupture and transient inertial cavitation of single UCA microbubbles. This time-domain analysis of the acoustic response provides a unique method for characterization of UCA destruction dynamics. The research contains a systematic documentation of single bubble postexcitation collapse through experimental measurement with the double passive cavitation detection (PCD) system at frequencies ranging from 0.9 to 7.1 MHz and peak rarefactional pressure amplitudes (PRPA) ranging from 230 kPa to 6.37 MPa. The double PCD setup is shown to improve the quality of collected data over previous setups by allowing symmetric responses from a localized confocal region to be identified. Postexcitation signal percentages are shown to generally follow trends consistent with other similar cavitation metrics such as inertial cavitation, with greater destruction observed at both increased PRPA and lower frequency over the tested ranges. Two different types of commercially available UCAs are characterized and found to have very different collapse thresholds; lipid-shelled Definity exhibits greater postexcitation at lower PRPAs than albumin-shelled Optison. Furthermore, by altering

Disruption of tumor neovasculature by microbubble enhanced ultrasound: a potential new physical therapy of anti-angiogenesis.

Science.gov (United States)

Liu, Zheng; Gao, Shunji; Zhao, Yang; Li, Peijing; Liu, Jia; Li, Peng; Tan, Kaibin; Xie, Feng

2012-02-01

Tumor angiogenesis is of vital importance to the growth and metastasis of solid tumors. The angiogenesis is featured with a defective, leaky and fragile vascular construction. Microbubble enhanced ultrasound (MEUS) cavitation is capable of mechanical disruption of small blood vessels depending on effective acoustic pressure amplitude. We hypothesized that acoustic cavitation combining high-pressure amplitude pulsed ultrasound (US) and circulating microbubble could potentially disrupt tumor vasculature. A high-pressure amplitude, pulsed ultrasound device was developed to induce inertial cavitation of circulating microbubbles. The tumor vasculature of rat Walker 256 was insonated percutaneously with two acoustic pressures, 2.6 MPa and 4.8 MPa, both with intravenous injection of a lipid microbubble. The controls were treated by the ultrasound only or sham ultrasound exposure. Contrast enhanced ultrasound (CEUS) and histology were performed to assess tumor circulation and pathological changes. The CEUS results showed that the circulation of Walker 256 tumors could be completely blocked off for 24 hours in 4.8 MPa treated tumors. The CEUS gray scale value (GSV) indicated that there was significant GSV drop-off in both of the two experimental groups but none in the controls. Histology showed that the tumor microvasculature was disrupted into diffuse hematomas accompanied by thrombosis, intercellular edema and multiple cysts formation. The 24 hours of tumor circulation blockage resulted in massive necrosis of the tumor. MEUS provides a new, simple physical method for anti-angiogenic therapy and may have great potential for clinical applications. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Microbubbles for medical applications

NARCIS (Netherlands)

Segers, T.J.; de Jong, N.; Lohse, Detlef; Versluis, Michel; van den Berg, A.; Segerink, L.

2015-01-01

Ultrasound contrast agent (UCA) suspensions contain encapsulated microbubbles with radii ranging from 1 to 10 micrometers. The bubbles oscillate to the driving ultrasound pulse generating harmonics of the driving ultrasound frequency. This feature allows for the discrimination of non-linear bubble

Ultrasound-mediated microbubble enhancement of radiation therapy studied using three-dimensional high-frequency power Doppler ultrasound.

Science.gov (United States)

Kwok, Sheldon J J; El Kaffas, Ahmed; Lai, Priscilla; Al Mahrouki, Azza; Lee, Justin; Iradji, Sara; Tran, William Tyler; Giles, Anoja; Czarnota, Gregory J

2013-11-01

Tumor responses to high-dose (>8 Gy) radiation therapy are tightly connected to endothelial cell death. In the study described here, we investigated whether ultrasound-activated microbubbles can locally enhance tumor response to radiation treatments of 2 and 8 Gy by mechanically perturbing the endothelial lining of tumors. We evaluated vascular changes resulting from combined microbubble and radiation treatments using high-frequency 3-D power Doppler ultrasound in a breast cancer xenograft model. We compared treatment effects and monitored vasculature damage 3 hours, 24 hours and 7 days after treatment delivery. Mice treated with 2 Gy radiation and ultrasound-activated microbubbles exhibited a decrease in vascular index to 48 ± 10% at 24 hours, whereas vascular indices of mice treated with 2 Gy radiation alone or microbubbles alone were relatively unchanged at 95 ± 14% and 78 ± 14%, respectively. These results suggest that ultrasound-activated microbubbles enhance the effects of 2 Gy radiation through a synergistic mechanism, resulting in alterations of tumor blood flow. This novel therapy may potentiate lower radiation doses to preferentially target endothelial cells, thus reducing effects on neighboring normal tissue and increasing the efficacy of cancer treatments. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis

Directory of Open Access Journals (Sweden)

Cuiyuan Huang

2017-07-01

Full Text Available Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble–mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

Theranostic Gd(III)-lipid microbubbles for MRI-guided focused ultrasound surgery.

Science.gov (United States)

Feshitan, Jameel A; Vlachos, Fotis; Sirsi, Shashank R; Konofagou, Elisa E; Borden, Mark A

2012-01-01

We have synthesized a biomaterial consisting of Gd(III) ions chelated to lipid-coated, size-selected microbubbles for utility in both magnetic resonance and ultrasound imaging. The macrocyclic ligand DOTA-NHS was bound to PE headgroups on the lipid shell of pre-synthesized microbubbles. Gd(III) was then chelated to DOTA on the microbubble shell. The reaction temperature was optimized to increase the rate of Gd(III) chelation while maintaining microbubble stability. ICP-OES analysis of the microbubbles determined a surface density of 7.5 × 10(5) ± 3.0 × 10(5) Gd(III)/μm(2) after chelation at 50 °C. The Gd(III)-bound microbubbles were found to be echogenic in vivo during high-frequency ultrasound imaging of the mouse kidney. The Gd(III)-bound microbubbles also were characterized by magnetic resonance imaging (MRI) at 9.4 T by a spin-echo technique and, surprisingly, both the longitudinal and transverse proton relaxation rates were found to be roughly equal to that of no-Gd(III) control microbubbles and saline. However, the relaxation rates increased significantly, and in a dose-dependent manner, after sonication was used to fragment the Gd(III)-bound microbubbles into non-gas-containing lipid bilayer remnants. The longitudinal (r(1)) and transverse (r(2)) molar relaxivities were 4.0 ± 0.4 and 120 ± 18 mM(-1)s(-1), respectively, based on Gd(III) content. The Gd(III)-bound microbubbles may find application in the measurement of cavitation events during MRI-guided focused ultrasound therapy and to track the biodistribution of shell remnants. Copyright © 2011 Elsevier Ltd. All rights reserved.

Nonlinear oscillation and interfacial stability of an encapsulated microbubble under dual-frequency ultrasound

Energy Technology Data Exchange (ETDEWEB)

Liu, Yunqiao [MOE Key Laboratory of Hydrodynamics, Department of Engineering Mechanics, Shanghai Jiao Tong University, Shanghai 200240 (China); Calvisi, Michael L [Department of Mechanical and Aerospace Engineering, University of Colorado, Colorado Springs, CO 80918, United States of America (United States); Wang, Qianxi, E-mail: yunqiaoliu@sjtu.edu.cn [School of Mathematics, University of Birmingham, Birmingham B15 2TT (United Kingdom)

2017-04-15

Encapsulated microbubbles (EMBs) are widely used in medical ultrasound imaging as contrast-enhanced agents. However, the potential damaging effects of violent collapsing EMBs to cells and tissues in clinical settings have remained a concern. Dual-frequency ultrasound is a promising technique for improving the efficacy and safety of sonography. The system modeled consists of the external liquid, membrane and internal gases of an EMB. The microbubble dynamics are simulated using a simple nonlinear interactive theory, considering the compressibility of the internal gas, viscosity of the liquid flow and viscoelasticity of the membrane. The radial oscillation and interfacial stability of an EMB under single- and dual-frequency excitations are compared. The simulation results show that the dual-frequency technique produces larger backscatter pressure at higher harmonics of the primary driving frequency—this enriched acoustic spectrum can enhance blood-tissue contrast and improve the quality of sonographic images. The results further show that the acoustic pressure threshold associated with the onset of shape instability is greater for dual-frequency driving. This suggests that the dual-frequency technique stabilizes the encapsulated bubble, thereby improving the efficacy and safety of contrast-enhanced agents. (paper)

Quantitative ultrasound characterization of tumor cell death: ultrasound-stimulated microbubbles for radiation enhancement.

Directory of Open Access Journals (Sweden)

Hyunjung Christina Kim

Full Text Available The aim of this study was to assess the efficacy of quantitative ultrasound imaging in characterizing cancer cell death caused by enhanced radiation treatments. This investigation focused on developing this ultrasound modality as an imaging-based non-invasive method that can be used to monitor therapeutic ultrasound and radiation effects. High-frequency (25 MHz ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human prostate xenografts grown in severe combined immunodeficiency (SCID mice were treated using 8, 80, or 1000 µL/kg of microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. The increase in backscatter intensity compared to the control ranged from 1.9±1.6 dB for the clinical imaging dose of microbubbles (8 µL/kg, 250 kPa, 2 Gy to 7.0±4.1 dB for the most extreme treatment condition (1000 µL/kg, 750 kPa, 8 Gy. In parallel, in situ end-labelling (ISEL staining, ceramide, and cyclophilin A staining demonstrated increases in cell death due to DNA fragmentation, ceramide-mediated apoptosis, and release of cyclophilin A as a result of cell membrane permeabilization, respectively. Quantitative ultrasound results indicated changes that paralleled increases in cell death observed from histology analyses supporting its use for non-invasive monitoring of cancer treatment outcomes.

Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery

OpenAIRE

Sirsi, Shashank R.; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y.; Mountford, Paul A.; Borden, Mark A.

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta?, Abbott Nutrition) as a microbubble shell material in order to improve dr...

Contrast-enhanced Ultrasound for Non-tumor Liver Diseases

Directory of Open Access Journals (Sweden)

H Maruyama

2012-03-01

Full Text Available Contrast-enhanced ultrasound (CEUS is a simple, safe and reliable technique for the clinical management of patients with various liver diseases. Although the major target of the technique may be focal hepatic lesions, it is also effective for the diagnosis of non-tumor liver diseases, such as grading hepatic fibrosis, characterization of chronic liver diseases and diagnosis of portal vein thrombosis. This review article aimed to overview the recent application of CEUS in the assessment of non-tumor liver diseases. Keywords: Cirrhosis, contrast agent, fibrosis, idiopathic portal hypertension, microbubble, portal vein thrombosis, ultrasound.

Effect of albumin and dextrose concentration on ultrasound and microbubble mediated gene transfection in vivo.

Science.gov (United States)

Browning, Richard J; Mulvana, Helen; Tang, Meng-Xing; Hajnal, Jo V; Wells, Dominic J; Eckersley, Robert J

2012-06-01

Ultrasound and microbubble mediated gene transfection has great potential for site-selective, safe gene delivery. Albumin-based microbubbles have shown the greatest transfection efficiency but have not been optimised specifically for this purpose. Additionally, few studies have highlighted desirable properties for transfection specific microbubbles. In this article, microbubbles were made with 2% or 5% (w/v) albumin and 20% or 40% (w/v) dextrose solutions, yielding four distinct bubble types. These were acoustically characterised and their efficiency in transfecting a luciferase plasmid (pGL4.13) into female, CD1 mice myocardia was measured. For either albumin concentration, increasing the dextrose concentration increased scattering, attenuation and resistance to ultrasound, resulting in significantly increased transfection. A significant interaction was noted between albumin and dextrose; 2% albumin bubbles made with 20% dextrose showed the least transfection but the most transfection with 40% dextrose. This trend was seen for both nonlinear scattering and attenuation behaviour but not for resistance to ultrasound or total scatter. We have determined that the attenuation behaviour is an important microbubble characteristic for effective gene transfection using ultrasound. Microbubble behaviour can also be simply controlled by altering the initial ingredients used during manufacture. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction.

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Xu, Yali; Cui, Hai; Zhu, Qiong; Hua, Xing; Xia, Hongmei; Tan, Kaibin; Gao, Yunhua; Zhao, Jing; Liu, Zheng

2016-01-01

Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p ultrasound-exposed hemisphere (4 ± 1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction

Directory of Open Access Journals (Sweden)

Yali Xu

2016-01-01

Full Text Available Objective. Blood-brain barrier (BBB is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p<0.01. Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4±1, grade 2 while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

Contrast-enhanced ultrasound imaging and in vivo circulatory kinetics with low-boiling-point nanoscale phase-change perfluorocarbon agents.

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Sheeran, Paul S; Rojas, Juan D; Puett, Connor; Hjelmquist, Jordan; Arena, Christopher B; Dayton, Paul A

2015-03-01

Many studies have explored phase-change contrast agents (PCCAs) that can be vaporized by an ultrasonic pulse to form microbubbles for ultrasound imaging and therapy. However, few investigations have been published on the utility and characteristics of PCCAs as contrast agents in vivo. In this study, we examine the properties of low-boiling-point nanoscale PCCAs evaluated in vivo and compare data with those for conventional microbubbles with respect to contrast generation and circulation properties. To do this, we develop a custom pulse sequence to vaporize and image PCCAs using the Verasonics research platform and a clinical array transducer. Results indicate that droplets can produce contrast enhancement similar to that of microbubbles (7.29 to 18.24 dB over baseline, depending on formulation) and can be designed to circulate for as much as 3.3 times longer than microbubbles. This study also reports for the first time the ability to capture contrast washout kinetics of the target organ as a measure of vascular perfusion. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Transient permeabilization of cell membranes by ultrasound-exposed microbubbles is related to formation of hydrogen peroxide.

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Juffermans, L J M; Dijkmans, P A; Musters, R J P; Visser, C A; Kamp, O

2006-10-01

In the present study, we addressed the interactions among ultrasound, microbubbles, and living cells as well as consequent arising bioeffects. We specifically investigated whether hydrogen peroxide (H(2)O(2)) is involved in transient permeabilization of cell membranes in vitro after ultrasound exposure at low diagnostic power, in the presence of stable oscillating microbubbles, by measuring the generation of H(2)O(2) and Ca(2+) influx. Ultrasound, in the absence or presence of SonoVue microbubbles, was applied to H9c2 cells at 1.8 MHz with a mechanical index (MI) of 0.1 or 0.5 during 10 s. This was repeated every minute, for a total of five times. The production of H(2)O(2) was measured intracellularly with CM-H(2)DCFDA. Cell membrane permeability was assessed by measuring real-time changes in intracellular Ca(2+) concentration with fluo-4 using live-cell fluorescence microscopy. Ultrasound, in the presence of microbubbles, caused a significant increase in intracellular H(2)O(2) at MI 0.1 of 50% and MI 0.5 of 110% compared with control (P ultrasound exposure was completely blocked at MI 0.1 (P ultrasound-exposed microbubbles.

Reversible and irreversible vascular bioeffects induced by ultrasound and microbubbles in chorioallantoic membrane model

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Tarapacki, Christine; Kuebler, Wolfgang M.; Tabuchi, Arata; Karshafian, Raffi

2017-03-01

Background: The application of ultrasound and microbubbles at therapeutic conditions has been shown to improve delivery of molecules, cause vasoconstriction, modulate blood flow and induce a vascular shut down in in vivo cancerous tissues. The underlying mechanism has been associated with the interaction of ultrasonically-induced microbubble oscillation and cavitation with the blood vessel wall. In this study, the effect of ultrasound and microbubbles on blood flow and vascular architecture was studied using a fertilized chicken egg CAM (chorioallantoic membrane) model. Methods: CAM at day 12 of incubation (Hamburger-Hamilton stage 38-40) were exposed to ultrasound at varying acoustic pressures (160, 240 and 320 kPa peak negative pressure) in the presence of Definity microbubbles and 70 kDa FITC dextran fluorescent molecules. A volume of 50 µL Definity microbubbles were injected into a large anterior vein of the CAM prior to ultrasound exposure. The ultrasound treatment sequence consisted of 5 s exposure at 500 kHz frequency, 8 cycles and 1 kHz pulse repetition frequency with 5 s off for a total exposure of 2 minutes. Fluorescent videos and images of the CAM vasculature were acquired using intravital microscopy prior, during and following the ultrasound exposure. Perfusion was quantified by measuring the length of capillaries in a region of interest using Adobe Illustrator. Results and Discussion: The vascular bioeffects induced by USMB increased with acoustic peak negative pressure. At 160 kPa, no visible differences were observed compared to the control. At 240 kPa, a transient decrease in perfusion with subsequent recovery within 15 minutes was observed, whereas at 320 kPa, the fluorescent images showed an irreversible vascular damage. The study indicates that a potential mechanism for the transient decrease in perfusion may be related to blood coagulation. The results suggest that ultrasound and microbubbles can induce reversible and irreversible vascular

Thrombin-Activatable Microbubbles as Potential Ultrasound Contrast Agents for the Detection of Acute Thrombosis.

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Lux, Jacques; Vezeridis, Alexander M; Hoyt, Kenneth; Adams, Stephen R; Armstrong, Amanda M; Sirsi, Shashank R; Mattrey, Robert F

2017-11-01

Acute deep vein thrombosis (DVT) is the formation of a blood clot in the deep veins of the body that can lead to fatal pulmonary embolism. Acute DVT is difficult to distinguish from chronic DVT by ultrasound (US), the imaging modality of choice, and is therefore treated aggressively with anticoagulants, which can lead to internal bleeding. Here we demonstrate that conjugating perfluorobutane-filled (PFB-filled) microbubbles (MBs) with thrombin-sensitive activatable cell-penetrating peptides (ACPPs) could lead to the development of contrast agents that detect acute thrombosis with US imaging. Successful conjugation of ACPP to PFB-filled MBs was confirmed by fluorescence microscopy and flow cytometry. Fluorescein-labeled ACPP was used to evaluate the efficiency of thrombin-triggered cleavage by measuring the mean fluorescence intensity of ACPP-labeled MBs (ACPP-MBs) before and after incubation at 37 °C with thrombin. Lastly, control MBs and ACPP-MBs were infused through a tube containing a clot, and US contrast enhancement was measured with or without the presence of a thrombin inhibitor after washing the clot with saline. With thrombin activity, 91.7 ± 14.2% of the signal was retained after ACPP-MB infusion and washing, whereas only 16.7 ± 4% of the signal was retained when infusing ACPP-MBs in the presence of hirudin, a potent thrombin inhibitor.

Rest-Stress Limb Perfusion Imaging in Humans with Contrast Ultrasound Using Intermediate-Power Imaging and Microbubbles Resistant to Inertial Cavitation.

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Davidson, Brian P; Hodovan, James; Belcik, J Todd; Moccetti, Federico; Xie, Aris; Ammi, Azzdine Y; Lindner, Jonathan R

2017-05-01

Contrast-enhanced ultrasound (CEU) limb perfusion imaging is a promising approach for evaluating peripheral artery disease (PAD). However, low signal enhancement in skeletal muscle has necessitated high-power intermittent imaging algorithms, which are not clinically feasible. We hypothesized that CEU using a combination of intermediate power and a contrast agent resistant to inertial cavitation would allow real-time limb stress perfusion imaging. In normal volunteers, CEU of the calf skeletal muscle was performed on separate days with Sonazoid, Optison, or Definity. Progressive reduction in the ultrasound pulsing interval was used to assess the balance between signal enhancement and agent destruction at escalating mechanical indices (MI, 0.1-0.4). Real-time perfusion imaging at MI 0.1-0.4 using postdestructive replenishment kinetics was performed at rest and during 25 W plantar flexion contractile exercise. For Optison, limb perfusion imaging was unreliable at rest due to very low signal enhancement generated at all MIs and was possible during exercise-induced hyperemia only at MI 0.1 due to agent destruction at higher MIs. For Definity, signal intensity progressively increased with MI but was offset by microbubble destruction, which resulted in modest signal enhancement during CEU perfusion imaging and distortion of replenishment curves at MI ≥ 0.2. For Sonazoid, there strong signal enhancement at MI ≥ 0.2, with little destruction detected only at MI 0.4. Accordingly, high signal intensity and nondistorted perfusion imaging was possible at MI 0.2-0.3 and detected an 8.0- ± 5.7-fold flow reserve. Rest-stress limb perfusion imaging in humans with real-time CEU, which requires only seconds to perform, is possible using microbubbles with viscoelastic properties that produce strong nonlinear signal generation without destruction at intermediate acoustic pressures. Copyright © 2016 American Society of Echocardiography. All rights reserved.

Ultrasound-targeted microbubble destruction improves the low density lipoprotein receptor gene expression in HepG2 cells

International Nuclear Information System (INIS)

Guo Dongping; Li Xiaoyu; Sun, Ping; Tang Yibo; Chen Xiuying; Chen Qi; Fan Leming; Zang Bin; Shao Lizheng; Li Xiaorong

2006-01-01

Ultrasound-targeted microbubble destruction had been employed in gene delivery and promised great potential. Liver has unique features that make it attractive for gene therapy. However, it poses formidable obstacles to hepatocyte-specific gene delivery. This study was designed to test the efficiency of therapeutic gene transfer and expression mediated by ultrasound/microbubble strategy in HepG 2 cell line. Air-filled albumin microbubbles were prepared and mixed with plasmid DNA encoding low density lipoprotein receptor (LDLR) and green fluorescent protein. The mixture of the DNA and microbubbles was administer to cultured HepG 2 cells under variable ultrasound conditions. Transfection rate of the transferred gene and cell viability were assessed by FACS analysis, confocal laser scanning microscopy, Western blot analysis and Trypan blue staining. The result demonstrated that microbubbles with ultrasound irradiation can significantly elevate exogenous LDLR gene expression and the expressed LDLRs were functional and active to uptake their ligands. We conclude that ultrasound-targeted microbubble destruction has the potential to promote safe and efficient LDLR gene transfer into hepatocytes. With further refinement, it may represent an effective nonviral avenue of gene therapy for liver-involved genetic diseases

Effects of microchannel confinement on acoustic vaporisation of ultrasound phase change contrast agents

Science.gov (United States)

Lin, Shengtao; Zhang, Ge; Hau Leow, Chee; Tang, Meng-Xing

2017-09-01

The sub-micron phase change contrast agent (PCCA) composed of a perfluorocarbon liquid core can be activated into gaseous state and form stable echogenic microbubbles for contrast-enhanced ultrasound imaging. It has shown great promise in imaging microvasculature, tumour microenvironment, and cancer cells. Although PCCAs have been extensively studied for different diagnostic and therapeutic applications, the effect of biologically geometrical confinement on the acoustic vaporisation of PCCAs is still not clear. We have investigated the difference in PCCA-produced ultrasound contrast enhancement after acoustic activation with and without a microvessel confinement on a microchannel phantom. The experimental results indicated more than one-order of magnitude less acoustic vaporisation in a microchannel than that in a free environment taking into account the attenuation effect of the vessel on the microbubble scattering. This may provide an improved understanding in the applications of PCCAs in vivo.

Non-linear Response and Viscoelastic Properties of Lipid-Coated Microbubbles: DSPC versus DPPC

NARCIS (Netherlands)

van Rooij, T.; Luan, Y.; Renaud, G.; van der Steen, A.F.W.; Versluis, Michel; de Jong, N.; Kooiman, K.

2015-01-01

For successful in vivo contrast-enhanced ultrasound imaging (CEUS) and ultrasound molecular imaging, detailed knowledge of stability and acoustical properties of the microbubbles is essential. Here, we compare these aspects of lipid-coated microbubbles that have either

Microbubbles as drug delivery systems in cerebrovascular diseases.

Science.gov (United States)

Spinelli, Mariacarmela; Demitri, Christian; Sannino, Alessandro; Peruzzotti-Jametti, Luca; Bacigaluppi, Marco; Comi, Giancarlo; Corea, Francesco

2009-11-01

The field of neurovascular ultrasound is growing rapidly with new applications. While ultrasound contrast agents were initially used to overcome poor transcranial bone windows for identification of cerebral arteries, newgeneration microbubbles in combination with innovative contrast-specific ultrasound techniques now enable potential therapeutic procedures. This article will provide a review of recent and emerging developments along with patents in ultrasound technology and contrast-specific therapeutic techniques for cerebrovascular patients.

Tanscranial Threshold of Inertial Cavitation Induced by Diagnosticc Ultrasound and Microbubbles

NARCIS (Netherlands)

Liu, J.; Gao, S.; Porter, T.R.; Everbach, C; Shi, W.; Vignon, F.; Powers, J.; Lof, J.; Turner, J.; Xie, F.

2011-01-01

Background: Inertial cavitation may cause hazardous bioeffects whileusing ultrasound and microbubble mediated thrombolysis. The purposeof this study was to investigate the influence of ultrasound pulselength and temporal bone on inertial cavitation thresholds within the brain utilizing transtemporal

Microbubbles-Assisted Ultrasound Triggers the Release of Extracellular Vesicles

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Yuana Yuana

2017-07-01

Full Text Available Microbubbles-assisted ultrasound (USMB has shown promise in improving local drug delivery. The formation of transient membrane pores and endocytosis are reported to be enhanced by USMB, and they contribute to cellular drug uptake. Exocytosis also seems to be linked to endocytosis upon USMB treatment. Based on this rationale, we investigated whether USMB triggers exocytosis resulting in the release of extracellular vesicles (EVs. USMB was performed on a monolayer of head-and-neck cancer cells (FaDu with clinically approved microbubbles and commonly used ultrasound parameters. At 2, 4, and 24 h, cells and EV-containing conditioned media from USMB and control conditions (untreated cells, cells treated with microbubbles and ultrasound only were harvested. EVs were measured using flow cytometric immuno-magnetic bead capture assay, immunogold electron microscopy, and western blotting. After USMB, levels of CD9 exposing-EVs significantly increased at 2 and 4 h, whereas levels of CD63 exposing-EVs increased at 2 h. At 24 h, EV levels were comparable to control levels. EVs released after USMB displayed a heterogeneous size distribution profile (30–1200 nm. Typical EV markers CD9, CD63, and alix were enriched in EVs released from USMB-treated FaDu cells. In conclusion, USMB treatment triggers exocytosis leading to the release of EVs from FaDu cells.

Fabrication and application of a magnetic-targeting and controlled-release system using ST68-based microbubbles

International Nuclear Information System (INIS)

Xing Zhanwen; Ke Hengte; Wang Jinrui; Zhao Bo; Qu Enze; Yue Xiuli; Dai Zhifei

2013-01-01

Objective: To manufacture magnetic microbubbles with dual-response to ultrasound and magnetic fields. Methods: Microbubbles of ultrasound contrast agent (ST68) based on a surfactant were prepared by the acoustic cavitation method. Fe 3 O 4 magnetic nanoparticles with negative charge were synthesized using the polyol procedure. Magnetic microbubbles were generated by depositing polyethylenimine and Fe 3 O 4 magnetic nanoparticles alternately onto the microbubbles using the layer-by-layer self-assembly. In vitro ultrasonography was performed on a silicone tube with/without magnetic microbubbles (3 × 10 8 /ml) by a self-made device to observe the movement of magnetic microbubbles under the effects of magnetic field. In vivo imaging was performed on the kidney of New Zealand rabbits before and after the injection of magnetic microbubbles. Results: The Fe 3 O 4 nanoparticles carried a stable negative charge of (-24.6 ± 6.7) mV and more than 98% of the particles were less than 8 μm in diameter, meeting the size requirement of an ultrasound contrast agent for intravenous administration. There was no echoic signal in the silicone tube before injection of magnetic microbubbles, but there were strong echoic signals after injection. After applying a magnetic field, the magnetic microbubbles moved along the direction of the magnetic flux. In vivo ultrasound imaging could not visualize the kidney before injection of magnetic microbubbles, but could remarkably visualize the kidney after injection. Conclusions: The magnetic microbubbles exhibit favorable magnetic targeting and ultrasound contrast enhancement characteristics. Such properties may serve as the foundation to study their potential for simultaneous diagnosis and treatment in the future. (authors)

Imaging of vaporised sub-micron phase change contrast agents with high frame rate ultrasound and optics

Science.gov (United States)

Lin, Shengtao; Zhang, Ge; Jamburidze, Akaki; Chee, Melisse; Hau Leow, Chee; Garbin, Valeria; Tang, Meng-Xing

2018-03-01

Phase-change ultrasound contrast agent (PCCA), or nanodroplet, shows promise as an alternative to the conventional microbubble agent over a wide range of diagnostic applications. Meanwhile, high-frame-rate (HFR) ultrasound imaging with microbubbles enables unprecedented temporal resolution compared to traditional contrast-enhanced ultrasound imaging. The combination of HFR ultrasound imaging and PCCAs can offer the opportunity to observe and better understand PCCA behaviour after vaporisation captures the fast phenomenon at a high temporal resolution. In this study, we utilised HFR ultrasound at frame rates in the kilohertz range (5-20 kHz) to image native and size-selected PCCA populations immediately after vaporisation in vitro within clinical acoustic parameters. The size-selected PCCAs through filtration are shown to preserve a sub-micron-sized (mean diameter  1 µm) that originate from native PCCA emulsion. The results demonstrate imaging signals with different amplitudes and temporal features compared to that of microbubbles. Compared with the microbubbles, both the B-mode and pulse-inversion (PI) signals from the vaporised PCCA populations were reduced significantly in the first tens of milliseconds, while only the B-mode signals from the PCCAs were recovered during the next 400 ms, suggesting significant changes to the size distribution of the PCCAs after vaporisation. It is also shown that such recovery in signal over time is not evident when using size-selective PCCAs. Furthermore, it was found that signals from the vaporised PCCA populations are affected by the amplitude and frame rate of the HFR ultrasound imaging. Using high-speed optical camera observation (30 kHz), we observed a change in particle size in the vaporised PCCA populations exposed to the HFR ultrasound imaging pulses. These findings can further the understanding of PCCA behaviour under HFR ultrasound imaging.

Photoacoustic/ultrasound dual-modality contrast agent and its application to thermotherapy.

Science.gov (United States)

Wang, Yu-Hsin; Liao, Ai-Ho; Chen, Jui-Hao; Wang, Churng-Ren Chris; Li, Pai-Chi

2012-04-01

This study investigates a photoacoustic/ultrasound dual-modality contrast agent, including extending its applications from image-contrast enhancement to combined diagnosis and therapy with site-specific targeting. The contrast agent comprises albumin-shelled microbubbles with encapsulated gold nanorods (AuMBs). The gas-filled microbubbles, whose diameters range from submicrometer to several micrometers, are not only echogenic but also can serve as drug-delivery vehicles. The gold nanorods are used to enhance the generation of both photoacoustic and photothermal signals. The optical absorption peak of the gold nanorods is tuned to 760 nm and is invariant after microbubble encapsulation. Dual-modality contrast enhancement is first described here, and the applications to cellular targeting and laser-induced thermotherapy in a phantom are demonstrated. Photoacoustic imaging can be used to monitor temperature increases during the treatment. The targeting capability of AuMBs was verified, and the temperature increased by 26°C for a laser power of 980 mW, demonstrating the potential of combined diagnosis and therapy with the dual-modality agent. Targeted photo- or acoustic-mediated delivery is also possible.

Microcapsules: Reverse Sonoporation and Long-lasting, Safe Contrast

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Wrenn, Steven; Dicker, Stephen; Small, Eleanor; Maghnouj, Abdelouahid; Hahn, Stephan A.; Mleczko, Michał; Hensel, Karin; Schmitz, Georg

We present a novel vehicle designed to serve the dual roles of enhanced ultrasound contrast and ultrasound-triggered drug delivery. The vehicle is comprised of a microcapsule that is filled with water in whose aqueous core a population of freely floating, phospholipid-coated microbubbles is suspended. At ultrasound intensities below the inertial cavitation threshold of the microbubbles, the microbubbles provide enhanced ultrasound contrast. The measured contrast is comparable in strength with SonoVue®. Encapsulation of microbubbles within microcapsules putatively eliminates - or at least significantly slows - dissolution of gas in the bulk aqueous medium, thereby avoiding disappearance of microbubbles that would otherwise occur due to pressure-induced gas diffusion across the surfactant monolayer coating the microbubble-water interface. Results suggest that our vehicle might provide longer lasting contrast in a clinical setting. We demonstrate that encapsulation of the microbubbles within microcapsules causes at least a doubling of the ultrasound intensity necessary to induce inertial cavitation. Moreover, no cell death was observed when cells were insonified in the presence of microbubble-containing microcapsules, whereas appreciable cell death occurs with unencapsulated microbubbles. These results point toward a potential safety benefit during ultrasound contrast imaging by using encapsulated microbubbles. Studies are underway to investigate the feasibility of ultrasound-triggered release of drug from the microcapsules, owing to inertial- or stable-cavitation, or both. Whereas leakage from polymeric microcapsule shells, such as poly(lactic acid), seemingly requires shell rupture and is exceedingly difficult to achieve, leakage across a lipid bilayer microcapsule shells appears feasible. Leakage across a bilayer shell has the additional benefit that the leakage mechanism can be tuned via phase behavior (liquid-ordered versus liquid-disordered) and cavitation

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function.

Science.gov (United States)

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2013-11-01

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

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Wang X

2014-10-01

Full Text Available Xiang Wang,1 Ping Liu,1 Weixiao Yang,1 Lu Li,1 Peijing Li,2 Zheng Liu,1 Zhongxiong Zhuo,1 Yunhua Gao1 1Department of Ultrasound, Xinqiao Hospital of the Third Military Medical University, Chongqing, 2Department of Ultrasound, General Hospital of the Jinan Military Area, Jinan, People’s Republic of China Abstract: Methotrexate (MTX is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 µm in diameter was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 µg/g > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 µg/g > MTX alone (6.97±0.75 µg/g > MTX-liposome-coupled microbubbles (2.92±0.39 µg/g. Therefore

Ex Vivo Perfusion-Simulation Measurements of Microbubbles as a Scattering Contrast Agent for Grating-Based X-Ray Dark-Field Imaging.

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Astrid Velroyen

Full Text Available The investigation of dedicated contrast agents for x-ray dark-field imaging, which exploits small-angle scattering at microstructures for contrast generation, is of strong interest in analogy to the common clinical use of high-atomic number contrast media in conventional attenuation-based imaging, since dark-field imaging has proven to provide complementary information. Therefore, agents consisting of gas bubbles, as used in ultrasound imaging for example, are of particular interest. In this work, we investigate an experimental contrast agent based on microbubbles consisting of a polyvinyl-alcohol shell with an iron oxide coating, which was originally developed for multimodal imaging and drug delivery. Its performance as a possible contrast medium for small-animal angiography was examined using a mouse carcass to realistically consider attenuating and scattering background signal. Subtraction images of dark field, phase contrast and attenuation were acquired for a concentration series of 100%, 10% and 1.3% to mimic different stages of dilution in the contrast agent in the blood vessel system. The images were compared to the gold-standard iodine-based contrast agent Solutrast, showing a good contrast improvement by microbubbles in dark-field imaging. This study proves the feasibility of microbubble-based dark-field contrast-enhancement in presence of scattering and attenuating mouse body structures like bone and fur. Therefore, it suggests a strong potential of the use of polymer-based microbubbles for small-animal dark-field angiography.

Robust microbubble tracking for super resolution imaging in ultrasound

DEFF Research Database (Denmark)

Hansen, Kristoffer B.; Villagómez Hoyos, Carlos Armando; Brasen, Jens Christian

2016-01-01

Currently ultrasound resolution is limited by diffraction to approximately half the wavelength of the sound wave employed. In recent years, super resolution imaging techniques have overcome the diffraction limit through the localization and tracking of a sparse set of microbubbles through...... the vasculature. However, this has only been performed on fixated tissue, limiting its clinical application. This paper proposes a technique for making super resolution images on non-fixated tissue by first compensating for tissue movement and then tracking the individual microbubbles. The experiment is performed...... on the kidney of a anesthetized Sprage-Dawley rat by infusing SonoVue at 0.1× original concentration. The algorithm demonstrated in vivo that the motion compensation was capable of removing the movement caused by the mechanical ventilator. The results shows that microbubbles were localized with a higher...

Investigation on the inertial cavitation threshold and shell properties of commercialized ultrasound contrast agent microbubbles.

Science.gov (United States)

Guo, Xiasheng; Li, Qian; Zhang, Zhe; Zhang, Dong; Tu, Juan

2013-08-01

The inertial cavitation (IC) activity of ultrasound contrast agents (UCAs) plays an important role in the development and improvement of ultrasound diagnostic and therapeutic applications. However, various diagnostic and therapeutic applications have different requirements for IC characteristics. Here through IC dose quantifications based on passive cavitation detection, IC thresholds were measured for two commercialized UCAs, albumin-shelled KangRun(®) and lipid-shelled SonoVue(®) microbubbles, at varied UCA volume concentrations (viz., 0.125 and 0.25 vol. %) and acoustic pulse lengths (viz., 5, 10, 20, 50, and 100 cycles). Shell elastic and viscous coefficients of UCAs were estimated by fitting measured acoustic attenuation spectra with Sarkar's model. The influences of sonication condition (viz., acoustic pulse length) and UCA shell properties on IC threshold were discussed based on numerical simulations. Both experimental measurements and numerical simulations indicate that IC thresholds of UCAs decrease with increasing UCA volume concentration and acoustic pulse length. The shell interfacial tension and dilatational viscosity estimated for SonoVue (0.7 ± 0.11 N/m, 6.5 ± 1.01 × 10(-8) kg/s) are smaller than those of KangRun (1.05 ± 0.18 N/m, 1.66 ± 0.38 × 10(-7) kg/s); this might result in lower IC threshold for SonoVue. The current results will be helpful for selecting and utilizing commercialized UCAs for specific clinical applications, while minimizing undesired IC-induced bioeffects.

Ultrasound-targeted microbubble destruction enhances naked plasmid DNA transfection in rabbit Achilles tendons in vivo.

Science.gov (United States)

Qiu, L; Zhang, L; Wang, L; Jiang, Y; Luo, Y; Peng, Y; Lin, L

2012-07-01

The study was to investigate the probability of increasing the transfection of the gene in tendons by ultrasound-targeted microbubble destruction (UTMD), and to search for the most suitable transfection conditions. A mixture of microbubbles and enhanced green fluorescent protein (EGFP) plasmids was injected into rabbit Achilles tendons by different administration routes and the tendons were ultrasound pulse by different ultrasonic conditions in order to determine the most appropriate conditions. Then, the rabbits were divided into four groups: (1) ultrasound + microbubbles + plasmid; (2) ultrasound+ plasmid; (3) microbubble + plasmid; (4) plasmid only. EGFP expression in the tendons and other tissues, and the damage to tendon and paratenon were all observed. The results showed that EGFP expression in the tendon was higher by ultrasound pulse with 2 W cm(-2) of output intensity and a 20% duty cycle for 10 min. Local injection was determined to be the better administration route. Among the four groups, EGFP expression in Group 1 was higher than that in other groups. EGFP expression was highest on seventh day, then it gradually decrease over time, and lasted more than 56 days. EGFP expression was not found in other tissues. There was no obvious injury caused by UTMD. Under suitable conditions, it is feasible to use UTMD as a safe and effective gene transfection therapy for tendon injuries.

Second harmonic inversion for ultrasound contrast harmonic imaging

Energy Technology Data Exchange (ETDEWEB)

Pasovic, Mirza; Danilouchkine, Mike; Faez, Telli; Van Neer, Paul L M J; Van der Steen, Antonius F W; De Jong, Nico [THORAXCENTER, Department of Biomedical Engineering Ee2302, Erasmus MC, Rotterdam (Netherlands); Cachard, Christian; Basset, Olivier, E-mail: mirza.pasovic@creatis.insa-lyon.fr [CREATIS-LRMN, Universite de Lyon, INSA-Lyon, Universite Lyon 1, Inserm U630, CNRS UMR 5220 (France)

2011-06-07

Ultrasound contrast agents (UCAs) are small micro-bubbles that behave nonlinearly when exposed to an ultrasound wave. This nonlinear behavior can be observed through the generated higher harmonics in a back-scattered echo. In past years several techniques have been proposed to detect or image harmonics produced by UCAs. In these proposed works, the harmonics generated in the medium during the propagation of the ultrasound wave played an important role, since these harmonics compete with the harmonics generated by the micro-bubbles. We present a method for the reduction of the second harmonic generated during nonlinear-propagation-dubbed second harmonic inversion (SHI). A general expression for the suppression signals is also derived. The SHI technique uses two pulses, p' and p'', of the same frequency f{sub 0} and the same amplitude P{sub 0} to cancel out the second harmonic generated by nonlinearities of the medium. Simulations show that the second harmonic is reduced by 40 dB on a large axial range. Experimental SHI B-mode images, from a tissue-mimicking phantom and UCAs, show an improvement in the agent-to-tissue ratio (ATR) of 20 dB compared to standard second harmonic imaging and 13 dB of improvement in harmonic power Doppler.

Second harmonic inversion for ultrasound contrast harmonic imaging

International Nuclear Information System (INIS)

Pasovic, Mirza; Danilouchkine, Mike; Faez, Telli; Van Neer, Paul L M J; Van der Steen, Antonius F W; De Jong, Nico; Cachard, Christian; Basset, Olivier

2011-01-01

Ultrasound contrast agents (UCAs) are small micro-bubbles that behave nonlinearly when exposed to an ultrasound wave. This nonlinear behavior can be observed through the generated higher harmonics in a back-scattered echo. In past years several techniques have been proposed to detect or image harmonics produced by UCAs. In these proposed works, the harmonics generated in the medium during the propagation of the ultrasound wave played an important role, since these harmonics compete with the harmonics generated by the micro-bubbles. We present a method for the reduction of the second harmonic generated during nonlinear-propagation-dubbed second harmonic inversion (SHI). A general expression for the suppression signals is also derived. The SHI technique uses two pulses, p' and p'', of the same frequency f 0 and the same amplitude P 0 to cancel out the second harmonic generated by nonlinearities of the medium. Simulations show that the second harmonic is reduced by 40 dB on a large axial range. Experimental SHI B-mode images, from a tissue-mimicking phantom and UCAs, show an improvement in the agent-to-tissue ratio (ATR) of 20 dB compared to standard second harmonic imaging and 13 dB of improvement in harmonic power Doppler.

Dynamic contrast enhanced ultrasound for therapy monitoring

Energy Technology Data Exchange (ETDEWEB)

Hudson, John M. [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Williams, Ross [Imaging Research, Sunnybrook Research Institute, Toronto, ON (Canada); Tremblay-Darveau, Charles; Sheeran, Paul S. [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Milot, Laurent [Department of Medical Imaging, University of Toronto, Toronto, ON (Canada); Bjarnason, Georg A. [Department of Medical Oncology, University of Toronto, and Sunnybrook Odette Cancer Centre, Toronto, ON (Canada); Burns, Peter N., E-mail: burns@sri.utoronto.ca [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Imaging Research, Sunnybrook Research Institute, Toronto, ON (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON (Canada)

2015-09-15

Quantitative imaging is a crucial component of the assessment of therapies that target the vasculature of angiogenic or inflamed tissue. Dynamic contrast-enhanced ultrasound (DCE-US) using microbubble contrast offers the advantages of being sensitive to perfusion, non-invasive, cost effective and well suited to repeated use at the bedside. Uniquely, it employs an agent that is truly intravascular. This papers reviews the principles and methodology of DCE-US, especially as applied to anti-angiogenic cancer therapies. Reproducibility is an important attribute of such a monitoring method: results are discussed. More recent technical advances in parametric and 3D DCE-US imaging are also summarised and illustrated.

Phase contrast imaging of preclinical portal vein embolization with CO2 microbubbles.

Science.gov (United States)

Tang, Rongbiao; Yan, Fuhua; Yang, Guo Yuan; Chen, Ke Min

2017-11-01

Preoperative portal vein embolization (PVE) is employed clinically to avoid postoperative liver insufficiency. Animal models are usually used to study PVE in terms of mechanisms and pathophysiological changes. PVE is formerly monitored by conventional absorption contrast imaging (ACI) with iodine contrast agent. However, the side effects induced by iodine can give rise to animal damage and death. In this study, the feasibility of using phase contrast imaging (PCI) to show PVE using homemade CO 2 microbubbles in living rats has been investigated. CO 2 gas was first formed from the reaction between citric acid and sodium bicarbonate. The CO 2 gas was then encapsulated by egg white to fabricate CO 2 microbubbles. ACI and PCI of CO 2 microbubbles were performed and compared in vitro. An additional increase in contrast was detected in PCI. PCI showed that CO 2 microbubbles gradually dissolved over time, and the remaining CO 2 microbubbles became larger. By PCI, the CO 2 microbubbles were found to have certain stability, suggesting their potential use as embolic agents. CO 2 microbubbles were injected into the main portal trunk to perform PVE in living rats. PCI exploited the differences in the refractive index and facilitated clear visualization of the PVE after the injection of CO 2 microbubbles. Findings from this study suggest that homemade CO 2 microbubbles-based PCI is a novel modality for preclinical PVE research.

Microbubble-Mediated Ultrasound Enhances the Lethal Effect of Gentamicin on Planktonic Escherichia coli

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Han-Xiao Zhu

2014-01-01

Full Text Available Previous research has found that low-intensity ultrasound enhanced the lethal effect of gentamicin on planktonic E. coli. We aimed to further investigate whether microbubble-mediated low-intensity ultrasound could further enhance the antimicrobial efficacy of gentamicin. The planktonic E. coli (ATCC 25922 was distributed to four different interventions: control (GCON, microbubble only (GMB, ultrasound only (GUS, and microbubble-mediated ultrasound (GMUS. Ultrasound was applied with 100 mW/cm2 (average intensity and 46.5 KHz, which presented no bactericidal activity. After 12 h, plate counting was used to estimate the number of bacteria, and bacterial micromorphology was observed with transmission electron microscope. The results showed that the viable counts of E. coli in GMUS were decreased by 1.01 to 1.42 log10 CFU/mL compared with GUS (P<0.01. The minimal inhibitory concentration (MIC of gentamicin against E. coli was 1 μg/mL in the GMUS and GUS groups, lower than that in the GCON and GMB groups (2 μg/mL. Transmission electron microscopy (TEM images exhibited more destruction and higher thickness of bacterial cell membranes in the GMUS than those in other groups. The reason might be the increased permeability of cell membranes for gentamicin caused by acoustic cavitation.

Ultrafast 2-dimensional image monitoring and array-based passive cavitation detection for ultrasound contrast agent destruction in a variably sized region.

Science.gov (United States)

Xu, Shanshan; Hu, Hong; Jiang, Hujie; Xu, Zhi'an; Wan, Mingxi

2014-11-01

A combined approach was proposed, based on programmable ultrasound equipment, to simultaneously monitor surviving microbubbles and detect cavitation activity during microbubble destruction in a variably sized region for use in ultrasound contrast agent (UCA)-enhanced therapeutic ultrasound applications. A variably sized focal region wherein the acoustic pressure was above the UCA fragmentation threshold was synthesized at frequencies of 3, 4, 5, and 6 MHz with a linear broadband imaging probe. The UCAs' temporal and spatial distribution during the microbubbles' destruction was monitored in a 2-dimensional imaging plane at 5 MHz and a frame rate of 400 Hz, and simultaneously, broadband noise emissions during the microbubbles' fragmentation were extracted by using the backscattered signals produced by the focused release bursts (ie, destruction pulses) themselves. Afterward, the temporal evolution of broadband noise emission, the surviving microbubbles in a region of interest (ROI), and the destruction area in a static UCA suspension were computed. Then the inertial cavitation dose, destruction rate of microbubbles in the ROI, and area of the destruction region were determined. It was found that an increasing pulse length and a decreasing transmit aperture and excitation frequency were correlated with an increased inertial cavitation dose, microbubble destruction rate, and destruction area. Furthermore, it was obvious that the microbubble destruction rate was significantly correlated with the inertial cavitation dose (P cavitation dose could be regulated by manipulating the transmission parameters. © 2014 by the American Institute of Ultrasound in Medicine.

Tunable microbubble generator using electrolysis and ultrasound

OpenAIRE

Younes Achaoui; Khaled Metwally; Damien Fouan; Zoubida Hammadi; Roger Morin; Eric Debieu; Cédric Payan; Serge Mensah

2017-01-01

This letter reports on a method for producing on demand calibrated bubbles in a non-chemically controlled solution using localized micro-electrolysis and ultrasound. Implementing a feedback loop in the process leads to a point source of stable mono-dispersed microbubbles. This approach overcomes the inertial constraints encountered in microfluidics with the possibility to produce from a single to an array of calibrated bubbles. Moreover, this method avoids the use of additional surfactant tha...

Experimental investigations of nonlinearities and destruction mechanisms of an experimental phospholipid-based ultrasound contrast agent.

Science.gov (United States)

Casciaro, Sergio; Palmizio Errico, Rosa; Errico, Rosa Palmizio; Conversano, Francesco; Demitri, Christian; Distante, Alessandro

2007-02-01

We sought to characterize the acoustical behavior of the experimental ultrasound contrast agent BR14 by determining the acoustic pressure threshold above which nonlinear oscillation becomes significant and investigating microbubble destruction mechanisms. We used a custom-designed in vitro setup to conduct broadband attenuation measurements at 3.5 MHz varying acoustic pressure (range, 50-190 kPa). We also performed granulometric analyses on contrast agent solutions to accurately measure microbubble size distribution and to evaluate insonification effects. Attenuation did not depend on acoustic pressure less than 100 kPa, indicating this pressure as the threshold for the appearance of microbubble nonlinear behavior. At the lowest excitation amplitude, attenuation increased during insonification, while, at higher excitation levels, the attenuation decreased over time, indicating microbubble destruction. The destruction rate changed with pressure amplitude suggesting different destruction mechanisms, as it was confirmed by granulometric analysis. Microbubbles showed a linear behavior until 100 kPa, whereas beyond this value significant nonlinearities occurred. Observed destruction phenomena seem to be mainly due to gas diffusion and bubble fragmentation mechanisms.

Modeling Encapsulated Microbubble Dynamics at High Pressure Amplitudes

Science.gov (United States)

Heyse, Jan F.; Bose, Sanjeeb; Iaccarino, Gianluca

2017-11-01

Encapsulated microbubbles are commonly used in ultrasound contrast imaging and are of growing interest in therapeutic applications where local cavitation creates temporary perforations in cell membranes allowing for enhanced drug delivery. Clinically used microbubbles are encapsulated by a shell commonly consisting of protein, polymer, or phospholipid; the response of these bubbles to externally imposed ultrasound waves is sensitive to the compressibility of the encapsulating shell. Existing models approximate the shell compressibility via an effective surface tension (Marmottant et al. 2005). We present simulations of microbubbles subjected to high amplitude ultrasound waves (on the order of 106 Pa) and compare the results with the experimental measurements of Helfield et al. (2016). Analysis of critical points (corresponding to maximum and minimum expansion) in the governing Rayleigh-Plesset equation is used to make estimates of the parameters used to characterize the effective surface tension of the encapsulating shell. Stanford Graduate Fellowship.

Microbubble acoustic signatures: bubble deflation

NARCIS (Netherlands)

ten Brinke, G.A.; Slump, Cornelis H.

2006-01-01

Ultrasound Contrast Agents (UCAs) are used in medical imaging to enhance the visibility of structures, especially blood vessels and the liver. An example application of UCAs is the detection and classification of tumors. The most common UCA consist of microbubbles, which have pronounced non-linear

An algorithm for sensing venous oxygenation using ultrasound-modulated light enhanced by microbubbles

Science.gov (United States)

Honeysett, Jack E.; Stride, Eleanor; Deng, Jing; Leung, Terence S.

2012-02-01

Near-infrared spectroscopy (NIRS) can provide an estimate of the mean oxygen saturation in tissue. This technique is limited by optical scattering, which reduces the spatial resolution of the measurement, and by absorption, which makes the measurement insensitive to oxygenation changes in larger deep blood vessels relative to that in the superficial tissue. Acousto-optic (AO) techniques which combine focused ultrasound (US) with diffuse light have been shown to improve the spatial resolution as a result of US-modulation of the light signal, however this technique still suffers from low signal-to-noise when detecting a signal from regions of high optical absorption. Combining an US contrast agent with this hybrid technique has been proposed to amplify an AO signal. Microbubbles are a clinical contrast agent used in diagnostic US for their ability to resonate in a sound field: in this work we also make use of their optical scattering properties (modelled using Mie theory). A perturbation Monte Carlo (pMC) model of light transport in a highly absorbing blood vessel containing microbubbles surrounded by tissue is used to calculate the AO signal detected on the top surface of the tissue. An algorithm based on the modified Beer-Lambert law is derived which expresses intravenous oxygen saturation in terms of an AO signal. This is used to determine the oxygen saturation in the blood vessel from a dual wavelength microbubble-contrast AO measurement. Applying this algorithm to the simulation data shows that the venous oxygen saturation is accurately recovered, and this measurement is robust to changes in the oxygenation of the superficial tissue layer.

Microbubbles induce renal hemorrhage when exposed to diagnostic ultrasound in anesthetized rats.

Science.gov (United States)

Wible, James H; Galen, Karen P; Wojdyla, Jolette K; Hughes, Michael S; Klibanov, Alexander L; Brandenburger, Gary H

2002-01-01

The generation of ultrasound (US) bioeffects using a clinical imaging system is controversial. We tested the hypothesis that the presence of microbubbles in the US field of a medical imager induces biologic effects. Both kidneys of anesthetized rats were insonified for 5 min using a medical imaging system after the administration of microbubbles. One kidney was insonified using a continuous mode (30 Hz) and the opposite kidney was insonified using an intermittent (1 Hz) technique. The microbubbles were exposed to three different transducer frequencies and four transducer output powers. After insonification, the animals were euthanized, the kidneys were removed and their gross appearance scored under "blinded" conditions using a defined scale. After the administration of microbubbles, US imaging of the kidney caused hemorrhage in the renal tissue. The severity and area of hemorrhage increased with an increase in the transducer power and a decrease in the transducer frequency. Intermittent insonification in the presence of microbubbles produced a greater degree of renal hemorrhage than continuous imaging techniques.

Ultrasound Mediated Microbubbles Destruction Augmented Sonolysis: An In Vitro and In Vivo Study.

Science.gov (United States)

Cui, Hai; Zhu, Qiong; Gao, Yunhua; Xia, Hongmei; Tan, Kaibin; He, Ying; Liu, Zheng; Xu, Yali

2017-01-01

This study was aimed at exploring ultrasound mediated microbubbles destruction (UMMD) assisted sonolysis in both the in vitro and in vivo clots. Therapeutic ultrasound (TUS) and lipid microbubbles (MBs) were used in whole blood clots and divided into the control, TUS group, and TUS + MB group. Thrombolytic rates and microscopy were performed. Color Doppler flow imaging (CDFI) and angiography were performed to evaluate the recanalization rates and flow scores in femoral arterial thrombus (FAT) in rabbits. FAT were dyed with H&E. The average thrombolytic ratios of TUS + MB group were significantly higher than those of TUS group and the control group (both P cavitation via UMMD.

Thermal dependence of ultrasound contrast agents scattering efficiency for echographic imaging techniques

Science.gov (United States)

Biagioni, Angelo; Bettucci, Andrea; Passeri, Daniele; Alippi, Adriano

2015-06-01

Ultrasound contrast agents are used in echographic imaging techniques to enhance image contrast. In addition, they may represent an interesting solution to the problem of non-invasive temperature monitoring inside the human body, based on some thermal variations of their physical properties. Contrast agents, indeed, are inserted into blood circulation and they reach the most important organs inside the human body; consequently, any thermometric property that they may possess, could be exploited for realizing a non-invasive thermometer. They essentially are a suspension of microbubbles containing a gas enclosed in a phospholipid membrane; temperature variations induce structural modifications of the microbubble phospholipid shell, thus causing thermal dependence of contrast agent's elastic characteristics. In this paper, the acoustic scattering efficiency of a bulk suspension of of SonoVue® (Bracco SpA Milan, Italy) has been studied using a pulse-echo technique in the frequency range 1-17 MHz, as it depends upon temperatures between 25 and 65°C. Experimental data confirm that the ultrasonic attenuation coefficient of SonoVue® depends on temperature between 25 and 60°C. Chemical composition of the bubble shell seem to support the hypothesis that a phase transition in the microstructure of lipid-coated microbubbles could play a key role in explaining such effect.

Effect of low-frequency low-intensity ultrasound with microbubbles on prostate cancer hypoxia.

Science.gov (United States)

Hou, Rui; Xu, Yanjun; Lu, Qijie; Zhang, Yang; Hu, Bing

2017-10-01

Angiogenesis plays an important role in tumor growth, invasiveness, and metastasis. It is well established that prostate cancer is exposed to fluctuating oxygen tensions and both acute and chronic hypoxia exist, and these conditions can upregulate angiogenesis-associated proteins such as hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A. Low-frequency low-intensity ultrasound with microbubbles can induce obvious microvessel damage in tumors, cause cell necrosis or apoptosis. However, there is no information about whether the blocking blood effect of low-frequency low-intensity ultrasound with microbubbles has an influence on hypoxia environment of prostate cancer. Therefore, we investigated the impact of different low-frequency low-intensity ultrasound with microbubbles radiation times on prostate tumors, observed the change in the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A protein levels, as well as cell proliferation, apoptosis, and tumor volume. The results indicated that as the radiation was repeated four times on each treatment day, the effects of interruption were durable, the cell proliferation was inhibited, and apoptosis was promoted, and the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were lower in the treatment group than in the control group. When the radiation was carried out once per treatment day, the hypoxia response was stimulated, the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were higher compared with the control group, and cell proliferation was promoted. In addition, the tumor volume increased obviously in the hypoxia-stimulated group, whereas tumors grew slowly in the hypoxia-suppressed group. The results of this work demonstrated that under the same conditions, different radiation times of low-frequency low-intensity ultrasound with microbubbles affect the hypoxia response differently, and the

Light and ultrasound activated microbubbles around gold nanorods for photoacoustic microsurgery

Science.gov (United States)

Cavigli, Lucia; Centi, Sonia; Lai, Sarah; Borri, Claudia; Micheletti, Filippo; Tortoli, Paolo; Panettieri, Ilaria; Streit, Ingolf; Rossi, Francesca; Ratto, Fulvio; Pini, Roberto

2017-07-01

Photoacoustic imaging and microsurgery have recently attracted attention for applications in oncology. Here, we present a versatile set-up to trigger vapor microbubbles around plasmonic nanoparticles by a combined light-ultrasound excitation. This system enables the detection and parametrization of bubbles as a function of several variables, such us optical fluence, ultrasound intensity, nanoparticles concentration, thus providing useful directions to the development of new strategies for treatments based on optical cavitation.

Contrast ultrasound targeted treatment of gliomas in mice via drug-bearing nanoparticle delivery and microvascular ablation.

Science.gov (United States)

Burke, Caitlin W; Price, Richard J

2010-12-15

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters. Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation. Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas.

Targeted gene delivery to the synovial pannus in antigen-induced arthritis by ultrasound-targeted microbubble destruction in vivo.

Science.gov (United States)

Xiang, Xi; Tang, Yuanjiao; Leng, Qianying; Zhang, Lingyan; Qiu, Li

2016-02-01

The purpose of this study was to optimize an ultrasound-targeted microbubble destruction (UTMD) technique to improve the in vivo transfection efficiency of the gene encoding enhanced green fluorescent protein (EGFP) in the synovial pannus in an antigen-induced arthritis rabbit model. A mixture of microbubbles and plasmids was locally injected into the knee joints of an antigen-induced arthritis (AIA) rabbits. The plasmid concentrations and ultrasound conditions were varied in the experiments. We also tested local articular and intravenous injections. The rabbits were divided into five groups: (1) ultrasound+microbubbles+plasmid; (2) ultrasound+plasmid; (3) microbubble+plasmid; (4) plasmid only; (5) untreated controls. EGFP expression was observed by fluorescent microscope and immunohistochemical staining in the synovial pannus of each group. The optimal plasmid dosage and ultrasound parameter were determined based on the results of EGFP expression and the present and absent of tissue damage under light microscopy. The irradiation procedure was performed to observe the duration of the EGFP expression in the synovial pannus and other tissues and organs, as well as the damage to the normal cells. The optimal condition was determined to be a 1-MHz ultrasound pulse applied for 5 min with a power output of 2 W/cm(2) and a 20% duty cycle along with 300 μg of plasmid. Under these conditions, the synovial pannus showed significant EGFP expression without significant damage to the surrounding normal tissue. The EGFP expression induced by the local intra-articular injection was significantly more increased than that induced by the intravenous injection. The EGFP expression in the synovial pannus of the ultrasound+microbubbles+plasmid group was significantly higher than that of the other four groups (Ppannus of an AIA model. Thus, this could become a safe and effective non-viral gene transfection procedure for arthritis therapy. Copyright © 2015 Elsevier B.V. All rights

Ultrasonic Analysis of Peptide- and Antibody-Targeted Microbubble Contrast Agents for Molecular Imaging of αvβ3-Expressing Cells

Directory of Open Access Journals (Sweden)

Paul A. Dayton

2004-04-01

Full Text Available The goal of targeted ultrasound contrast agents is to significantly and selectively enhance the detection of a targeted vascular site. In this manuscript, three distinct contrast agents targeted to the αvβ3 integrin are examined. The αvβ3 integrin has been shown to be highly expressed on metastatic tumors and endothelial cells during neovascularization, and its expression has been shown to correlate with tumor grade. Specific adhesion of these contrast agents to αvβ3-expressing cell monolayers is demonstrated in vitro, and compared with that of nontargeted agents. Acoustic studies illustrate a backscatter amplitude increase from monolayers exposed to the targeted contrast agents of up to 13-fold (22 dB relative to enhancement due to control bubbles. A linear dependence between the echo amplitude and bubble concentration was observed for bound agents. The decorrelation of the echo from adherent targeted agents is observed over successive pulses as a function of acoustic pressure and bubble density. Frequency–domain analysis demonstrates that adherent targeted bubbles exhibit high-amplitude narrowband echo components, in contrast to the primarily wideband response from free microbubbles. Results suggest that adherent targeted contrast agents are differentiable from free-floating microbubbles, that targeted contrast agents provide higher sensitivity in the detection of angiogenesis, and that conventional ultrasound imaging techniques such as signal subtraction or decorrelation detection can be used to detect integrin-expressing vasculature with sufficient signal-to-noise.

Pulsed focused ultrasound combined with micro-bubble contrast agent can open the blood-brain barrier of gliblastoma patients and improve the efficacy of Temozolomide treatment

Directory of Open Access Journals (Sweden)

Qian DONG

2017-06-01

Full Text Available Objective This research examined the effect of microbubble contrast agent plus ultrasound on the permeability of blood-brain barrier, and explored whether it affects the efficacy of chemotherapeutic drugs on cerebral glioblastoma. Methods Wistar rats were divided into three groups to find the optimal concentration of ultrasonic contrast agent. To identify the best ultrasound mode that affected the permeability of blood brain barrier, we employed transmission electron microscopy for study of brain ultrastructure. Western blotting was used to detect the tight junction protein claudin-5. Evans blue staining of brain tissues was utilized to identify the best ultrasonic contrast agent concentration and mode. Rat glioma cells (line 9L were injected into Wistar rats. After temozolomide chemotherapy, the tumor size was measured and the tumor marker GFAP in serum was detected by ELISA. Results The best contrast agent concentration which increases permeability of BBB in rats was found to be 1ml/kg and the best ultrasound mode was intermittently- triggered pulses lasting for 10min (with interval was set at 400ms. More Evans blue passed the blood-brain barrier in ultrasonic cavitation effect group than in control group (P<0.05. After temozolomide chemotherapy, more tumor marker GFAP was detected in ultrasonic cavitation effect group than in control group (P<0.05. Conclusion The permeability of BBB was increased and more temozolomide went through BBB when the rats were subjected to intermittently triggered ultrasonic pulses and were injected at contrast agent at 1ml/kg, which could help to achieve better therapeutic efficacy for glioblastoma. DOI: 10.11855/j.issn.0577-7402.2017.05.06

[Preparation and preliminary evaluation of KGDS-targeted ultrasound contrast agent].

Science.gov (United States)

Gao, Feng; Ding, Yanfei; Sheng, Xiaoxi; Wang, Wei; Liang, Qi; Luo, Zhuoqiong; Zhou, Ping; Li, Hui

2009-12-01

To prepare a thrombus-targeted ultrasonic contrast agent and to investigate its targeted ability to fresh blood clots. We first synthesized FITC-KGDS-Palm compound, and then prepared thrombus-targeted microbubbles using "ultrasound & high speed shearing method". Fluorescence labeling thrombus-specific peptides and KGDS, directed at the activated glycoprotein(GP)IIb/IIIa receptor of platelets were attached to the surface of lipid microbubbles. The concentration and size of TUCA were measured by Malvern Zeta Sizer Nano-ZS590 and Coulter counter. Immunofluorescence was applied to confirm the conjugation. The conjunct ratio was assessed by flow cytometer (FCM). The KGDS-TUCA was straw yellow turbid liquor, and the concentration was 1.5 x 10(9)/mL, and the average size was 1.5 microm. The targeted microbubbles conjugated with the thrombus-specific peptides showed bright green rings by fluorescence microscope. FCM demonstrated that the wavelength of shell of KGDS-TUCA changed greatly, and the conjunct ratio was 90.04%. In vitro study showed KGDS-TUCA remained stable for 48 h at 4 degree C and target-attached to blood clots and showed good stability. The ultrasound & high speed shearing method to prepare TUCA is easy and in favor of purification. KGDS-TUCA has high specific biological activity. The conjunct ratio and stability of KGDS-TUCA are excellent.

[Molecular imaging of thrombus with microbubbles targeted to alphavbeta3-integrin using an agarose flow chamber model].

Science.gov (United States)

Hu, Guang-quan; Liu, Jian; Yang, Li; Yan, Yi; Wu, Jue-fei; Xie, Jia-jia; Cai, Jing-jing; Ji, Li-jing; Bin, Jian-ping

2010-03-01

To assess the binding ability of microbubbles targeted to alphavbeta3-integrin (MBp) for thrombus-targeted contrast-enhanced ultrasound. Targeted microbubbles were prepared by conjugating the monoclonal antibody against alphavbeta3-integrin to lipid shell of the microbubble via the avidin-biotin bridges. Equivalent isotype control microbubbles (MB) or targeted ultrasound microbubbles (MBp) were randomly added into the flow chamber. After a 30-min incubation with the thrombus fixed in an agarose flow chamber model, the thrombus was washed with a continuous flow of PBS solution (15 cm/s) for 2, 4, 6, 8 and 10 min, followed by thrombus imaging using contrast-enhanced ultrasound and measurement of the video intensity (VI) values of the images. The VI of the thrombus in MBp group was reduced by 28%-66%, while that in control MB group was decreased by 87%-94%, and the VI values of the thrombus group were significantly greater in former group at each of the time points (Pevaluation of the thrombus-binding capability of the targeted microbubble (MBp) by simulating the shear stress in vivo can be helpful for predicting the in vivo effects of ultrasonic molecular imaging using MBp.

The Use of Acoustic Radiation Force Decorrelation-Weighted Pulse Inversion for Enhanced Ultrasound Contrast Imaging.

Science.gov (United States)

Herbst, Elizabeth B; Unnikrishnan, Sunil; Wang, Shiying; Klibanov, Alexander L; Hossack, John A; Mauldin, Frank William

2017-02-01

The use of ultrasound imaging for cancer diagnosis and screening can be enhanced with the use of molecularly targeted microbubbles. Nonlinear imaging strategies such as pulse inversion (PI) and "contrast pulse sequences" (CPS) can be used to differentiate microbubble signal, but often fail to suppress highly echogenic tissue interfaces. This failure results in false-positive detection and potential misdiagnosis. In this study, a novel acoustic radiation force (ARF)-based approach was developed for superior microbubble signal detection. The feasibility of this technique, termed ARF decorrelation-weighted PI (ADW-PI), was demonstrated in vivo using a subcutaneous mouse tumor model. Tumors were implanted in the hindlimb of C57BL/6 mice by subcutaneous injection of MC38 cells. Lipid-shelled microbubbles were conjugated to anti-VEGFR2 antibody and administered via bolus injection. An image sequence using ARF pulses to generate microbubble motion was combined with PI imaging on a Verasonics Vantage programmable scanner. ADW-PI images were generated by combining PI images with interframe signal decorrelation data. For comparison, CPS images of the same mouse tumor were acquired using a Siemens Sequoia clinical scanner. Microbubble-bound regions in the tumor interior exhibited significantly higher signal decorrelation than static tissue (n = 9, P < 0.001). The application of ARF significantly increased microbubble signal decorrelation (n = 9, P < 0.01). Using these decorrelation measurements, ADW-PI imaging demonstrated significantly improved microbubble contrast-to-tissue ratio when compared with corresponding CPS or PI images (n = 9, P < 0.001). Contrast-to-tissue ratio improved with ADW-PI by approximately 3 dB compared with PI images and 2 dB compared with CPS images. Acoustic radiation force can be used to generate adherent microbubble signal decorrelation without microbubble bursting. When combined with PI, measurements of the resulting microbubble signal

Introduction to the ultrasound targeted microbubble destruction technique.

Science.gov (United States)

Walton, Chad B; Anderson, Cynthia D; Boulay, Rachel; Shohet, Ralph V

2011-06-12

In UTMD, bioactive molecules, such as negatively charged plasmid DNA vectors encoding a gene of interest, are added to the cationic shells of lipid microbubble contrast agents. In mice these vector-carrying microbubbles can be administered intravenously or directly to the left ventricle of the heart. In larger animals they can also be infused through an intracoronary catheter. The subsequent delivery from the circulation to a target organ occurs by acoustic cavitation at a resonant frequency of the microbubbles. It seems likely that the mechanical energy generated by the microbubble destruction results in transient pore formation in or between the endothelial cells of the microvasculature of the targeted region. As a result of this sonoporation effect, the transfection efficiency into and across the endothelial cells is enhanced, and transgene-encoding vectors are deposited into the surrounding tissue. Plasmid DNA remaining in the circulation is rapidly degraded by nucleases in the blood, which further reduces the likelihood of delivery to non-sonicated tissues and leads to highly specific target-organ transfection.

Synergistic enhancement of micro-bubble formation in ultrasound irradiated H2O-CH3OH mixtures probed by dynamic light scattering

International Nuclear Information System (INIS)

Pai, M.R.; Hassan, P.A.; Bharadwaj, S.R.; Kulshreshtha, S.K.

2008-01-01

This report investigates the formation of micro-bubbles in water-methanol mixtures upon ultrasound irradiation and its correlation with the yield of H 2 obtained as a result of sono-chemical splitting of water. The yield of hydrogen produced by sono-chemical reaction is monitored at different compositions of water-methanol mixtures. The evidence for the formation of micro-bubbles upon ultrasound irradiation is obtained by the dynamic light scattering technique. Micro-bubble formation during ultrasound irradiation of water-methanol mixtures, their stability and size distribution, has been quantitatively estimated. The effect of composition of the water-methanol mixture and duration of irradiation on the extent of bubble formation has been inferred from the changes in the light scattering intensity and its time correlation function. Exceptional stability of micro-bubbles without any additives is observed at a certain composition of the water-methanol mixture (4:3, v/v). The extent of micro-bubbles formed in the mixture correlates well with the yield of hydrogen detected. (authors)

Manipulation of Microbubble Clusters Using Focused Ultrasound

Science.gov (United States)

Matsuzaki, Hironobu; Osaki, Taichi; Kawaguchi, Kei; Unga, Johan; Ichiyanagi, Mitsuhisa; Azuma, Takashi; Suzuki, Ryo; Maruyama, Kazuo; Takagi, Shu

2017-11-01

In recent years, microbubbles (MBs) are expected to be utilized for the ultrasound drug delivery system (DDS). For the MB-DDS, it is important to establish a method of controlling bubbles and bubble clusters using ultrasound field. The objective of this study is to clarify behaviors of bubble clusters with various physical conditions. MBs in the ultrasound field are subjected to the primary Bjerknes force. The force traps MBs at the focal region of the focused ultrasound field. The trapped MBs form a bubble cluster at the region. A bubble cluster continues growing with absorbing surrounding bubbles until it reaches a maximum size beyond which it disappears from the focal region. In the present study, two kinds of MBs are used for the experiment. One is Sonazoid with average diameter of 2.6 um and resonant frequency of 5 MHz. The other is developed by Teikyo Univ., with average diameter of 1.5 um and presumed resonant frequency of 4 MHz. The bubble cluster's behaviors are analyzed using the high-speed camera. Sonazoid clusters have larger critical size than the other in every frequency, and its cluster size is inversely proportional to the ultrasound frequency, while Teikyo-bubble clusters have different tendency. These results are discussed in the presentation.

Microbubble Cavitation Imaging

Science.gov (United States)

Vignon, Francois; Shi, William T.; Powers, Jeffry E.; Everbach, E. Carr; Liu, Jinjin; Gao, Shunji; Xie, Feng; Porter, Thomas R.

2014-01-01

Ultrasound cavitation of microbubble contrast agents has a potential for therapeutic applications such as sonothrombolysis (STL) in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (moderate oscillations, stable cavitation, and inertial cavitation) and activity level in and around a treatment area. Acoustic passive cavitation detectors (PCDs) have been used to this end but do not provide spatial information. This paper presents a prototype of a 2-D cavitation imager capable of producing images of the dominant cavitation state and activity level in a region of interest. Similar to PCDs, the cavitation imaging described here is based on the spectral analysis of the acoustic signal radiated by the cavitating microbubbles: ultraharmonics of the excitation frequency indicate stable cavitation, whereas elevated noise bands indicate inertial cavitation; the absence of both indicates moderate oscillations. The prototype system is a modified commercially available ultrasound scanner with a sector imaging probe. The lateral resolution of the system is 1.5 mm at a focal depth of 3 cm, and the axial resolution is 3 cm for a therapy pulse length of 20 µs. The maximum frame rate of the prototype is 2 Hz. The system has been used for assessing and mapping the relative importance of the different cavitation states of a microbubble contrast agent. In vitro (tissue-mimicking flow phantom) and in vivo (heart, liver, and brain of two swine) results for cavitation states and their changes as a function of acoustic amplitude are presented. PMID:23549527

Acoustic Studies on Nanodroplets, Microbubbles and Liposomes

Science.gov (United States)

Kumar, Krishna Nandan

in vitro study aimed at developing an ultrasound-aided noninvasive pressure estimation technique using contrast agents-DefinityRTM, a lipid coated microbubble, and an experimental PLA (Poly lactic acid) microbubbles. Scattered responses from these bubbles have been measured in vitro as a function of ambient pressure using a 3.5 MHz acoustic excitation of varying amplitude. At an acoustic pressure of 670 kPa, Definity RTM microbubbles showed a linear decrease in subharmonic signal with increasing ambient pressure, registering a 12dB reduction at an overpressure of 120 mm Hg. Ultrasound contrast microbubbles experience widely varying ambient blood pressure in different organs, which can also change due to diseases. Pressure change can alter the material properties of the encapsulation of these microbubbles. Here the characteristic rheological parameters of contrast agent Definity and Targestar are determined by varying the ambient pressure (in a physiologically relevant range 0-200 mmHg). Four different interfacial rheological models are used to characterize the microbubbles. Both the contrast agents show an increase in their interfacial dilatational viscosity and interfacial dilatational elasticity with ambient pressure. It has been well established that liposomes prepared following a careful multi-step procedure can be made echogenic. Our group as well as others experimentally demonstrated that freeze-drying in the presence of mannitol is a crucial component to ensure echogenicity. Here, we showed that freeze-dried aqueous solutions of excipients such as mannitol, meso-erythritol, glycine, and glucose that assume a crystalline state, when dispersed in water creates bubbles and are echogenic even without any lipids. We also present an explanation for the bubble generation process because of dissolution of mannitol.

Microbubble Cavitation Imaging

OpenAIRE

Vignon, Francois; Shi, William T.; Powers, Jeffry E.; Everbach, E. Carr; Liu, Jinjin; Gao, Shunji; Xie, Feng; Porter, Thomas R.

2013-01-01

Ultrasound cavitation of microbubble contrast agents has a potential for therapeutic applications such as sonothrombolysis (STL) in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (moderate oscillations, stable cavitation, and inertial cavitation) and activity level in and around a treatment area. Acoustic passive cavitation detectors (PCDs) have been used to this end but do not provide spatial information.

Ultrasonically induced dynamics of a contrast agent microbubble between two parallel elastic walls

International Nuclear Information System (INIS)

Doinikov, Alexander A; Bouakaz, Ayache

2013-01-01

This work presents the derivation of a Rayleigh–Plesset-like equation that describes the radial oscillation of a contrast agent microbubble between two elastic walls, assuming that the bubble is attached to one of them. The obtained equation is then used in numerical simulations in order to establish how the presence of the second wall affects the resonance properties and the scattered echo of the contrast microbubble. The effect of encapsulation on the dynamics of the microbubble is simulated by the Marmottant shell model which is commonly used for the modeling of the dynamics of lipid-shelled contrast agents. Two cases are examined. In the first, the mechanical properties of the walls are set to correspond to OptiCell chambers which are widely used in experiments on microbubble contrast agents. In the second, the properties of the walls correspond to walls of blood vessels. It is shown that the presence of the second wall increases the resonance frequency of the contrast microbubble and decreases the amplitudes of the radial oscillation and the scattered echo of the microbubble as compared to the case that the second wall is absent. It is also shown that the presence of the second wall can change noticeably the intensity of the second harmonic in the spectrum of the scattered pressure. It is demonstrated that, depending on the value of the driving frequency, the presence of the second wall can either increase or decrease the intensity of the second harmonic as compared to its intensity in the case that the second wall is absent. (paper)

Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles.

Science.gov (United States)

Meairs, Stephen

2015-08-31

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer's disease is presented.

Real-Time Two-Dimensional Imaging of Microbubble Cavitation

NARCIS (Netherlands)

Vignon, F.; Shi, W.T.; Powers, J.E.; Liu, J.; Drvol, L.; Lof, J.; Everbach, C.; Gao, S.; Xie, F.; Porter, T.

2011-01-01

Ultrasound cavitation of microbubble contrast agents has a potentialfor therapeutic applications, including sonothrombolysis in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (e.g. stable versus inertial forms of

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening.

Science.gov (United States)

Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel; Konofagou, Elisa E

2017-04-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

Ultrasound mediated nanoparticle drug delivery

Science.gov (United States)

Mullin, Lee B.

Ultrasound is not only a powerful diagnostic tool, but also a promising therapeutic technology that can be used to improve localized drug delivery. Microbubble contrast agents are micron sized encapsulated gas filled bubbles that are administered intravenously. Originally developed to enhance ultrasound images, microbubbles are highly echogenic due to the gas core that provides a detectable impedance difference from the surrounding medium. The core also allows for controlled response of the microbubbles to ultrasound pulses. Microbubbles can be pushed using acoustic radiation force and ruptured using high pressures. Destruction of microbubbles can increase permeability at the cellular and vascular level, which can be advantageous for drug delivery. Advances in drug delivery methods have been seen with the introduction of nanoparticles, nanometer sized objects often carrying a drug payload. In chemotherapy, nanoparticles can deliver drugs to tumors while limiting systemic exposure due to abnormalities in tumor vasculature such large gaps between endothelial cells that allow nanoparticles to enter into the interstitial space; this is referred to as the enhanced permeability and retention (EPR) effect. However, this effect may be overestimated in many tumors. Additionally, only a small percentage of the injected dose accumulates in the tumor, which most the nanoparticles accumulating in the liver and spleen. It is hypothesized that combining the acoustic activity of an ultrasound contrast agent with the high payload and extravasation ability of a nanoparticle, localized delivery to the tumor with reduced systemic toxicity can be achieved. This method can be accomplished by either loading nanoparticles onto the shell of the microbubble or through a coadministration method of both nanoparticles and microbubbles. The work presented in this dissertation utilizes novel and commercial nanoparticle formulations, combined with microbubbles and a variety of ultrasound systems

Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging: In Vitro and in Vivo Evaluation

NARCIS (Netherlands)

V. Daeichin (Verya); T. van Rooij (Tom); I. Skachkov (Ilya); B. Ergin (Bulent); P. Specht (Patricia); A.A.P. Lima (Alexandre ); C. Ince (Can); J.G. Bosch (Hans); A.F.W. van der Steen (Ton); N. de Jong (Nico); K. Kooiman (Klazina)

2017-01-01

textabstractAlthough high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited

Tunable microbubble generator using electrolysis and ultrasound

Science.gov (United States)

Achaoui, Younes; Metwally, Khaled; Fouan, Damien; Hammadi, Zoubida; Morin, Roger; Debieu, Eric; Payan, Cédric; Mensah, Serge

2017-01-01

This letter reports on a method for producing on demand calibrated bubbles in a non-chemically controlled solution using localized micro-electrolysis and ultrasound. Implementing a feedback loop in the process leads to a point source of stable mono-dispersed microbubbles. This approach overcomes the inertial constraints encountered in microfluidics with the possibility to produce from a single to an array of calibrated bubbles. Moreover, this method avoids the use of additional surfactant that may modify the composition of the host fluid. It impacts across a broad range of scientific domains from bioengineering, sensing to environment.

Tunable microbubble generator using electrolysis and ultrasound

Directory of Open Access Journals (Sweden)

Younes Achaoui

2017-01-01

Full Text Available This letter reports on a method for producing on demand calibrated bubbles in a non-chemically controlled solution using localized micro-electrolysis and ultrasound. Implementing a feedback loop in the process leads to a point source of stable mono-dispersed microbubbles. This approach overcomes the inertial constraints encountered in microfluidics with the possibility to produce from a single to an array of calibrated bubbles. Moreover, this method avoids the use of additional surfactant that may modify the composition of the host fluid. It impacts across a broad range of scientific domains from bioengineering, sensing to environment.

Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging : In Vitro and in Vivo Evaluation

NARCIS (Netherlands)

Daeichin, Verya; van Rooij, Tom; Skachkov, Ilya; Ergin, Bulent; Specht, Patricia A.C.; Lima, Alexandre; Ince, Can; Bosch, Johan G.; van der Steen, A.F.W.; de Jong, N.; Kooiman, Klazina

2017-01-01

Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially

Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging: In Vitro and In Vivo Evaluation

NARCIS (Netherlands)

Daeichin, Verya; van Rooij, Tom; Skachkov, Ilya; Ergin, Bulent; Specht, Patricia A. C.; Lima, Alexandre; Ince, Can; Bosch, Johan G.; van der Steen, Antonius F. W.; de Jong, Nico; Kooiman, Klazina

2017-01-01

Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially available

Changes in tumor vascularity precede microbubble contrast accumulation deficit in the process of dedifferentiation of hepatocellular carcinoma

International Nuclear Information System (INIS)

Maruyama, Hitoshi; Takahashi, Masanori; Ishibashi, Hiroyuki; Okabe, Shinichiro; Yoshikawa, Masaharu; Yokosuka, Osamu

2010-01-01

Purpose: To elucidate the changes in tumor vascularity and microbubble accumulation on contrast-enhanced sonograms, in relation to the dedifferentiation of hepatocellular carcinoma (HCC). Materials and methods: This prospective study enrolled 10 patients with histologically proven HCC (14.4-39.0 mm, 26.1 ± 7.4) showing nodule-in-nodule appearance upon contrast-enhanced computed tomography. Contrast-enhanced ultrasound was performed by harmonic imaging under a low mechanical index (0.22-0.25) during the vascular phase (agent injection to 1 min) and late phase (15 min) following the injection of Sonazoid TM (0.0075 ml/kg). Contrast enhancement in the inner and outer nodules was assessed in comparison with that in adjacent liver parenchyma as hyper-, iso-, or hypo-enhanced. Results: Vascular-phase enhancement of all 10 inner nodules was hyper-enhanced, and that of outer nodules was hyper-enhanced in 3, iso-enhanced in 2, and hypo-enhanced in 5. Late-phase enhancement of inner nodules was hypo-enhanced in 8 and iso-enhanced in 2. Furthermore, late-phase enhancement of outer nodules was iso-enhanced in the 7 lesions that showed iso- or hypo-enhancement in the vascular phase, and hypo-enhanced in the 3 with hyper-enhancement in the vascular phase. Late-phase hypo-enhancement was significantly more frequent in the nodules showing early-phase hyper-enhancement (11/13) than in the nodules showing early-phase iso- or hypo-enhancement (0/7) in both the inner and outer nodules. Conclusion: Dedifferentiation of HCC may be accompanied by changes in tumor vascularity prior to a reduction in microbubble accumulation. Observation of the vascular phase may be more useful than late-phase imaging for the early recognition of HCC dedifferentiation when using contrast-enhanced ultrasound with Sonazoid.

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles

Directory of Open Access Journals (Sweden)

Stephen Meairs

2015-08-01

Full Text Available Medical treatment options for central nervous system (CNS diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB. Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer’s disease is presented.

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

Science.gov (United States)

Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel

2016-01-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo. PMID:27278929

Renal perfusion image using harmonic ultrasound with microbble contrast agent: preliminary study

International Nuclear Information System (INIS)

Kim, Jung Hoon; Choi, Jae Ho; Han, Dong Chul; Lee, Hi Bahl; Choi, Deuk Lin; Eun, Hyo Won; Lee, Hun Jae

2003-01-01

To compare, in terms of their feasibility and normal range, 99m Tc-DTPA renal perfusion imaging and renal perfusion imaging using harmonic ultrasound (US) with a microbubble contrast agent for the evaluation of renal perfusion after renal transplantation. During a six-month period, thirty patients who had received a renal transplant underwent both 99m Tc-DTPA renal perfusion imaging and renal perfusion imaging using harmonic US with a microbubble contrast agent. Sonographic renal perfusion images were obtained before and after a bolus injection of the microbubble contrast agent Levovist TM (SH U 5084; Schering AG, Berlin, Germany) every 3 seconds for 3 minutes. Sonographic renal perfusion images were converted into a renal perfusion curve by a computer program and T peak of the curve thus obtained was compared with that of the 99m Tc-DTPA curve. Average T peak of the 99m Tc-DTPA renal perfusion curve was 16.2 seconds in the normal group and 39.6 seconds in the delayed perfusion group, while average T peak of the sonographic renal perfusion curve was 23.7 seconds and 46.2 seconds, respectively. T peak of the sonographic renal perfusion curve showed a good correlation with that of the 99m Tc-DTPA curve (correlation coefficient=0.8209; p=0.0001). The cut-off value of T peak of the sonographic renal perfusion curve was 35 seconds (sensitivity=90%, specificity=95%). In patients who have received a renal transplant, the findings of renal perfusion imaging using harmonic US with a microbubble contrast agent show close correlation with those of 99m Tc-DTPA renal perfusion imaging. The optimal cut-off value of T peak of the sonographic renal perfusion curve was 35 seconds

Spatiotemporal evolution of cavitation dynamics exhibited by flowing microbubbles during ultrasound exposure.

Science.gov (United States)

Choi, James J; Coussios, Constantin-C

2012-11-01

Ultrasound and microbubble-based therapies utilize cavitation to generate bioeffects, yet cavitation dynamics during individual pulses and across consecutive pulses remain poorly understood under physiologically relevant flow conditions. SonoVue(®) microbubbles were made to flow (fluid velocity: 10-40 mm/s) through a vessel in a tissue-mimicking material and were exposed to ultrasound [frequency: 0.5 MHz, peak-rarefactional pressure (PRP): 150-1200 kPa, pulse length: 1-100,000 cycles, pulse repetition frequency (PRF): 1-50 Hz, number of pulses: 10-250]. Radiated emissions were captured on a linear array, and passive acoustic mapping was used to spatiotemporally resolve cavitation events. At low PRPs, stable cavitation was maintained throughout several pulses, thus generating a steady rise in energy with low upstream spatial bias within the focal volume. At high PRPs, inertial cavitation was concentrated in the first 6.3 ± 1.3 ms of a pulse, followed by an energy reduction and high upstream bias. Multiple pulses at PRFs below a flow-dependent critical rate (PRF(crit)) produced predictable and consistent cavitation dynamics. Above the PRF(crit), energy generated was unpredictable and spatially biased. In conclusion, key parameters in microbubble-seeded flow conditions were matched with specific types, magnitudes, distributions, and durations of cavitation; this may help in understanding empirically observed in vivo phenomena and guide future pulse sequence designs.

Contrast enhanced ultrasound in the assessment of urogenital pathology

Directory of Open Access Journals (Sweden)

Libero Barozzi

2014-12-01

Full Text Available Contrast enhanced ultrasound (CEUS is an innovative technique that employs microbubble contrast agents to demonstrate parenchymal perfusion. Although initial clinical application was focused on the liver pathology, a wide variety of clinical conditions can be assessed now with CEUS. CEUS is a well-tolerated technique and is acquiring an increasing role in the assessment of renal pathology because contrast agents are not excreted by the kidney and do not affect the renal function. CEUS demonstrated an accuracy similar to contrast enhanced multi-detector computed tomography (CEMDCT in detecting focal lesions, with the advantage of the real-time assessment of microvascular perfusion by using time-intensity curves. The aim of this paper is to review the main indications of CEUS in the assessment of renal and urogenital pathology. Imaging examples are presented and described. Advantages and limitations of CEUS with reference to conventional US and CE-MDCT are discussed.

Acoustic scattering from a contrast agent microbubble near an elastic wall of finite thickness

International Nuclear Information System (INIS)

Doinikov, Alexander A; Aired, Leila; Bouakaz, Ayache

2011-01-01

Interest in the problem under consideration in this study is motivated by targeted ultrasound imaging where one has to deal with microbubble contrast agents pulsating near blood vessel walls. A modified Rayleigh–Plesset equation is derived that describes the oscillation of a contrast agent microbubble near an elastic wall of finite thickness. It is assumed that the medium behind the wall is a fluid but it is shown that the equation obtained is easily transformable to the case that the medium behind the wall is an elastic solid. In contrast to the model of a rigid wall, which predicts decreasing natural frequency of a bubble near the wall, the elastic wall model reveals that the bubble natural frequency can both decrease and increase, and in cases of interest for medical applications, the bubble natural frequency usually increases. It is found that the influence of an elastic wall on the acoustic response of a bubble is determined by the ratio between a cumulative parameter, which integrally characterizes the mechanical properties of the wall and has the dimension of density, and the density of the liquid surrounding the bubble. It is shown that the acoustic influence of the arterial wall on the bubble is weak and apparently cannot be used to recognize the moment when the bubble approaches the wall. However, in experiments where the behavior of bubbles near various plastic walls is observed, changes in the bubble response, such as increasing natural frequency and decreasing oscillation amplitude, are detectable.

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping.

Science.gov (United States)

Deng, Lulu; O'Reilly, Meaghan A; Jones, Ryan M; An, Ran; Hynynen, Kullervo

2016-12-21

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612, and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning (-40, 40) and (-30, 50) mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi-foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning (-25, 25) mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in vivo experiments demonstrated the system's ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non

Biological in situ characterization of polymeric microbubble contrast agents

NARCIS (Netherlands)

Wan, Sha; Egri, Gabriella; Oddo, Letizia; Cerroni, Barbara; Dähne, Lars; Paradossi, Gaio; Salvati, Anna; Lynch, Iseult; Dawson, Kenneth A; Monopoli, Marco P

Polymeric microbubbles (MBs) are gas filled particles composed of a thin stabilized polymer shell that have been recently developed as valid contrast agents for the combined use of ultrasonography (US), magnetic resonance imaging (MRI) and single photon emission computer tomography (SPECT) imaging.

PBCA-based polymeric microbubbles for molecular imaging and drug delivery

NARCIS (Netherlands)

Koczera, Patrick; Appold, Lia; Shi, Yang; Liu, Mengjiao; Dasgupta, Anshuman; Pathak, Vertika; Ojha, Tarun; Fokong, Stanley; Wu, Zhuojun; Van Zandvoort, Marc; Iranzo, Olga; Kuehne, Alexander J C; Pich, Andrij; Kiessling, Fabian; Lammers, Twan

2017-01-01

Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. We describe different types of targeted and drug-loaded poly(n-butyl cyanoacrylate) (PBCA) MB, and demonstrate their suitability for multiple biomedical applications, including molecular US imaging and US-mediated

Contrast-enhanced voiding urosonography: in vitro evaluation of a second-generation ultrasound contrast agent for in vivo optimization.

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Back, Susan J; Edgar, J Christopher; Canning, Douglas A; Darge, Kassa

2015-09-01

Pediatric contrast-enhanced ultrasound (CEUS) is primarily performed outside the United States where a track record for safety in intravenous and intravesical applications has been established. Contrast-enhanced voiding urosonography (ceVUS) has also been shown to have a much higher rate of vesicoureteral reflux detection compared to voiding cystourethrography. US contrast agents available in the United States differ from those abroad. Optison® (GE Healthcare, Princeton, NJ) is such an US contrast agent. While Optison® has similar characteristics to other second-generation agents, it has never been used for ceVUS. In vitro optimization of dose and imaging parameters as well as assessment of contrast visualization when delivered in conditions similar to ceVUS are necessary starting points prior to in vivo applications. To optimize the intravesical use of Optison® in vitro for ceVUS before its use in pediatric studies. The experimental design simulated intravesical use. Using 9- and 12-MHz linear transducers, we scanned 20-mL syringes varying mechanical index, US contrast agent concentration (0.25%, 0.5%, 1.0%), solvent (saline, urine, radiographic contrast agent) and time out of refrigeration. We evaluated mechanical index settings and contrast duration, optimized the contrast dose, measured the effect of urine and radiographic contrast agent, and the impact of length of time of contrast outside of the refrigerator on US contrast appearance. We scanned 50-ml saline bags to assess the appearance and duration of US contrast with different delivery systems (injection vs. infusion). Consistent contrast visualization was achieved at a mechanical index of 0.06-0.17 and 0.11-0.48 for the L9 and L12 MHz transducers (P contrast visualization of the microbubbles with a higher transducer frequency. The lowest mechanical index for earliest visible microbubble destruction was 0.21 for the 9 MHz and 0.39 for the 12 MHz (P contrast agent volume to bladder filling was the

Assessment of portal venous system patency in the liver transplant candidate: A prospective study comparing ultrasound, microbubble-enhanced colour Doppler ultrasound, with arteriography and surgery

International Nuclear Information System (INIS)

Marshall, M.M.; Beese, R.C.; Muiesan, P.; Sarma, D.I.; O'Grady, J.; Sidhu, P.S.

2002-01-01

AIM: To determine the role of microbubble-enhanced colour Doppler ultrasound (CDUS) in assessing portal venous patency prior to liver transplantation. MATERIALS AND METHODS: Over a 2-year period, all patients with chronic liver disease undergoing routine pre-transplant CDUS examination in whom the portal venous system was inadequately demonstrated were recruited to the study. CDUS was performed in 368 patients and 33 patients (9%) were recruited. A repeat CDUS examination following an intravenous bolus injection of the microbubble contrast agent Levovist[reg] (Schering Healthcare AG, Berlin, Germany) was performed. Diagnostic confidence was recorded on a free linear analogue scale for both examinations. Findings were compared with indirect portography and surgery. RESULTS: Of the 33 patients with sub-optimal baseline examinations, improvement in portal vein visualization was achieved in 31 patients (94%). Median diagnostic confidence increased from 50% (interquartile range 30-60) to 90% (interquartile range 75-98) (P < 0.001) following administration of Levovist[reg]. Overall accuracy of portal vein assessment using microbubble-enhanced CDUS in 15 patients in whom a definitive diagnosis was made within 2 months was 87%. CONCLUSION: Microbubble-enhanced CDUS is a simple, inexpensive adjunct to standard pre liver transplant screening of the portal vein. It is particularly helpful in patients with end-stage cirrhosis who are at high risk of portal vein thrombosis and in whom the conventional examination is sub-optimal.Marshall, M.M. et al. (2002)

The use of Acoustic Radiation Force decorrelation-weighted pulse inversion (ADW-PI) for enhanced ultrasound contrast imaging

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Herbst, Elizabeth; Unnikrishnan, Sunil; Wang, Shiying; Klibanov, Alexander L.; Hossack, John A.; Mauldin, F. William

2016-01-01

Objectives The use of ultrasound imaging for cancer diagnosis and screening can be enhanced with the use of molecularly targeted microbubbles. Nonlinear imaging strategies such as pulse inversion (PI) and “contrast pulse sequences” (CPS) can be used to differentiate microbubble signal, but often fail to suppress highly echogenic tissue interfaces. This failure results in false positive detection and potential misdiagnosis. In this study, a novel Acoustic Radiation Force (ARF) based approach was developed for superior microbubble signal detection. The feasibility of this technique, termed ARF-decorrelation-weighted PI (ADW-PI), was demonstrated in vivo using a subcutaneous mouse tumor model. Materials and Methods Tumors were implanted in the hindlimb of C57BL/6 mice by subcutaneous injection of MC38 cells. Lipid-shelled microbubbles were conjugated to anti-VEGFR2 antibody and administered via bolus injection. An image sequence using ARF pulses to generate microbubble motion was combined with PI imaging on a Verasonics Vantage programmable scanner. ADW-PI images were generated by combining PI images with inter-frame signal decorrelation data. For comparison, CPS images of the same mouse tumor were acquired using a Siemens Sequoia clinical scanner. Results Microbubble-bound regions in the tumor interior exhibited significantly higher signal decorrelation than static tissue (n = 9, p < 0.001). The application of ARF significantly increased microbubble signal decorrelation (n = 9, p < 0.01). Using these decorrelation measurements, ADW-PI imaging demonstrated significantly improved microbubble contrast-to-tissue ratio (CTR) when compared to corresponding CPS or PI images (n = 9, p < 0.001). CTR improved with ADW-PI by approximately 3 dB compared to PI images and 2 dB compared to CPS images. Conclusions Acoustic radiation force can be used to generate adherent microbubble signal decorrelation without microbubble bursting. When combined with pulse inversion

Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.

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Chu, Po-Chun; Chai, Wen-Yen; Tsai, Chih-Hung; Kang, Shih-Tsung; Yeh, Chih-Kuang; Liu, Hao-Li

2016-09-15

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

The Thrombolytic Effect of Diagnostic Ultrasound-Induced Microbubble Cavitation in Acute Carotid Thromboembolism.

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Porter, Thomas R; Xie, Feng; Lof, John; Powers, Jeffry; Vignon, Francois; Shi, William; White, Matthew

2017-08-01

Acute ischemic stroke is often due to thromboembolism forming over ruptured atherosclerotic plaque in the carotid artery (CA). The presence of intraluminal CA thrombus is associated with a high risk of thromboembolic cerebral ischemic events. The cavitation induced by diagnostic ultrasound high mechanical index (MI) impulses applied locally during a commercially available intravenous microbubble infusion has dissolved intravascular thrombi, especially when using longer pulse durations. The beneficial effects of this in acute carotid thromboembolism is not known. An oversized balloon injury was created in the distal extracranial common CA of 38 porcine carotid arteries. After this, a 70% to 80% stenosis was created in the mid common CA proximal to the injury site using partial balloon inflation. Acute thrombotic CA occlusions were created just distal to the balloon catheter by injecting fresh autologous arterial thrombi. After angiographic documentation of occlusion, the common carotid thrombosis was treated with either diagnostic low MI imaging alone (0.2 MI; Philips S5-1) applied through a tissue mimicking phantom (TMP) or intermittent diagnostic high MI stable cavitation (SC)-inducing impulses with a longer pulse duration (0.8 MI; 20 microseconds' pulse duration) or inertial cavitation (IC) impulses (1.2 MI; 20 microseconds' pulse duration). All treatment times were for 30 minutes. Intravenous ultrasound contrast (2% Definity; Lantheus Medical) was infused during the treatment period. Angiographic recanalization in 4 intracranial and extracranial vessels downstream from the CA occlusion (auricular, ascending pharyngeal, buccinator, and maxillary) was assessed with both magnetic resonance 3-dimensional time-of-flight and phase contrast angiography. All magnetic resonance images were interpreted by an independent neuroradiologist using the thrombolysis in cerebral infarction (TICI) scoring system. By phase contrast angiography, at least mild recanalization (TICI 2a

Crucial factors and emerging concepts in ultrasound-triggered drug delivery.

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Geers, Bart; Dewitte, Heleen; De Smedt, Stefaan C; Lentacker, Ine

2012-12-28

Time and space controlled drug delivery still remains a huge challenge in medicine. A novel approach that could offer a solution is ultrasound guided drug delivery. “Ultrasonic drug delivery” is often based on the use of small gas bubbles (so-called microbubbles) that oscillate and cavitate upon exposure to ultrasound waves. Some microbubbles are FDA approved contrast agents for ultrasound imaging and are nowadays widely investigated as promising drug carriers. Indeed, it has been observed that upon exposure to ultrasound waves, microbubbles may (a) release the encapsulated drugs and (b) simultaneously change the structure of the cell membranes in contact with the microbubbles which may facilitate drug entrance into cells. This review aims to highlight (a) major factors known so far which affect ultrasonic drug delivery (like the structure of the microbubbles, acoustic settings, etc.) and (b) summarizes the recent preclinical progress in this field together with a number of promising new concepts and applications.

A high pulse repetition frequency ultrasound system for the ex vivo measurement of mechanical properties of crystalline lenses with laser-induced microbubbles interrogated by acoustic radiation force

International Nuclear Information System (INIS)

Yoon, Sangpil; Emelianov, Stanislav; Aglyamov, Salavat; Karpiouk, Andrei

2012-01-01

A high pulse repetition frequency ultrasound system for an ex vivo measurement of mechanical properties of an animal crystalline lens was developed and validated. We measured the bulk displacement of laser-induced microbubbles created at different positions within the lens using nanosecond laser pulses. An impulsive acoustic radiation force was applied to the microbubble, and spatio-temporal measurements of the microbubble displacement were assessed using a custom-made high pulse repetition frequency ultrasound system consisting of two 25 MHz focused ultrasound transducers. One of these transducers was used to emit a train of ultrasound pulses and another transducer was used to receive the ultrasound echoes reflected from the microbubble. The developed system was operating at 1 MHz pulse repetition frequency. Based on the measured motion of the microbubble, Young’s moduli of surrounding tissue were reconstructed and the values were compared with those measured using the indentation test. Measured values of Young’s moduli of four bovine lenses ranged from 2.6 ± 0.1 to 26 ± 1.4 kPa, and there was good agreement between the two methods. Therefore, our studies, utilizing the high pulse repetition frequency ultrasound system, suggest that the developed approach can be used to assess the mechanical properties of ex vivo crystalline lenses. Furthermore, the potential of the presented approach for in vivo measurements is discussed. (paper)

Noninvasive, localized, and transient brain drug delivery using focused ultrasound and microbubbles

Science.gov (United States)

Choi, James J.

In the United States, Alzheimer's disease (AD), Parkinson's disease (PD), and brain cancer caused 72,432, 19,566 and 12,886 deaths in 2006, respectively. Whereas the number of deaths due to major disorders such as heart disease, stroke, and prostate cancer have decreased since 2006, deaths attributed to AD, PD, and brain cancer have not. Treatment options for patients with CNS disorders remain limited despite significant advances in knowledge of CNS disease pathways and development of neurologically potent agents. One of the major obstacles is that the cerebral microvasculature is lined by a specialized and highly regulated blood-brain barrier (BBB) that prevents large agents from entering the brain extracellular space. The purpose of this dissertation is to design a noninvasive, localized, and transient BBB opening system using focused ultrasound (FUS) and determine ultrasound and microbubble conditions that can effectively and safely deliver large pharmacologically-relevant-sized agents to the brain. To meet this end, an in vivo mouse brain drug delivery system using a stereotactic-based targeting method was developed. FUS was applied noninvasively through the intact skin and skull, which allowed for long-term and high-throughput studies. With this system, more than 150 mice were exposed to one of 31 distinct acoustic and microbubble conditions. The feasibility of delivering a large MRI contrast agent was first demonstrated in vivo in both wild-type and transgenic Alzheimer's disease model (APP/PS1) mice. A wide range of acoustic and microbubble conditions were then evaluated for their ability to deliver agents to a target region. Interestingly, the possible design space of parameters was found to be vast and different conditions resulted in distinct spatial distributions and doses delivered. In particular, BBB opening was shown to be dependent on the microbubble diameter, acoustic pressure, pulse repetition frequency (PRF), and pulse length (PL). Each set of

Mechanical and dynamic characteristics of encapsulated microbubbles coupled by magnetic nanoparticles as multifunctional imaging and drug delivery agents

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Guo, Gepu; Lu, Lu; Yin, Leilei; Tu, Juan; Guo, Xiasheng; Wu, Junru; Xu, Di; Zhang, Dong

2014-11-01

Development of magnetic encapsulated microbubble agents that can integrate multiple diagnostic and therapeutic functions is a key focus in both biomedical engineering and nanotechnology and one which will have far-reaching impact on medical diagnosis and therapies. However, properly designing multifunctional agents that can satisfy particular diagnostic/therapeutic requirements has been recognized as rather challenging, because there is a lack of comprehensive understanding of how the integration of magnetic nanoparticles to microbubble encapsulating shells affects their mechanical properties and dynamic performance in ultrasound imaging and drug delivery. Here, a multifunctional imaging contrast and in-situ gene/drug delivery agent was synthesized by coupling super paramagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles. Systematical studies were performed to investigate the SPIO-concentration-dependence of microbubble mechanical properties, acoustic scattering response, inertial cavitation activity and ultrasound-facilitated gene transfection effect. These demonstrated that, with the increasing SPIO concentration, the microbubble mean diameter and shell stiffness increased and ultrasound scattering response and inertial cavitation activity could be significantly enhanced. However, an optimized ultrasound-facilitated vascular endothelial growth factor transfection outcome would be achieved by adopting magnetic albumin-shelled microbubbles with an appropriate SPIO concentration of 114.7 µg ml-1. The current results would provide helpful guidance for future development of multifunctional agents and further optimization of their diagnostic/therapeutic performance in clinic.

Mechanical and dynamic characteristics of encapsulated microbubbles coupled by magnetic nanoparticles as multifunctional imaging and drug delivery agents

International Nuclear Information System (INIS)

Guo, Gepu; Lu, Lu; Tu, Juan; Guo, Xiasheng; Zhang, Dong; Yin, Leilei; Wu, Junru; Xu, Di

2014-01-01

Development of magnetic encapsulated microbubble agents that can integrate multiple diagnostic and therapeutic functions is a key focus in both biomedical engineering and nanotechnology and one which will have far-reaching impact on medical diagnosis and therapies. However, properly designing multifunctional agents that can satisfy particular diagnostic/therapeutic requirements has been recognized as rather challenging, because there is a lack of comprehensive understanding of how the integration of magnetic nanoparticles to microbubble encapsulating shells affects their mechanical properties and dynamic performance in ultrasound imaging and drug delivery. Here, a multifunctional imaging contrast and in-situ gene/drug delivery agent was synthesized by coupling super paramagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles. Systematical studies were performed to investigate the SPIO-concentration-dependence of microbubble mechanical properties, acoustic scattering response, inertial cavitation activity and ultrasound-facilitated gene transfection effect. These demonstrated that, with the increasing SPIO concentration, the microbubble mean diameter and shell stiffness increased and ultrasound scattering response and inertial cavitation activity could be significantly enhanced. However, an optimized ultrasound-facilitated vascular endothelial growth factor transfection outcome would be achieved by adopting magnetic albumin-shelled microbubbles with an appropriate SPIO concentration of 114.7 µg ml −1 . The current results would provide helpful guidance for future development of multifunctional agents and further optimization of their diagnostic/therapeutic performance in clinic. (paper)

Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation.

Directory of Open Access Journals (Sweden)

Ralf Stefan Eschbach

Full Text Available To investigate contrast-enhanced ultrasound (CEUS with VEGFR2-targeted microbubbles for monitoring therapy effects of regorafenib on experimental colon carcinomas in rats with correlation to dynamic contrast-enhanced MRI (DCE-MRI and immunohistochemistry.Human colorectal adenocarcinoma xenografts (HT-29 were implanted subcutaneously in n = 21 (n = 11 therapy group; n = 10 control group female athymic nude rats (Hsd: RH-Foxn1rnu. Animals were imaged at baseline and after a one-week daily treatment with regorafenib or a placebo (10 mg/kg bodyweight, using CEUS with VEGFR2-targeted microbubbles and DCE-MRI. In CEUS tumor perfusion was assessed during an early vascular phase (wash-in area under the curve = WiAUC and VEGFR2-specific binding during a late molecular phase (signal intensity after 8 (SI8min and 10 minutes (SI10min, using a conventional 15L8 linear transducer (transmit frequency 7 MHz, dynamic range 80 dB, depth 25 mm. In DCE-MRI functional parameters plasma flow (PF and plasma volume (PV were quantified. For validation purposes, CEUS parameters were correlated with DCE-MRI parameters and immunohistochemical VEGFR2, CD31, Ki-67 and TUNEL stainings.CEUS perfusion parameter WiAUC decreased significantly (116,989 ± 77,048 a.u. to 30,076 ± 27,095a.u.; p = 0.005 under therapy with no significant changes (133,932 ± 65,960 a.u. to 84,316 ± 74,144 a.u.; p = 0.093 in the control group. In the therapy group, the amount of bound microbubbles in the late phase was significantly lower in the therapy than in the control group on day 7 (SI8min: 283 ± 191 vs. 802 ± 460 a.u.; p = 0.006; SI10min: 226 ± 149 vs. 645 ± 461 a.u.; p = 0.009. PF and PV decreased significantly (PF: 147 ± 58 mL/100 mL/min to 71 ± 15 mL/100 mL/min; p = 0.003; PV: 13 ± 3% to 9 ± 4%; p = 0.040 in the therapy group. Immunohistochemistry revealed significantly fewer VEGFR2 (7.2 ± 1.8 vs. 17.8 ± 4.6; p < 0.001, CD31 (8.1 ± 3.0 vs. 20.8 ± 5.7; p < 0.001 and Ki-67 (318.7 �

Inertial cavitation threshold of nested microbubbles.

Science.gov (United States)

Wallace, N; Dicker, S; Lewin, Peter; Wrenn, S P

2015-04-01

Cavitation of ultrasound contrast agents (UCAs) promotes both beneficial and detrimental bioeffects in vivo (Radhakrishnan et al., 2013) [1]. The ability to determine the inertial cavitation threshold of UCA microbubbles has potential application in contrast imaging, development of therapeutic agents, and evaluation of localized effects on the body (Ammi et al., 2006) [2]. This study evaluates a novel UCA and its inertial cavitation behavior as determined by a home built cavitation detection system. Two 2.25 MHz transducers are placed at a 90° angle to one another where one transducer is driven by a high voltage pulser and the other transducer receives the signal from the oscillating microbubble. The sample chamber is placed in the overlap of the focal region of the two transducers where the microbubbles are exposed to a pulser signal consisting of 600 pulse trains per experiment at a pulse repetition frequency of 5 Hz where each train has four pulses of four cycles. The formulation being analyzed is comprised of an SF6 microbubble coated by a DSPC PEG-3000 monolayer nested within a poly-lactic acid (PLA) spherical shell. The effect of varying shell diameters and microbubble concentration on cavitation threshold profile for peak negative pressures ranging from 50 kPa to 2 MPa are presented and discussed in this paper. The nesting shell decreases inertial cavitation events from 97.96% for an un-nested microbubble to 19.09% for the same microbubbles nested within a 2.53 μm shell. As shell diameter decreases, the percentage of inertially cavitating microbubbles also decreases. For nesting formulations with average outer capsule diameters of 20.52, 14.95, 9.95, 5.55, 2.53, and 1.95 μm, the percentage of sample destroyed at 1 MPa was 51.02, 38.94, 33.25, 25.27, 19.09, and 5.37% respectively. Copyright © 2015 Elsevier B.V. All rights reserved.

Usage of CO2 microbubbles as flow-tracing contrast media in X-ray dynamic imaging of blood flows.

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Lee, Sang Joon; Park, Han Wook; Jung, Sung Yong

2014-09-01

X-ray imaging techniques have been employed to visualize various biofluid flow phenomena in a non-destructive manner. X-ray particle image velocimetry (PIV) was developed to measure velocity fields of blood flows to obtain hemodynamic information. A time-resolved X-ray PIV technique that is capable of measuring the velocity fields of blood flows under real physiological conditions was recently developed. However, technical limitations still remained in the measurement of blood flows with high image contrast and sufficient biocapability. In this study, CO2 microbubbles as flow-tracing contrast media for X-ray PIV measurements of biofluid flows was developed. Human serum albumin and CO2 gas were mechanically agitated to fabricate CO2 microbubbles. The optimal fabricating conditions of CO2 microbubbles were found by comparing the size and amount of microbubbles fabricated under various operating conditions. The average size and quantity of CO2 microbubbles were measured by using a synchrotron X-ray imaging technique with a high spatial resolution. The quantity and size of the fabricated microbubbles decrease with increasing speed and operation time of the mechanical agitation. The feasibility of CO2 microbubbles as a flow-tracing contrast media was checked for a 40% hematocrit blood flow. Particle images of the blood flow were consecutively captured by the time-resolved X-ray PIV system to obtain velocity field information of the flow. The experimental results were compared with a theoretically amassed velocity profile. Results show that the CO2 microbubbles can be used as effective flow-tracing contrast media in X-ray PIV experiments.

On the relationship between microbubble fragmentation, deflation and broadband superharmonic signal production.

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Lindsey, Brooks D; Rojas, Juan D; Dayton, Paul A

2015-06-01

Acoustic angiography imaging of microbubble contrast agents uses the superharmonic energy produced from excited microbubbles and enables high-contrast, high-resolution imaging. However, the exact mechanism by which broadband harmonic energy is produced is not fully understood. To elucidate the role of microbubble shell fragmentation in superharmonic signal production, simultaneous optical and acoustic measurements were performed on individual microbubbles at transmit frequencies from 1.75 to 3.75 MHz and pressures near the shell fragmentation threshold for microbubbles of varying diameter. High-amplitude, broadband superharmonic signals were produced with shell fragmentation, whereas weaker signals (approximately 25% of peak amplitude) were observed in the presence of shrinking bubbles. Furthermore, when populations of stationary microbubbles were imaged with a dual-frequency ultrasound imaging system, a sharper decline in image intensity with respect to frame number was observed for 1-μm bubbles than for 4-μm bubbles. Finally, in a study of two rodents, increasing frame rate from 4 to 7 Hz resulted in decreases in mean steady-state image intensity of 27% at 1000 kPa and 29% at 1300 kPa. Although the existence of superharmonic signals when bubbles shrink has the potential to prolong the imaging efficacy of microbubbles, parameters such as frame rate and peak pressure must be balanced with expected re-perfusion rate to maintain adequate contrast during in vivo imaging. Copyright © 2015. Published by Elsevier Inc.

Correction of Non-Linear Propagation Artifact in Contrast-Enhanced Ultrasound Imaging of Carotid Arteries: Methods and in Vitro Evaluation.

Science.gov (United States)

Yildiz, Yesna O; Eckersley, Robert J; Senior, Roxy; Lim, Adrian K P; Cosgrove, David; Tang, Meng-Xing

2015-07-01

Non-linear propagation of ultrasound creates artifacts in contrast-enhanced ultrasound images that significantly affect both qualitative and quantitative assessments of tissue perfusion. This article describes the development and evaluation of a new algorithm to correct for this artifact. The correction is a post-processing method that estimates and removes non-linear artifact in the contrast-specific image using the simultaneously acquired B-mode image data. The method is evaluated on carotid artery flow phantoms with large and small vessels containing microbubbles of various concentrations at different acoustic pressures. The algorithm significantly reduces non-linear artifacts while maintaining the contrast signal from bubbles to increase the contrast-to-tissue ratio by up to 11 dB. Contrast signal from a small vessel 600 μm in diameter buried in tissue artifacts before correction was recovered after the correction. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Droplets, Bubbles and Ultrasound Interactions

NARCIS (Netherlands)

Shpak, O.; Verweij, M.; de Jong, N.; Versluis, Michel; Escoffre, J.M.; Bouakaz, A.

2016-01-01

The interaction of droplets and bubbles with ultrasound has been studied extensively in the last 25 years. Microbubbles are broadly used in diagnostic and therapeutic medical applications, for instance, as ultrasound contrast agents. They have a similar size as red blood cells, and thus are able to

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles

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Burgess, M. T.; Apostolakis, I.; Konofagou, E. E.

2018-03-01

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Influence of contrast agent dose and ultrasound exposure on cardiomyocyte injury induced by myocardial contrast echocardiography in rats.

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Miller, Douglas L; Li, Peng; Dou, Chunyan; Gordon, David; Edwards, Chris A; Armstrong, William F

2005-10-01

To detect specific cardiomyocyte injury induced by myocardial contrast material-enhanced echocardiography (ie, myocardial contrast echocardiography) in rats and to ascertain the influences of contrast material dose and ultrasound exposure on this injury. All animal procedures were approved by the university committee for the use and care of animals. Myocardial contrast echocardiography with 1:4 electrocardiographic (ECG) triggering was performed at 1.5 MHz in 61 anesthetized rats. Evans blue (EB) dye was injected as the vital stain for cardiomyocyte injury. At the start of myocardial contrast echocardiography, which lasted 10 minutes, perflutren lipid microsphere-based contrast material was infused through the tail vein for 5 minutes. Premature heartbeats were counted from the ECG record. The numbers of EB-stained cells counted on sections of heart specimens obtained 24 hours after myocardial contrast echocardiography and then either fresh frozen or embedded in paraffin were determined by using fluorescence microscopy. Results were compared statistically by using t tests and Mann-Whitney rank sum tests. EB-stained cells were concentrated in the anterior region of the myocardium. In the paraffin-embedded specimens, EB-stained cells were often accompanied by but largely separate from areas of inflammatory cell infiltration. At end-systolic triggering with a 50 microL/kg dose of microsphere contrast material, the EB-stained cell count increased with increasing peak rarefactional pressure amplitude, with significantly increased cell counts at 1.6 MPa (P .1). EB-stained cell counts increased with increasing contrast material dose, from 10 to 50 microL/kg, at 2.0 MPa. Cardiomyocyte injury was induced by the interaction of ultrasound pulses with contrast agent microbubbles during myocardial contrast echocardiography in rats, and the numbers of injured cells increased with increasing contrast agent dose and ultrasound exposure. RSNA, 2005

Molecular evaluation of thrombosis using X-ray phase contrast imaging with microbubbles targeted to P-selectin in mice

International Nuclear Information System (INIS)

Tang, Rongbiao; Chai, Wei-Min; Yan, Fuhua; Chen, Ke-Min; Yang, Guo-Yuan

2016-01-01

X-ray phase contrast imaging (PCI) provides excellent image contrast by utilizing the phase shift. The introduction of microbubbles into tissues can cause a phase shift to make microbubbles visibly identified on PCI. In this study, we assessed the feasibility of targeted microbubble-based PCI for the detection of thrombosis. The absorption and phase contrast images of P-selectin-targeted microbubbles (MB P ) were obtained and compared in vitro. MB P , control IgG-targeted microbubbles (MB C ), and unbound microbubbles (MB U ) were tested for binding specificity on thrombi expressing P-selectin. MB P were used as molecular PCI probes to evaluate P-selectin expression in a mouse model of arteriovenous shunt thrombosis that was created using PE tubes in the bypass outside of the mouse body. PCI clearly showed the microbubbles not viewable via absorption contrast imaging (ACI). In vitro attachment of MB P (91.60 ± 11.63) to thrombi was significantly higher than attachment of MB C (17.80 ± 4.02, P < 0.001) or MB U (9.80 ± 2.59, P < 0.001). In the mouse model of arteriovenous shunt thrombosis, the binding affinity of MB P (15.50 ± 6.25) was significantly greater than that of MB C (0.50 ± 0.84, P < 0.001) or MB U (0.33 ± 0.52, P < 0.001). Our results indicate that molecular PCI may be considered as a novel and promising imaging modality for the investigation of thrombosis. (orig.)

Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain.

Science.gov (United States)

Wu, Shih-Ying; Chen, Cherry C; Tung, Yao-Sheng; Olumolade, Oluyemi O; Konofagou, Elisa E

2015-08-28

Lipid-shelled microbubbles have been used in ultrasound-mediated drug delivery. The physicochemical properties of the microbubble shell could affect the delivery efficiency since they determine the microbubble mechanical properties, circulation persistence, and dissolution behavior during cavitation. Therefore, the aim of this study was to investigate the shell effects on drug delivery efficiency in the brain via blood-brain barrier (BBB) opening in vivo using monodisperse microbubbles with different phospholipid shell components. The physicochemical properties of the monolayer were varied by using phospholipids with different hydrophobic chain lengths (C16, C18, and C24). The dependence on the molecular size and acoustic energy (both pressure and pulse length) were investigated. Our results showed that a relatively small increase in the microbubble shell rigidity resulted in a significant increase in the delivery of 40-kDa dextran, especially at higher pressures. Smaller (3kDa) dextran did not show significant difference in the delivery amount, suggesting that the observed shell effect was molecular size-dependent. In studying the impact of acoustic energy on the shell effects, it was found that they occurred most significantly at pressures causing microbubble destruction (450kPa and 600kPa); by increasing the pulse length to deliver the 40-kDa dextran, the difference between C16 and C18 disappeared while C24 still achieved the highest delivery efficiency. These indicated that the acoustic energy could be used to modulate the shell effects. The acoustic cavitation emission revealed the physical mechanisms associated with different shells. Overall, lipid-shelled microbubbles with long hydrophobic chain length could achieve high delivery efficiency for larger molecules especially with high acoustic energy. Our study, for the first time, offered evidence directly linking the microbubble monolayer shell with their efficacy for drug delivery in vivo. Copyright © 2015

Quantitation of MRI sensitivity to quasi-monodisperse microbubble contrast agents for spatially resolved manometry.

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Bencsik, Martin; Al-Rwaili, Amgad; Morris, Robert; Fairhurst, David J; Mundell, Victoria; Cave, Gareth; McKendry, Jonathan; Evans, Stephen

2013-11-01

The direct in-vivo measurement of fluid pressure cannot be achieved with MRI unless it is done with the contribution of a contrast agent. No such contrast agents are currently available commercially, whilst those demonstrated previously only produced qualitative results due to their broad size distribution. Our aim is to quantitate then model the MR sensitivity to the presence of quasi-monodisperse microbubble populations. Lipid stabilised microbubble populations with mean radius 1.2 ± 0.8 μm have been produced by mechanical agitation. Contrast agents with increasing volume fraction of bubbles up to 4% were formed and the contribution the bubbles bring to the relaxation rate was quantitated. A periodic pressure change was also continuously applied to the same contrast agent, until MR signal changes were only due to bubble radius change and not due to a change in bubble density. The MR data compared favourably with the prediction of an improved numerical simulation. An excellent MR sensitivity of 23 % bar(-1) has been demonstrated. This work opens up the possibility of generating microbubble preparations tailored to specific applications with optimised MR sensitivity, in particular MRI based in-vivo manometry. Copyright © 2012 Wiley Periodicals, Inc.

Image-guided, targeted and triggered drug delivery to tumors using polymer-based microbubbles.

NARCIS (Netherlands)

Fokong, S.; Theek, B.; Koczera, P.; Appold, L.; Resch-Genger, U.; van Zandvoort, M.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

2012-01-01

Abstract Microbubbles (MB) are routinely used contrast agents for functional and molecular ultrasound (US) imaging. In addition, they have been attracting more and more attention for drug delivery purposes, enabling e.g. US-mediated drug delivery across biological barriers and US-induced triggered

Microbubble Enzyme-Linked Immunosorbent Assay for the Detection of Targeted Microbubbles in in Vitro Static Binding Assays.

Science.gov (United States)

Wischhusen, Jennifer; Padilla, Frederic

2017-07-01

Targeted microbubbles (MBs) are ultrasound contrast agents that are functionalized with a ligand for ultrasound molecular imaging of endothelial markers. Novel targeted MBs are characterized in vitro by incubation in protein-coated wells, followed by binding quantification by microscopy or ultrasound imaging. Both methods provide operator-dependent results: Between 3 and 20 fields of view from a heterogeneous sample are typically selected for analysis by microscopy, and in ultrasound imaging, different acoustic settings affect signal intensities. This study proposes a new method to reproducibly quantify MB binding based on enzyme-linked immunosorbent assay (ELISA), in which bound MBs are revealed with an enzyme-linked antibody. MB-ELISA was adapted to in vitro static binding assays, incubating the MBs in inverted position or by agitation, and compared with microscopy. The specificity and sensitivity of MB-ELISA enable the reliable quantification of MB binding in a rapid, high-throughput and whole-well analysis, facilitating the characterization of new targeted contrast agents. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Therapeutic effects of microbubble added to combined high-intensity focused ultrasound and chemotherapy in a pancreatic cancer xenograft model

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Yu, Mi Hye [Dept. of Radiology, Konkuk University Medical Center, Seoul (Korea, Republic of); Lee, Jae Young; Kim, Bo Ram; Park, Eun Joo; Kim, Hoe Suk; Han, Joon Koo [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Kim, Hae Ri [Dept. of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry, Gangneung (Korea, Republic of); Choi, Byung Ihn [Dept. of Radiology, Chung-Ang University Hospital, Seoul (Korea, Republic of)

2016-09-15

To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

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Yu, Mi Hye [Department of Radiology, Konkuk University Medical Center, Seoul 05030 (Korea, Republic of); Lee, Jae Young [Department of Radiology, Seoul National University Hospital, Seoul 03080 (Korea, Republic of); Kim, Hae Ri [Department of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry, Gangneung 25457 (Korea, Republic of); Kim, Bo Ram; Park, Eun-Joo; Kim, Hoe Suk; Han, Joon Koo [Department of Radiology, Seoul National University Hospital, Seoul 03080 (Korea, Republic of); Choi, Byung Ihn [Department of Radiology, Chung-Ang University Hospital, Seoul 06973 (Korea, Republic of)

2016-11-01

To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

Synthesis of ultrasound contrast agents: characteristics and size distribution analysis (secondary publication)

Energy Technology Data Exchange (ETDEWEB)

Lee, Hak Jong [Program in Nano Science and Technology, Dept. of Transdisciplinary Studies, Seoul National University Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of); Yoon, Tae Jong [Dept. of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam (Korea, Republic of); Yoon, Young Il [Dept. of Applied Bioscience, CHA University, Pocheon (Korea, Republic of)

2017-10-15

The purpose of this study was to establish a method for ultrasound (US) contrast agent synthesis and to evaluate the characteristics of the synthesized US contrast agent. A US contrast agent, composed of liposome and sulfur hexafluoride (SF6), was synthesized by dissolving 21 μmol 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC, C40H80NO8P), 9 μmol cholesterol, and 1.9 μmol of dihexadecylphosphate (DCP, [CH3(CH2)15O]2P(O)OH) in chloroform. After evaporation in a warm water bath and drying for 12-24 hours, the contrast agent was synthesized using the sonication process by the addition of a buffer and SF6 gas. The size distribution of the bubbles was analyzed using dynamic light scattering measurement methods. The degradation curve was evaluated by assessing the change in the number of contrast agent bubbles using light microscopy immediately, 12, 24, 36, 48, 60, 72, and 84 hours after synthesis. The echogenicity of the synthesized microbubbles was compared with commercially available microbubbles (SonoVue, Bracco). contrast agent was synthesized successfully using an evaporation-drying-sonication method. Most bubbles had a mean diameter of 154.2 nm and showed marked degradation 24 hours after synthesis. Although no statistically significant differences were observed between SonoVue and the synthesized contrast agent, a difference in echogenicity was observed between the synthesized contrast agent and saline (P<0.01). We successfully synthesized a US contrast agent using an evaporation-dryingsonication method. These results may help future research in the fields of anticancer drug delivery, gene delivery, targeted molecular imaging, and targeted therapy.

Synthesis of ultrasound contrast agents: characteristics and size distribution analysis (secondary publication)

International Nuclear Information System (INIS)

Lee, Hak Jong; Yoon, Tae Jong; Yoon, Young Il

2017-01-01

The purpose of this study was to establish a method for ultrasound (US) contrast agent synthesis and to evaluate the characteristics of the synthesized US contrast agent. A US contrast agent, composed of liposome and sulfur hexafluoride (SF6), was synthesized by dissolving 21 μmol 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC, C40H80NO8P), 9 μmol cholesterol, and 1.9 μmol of dihexadecylphosphate (DCP, [CH3(CH2)15O]2P(O)OH) in chloroform. After evaporation in a warm water bath and drying for 12-24 hours, the contrast agent was synthesized using the sonication process by the addition of a buffer and SF6 gas. The size distribution of the bubbles was analyzed using dynamic light scattering measurement methods. The degradation curve was evaluated by assessing the change in the number of contrast agent bubbles using light microscopy immediately, 12, 24, 36, 48, 60, 72, and 84 hours after synthesis. The echogenicity of the synthesized microbubbles was compared with commercially available microbubbles (SonoVue, Bracco). contrast agent was synthesized successfully using an evaporation-drying-sonication method. Most bubbles had a mean diameter of 154.2 nm and showed marked degradation 24 hours after synthesis. Although no statistically significant differences were observed between SonoVue and the synthesized contrast agent, a difference in echogenicity was observed between the synthesized contrast agent and saline (P<0.01). We successfully synthesized a US contrast agent using an evaporation-dryingsonication method. These results may help future research in the fields of anticancer drug delivery, gene delivery, targeted molecular imaging, and targeted therapy

Sonodynamically-induced cytotoxicity by rose bengal derivative and microbubbles in isolated sarcoma 180 cells

Science.gov (United States)

Sugita, Nami; Hosokawa, Mami; Sunaga, Naoki; Iwase, Yumiko; Yumita, Nagahiko; Ikeda, Toshihiko; Umemura, Shin-ichiro

2015-07-01

It is known that the combination of ultrasound and sonodynamic sensitizer (SDS) is effective in noninvasive tumor treatment, referred to as sonodynamic therapy (SDT). Microbubbles have been used in ultrasound therapy as well. The purpose of this paper is to clarify the effect of microbubbles on SDT. Sarcoma 180 cells were suspended in air-saturated phosphate-buffered saline and exposed to ultrasound with the SDS rose bengal derivative (RBD) in standing wave mode in the presence and absence of microbubbles [sonazoid (SZ)]. The ultrasonically induced cytotoxicity with RBD and SZ was about 20 times higher than without either, and about 80% of the SZ microbubbles were destructed by ultrasonic exposure in as short as five seconds. Since microbubbles induce significant cytotoxicity even with short duration, low intensity ultrasound, the application of microbubbles in SDT shows promise in anti-tumor treatment.

Hemocoagulase Combined with Microbubble-Enhanced Ultrasound Cavitation for Augmented Ablation of Microvasculature in Rabbit VX2 Liver Tumors.

Science.gov (United States)

Yang, Qian; Tang, Peng; He, Guangbin; Ge, Shuping; Liu, Liwen; Zhou, Xiaodong

2017-08-01

We investigated a new method for combining microbubble-enhanced ultrasound cavitation (MEUC) with hemocoagulase (HC) atrox. Our goal was to induce embolic effects in the vasculature and combine these with an anti-angiogenic treatment strategy. Fourteen days after being implanted with a single slice of the liver VX2 tumor, rabbits were randomly divided into five groups: (i) a control group injected intra-venously with saline using a micropump; (ii) a group given only an injection of HC; (iii) a group treated only with ultrasound cavitation; (iv) a group treated with MEUC; (v) a group treated with MEUC + HC. Contrast-enhanced ultrasound was performed before treatment and 1 h and 7 d post-treatment to measure tumor size, enhancement and necrosis range. QontraXt software was used to determine the time-intensity curve of tumor blood perfusion and microvascular changes. At 1 h and 7 d after treatment with MEUC + HC, the parameters of the time-intensity curve, which included peak value, regional blood volume, regional blood flow and area under the curve value and which were measured using contrast-enhanced ultrasound, were significantly lower than those of the other treatment groups. The MEUC + HC treatment group exhibited significant growth inhibition relative to the ultrasound cavitation only, HC and MEUC treatment groups. No damage was observed in the surrounding normal tissues. These results support the feasibility of reducing the blood perfusion of rabbit VX2 liver tumors using a new method that combines MEUC and HC. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

Influence of ultrasound power on acoustic streaming and micro-bubbles formations in a low frequency sono-reactor: mathematical and 3D computational simulation.

Science.gov (United States)

Sajjadi, Baharak; Raman, Abdul Aziz Abdul; Ibrahim, Shaliza

2015-05-01

This paper aims at investigating the influence of ultrasound power amplitude on liquid behaviour in a low-frequency (24 kHz) sono-reactor. Three types of analysis were employed: (i) mechanical analysis of micro-bubbles formation and their activities/characteristics using mathematical modelling. (ii) Numerical analysis of acoustic streaming, fluid flow pattern, volume fraction of micro-bubbles and turbulence using 3D CFD simulation. (iii) Practical analysis of fluid flow pattern and acoustic streaming under ultrasound irradiation using Particle Image Velocimetry (PIV). In mathematical modelling, a lone micro bubble generated under power ultrasound irradiation was mechanistically analysed. Its characteristics were illustrated as a function of bubble radius, internal temperature and pressure (hot spot conditions) and oscillation (pulsation) velocity. The results showed that ultrasound power significantly affected the conditions of hotspots and bubbles oscillation velocity. From the CFD results, it was observed that the total volume of the micro-bubbles increased by about 4.95% with each 100 W-increase in power amplitude. Furthermore, velocity of acoustic streaming increased from 29 to 119 cm/s as power increased, which was in good agreement with the PIV analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

Instrumentation for contrast echocardiography: technology and techniques.

Science.gov (United States)

Kaul, Sanjiv

2002-11-18

Contrast echocardiography is the only clinical imaging technique in which the imaging modality (ultrasound) can cause a change in the contrast agent (microbubbles). The change in the contrast agent can range from small oscillations of the microbubbles at a low mechanical index to their disruption at a high mechanical index. The specific mechanical index required to produce these various effects may be different for each contrast agent, depending on the bubble dimension as well as shell and gas characteristics. These alterations in bubbles result in changes in ultrasound backscatter that are specific for the bubbles themselves, rather than for tissue, and are therefore exploited for imaging their presence in tissue. These signal-processing techniques have resulted in an increased signal-to-noise ratio from bubbles vis-à-vis the tissue and have made online assessment of myocardial perfusion possible.

Ultrasound Mediated Microbubbles Destruction Augmented Sonolysis: An In Vitro and In Vivo Study

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Hai Cui

2017-01-01

Full Text Available Objective. This study was aimed at exploring ultrasound mediated microbubbles destruction (UMMD assisted sonolysis in both the in vitro and in vivo clots. Methods. Therapeutic ultrasound (TUS and lipid microbubbles (MBs were used in whole blood clots and divided into the control, TUS group, and TUS + MB group. Thrombolytic rates and microscopy were performed. Color Doppler flow imaging (CDFI and angiography were performed to evaluate the recanalization rates and flow scores in femoral arterial thrombus (FAT in rabbits. FAT were dyed with H&E. Results. The average thrombolytic ratios of TUS + MB group were significantly higher than those of TUS group and the control group (both P<0.05. Clots had different pathological changes. Recanalization rates and flow scores in TUS + MB group were significantly higher than the control and TUS group. Flow scores and recanalization ratios were grade 0 in 0% of the control group, grade I in 25% of TUS group, and grade II or higher in 87.5% of TUS + MB group after 30 min sonolysis. Conclusions. Both the in vitro and in vivo sonolysis can be significantly augmented by the introduction of MBs without thrombolytic agents, which might be induced by the enhanced cavitation via UMMD.

Jetting of a ultrasound contrast microbubble near a rigid wall

Science.gov (United States)

Sarkar, Kausik; Mobadersany, Nima

2017-11-01

Micron sized gas-bubbles coated with a stabilizing shell of lipids or proteins, are used as contrast enhancing agents for ultrasound imaging. However, they are increasingly being explored for novel applications in drug delivery through a process called sonoporation, the reversible permeabilization of the cell membrane. Under sufficiently strong acoustic excitations, bubbles form a jet and collapse near a wall. The jetting of free bubbles has been extensively studied by boundary element method (BEM). Here, for the first time, we implemented a rigorous interfacial rheological model of the shell into BEM and investigated the jet formation. The code has been carefully validated against past results. Increasing shell elasticity decreases the maximum bubble volume and the collapse time, while the jet velocity increases. The shear stress on the wall is computed and analyzed. A phase diagram as functions of excitation pressure and wall separation describes jet formation. Effects of shell elasticity and frequency on the phase diagram are investigated. Partially supported by National Science Foundation.

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles

OpenAIRE

Meairs, Stephen

2015-01-01

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This techni...

Contrast-enhanced ultrasound-guided radiofrequency ablation in inconspicuous hepatocellular carcinoma on B-mode ultrasound.

Science.gov (United States)

Kim, Eui Joo; Kim, Yun Soo; Shin, Seung Kak; Kwon, Oh Sang; Choi, Duck Joo; Kim, Ju Hyun

2017-11-01

B-mode ultrasound (US) has difficulty targeting small hepatocellular carcinomas (HCCs) with poor conspicuity during radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) can improve visualization of small or inconspicuous HCCs. This study was conducted to evaluate the effectiveness of CEUS-guided RFA electrode insertion during the arterial phase in inconspicuous HCCs. Ninety-three treatment-naïve HCCs from 80 patients treated with RFA from August 2012 to December 2014 were retrospectively reviewed. Seventy-five HCCs from 65 patients underwent B-mode US-guided RFA, and 15 HCCs from 14 patients that were inconspicuous on B-mode US underwent CEUS-guided RFA during the arterial phase after injection of sulfur hexafluoride microbubbles (SonoVue®). Technical success was assessed by contrast-enhanced computed tomography within 1 week and 3 months after the procedure. The mean size of HCCs treated with CEUS-guided RFA was smaller than that of HCCs treated with B-mode US-guided RFA (1.17±0.36 vs. 1.63±0.55 cm, p=0.003). Technical success rates of CEUS-guided RFA within 1 week and 3 months were 100% (15/15) and 93.3% (14/15), respectively. Technical success rates of B-mode US-guided RFA were 97.3% (73/75) and 94.5% (69/73), respectively. CEUS-guided RFA is highly efficacious for ablation of very small and inconspicuous HCCs.

Advanced ultrasound applications in the assessment of renal transplants: contrast-enhanced ultrasound, elastography, and B-flow.

Science.gov (United States)

Morgan, Tara A; Jha, Priyanka; Poder, Liina; Weinstein, Stefanie

2018-04-09

Ultrasound is routinely used as the first imaging exam for evaluation of renal transplants and can identify most major surgical complications and evaluate vascularity with color Doppler. Ultrasound is limited, however, in the detection of parenchymal disease processes and Doppler evaluation is also prone to technical errors. Multiple new ultrasound applications have been developed and are under ongoing investigation which could add additional diagnostic capability to the routine ultrasound exam with minimal additional time, cost, and patient risk. Contrast-enhanced ultrasound (CEUS) can be used off-label in the transplant kidney, and can assist in detection of infection, trauma, and vascular complications. CEUS also can demonstrate perfusion of the transplant assessed quantitatively with generation of time-intensity curves. Future directions of CEUS include monitoring treatment response and microbubble targeted medication delivery. Elastography is an ultrasound application that can detect changes in tissue elasticity, which is useful to diagnose diffuse parenchymal disease, such as fibrosis, otherwise unrecognizable with ultrasound. Elastography has been successfully applied in other organs including the liver, thyroid, and breast; however, it is still under development for use in the transplant kidney. Unique properties of the transplant kidney including its heterogeneity, anatomic location, and other technical factors present challenges in the development of reference standard measurements. Lastly, B-flow imaging is a flow application derived from B-mode. This application can show the true lumen size of a vessel which is useful to depict vascular anatomy and bypasses some of the pitfalls of color Doppler such as demonstration of slow flow.

Ablation of synovial pannus using microbubble-mediated ultrasonic cavitation in antigen-induced arthritis in rabbits.

Science.gov (United States)

Qiu, Li; Jiang, Yong; Zhang, Lingyan; Wang, Lei; Luo, Yan

2012-12-01

To investigate the ablative effectiveness of microbubble-mediated ultrasonic cavitation for treating synovial pannus and to determine a potential mechanism using the antigen-induced arthritis model (AIA). Ultrasonic ablation was performed on the knee joints of AIA rabbits using optimal ultrasonic ablative parameters. Rabbits with antigen-induced arthritis were randomly assigned to 4 groups: (1) the ultrasound (US) + microbubble group; (2) the US only group; (3) the microbubble only group, and (4) the control group. At 1 h and 14 days after the first ablation, contrast-enhanced ultrasonography (CEUS) monitoring and pathology synovitis score were used to evaluate the therapeutic effects. Synovial necrosis and microvascular changes were also measured. After the ablation treatment, the thickness of synovium and parameters of time intensity curve including derived peak intensity and area under curve were measured using CEUS, and the pathology synovitis score in the ultrasound + microbubble group was significantly lower than that found in the remaining groups. No damage was observed in the surrounding normal tissues. The mechanism underlying the ultrasonic ablation was related to microthrombosis and microvascular rupture that resulted in synovial necrosis. The results suggest that microbubble-mediated ultrasonic cavitation should be applied as a non-invasive strategy for the treatment of synovial pannus in arthritis under optimal conditions.

Ultrasound contrast agent imaging: Real-time imaging of the superharmonics

Energy Technology Data Exchange (ETDEWEB)

Peruzzini, D.; Viti, J. [MSD lab, Department of Information Engineering, Univ of Florence, Via S.Marta, 3, 50139 Firenze (Italy); Erasmus MC, ’s-Gravendijkwal 230, Faculty Building, Ee 2302, 3015 CE Rotterdam (Netherlands); Tortoli, P. [MSD lab, Department of Information Engineering, Univ of Florence, Via S.Marta, 3, 50139 Firenze (Italy); Verweij, M. D. [Acoustical Wavefield Imaging, ImPhys, Delft Univ Technology, van der Waalsweg 8, 2628 CH Delft (Netherlands); Jong, N. de; Vos, H. J., E-mail: h.vos@erasmusmc.nl [Erasmus MC, ’s-Gravendijkwal 230, Faculty Building, Ee 2302, 3015 CE Rotterdam (Netherlands); Acoustical Wavefield Imaging, ImPhys, Delft Univ Technology, van der Waalsweg 8, 2628 CH Delft (Netherlands)

2015-10-28

Currently, in medical ultrasound contrast agent (UCA) imaging the second harmonic scattering of the microbubbles is regularly used. This scattering is in competition with the signal that is caused by nonlinear wave propagation in tissue. It was reported that UCA imaging based on the third or higher harmonics, i.e. “superharmonic” imaging, shows better contrast. However, the superharmonic scattering has a lower signal level compared to e.g. second harmonic signals. This study investigates the contrast-to-tissue ratio (CTR) and signal to noise ratio (SNR) of superharmonic UCA scattering in a tissue/vessel mimicking phantom using a real-time clinical scanner. Numerical simulations were performed to estimate the level of harmonics generated by the microbubbles. Data were acquired with a custom built dual-frequency cardiac phased array probe. Fundamental real-time images were produced while beam formed radiofrequency (RF) data was stored for further offline processing. The phantom consisted of a cavity filled with UCA surrounded by tissue mimicking material. The acoustic pressure in the cavity of the phantom was 110 kPa (MI = 0.11) ensuring non-destructivity of UCA. After processing of the acquired data from the phantom, the UCA-filled cavity could be clearly observed in the images, while tissue signals were suppressed at or below the noise floor. The measured CTR values were 36 dB, >38 dB, and >32 dB, for the second, third, and fourth harmonic respectively, which were in agreement with those reported earlier for preliminary contrast superharmonic imaging. The single frame SNR values (in which ‘signal’ denotes the signal level from the UCA area) were 23 dB, 18 dB, and 11 dB, respectively. This indicates that noise, and not the tissue signal, is the limiting factor for the UCA detection when using the superharmonics in nondestructive mode.

Correlation between microbubble-induced acoustic cavitation and hemolysis in vitro

International Nuclear Information System (INIS)

Zhang Chun-Bing; Liu Zheng; Guo Xia-Sheng; Zhang Dong

2011-01-01

Microbubbles promise to enhance the efficiency of ultrasound-mediated drug delivery and gene therapy by taking advantage of artificial cavitation nuclei. The purpose of this study is to examine the ultrasound-induced hemolysis in the application of drug delivery in the presence of microbubbles. To achieve this goal, human red blood cells mixed with microbubbles were exposed to 1-MHz pulsed ultrasound. The hemolysis level was measured by a flow cytometry, and the cavitation dose was detected by a passive cavitation detecting system. The results demonstrate that larger cavitation dose would be generated with the increase of acoustic pressure, which might give rise to the enhancement of hemolysis. Besides the experimental observations, the acoustic pressure dependence of the radial oscillation of microbubble was theoretically estimated. The comparison between the experimental and calculation results indicates that the hemolysis should be highly correlated to the acoustic cavitation. (classical areas of phenomenology)

Detection of cavernous transformation of the portal vein by contrast-enhanced ultrasound.

Science.gov (United States)

Hwang, Misun; Thimm, Matthew A; Guerrerio, Anthony L

2018-06-01

Cavernous transformation of the portal vein can be missed on color Doppler exam or arterial phase cross-sectional imaging due to their slow flow and delayed enhancement. Contrast-enhanced ultrasound (CEUS) offers many advantages over other imaging techniques and can be used to successfully detect cavernous transformations of the portal vein. A 10-month-old female was followed for repeat episodes of hematemesis. Computed tomography angiography (CTA) and magnetic resonance arteriogram (MRA) and portal venography were performed. Color Doppler exam of the portal vein was performed followed by administration of Lumason, a microbubble US contrast agent. Magnetic resonance arteriogram, CTA, and color Doppler exam at the time of initial presentation was unremarkable without obvious vascular malformation within the limits of motion degraded exam. At 8-month follow-up, esophagogastroduodenoscopy revealed a vascular malformation in the distal esophagus which was sclerosed. At 6 month after sclerosis of the lesion, portal venography revealed occlusion of the portal vein with extensive collateralization. Color Doppler revealed subtle hyperarterialization and periportal collaterals. CEUS following color Doppler exam demonstrated extensive enhancement of periportal collaterals. Repeat color Doppler after contrast administration demonstrated extensive Doppler signal in the collateral vessels, suggestive of cavernous transformation. We describe a case of cavernous transformation of the portal vein missed on initial color Doppler, CTA and MRA, but detected with contrast-enhanced ultrasound technique.

Magnetic resonance properties of Gd(III)-bound lipid-coated microbubbles and their cavitation fragments.

Science.gov (United States)

Feshitan, Jameel A; Boss, Michael A; Borden, Mark A

2012-10-30

Gas-filled microbubbles are potentially useful theranostic agents for magnetic resonance imaging-guided focused ultrasound surgery (MRIgFUS). Previously, MRI at 9.4 T was used to measure the contrast properties of lipid-coated microbubbles with gadolinium (Gd(III)) bound to lipid headgroups, which revealed that the longitudinal molar relaxivity (r(1)) increased after microbubble fragmentation. This behavior was attributed to an increase in water proton exchange with the Gd(III)-bound lipid fragments caused by an increase in the lipid headgroup area that accompanied the lipid shell monolayer-to-bilayer transition. In this article, we explore this mechanism by comparing the changes in r(1) and its transverse counterpart, r(2)*, after the fragmentation of microbubbles consisting of Gd(III) bound to two different locations on the lipid monolayer shell: the phosphatidylethanolamine (PE) lipid headgroup region or the distal region of the poly(ethylene glycol) (PEG) brush. Nuclear magnetic resonance (NMR) at 1.5 T was used to measure the contrast properties of the various microbubble constructs because this is the most common field strength used in clinical MRI. Results for the lipid-headgroup-labeled Gd(III) microbubbles revealed that r(1) increased after microbubble fragmentation, whereas r(2)* was unchanged. An analysis of PEG-labeled Gd(III) microbubbles revealed that both r(1) and r(2)* decreased after microbubble fragmentation. Further analysis revealed that the microbubble gas core enhanced the transverse MR signal (T(2)*) in a concentration-dependent manner but minimally affected the longitudinal (T(1)) signal. These results illustrate a new method for the use of NMR to measure the biomembrane packing structure and suggest that two mechanisms, proton-exchange enhancement by lipid membrane relaxation and magnetic field inhomogeneity imposed by the gas/liquid interface, may be used to detect and differentiate Gd(III)-labeled microbubbles and their cavitation

Cyanine 5.5 conjugated nanobubbles as a tumor selective contrast agent for dual ultrasound-fluorescence imaging in a mouse model.

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Liyi Mai

Full Text Available Nanobubbles and microbubbles are non-invasive ultrasound imaging contrast agents that may potentially enhance diagnosis of tumors. However, to date, both nanobubbles and microbubbles display poor in vivo tumor-selectivity over non-targeted organs such as liver. We report here cyanine 5.5 conjugated nanobubbles (cy5.5-nanobubbles of a biocompatible chitosan-vitamin C lipid system as a dual ultrasound-fluorescence contrast agent that achieved tumor-selective imaging in a mouse tumor model. Cy5.5-nanobubble suspension contained single bubble spheres and clusters of bubble spheres with the size ranging between 400-800 nm. In the in vivo mouse study, enhancement of ultrasound signals at tumor site was found to persist over 2 h while tumor-selective fluorescence emission was persistently observed over 24 h with intravenous injection of cy5.5-nanobubbles. In vitro cell study indicated that cy5.5-flurescence dye was able to accumulate in cancer cells due to the unique conjugated nanobubble structure. Further in vivo fluorescence study suggested that cy5.5-nanobubbles were mainly located at tumor site and in the bladder of mice. Subsequent analysis confirmed that accumulation of high fluorescence was present at the intact subcutaneous tumor site and in isolated tumor tissue but not in liver tissue post intravenous injection of cy5.5-nanobubbles. All these results led to the conclusion that cy5.5-nanobubbles with unique crosslinked chitosan-vitamin C lipid system have achieved tumor-selective imaging in vivo.

Modeling photothermal and acoustical induced microbubble generation and growth.

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Krasovitski, Boris; Kislev, Hanoch; Kimmel, Eitan

2007-12-01

Previous experimental studies showed that powerful heating of nanoparticles by a laser pulse using energy density greater than 100 mJ/cm(2), could induce vaporization and generate microbubbles. When ultrasound is introduced at the same time as the laser pulse, much less laser power is required. For therapeutic applications, generation of microbubbles on demand at target locations, e.g. cells or bacteria can be used to induce hyperthermia or to facilitate drug delivery. The objective of this work is to develop a method capable of predicting photothermal and acoustic parameters in terms of laser power and acoustic pressure amplitude that are needed to produce stable microbubbles; and investigate the influence of bubble coalescence on the thresholds when the microbubbles are generated around nanoparticles that appear in clusters. We develop and solve here a combined problem of momentum, heat and mass transfer which is associated with generation and growth of a microbubble, filled with a mixture of non-vaporized gas (air) and water vapor. The microbubble's size and gas content vary as a result of three mechanisms: gas expansion or compression, evaporation or condensation on the bubble boundary, and diffusion of dissolved air in the surrounding water. The simulations predict that when ultrasound is applied relatively low threshold values of laser and ultrasound power are required to obtain a stable microbubble from a single nanoparticle. Even lower power is required when microbubbles are formed by coalescence around a cluster of 10 nanoparticles. Laser pulse energy density of 21 mJ/cm(2) is predicted for instance together with acoustic pressure of 0.1 MPa for a cluster of 10 or 62 mJ/cm(2) for a single nanoparticle. Those values are well within the safety limits, and as such are most appealing for targeted therapeutic purposes.

Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats

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Wu S

2014-12-01

Full Text Available Shengzheng Wu,1 Lu Li,1 Gong Wang,1 Weiwei Shen,2 Yali Xu,1 Zheng Liu,1 Zhongxiong Zhuo,1 Hongmei Xia,1 Yunhua Gao,1 Kaibin Tan1 1Department of Ultrasound, 2Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China Abstract: Mesenchymal stem cell (MSC therapy has been considered a promising strategy to cure diabetic nephropathy (DN. However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1 plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MBSDF-1 via covalent conjugation. The characterization and bioactivity of MBSDF-1 were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MBSDF-1. The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 µg/mL. MBSDF-1 remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with

Contrast Enhanced US in the Abdomen

International Nuclear Information System (INIS)

Chung, Yong Eun; Kim, Ki Whang

2012-01-01

Contrast enhanced ultrasound, which was introduced in 1996, has been widely used in Europe and Eastern Asia. Ultrasound contrast agent can be classified as first generation and second generation, depending on the gas within the microbubble. With the first generation contrast agent, the high MI technique was used, and only intermittent scanning was possible due to destruction of the microbubble during scanning. Use of the second generation contrast agent with the low MI technique makes continuous scanning possible. Contrast enhanced US can be used in detection and differentiation of focal liver lesions. It is also helpful for monitoring of radiofrequency ablation and for targeting of US guided biopsy. Currently, because morphologic criteria alone may not reflect the response of the tumor to treatment, new criteria are needed for treatment evaluation after administration of anti-angiogenic agents. Contrast enhanced US could provide quantitative markers for evaluation of the response to treatment via use of dynamic contrast enhanced US. Due to cost-effectiveness, contrast enhanced US is not yet widely used in Korea; however, considering recent issues regarding contrast agent related adverse reaction, such as contrast induced nephropathy and nephrogenic systemic fibrosis, and radiation exposure, contrast enhanced US might be more widely used in Korea, as an alternative imaging modality in the future.

Microbubbles in macrocysts - Contrast-enhanced ultrasound assisted sclerosant therapy of a congenital macrocystic lymphangioma: a case report.

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Menendez-Castro, Carlos; Zapke, Maren; Fahlbusch, Fabian; von Goessel, Heiko; Rascher, Wolfgang; Jüngert, Jörg

2017-07-06

Congenital cystic lymphangiomas are benign malformations due to a developmental disorder of lymphatic vessels. Besides surgical excision, sclerosant therapy of these lesions by intracavitary injection of OK-432 (Picibanil®), a lyophilized mixture of group A Streptococcus pyogenes, is a common therapeutical option. For an appropriate application of OK-432, a detailed knowledge about the structure and composition of the congenital cystic lymphangioma is essential. SonoVue® is a commercially available contrast agent commonly used in sonography by intravenous and intracavitary application. Here we report the case of 2 month old male patient with a large thoracic congenital cystic lymphangioma. Preinterventional imaging of the malformation was performed by contrast-enhanced ultrasound after intracavitary application of SonoVue® immediately followed by a successful sclerotherapy with OK-432. Contrast agent-enhanced ultrasound imaging offers a valuable option to preinterventionally clarify the anatomic specifications of a congenital cystic lymphangioma in more detail than by single conventional sonography. By the exact knowledge about the composition and especially about the intercystic communications of the lymphangioma sclerosant therapy becomes safer and more efficient.

Wavelength-dependent Faraday–Tyndall effect on laser-induced microbubble in gold colloid

International Nuclear Information System (INIS)

Liaw, Jiunn-Woei; Tsai, Shiao-Wen; Lin, Hung-Hsun; Yen, Tzu-Chen; Chen, Bae-Renn

2012-01-01

The cavitation microbubbles in dilute gold colloids of different concentrations (2–10 ppm) induced by a focused nanosecond-pulsed laser beam were measured and characterized at different wavelengths by using the passive and active ultrasound measurements. Three colloids with gold nanoparticles (GNPs) of different sizes (10, 45, and 75 nm) were used for experiment. The results show that the lifespan of the microbubble is reduced as the concentration of GNP increases, particularly at the wavelength of 532 nm, the surface plasmon resonance (SPR) of GNP. In contrast, at the off-resonant wavelength (e.g. 700 nm), the lifespan reduction is relatively small. This wavelength-dependent cavitation is attributed to the Faraday–Tyndall effect, a strong light scattering by GNPs. A slight defocusing of the Gaussian beam in gold colloid was proposed. Hence, the waist of the focused beam increases to reduce the optical breakdown in gold colloid. For simplicity, a linear relation between the incremental waist radius of Gaussian beam and the concentration of GNP was assumed. According to this formulation, the theoretical results are consistent with the experimental ones. In addition, the dynamics of the microbubble in gold colloid measured by the active ultrasound method agree with the Rayleigh–Plesset model. -- Highlights: ► The Faraday–Tyndall effect of gold colloid on laser induced microbubble is studied. ► Faraday–Tyndall effect of gold colloid causes the defocusing of laser beam. ► Lifespan of the microbubble is reduced as the concentration of GNP increases. ► Light scattering of laser beam at the surface plasmon resonance of GNP is the maximum.

Passive acoustic mapping of magnetic microbubbles for cavitation enhancement and localization

International Nuclear Information System (INIS)

Crake, Calum; Victor, Marie de Saint; Owen, Joshua; Coviello, Christian; Collin, Jamie; Coussios, Constantin-C; Stride, Eleanor

2015-01-01

Magnetic targeting of microbubbles functionalized with superparamagnetic nanoparticles has been demonstrated previously for diagnostic (B-mode) ultrasound imaging and shown to enhance gene delivery in vitro and in vivo. In the present work, passive acoustic mapping (PAM) was used to investigate the potential of magnetic microbubbles for localizing and enhancing cavitation activity under focused ultrasound. Suspensions of magnetic microbubbles consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), air and 10 nm diameter iron oxide nanoparticles were injected into a tissue mimicking phantom at different flow velocities (from 0 to 50 mm s −1 ) with or without an applied magnetic field. Microbubbles were excited using a 500 kHz single element focused transducer at peak negative focal pressures of 0.1–1.0 MPa, while a 64 channel imaging array passively recorded their acoustic emissions. Magnetic localization of microbubble-induced cavitation activity was successfully achieved and could be resolved using PAM as a shift in the spatial distribution and increases in the intensity and sustainability of cavitation activity under the influence of a magnetic field. Under flow conditions at shear rates of up to 100 s −1 targeting efficacy was maintained. Application of a magnetic field was shown to consistently increase the energy of cavitation emissions by a factor of 2–5 times over the duration of exposures compared to the case without targeting, which was approximately equivalent to doubling the injected microbubble dose. These results suggest that magnetic targeting could be used to localize and increase the concentration of microbubbles and hence cavitation activity for a given systemic dose of microbubbles or ultrasound intensity. (paper)

Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection.

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Chen, Xucai; Wang, Jianjun; Pacella, John J; Villanueva, Flordeliza S

2016-02-01

Ultrasound (US)-microbubble (MB)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. On the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes use short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore, we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic pressures and MB concentrations via direct high-speed optical observation and passive cavitation detection. MBs first underwent stable or inertial cavitation depending on the acoustic pressure and then formed gas-filled clusters that continued to oscillate, break up and form new clusters. Cavitation detection confirmed continued, albeit diminishing, acoustic activity throughout the 5-ms US excitation. These data suggest that persisting cavitation activity during long tone bursts may confer additional therapeutic effects. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Transfection effect of microbubbles on cells in superposed ultrasound waves and behavior of cavitation bubble.

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Kodama, Tetsuya; Tomita, Yukio; Koshiyama, Ken-Ichiro; Blomley, Martin J K

2006-06-01

The combination of ultrasound and ultrasound contrast agents (UCAs) is able to induce transient membrane permeability leading to direct delivery of exogenous molecules into cells. Cavitation bubbles are believed to be involved in the membrane permeability; however, the detailed mechanism is still unknown. In the present study, the effects of ultrasound and the UCAs, Optison on transfection in vitro for different medium heights and the related dynamic behaviors of cavitation bubbles were investigated. Cultured CHO-E cells mixed with reporter genes (luciferase or beta-gal plasmid DNA) and UCAs were exposed to 1 MHz ultrasound in 24-well plates. Ultrasound was applied from the bottom of the well and reflected at the free surface of the medium, resulting in the superposition of ultrasound waves within the well. Cells cultured on the bottom of 24-well plates were located near the first node (displacement node) of the incident ultrasound downstream. Transfection activity was a function determined with the height of the medium (wave traveling distance), as well as the concentration of UCAs and the exposure time was also determined with the concentration of UCAs and the exposure duration. Survival fraction was determined by MTT assay, also changes with these values in the reverse pattern compared with luciferase activity. With shallow medium height, high transfection efficacy and high survival fraction were obtained at a low concentration of UCAs. In addition, capillary waves and subsequent atomized particles became significant as the medium height decreased. These phenomena suggested cavitation bubbles were being generated in the medium. To determine the effect of UCAs on bubble generation, we repeated the experiments using crushed heat-treated Optison solution instead of the standard microbubble preparation. The transfection ratio and survival fraction showed no additional benefit when ultrasound was used. These results suggested that cavitation bubbles created by the

Application of a drug delivery system using ultrasound and nano/microbubbles for anti-angiogenic therapy

International Nuclear Information System (INIS)

Horie, Sachiko; Kodama, Tetsuya; Sato, Yasushi

2017-01-01

The drug delivery system using ultrasound and nano/microbubbles is a molecular delivery approach using the mechanism of sonoporation. With sonoporation, an endothelium-derived negative-feedback regulator of angiogenesis, Vasohibin-1 (VASH1), was introduced specifically into tumor vessels. We found VASH1 in tumor vessels induce normalization of tumor vessels and inhibited tumor growth. A recent topic regarding tumor angiogenesis is vascular normalization. Tumor vessels are abnormal or immature that cause hyperpermeability and impaired blood flow. Tumor vascular normalization improves blood flow and tissue hypoxia, which increase the effectiveness of chemotherapy and radiotherapy and reduce tumor cell malignancy. In this review, application of drug delivery system using ultrasound for an anti-angiogenic therapy, a tumor vessel normalization therapy to treat cancer, is summarized. (author)

Self-demodulation effect on subharmonic response of ultrasound contrast agent

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Daeichin, V.; Faez, T.; Needles, A.; Renaud, G.; Bosch, J. G.; van der Steen, A. F. W.; de Jong, N.

2012-03-01

In this work the use of the self-demodulation (S-D) signal as a mean of microbubble excitation at the subharmonic (SH) frequency to enhance the SH emission of ultrasound contrast agent (UCA) is studied. SH emission from the UCA is of interest since it is produced only by the UCA and is free of the artifacts produced in harmonic imaging modes. The S-D wave is a low-frequency signal produced by nonlinear propagation of an ultrasound wave in the medium. Single element transducer experiments and numerical simulations were conducted at 10 MHz to study the effect of the S-D signal on the SH response of the UCA by modifying the envelope of the excitation bursts. For 6 and 20 transmitted cycles, the SH response is increased up to 25 dB and 22 dB because of the S-D stimulation for a burst with a rectangular envelope compared with a Gaussian envelope burst. Such optimized excitations were used in an array-based micro-ultrasound system (Vevo 2100, VisualSonics Inc., Toronto, ON, Canada) at 18 MHz for in vitro validation of SH imaging. This study suggests that a suitable design of the envelope of the transmit excitation to generate a S-D signal at the SH frequency can enhance the SH emission of UCA and real-time SH imaging is feasible with shorter transmit burst (6- cycle) and low acoustic pressure (~150 KPa) at high frequencies (>15 MHz).

Contrast-enhanced ultrasound in the diagnosis of nodules in liver cirrhosis.

Science.gov (United States)

Kim, Tae Kyoung; Jang, Hyun-Jung

2014-04-07

Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents are useful for the diagnosis of the nodules in liver cirrhosis. CEUS can be used as a problem-solving method for indeterminate nodules on computed tomography (CT) or magnetic resonance imaging (MRI) or as an initial diagnostic test for small newly detected liver nodules. CEUS has unique advantages over CT and MRI including no renal excretion of contrast, real-time imaging capability, and purely intravascular contrast. Hepatocellular carcinoma (HCC) is characterized by arterial-phase hypervascularity and later washout (negative enhancement). Benign nodules such as regenerative nodules or dysplastic nodules are usually isoechoic or slightly hypoechoic in the arterial phase and isoechoic in the late phase. However, there are occasional HCC lesions with atypical enhancement including hypovascular HCC and hypervascular HCC without washout. Cholangiocarcinomas are infrequently detected during HCC surveillance and mostly show rim-like or diffuse hypervascularity followed by rapid washout. Hemangiomas are often found at HCC surveillance and are easily diagnosed by CEUS. CEUS can be effectively used in the diagnostic work-up of small nodules detected at HCC surveillance. CEUS is also useful to differentiate malignant and benign venous thrombosis and to guide and monitor the local ablation therapy for HCC.

Engineering brown fat into skeletal muscle using ultrasound-targeted microbubble destruction gene delivery in obese Zucker rats: Proof of concept design.

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Bastarrachea, Raul A; Chen, Jiaxi; Kent, Jack W; Nava-Gonzalez, Edna J; Rodriguez-Ayala, Ernesto; Daadi, Marcel M; Jorge, Barbara; Laviada-Molina, Hugo; Comuzzie, Anthony G; Chen, Shuyuan; Grayburn, Paul A

2017-09-01

Ultrasound-targeted microbubble destruction (UTMD) is a novel means of tissue-specific gene delivery. This approach systemically infuses transgenes precoupled to gas-filled lipid microbubbles that are burst within the microvasculature of target tissues via an ultrasound signal resulting in release of DNA and transfection of neighboring cells within the tissue. Previous work has shown that adenovirus containing cDNA of UCP-1, injected into the epididymal fat pads in mice, induced localized fat depletion, improving glucose tolerance, and decreasing food intake in obese diabetic mice. Our group recently demonstrated that gene therapy by UTMD achieved beta cell regeneration in streptozotocin (STZ)-treated mice and baboons. We hypothesized that gene therapy with BMP7/PRDM16/PPARGC1A in skeletal muscle (SKM) of obese Zucker diabetic fatty (fa/fa) rats using UTMD technology would produce a brown adipose tissue (BAT) phenotype with UCP-1 overexpression. This study was designed as a proof of concept (POC) project. Obese Zucker rats were administered plasmid cDNA contructs encoding a gene cocktail with BMP7/PRDM16/PPARGC1A incorporated within microbubbles and intravenously delivered into their left thigh. Controls received UTMD with plasmids driving a DsRed reporter gene. An ultrasound transducer was directed to the thigh to disrupt the microbubbles within the microcirculation. Blood samples were drawn at baseline, and after treatment to measure glucose, insulin, and free fatty acids levels. SKM was harvested for immunohistochemistry (IHC). Our IHC results showed a reliable pattern of effective UTMD-based gene delivery in enhancing SKM overexpression of the UCP-1 gene. This clearly indicates that our plasmid DNA construct encoding the gene combination of PRDM16, PPARGC1A, and BMP7 reprogrammed adult SKM tissue into brown adipose cells in vivo. Our pilot established POC showing that the administration of the gene cocktail to SKM in this rat model of genetic obesity using UTMD

Ultrasound-guided delivery of siRNA and a chemotherapeutic drug by using microbubble complexes: In vitro and in vivo evaluations in a prostate cancer model

Energy Technology Data Exchange (ETDEWEB)

Bae, Yun Jung; Yoon, Young Il; Lee, Hak Jong [Dept. of Radiology, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Yoon, Tae Jong [Dept. of Applied Bioscience, College of Life Science, CHA University, Pocheon (Korea, Republic of)

2016-07-15

To evaluate the effectiveness of ultrasound and microbubble-liposome complex (MLC)-mediated delivery of siRNA and doxorubicin into prostate cancer cells and its therapeutic capabilities both in vitro and in vivo. Microbubble-liposome complexes conjugated with anti-human epidermal growth factor receptor type 2 (Her2) antibodies were developed to target human prostate cancer cell lines PC-3 and LNCaP. Intracellular delivery of MLC was observed by confocal microscopy. We loaded MLC with survivin-targeted small interfering RNA (siRNA) and doxorubicin, and delivered it into prostate cancer cells. The release of these agents was facilitated by ultrasound application. Cell viability was analyzed by MTT assay after the delivery of siRNA and doxorubicin. Survivin-targeted siRNA loaded MLC was delivered into the xenograft mouse tumor model. Western blotting was performed to quantify the expression of survivin in vivo. Confocal microscopy demonstrated substantial intracellular uptake of MLCs in LNCaP, which expresses higher levels of Her2 than PC-3. The viability of LNCaP cells was significantly reduced after the delivery of MLCs loaded with siRNA and doxorubicin (85.0 ± 2.9%), which was further potentiated by application of ultrasound (55.0 ± 3.5%, p = 0.009). Survivin expression was suppressed in vivo in LNCaP tumor xenograft model following the ultrasound and MLC-guided delivery of siRNA (77.4 ± 4.90% to 36.7 ± 1.34%, p = 0.027). Microbubble-liposome complex can effectively target prostate cancer cells, enabling intracellular delivery of the treatment agents with the use of ultrasound. Ultrasound and MLC-mediated delivery of survivin-targeted siRNA and doxorubicin can induce prostate cell apoptosis and block survivin expression in vitro and in vivo.

Ultrasound-Guided Delivery of siRNA and a Chemotherapeutic Drug by Using Microbubble Complexes: In Vitro and In Vivo Evaluations in a Prostate Cancer Model

Energy Technology Data Exchange (ETDEWEB)

Bae, Yun Jung [Department of Radiology, Seoul National University Bundang Hospital, Seongnam 13620 (Korea, Republic of); Department of Radiology, Seoul National University College of Medicine, Seoul 03080 (Korea, Republic of); Yoon, Young Il [Department of Radiology, Seoul National University Bundang Hospital, Seongnam 13620 (Korea, Republic of); Department of Radiology, Seoul National University College of Medicine, Seoul 03080 (Korea, Republic of); Program in Nano Science and Technology, Department of Transdisciplinary Studies, Seoul National University Graduate School of Convergence Science and Technology, Suwon 16229 (Korea, Republic of); Yoon, Tae-Jong [Department of Applied Bioscience, College of Life Science, CHA University, Pocheon 11160 (Korea, Republic of); College of Pharmacy, Ajou University, Suwon 16499 (Korea, Republic of); Lee, Hak Jong [Department of Radiology, Seoul National University Bundang Hospital, Seongnam 13620 (Korea, Republic of); Department of Radiology, Seoul National University College of Medicine, Seoul 03080 (Korea, Republic of); Program in Nano Science and Technology, Department of Transdisciplinary Studies, Seoul National University Graduate School of Convergence Science and Technology, Suwon 16229 (Korea, Republic of)

2016-11-01

To evaluate the effectiveness of ultrasound and microbubble-liposome complex (MLC)-mediated delivery of siRNA and doxorubicin into prostate cancer cells and its therapeutic capabilities both in vitro and in vivo. Microbubble-liposome complexes conjugated with anti-human epidermal growth factor receptor type 2 (Her2) antibodies were developed to target human prostate cancer cell lines PC-3 and LNCaP. Intracellular delivery of MLC was observed by confocal microscopy. We loaded MLC with survivin-targeted small interfering RNA (siRNA) and doxorubicin, and delivered it into prostate cancer cells. The release of these agents was facilitated by ultrasound application. Cell viability was analyzed by MTT assay after the delivery of siRNA and doxorubicin. Survivin-targeted siRNA loaded MLC was delivered into the xenograft mouse tumor model. Western blotting was performed to quantify the expression of survivin in vivo. Confocal microscopy demonstrated substantial intracellular uptake of MLCs in LNCaP, which expresses higher levels of Her2 than PC-3. The viability of LNCaP cells was significantly reduced after the delivery of MLCs loaded with siRNA and doxorubicin (85.0 ± 2.9%), which was further potentiated by application of ultrasound (55.0 ± 3.5%, p = 0.009). Survivin expression was suppressed in vivo in LNCaP tumor xenograft model following the ultrasound and MLC-guided delivery of siRNA (77.4 ± 4.90% to 36.7 ± 1.34%, p = 0.027). Microbubble-liposome complex can effectively target prostate cancer cells, enabling intracellular delivery of the treatment agents with the use of ultrasound. Ultrasound and MLC-mediated delivery of survivin-targeted siRNA and doxorubicin can induce prostate cell apoptosis and block survivin expression in vitro and in vivo.

Ultrasound-Guided Delivery of siRNA and a Chemotherapeutic Drug by Using Microbubble Complexes: In Vitro and In Vivo Evaluations in a Prostate Cancer Model

International Nuclear Information System (INIS)

Bae, Yun Jung; Yoon, Young Il; Yoon, Tae-Jong; Lee, Hak Jong

2016-01-01

To evaluate the effectiveness of ultrasound and microbubble-liposome complex (MLC)-mediated delivery of siRNA and doxorubicin into prostate cancer cells and its therapeutic capabilities both in vitro and in vivo. Microbubble-liposome complexes conjugated with anti-human epidermal growth factor receptor type 2 (Her2) antibodies were developed to target human prostate cancer cell lines PC-3 and LNCaP. Intracellular delivery of MLC was observed by confocal microscopy. We loaded MLC with survivin-targeted small interfering RNA (siRNA) and doxorubicin, and delivered it into prostate cancer cells. The release of these agents was facilitated by ultrasound application. Cell viability was analyzed by MTT assay after the delivery of siRNA and doxorubicin. Survivin-targeted siRNA loaded MLC was delivered into the xenograft mouse tumor model. Western blotting was performed to quantify the expression of survivin in vivo. Confocal microscopy demonstrated substantial intracellular uptake of MLCs in LNCaP, which expresses higher levels of Her2 than PC-3. The viability of LNCaP cells was significantly reduced after the delivery of MLCs loaded with siRNA and doxorubicin (85.0 ± 2.9%), which was further potentiated by application of ultrasound (55.0 ± 3.5%, p = 0.009). Survivin expression was suppressed in vivo in LNCaP tumor xenograft model following the ultrasound and MLC-guided delivery of siRNA (77.4 ± 4.90% to 36.7 ± 1.34%, p = 0.027). Microbubble-liposome complex can effectively target prostate cancer cells, enabling intracellular delivery of the treatment agents with the use of ultrasound. Ultrasound and MLC-mediated delivery of survivin-targeted siRNA and doxorubicin can induce prostate cell apoptosis and block survivin expression in vitro and in vivo

Enhanced cell killing and apoptosis of oral squamous cell carcinoma cells with ultrasound in combination with cetuximab coated albumin microbubbles.

Science.gov (United States)

Narihira, Kyoichi; Watanabe, Akiko; Sheng, Hong; Endo, Hitomi; Feril, Loreto B; Irie, Yutaka; Ogawa, Koichi; Moosavi-Nejad, Seyedeh; Kondo, Seiji; Kikuta, Toshihiro; Tachibana, Katsuro

2018-03-01

Targeted microbubbles have the potential to be used for ultrasound (US) therapy and diagnosis of various cancers. In the present study, US was irradiated to oral squamous cell carcinoma cells (HSC-2) in the presence of cetuximab-coated albumin microbubbles (CCAM). Cell killing rate with US treatment at 0.9 W/cm 2 and 1.0 W/cm 2 in the presence of CCAM was greater compared to non-targeted albumin microbubbles (p < .05). On the other hand, selective cell killing was not observed in human myelomonocytic lymphoma cell line (U937) that had no affinity to cetuximab. Furthermore, US irradiation in the presence of CCAM showed a fivefold increase of cell apoptotic rate for HSC-2 cells (21.0 ± 3.8%) as compared to U937 cells (4.0 ± 0.8%). Time-signal intensity curve in a tissue phantom demonstrated clear visualisation of CCAM with conventional US imaging device. Our experiment verifies the hypothesis that CCAM was selective to HSC-2 cells and may be applied as a novel therapeutic/diagnostic microbubble for oral squamous cell carcinoma.

Quantitative investigation of the edge enhancement in in-line phase contrast projections and tomosynthesis provided by distributing microbubbles on the interface between two tissues: a phantom study

Science.gov (United States)

Wu, Di; Donovan Wong, Molly; Li, Yuhua; Fajardo, Laurie; Zheng, Bin; Wu, Xizeng; Liu, Hong

2017-12-01

The objective of this study was to quantitatively investigate the ability to distribute microbubbles along the interface between two tissues, in an effort to improve the edge and/or boundary features in phase contrast imaging. The experiments were conducted by employing a custom designed tissue simulating phantom, which also simulated a clinical condition where the ligand-targeted microbubbles are self-aggregated on the endothelium of blood vessels surrounding malignant cells. Four different concentrations of microbubble suspensions were injected into the phantom: 0%, 0.1%, 0.2%, and 0.4%. A time delay of 5 min was implemented before image acquisition to allow the microbubbles to become distributed at the interface between the acrylic and the cavity simulating a blood vessel segment. For comparison purposes, images were acquired using three system configurations for both projection and tomosynthesis imaging with a fixed radiation dose delivery: conventional low-energy contact mode, low-energy in-line phase contrast and high-energy in-line phase contrast. The resultant images illustrate the edge feature enhancements in the in-line phase contrast imaging mode when the microbubble concentration is extremely low. The quantitative edge-enhancement-to-noise ratio calculations not only agree with the direct image observations, but also indicate that the edge feature enhancement can be improved by increasing the microbubble concentration. In addition, high-energy in-line phase contrast imaging provided better performance in detecting low-concentration microbubble distributions.

Comparison of microbubble presence in the right heart during mechanochemical and radiofrequency ablation for varicose veins.

Science.gov (United States)

Moon, K H; Dharmarajah, B; Bootun, R; Lim, C S; Lane, Tra; Moore, H M; Sritharan, K; Davies, A H

2017-07-01

Objective Mechanochemical ablation is a novel technique for ablation of varicose veins utilising a rotating catheter and liquid sclerosant. Mechanochemical ablation and radiofrequency ablation have no reported neurological side-effect but the rotating mechanism of mechanochemical ablation may produce microbubbles. Air emboli have been implicated as a cause of cerebrovascular events during ultrasound-guided foam sclerotherapy and microbubbles in the heart during ultrasound-guided foam sclerotherapy have been demonstrated. This study investigated the presence of microbubbles in the right heart during varicose vein ablation by mechanochemical abaltion and radiofrequency abaltion. Methods Patients undergoing great saphenous vein ablation by mechanochemical abaltion or radiofrequency ablation were recruited. During the ablative procedure, the presence of microbubbles was assessed using transthoracic echocardiogram. Offline blinded image quantification was performed using International Consensus Criteria grading guidelines. Results From 32 recruited patients, 28 data sets were analysed. Eleven underwent mechanochemical abaltion and 17 underwent radiofrequency abaltion. There were no neurological complications. In total, 39% (11/28) of patients had grade 1 or 2 microbubbles detected. Thirty-six percent (4/11) of mechanochemical abaltion patients and 29% (5/17) of radiofrequency ablation patients had microbubbles with no significant difference between the groups ( p=0.8065). Conclusion A comparable prevalence of microbubbles between mechanochemical abaltion and radiofrequency ablation both of which are lower than that previously reported for ultrasound-guided foam sclerotherapy suggests that mechanochemical abaltion may not confer the same risk of neurological events as ultrasound-guided foam sclerotherapy for treatment of varicose veins.

Ultrasonic destruction of albumin microbubbles enhances gene transfection and expression in cardiac myocytes.

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Wang, Guo-zhong; Liu, Jing-hua; Lü, Shu-zheng; Lü, Yun; Guo, Cheng-jun; Zhao, Dong-hui; Fang, Dong-ping; He, Dong-fang; Zhou, Yuan; Ge, Chang-jiang

2011-05-01

It has been proven that ultrasonic destruction of microbubbles can enhance gene transfection efficiency into the noncardiac cells, but there are few reports about cardiac myocytes. Moreover, the exact mechanisms are not yet clear; whether the characteristic of microbubbles can affect the gene transfection efficiency or not is still controversial. This study was designed to investigate whether the ultrasound destruction of gene-loaded microbubbles could enhance the plasmids carried reporter gene transfection in primary cultured myocardial cell, and evaluate the effects of microbubbles characteristics on the transgene expression in cardiac myocytes. The β-galactosidase plasmids attached to the two types of microbubbles, air-contained sonicated dextrose albumin (ASDA) and perfluoropropane-exposed sonicated dextrose albumin (PESDA) were prepared. The gene transfection into cardiac myocytes was performed in vitro by naked plasmids, ultrasound exposure, ultrasonic destruction of gene-loaded microbubbles and calcium phosphate precipitation, and then the gene expression and cell viability were analyzed. The ultrasonic destruction of gene-loaded microbubbles enhanced gene expression in cardiac myocytes compared with naked plasmid transfection ((51.95 ± 2.41) U/g or (29.28 ± 3.65) U/g vs. (0.84 ± 0.21) U/g, P ASDA ((51.95 ± 2.41) U/g vs. (29.28 ± 3.65) U/g, P < 0.05). Ultrasonic destruction of microbubbles during calcium phosphate precipitation gene transfection enhanced β-galactosidase activity nearly 8-fold compared with calcium phosphate precipitation gene transfection alone ((111.35 ± 11.21) U/g protein vs. (14.13 ± 2.58) U/g protein, P < 0.01). Even 6 hours after calcium phosphate precipitation gene transfection, ultrasound-mediated microbubbles destruction resulted in more intense gene expression ((35.63 ± 7.65) U/g vs. (14.13 ± 2.58) U/g, P < 0.05). Ultrasonic destruction of microbubbles might be a promising method for the delivery of non-viral DNA into

Contrast enhanced ultrasound in liver imaging

International Nuclear Information System (INIS)

Nielsen, Michael Bachmann; Bang, Nanna

2004-01-01

Ultrasound contrast agents were originally introduced to enhance the Doppler signals when detecting vessels with low velocity flow or when imaging conditions were sub-optimal. Contrast agents showed additional properties, it was discovered that a parenchymal enhancement phase in the liver followed the enhancement of the blood pool. Contrast agents have made ultrasound scanning more accurate in detection and characterization of focal hepatic lesions and the sensitivity is now comparable with CT and MRI scanning. Further, analysis of the transit time of contrast agent through the liver seems to give information on possible hepatic involvement, not only from focal lesions but also from diffuse benign parenchymal disease. The first ultrasound contrast agents were easily destroyed by the energy from the sound waves but newer agents have proved to last for longer time and hereby enable real-time scanning and make contrast enhancement suitable for interventional procedures such as biopsies and tissue ablation. Also, in monitoring the effect of tumour treatment contrast agents have been useful. A brief overview is given on some possible applications and on different techniques using ultrasound contrast agents in liver imaging. At present, the use of an ultrasound contrast agent that allows real-time scanning with low mechanical index is to be preferred

Enhanced intracellular delivery of a model drug using microbubbles produced by a microfluidic device.

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Dixon, Adam J; Dhanaliwala, Ali H; Chen, Johnny L; Hossack, John A

2013-07-01

Focal drug delivery to a vessel wall facilitated by intravascular ultrasound and microbubbles holds promise as a potential therapy for atherosclerosis. Conventional methods of microbubble administration result in rapid clearance from the bloodstream and significant drug loss. To address these limitations, we evaluated whether drug delivery could be achieved with transiently stable microbubbles produced in real time and in close proximity to the therapeutic site. Rat aortic smooth muscle cells were placed in a flow chamber designed to simulate physiological flow conditions. A flow-focusing microfluidic device produced 8 μm diameter monodisperse microbubbles within the flow chamber, and ultrasound was applied to enhance uptake of a surrogate drug (calcein). Acoustic pressures up to 300 kPa and flow rates up to 18 mL/s were investigated. Microbubbles generated by the flow-focusing microfluidic device were stabilized with a polyethylene glycol-40 stearate shell and had either a perfluorobutane (PFB) or nitrogen gas core. The gas core composition affected stability, with PFB and nitrogen microbubbles exhibiting half-lives of 40.7 and 18.2 s, respectively. Calcein uptake was observed at lower acoustic pressures with nitrogen microbubbles (100 kPa) than with PFB microbubbles (200 kPa) (p 3). In addition, delivery was observed at all flow rates, with maximal delivery (>70% of cells) occurring at a flow rate of 9 mL/s. These results demonstrate the potential of transiently stable microbubbles produced in real time and in close proximity to the intended therapeutic site for enhancing localized drug delivery. Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

The partitioning of nanoparticles to endothelium or interstitium during ultrasound-microbubble-targeted delivery depends on peak-negative pressure

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Hsiang, Y.-H.; Song, J.; Price, R. J., E-mail: rprice@virginia.edu [University of Virginia, Department of Biomedical Engineering (United States)

2015-08-15

Patients diagnosed with advanced peripheral arterial disease often face poor prognoses and have limited treatment options. For some patient populations, the therapeutic growth of collateral arteries (i.e. arteriogenesis) that bypass regions affected by vascular disease may become a viable treatment option. Our group and others are developing therapeutic approaches centered on the ability of ultrasound-activated microbubbles to permeabilize skeletal muscle capillaries and facilitate the targeted delivery of pro-arteriogenic growth factor-bearing nanoparticles. The development of such approaches would benefit significantly from a better understanding of how nanoparticle diameter and ultrasound peak-negative pressure affect both total nanoparticle delivery and the partitioning of nanoparticles to endothelial or interstitial compartments. Toward this goal, using Balb/C mice that had undergone unilateral femoral artery ligation, we intra-arterially co-injected nanoparticles (50 and 100 nm) with microbubbles, applied 1 MHz ultrasound to the gracilis adductor muscle at peak-negative pressures of 0.7, 0.55, 0.4, and 0.2 MPa, and analyzed nanoparticle delivery and distribution. As expected, total nanoparticle (50 and 100 nm) delivery increased with increasing peak-negative pressure, with 50 nm nanoparticles exhibiting greater tissue coverage than 100 nm nanoparticles. Of particular interest, increasing peak-negative pressure resulted in increased delivery to the interstitium for both nanoparticle sizes, but had little influence on nanoparticle delivery to the endothelium. Thus, we conclude that alterations to peak-negative pressure may be used to adjust the fraction of nanoparticles delivered to the interstitial compartment. This information will be useful when designing ultrasound protocols for delivering pro-arteriogenic nanoparticles to skeletal muscle.

The partitioning of nanoparticles to endothelium or interstitium during ultrasound-microbubble-targeted delivery depends on peak-negative pressure

International Nuclear Information System (INIS)

Hsiang, Y.-H.; Song, J.; Price, R. J.

2015-01-01

Patients diagnosed with advanced peripheral arterial disease often face poor prognoses and have limited treatment options. For some patient populations, the therapeutic growth of collateral arteries (i.e. arteriogenesis) that bypass regions affected by vascular disease may become a viable treatment option. Our group and others are developing therapeutic approaches centered on the ability of ultrasound-activated microbubbles to permeabilize skeletal muscle capillaries and facilitate the targeted delivery of pro-arteriogenic growth factor-bearing nanoparticles. The development of such approaches would benefit significantly from a better understanding of how nanoparticle diameter and ultrasound peak-negative pressure affect both total nanoparticle delivery and the partitioning of nanoparticles to endothelial or interstitial compartments. Toward this goal, using Balb/C mice that had undergone unilateral femoral artery ligation, we intra-arterially co-injected nanoparticles (50 and 100 nm) with microbubbles, applied 1 MHz ultrasound to the gracilis adductor muscle at peak-negative pressures of 0.7, 0.55, 0.4, and 0.2 MPa, and analyzed nanoparticle delivery and distribution. As expected, total nanoparticle (50 and 100 nm) delivery increased with increasing peak-negative pressure, with 50 nm nanoparticles exhibiting greater tissue coverage than 100 nm nanoparticles. Of particular interest, increasing peak-negative pressure resulted in increased delivery to the interstitium for both nanoparticle sizes, but had little influence on nanoparticle delivery to the endothelium. Thus, we conclude that alterations to peak-negative pressure may be used to adjust the fraction of nanoparticles delivered to the interstitial compartment. This information will be useful when designing ultrasound protocols for delivering pro-arteriogenic nanoparticles to skeletal muscle

Assessment of renal perfusion with contrast-enhanced ultrasound: Preliminary results in early diabetic nephropathies.

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Dong, Yi; Wang, Wen-Ping; Lin, Pan; Fan, Peili; Mao, Feng

2016-01-01

We performed a prospective study to evaluate the value of contrast-enhanced ultrasound (CEUS) in quantitative evaluation of renal cortex perfusion in patients suspected of early diabetic nephropathies (DN), with the estimated GFR (MDRD equation) as the gold standard. The study protocol was approved by the hospital review board; each patient gave written informed consent. Our study included 46 cases (21 males and 25 females, mean age 55.6 ± 4.14 years) of clinical confirmed early DN patients. After intravenous bolus injection of 1 ml sulfur hexafluoride microbubbles of ultrasound contrast agent, real time CEUS of renal cortex was performed successively using a 2-5 MHz convex probe. Time-intensity curves (TICs) and quantitative indexes were created with Qlab software. Receiver operating characteristic (ROC) curves were used to predict the diagnostic criteria of CEUS quantitative indexes, and their diagnostic efficiencies were compared with resistance index (RI) and peak systolic velocity (PSV) of renal segmental arteries by chi square test. Our control group included forty-five healthy volunteers. Difference was considered statistically significant with P  0.05). CEUS might be helpful to improve early diagnosis of DN by quantitative analyses. AUC and DPI might be valuable quantitative indexes.

Paramagnetic perfluorocarbon-filled albumin-(Gd-DTPA) microbubbles for the induction of focused-ultrasound-induced blood-brain barrier opening and concurrent MR and ultrasound imaging.

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Liao, Ai-Ho; Liu, Hao-Li; Su, Chia-Hao; Hua, Mu-Yi; Yang, Hung-Wei; Weng, Yu-Ting; Hsu, Po-Hung; Huang, Sheng-Min; Wu, Shih-Yen; Wang, Hsin-Ell; Yen, Tzu-Chen; Li, Pai-Chi

2012-05-07

This paper presents new albumin-shelled Gd-DTPA microbubbles (MBs) that can concurrently serve as a dual-modality contrast agent for ultrasound (US) imaging and magnetic resonance (MR) imaging to assist blood-brain barrier (BBB) opening and detect intracerebral hemorrhage (ICH) during focused ultrasound brain drug delivery. Perfluorocarbon-filled albumin-(Gd-DTPA) MBs were prepared with a mean diameter of 2320 nm and concentration of 2.903×10(9) MBs ml(-1) using albumin-(Gd-DTPA) and by sonication with perfluorocarbon (C(3)F(8)) gas. The albumin-(Gd-DTPA) MBs were then centrifuged and the procedure was repeated until the free Gd(3+) ions were eliminated (which were detected by the xylenol orange sodium salt solution). The albumin-(Gd-DTPA) MBs were also characterized and evaluated both in vitro and in vivo by US and MR imaging. Focused US was used with the albumin-(Gd-DTPA) MBs to induce disruption of the BBB in 18 rats. BBB disruption was confirmed with contrast-enhanced T(1)-weighted turbo-spin-echo sequence MR imaging. Heavy T(2)*-weighted 3D fast low-angle shot sequence MR imaging was used to detect ICH. In vitro US imaging experiments showed that albumin-(Gd-DTPA) MBs can significantly enhance the US contrast in T(1)-, T(2)- and T(2)*-weighted MR images. The r(1) and r(2) relaxivities for Gd-DTPA were 7.69 and 21.35 s(-1)mM(-1), respectively, indicating that the MBs represent a positive contrast agent in T(1)-weighted images. In vivo MR imaging experiments on 18 rats showed that focused US combined with albumin-(Gd-DTPA) MBs can be used to both induce disruption of the BBB and detect ICH. To compare the signal intensity change between pure BBB opening and BBB opening accompanying ICH, albumin-(Gd-DTPA) MB imaging can provide a ratio of 5.14 with significant difference (p = 0.026), whereas Gd-DTPA imaging only provides a ratio of 2.13 and without significant difference (p = 0.108). The results indicate that albumin-(Gd-DTPA) MBs have potential as a US/MR dual

B-mode and contrast-enhanced sonographic assessment of accessory spleen in the dog.

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Rossi, Federica; Rabba, Silvia; Vignoli, Massimo; Haers, Hendrik; Terragni, Rossella; Saunders, Jimmy H

2010-01-01

Four dogs with an accessory spleen are described. The accessory spleens appeared as a round-to-triangular structure located in the perisplenic area. They were homogeneous and isoechoic with the adjacent spleen. Contrast-enhanced ultrasound was performed using a second generation microbubble contrast medium (sulfur hexafluoride). The type and timing of enhancement of the accessory spleen was similar to that of the parent spleen. Contrast-enhanced ultrasound is a noninvasive modality useful in distinguishing an accessory spleen from a mass of another origin.

Streaming flow from ultrasound contrast agents by acoustic waves in a blood vessel model.

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Cho, Eunjin; Chung, Sang Kug; Rhee, Kyehan

2015-09-01

To elucidate the effects of streaming flow on ultrasound contrast agent (UCA)-assisted drug delivery, streaming velocity fields from sonicated UCA microbubbles were measured using particle image velocimetry (PIV) in a blood vessel model. At the beginning of ultrasound sonication, the UCA bubbles formed clusters and translated in the direction of the ultrasound field. Bubble cluster formation and translation were faster with 2.25MHz sonication, a frequency close to the resonance frequency of the UCA. Translation of bubble clusters induced streaming jet flow that impinged on the vessel wall, forming symmetric vortices. The maximum streaming velocity was about 60mm/s at 2.25MHz and decreased to 15mm/s at 1.0MHz for the same acoustic pressure amplitude. The effect of the ultrasound frequency on wall shear stress was more noticeable. Maximum wall shear stress decreased from 0.84 to 0.1Pa as the ultrasound frequency decreased from 2.25 to 1.0MHz. The maximum spatial gradient of the wall shear stress also decreased from 1.0 to 0.1Pa/mm. This study showed that streaming flow was induced by bubble cluster formation and translation and was stronger upon sonication by an acoustic wave with a frequency near the UCA resonance frequency. Therefore, the secondary radiant force, which is much stronger at the resonance frequency, should play an important role in UCA-assisted drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Blood-brain barrier disruption induced by diagnostic ultrasound combined with microbubbles in mice.

Science.gov (United States)

Zhao, Bingxia; Chen, Yihan; Liu, Jinfeng; Zhang, Li; Wang, Jing; Yang, Yali; Lv, Qing; Xie, Mingxing

2018-01-12

To investigate the effects of the microbubble (MB) dose, mechanism index (MI) and sonication duration on blood-brain barrier (BBB) disruption induced by diagnostic ultrasound combined with MBs as well as to investigate the potential molecular mechanism. The extent of BBB disruption increased with MB dose, MI and sonication duration. A relatively larger extent of BBB disruption associated with minimal tissue damage was achieved by an appropriate MB dose and ultrasound exposure parameters with diagnostic ultrasound. Decreased expression of ZO-1, occludin and claudin-5 were correlated with disruption of the BBB, as confirmed by paracellular passage of the tracer lanthanum nitrate into the brain parenchyma after BBB disruption. These findings indicated that this technique is a promising tool for promoting brain delivery of diagnostic and therapeutic agents in the diagnosis and treatment of brain diseases. The extent of BBB disruption was qualitatively assessed by Evans blue (EB) staining and quantitatively analyzed by an EB extravasation measurement. A histological examination was performed to evaluate tissue damage. Expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5 was determined by western blotting analysis and immunohistofluorescence. Transmission electron microscopy was performed to observe ultrastructure changes of TJs after BBB disruption.

Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

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Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-03-01

Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.

Biodistribution, kinetics, and biological fate of SPION microbubbles in the rat

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Barrefelt A

2013-08-01

the first time point investigated (10 minutes. The frequency of microbubbles declined in the pulmonary vasculature and increased in pulmonary, hepatic, and splenic macrophages over time, resulting in a relative shift from the lungs to the spleen and liver. Meanwhile, macrophages showed increasing signs of cytoplasmic iron accumulation, initially in the lungs, then followed by other organs. Conclusion: The present investigation highlights the biological behavior of SPION microbubbles, including organ distribution over time and indications for biodegradation. The present results are essential for developing SPION microbubbles as a potential contrast agent and/or a drug delivery vehicle for specific organs. Such a vehicle will facilitate the use of multimodality imaging techniques, including ultrasound, magnetic resonance imaging, and single positron emission computed tomography, and hence improve diagnostics, therapy, and the ability to monitor the efficacy of treatment. Keywords: biodistribution, microbubbles, superparamagnetic iron oxide, pharmacokinetics, magnetic resonance imaging, histopathology

The dynamic behavior of microbubbles during long ultrasound tone-burst excitation: mechanistic insights into ultrasound-microbubble mediated therapeutics using high-speed imaging and cavitation detection

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Pacella, John J.; Villanueva, Flordeliza S.

2015-01-01

Ultrasound (US)-microbubble (MB) mediated therapies have been shown to restore perfusion and enhance drug/gene delivery. Due to the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes utilize short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic pressures and MB concentrations via direct high-speed optical observation and passive cavitation detection. MBs first underwent stable or inertial cavitation depending on the acoustic pressure, and then formed gas-filled clusters that continued to oscillate, break up, and form new clusters. Cavitation detection confirmed continued, albeit diminishing acoustic activity throughout the 5-ms US excitation. These data suggest that persisting cavitation activity during long tone-bursts may confer additional therapeutic effects. PMID:26603628

Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response.

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Liu, Hao-Li; Hsieh, Han-Yi; Lu, Li-An; Kang, Chiao-Wen; Wu, Ming-Fang; Lin, Chun-Yen

2012-11-11

High-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth. A total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature. Tumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited. Our findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.

Fluid Viscosity Affects the Fragmentation and Inertial Cavitation Threshold of Lipid-Encapsulated Microbubbles.

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Helfield, Brandon; Black, John J; Qin, Bin; Pacella, John; Chen, Xucai; Villanueva, Flordeliza S

2016-03-01

Ultrasound and microbubble optimization studies for therapeutic applications are often conducted in water/saline, with a fluid viscosity of 1 cP. In an in vivo context, microbubbles are situated in blood, a more viscous fluid (∼4 cP). In this study, ultrahigh-speed microscopy and passive cavitation approaches were employed to investigate the effect of fluid viscosity on microbubble behavior at 1 MHz subject to high pressures (0.25-2 MPa). The propensity for individual microbubble (n = 220) fragmentation was found to significantly decrease in 4-cP fluid compared with 1-cP fluid, despite achieving similar maximum radial excursions. Microbubble populations diluted in 4-cP fluid exhibited decreased wideband emissions (up to 10.2 times), and increasingly distinct harmonic emission peaks (e.g., ultraharmonic) with increasing pressure, compared with those in 1-cP fluid. These results suggest that in vitro studies should consider an evaluation using physiologic viscosity perfusate before transitioning to in vivo evaluations. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

WE-D-210-04: Radiation-Induced Polymerization of Ultrasound Contrast Agents in View of Non-Invasive Dosimetry in External Beam Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Callens, M; Verboven, E; Van Den Abeele, K [Department of Physics, Wave Propagation and Signal Processing, KU Leuven KULAK, Kortrijk (Belgium); D’Agostino, E [DoseVue NV, Hasselt (Belgium); Pfeiffer, H [Department of Materials Engineering, KU Leuven, Leuven (Belgium); D’hooge, J [Department of Cardiovascular Sciences, Bio-Medical Science Group, KU Leuven, Leuven (Belgium)

2015-06-15

Purpose: Ultrasound contrast agents (UCA’s) based on gas-filled microbubbles encapsulated by an amphiphilic shell are well established as safe and effective echo-enhancers in diagnostic imaging. In view of an alternative application of UCA’s, we investigated the use of targeted microbubbles as radiation sensors for external beam radiation therapy. As radiation induces permanent changes in the microbubble’s physico-chemical properties, a robust measure of these changes can provide a direct or indirect estimate of the applied radiation dose. For instance, by analyzing the ultrasonic dispersion characteristics of microbubble distributions before and after radiation treatment, an estimate of the radiation dose at the location of the irradiated volume can be made. To increase the radiation sensitivity of microbubbles, polymerizable diacetylene molecules can be incorporated into the shell. This study focuses on characterizing the acoustic response and quantifying the chemical modifications as a function of radiation dose. Methods: Lipid/diacetylene microbubbles were irradiated with a 6 MV photon beam using dose levels in the range of 0–150 Gy. The acoustic response of the microbubbles was monitored by ultrasonic through-transmission measurements in the range of 500 kHz to 20 MHz, thereby providing the dispersion relations of the phase velocity, attenuation and nonlinear coefficient. In addition, the radiation-induced chemical modifications were quantified using UV-VIS spectroscopy. Results: UV-VIS spectroscopy measurements indicate that ionizing radiation induces the polymerization of diacetylenes incorporated in the microbubble shell. The polymer yield strongly depends on the shell composition and the radiation-dose. The acoustic response is inherently related to the visco-elastic properties of the shell and is strongly influenced by the shell composition and the physico-chemical changes in the environment. Conclusion: Diacetylene-containing microbubbles are

Balancing stealth and echogenic properties in an ultrasound contrast agent with drug delivery potential.

Science.gov (United States)

Jablonowski, Lauren J; Alfego, David; Andorko, James I; Eisenbrey, John R; Teraphongphom, Nutte; Wheatley, Margaret A

2016-10-01

Contrast agents are currently being modified to combine diagnostic and therapeutic capabilities. For ultrasound (US) imaging with polymeric contrast agents, it is necessary to modify the shell to create "stealth" microbubbles but without these modifications sacrificing the agent's ability to interact with the focused US beam. We hypothesize that addition of the classic immune shielding molecule polyethylene glycol (PEG) to a polylactide (PLA) microbubble shell will affect the acoustic and physical properties of the resulting agents. In an effort to determine the best formulation to achieve a balance between stealth and acoustic activity, we compared two PEGylation techniques; addition of increasing amounts of PEG-PLA copolymer and employing incorporation of a PEG lipid (LipidPEG) into the shell. Loss of acoustic enhancement occurred in a dose-dependent manner for both types of PEGylated agents (loss of signal occurred at >5 wt% PEG-PLA and >1 wt% LipidPEG), while immune activation was also reduced in a dose-dependent manner for the PEG-PLA agents. This study shows that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with both PEGylation methods, and was best achieved using for PEG-PLA at 5 wt% and for LipidPEG at 1 wt%. Studies are ongoing to evaluate the best method for the targeting and drug delivery capabilities of these agents for applications in cancer treatment. This study represents the basis for understanding the consequences of making modifications to the native polymeric shell. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inflammatory activity in Crohn disease: ultrasound findings.

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Migaleddu, Vincenzo; Quaia, Emilio; Scano, Domenico; Virgilio, Giuseppe

2008-01-01

Improvements in the ultrasound examination of bowel disease have registered in the last years the introduction of new technologies regarding high frequency probes (US), highly sensitive color or power Doppler units (CD-US), and the development of new non-linear technologies that optimize detection of contrast agents. Contrast-enhanced ultrasound (CE-US) most importantly increases the results in sonographic evaluation of Crohn disease inflammatory activity. CE-US has become an imaging modality routinely employed in the clinical practice for the evaluation of parenchymal organs due to the introduction of new generation microbubble contrast agents which persist in the bloodstream for several minutes after intravenous injection. The availability of high frequency dedicated contrast-specific US techniques provide accurate depiction of small bowel wall perfusion due to the extremely high sensitivity of non-linear signals produced by microbubble insonation. In Crohn's disease, CE-US may characterize the bowel wall thickness by differentiating fibrosis from edema and may grade the inflammatory disease activity by assessing the presence and distribution of vascularity within the layers of the bowel wall (submucosa alone or the entire bowel wall). Peri-intestinal inflammatory involvement can be also characterized. CE-US can provide prognostic data concerning clinical recurrence of the inflammatory disease and evaluate the efficacy of drugs treatments.

Droplets, Bubbles and Ultrasound Interactions.

Science.gov (United States)

Shpak, Oleksandr; Verweij, Martin; de Jong, Nico; Versluis, Michel

2016-01-01

The interaction of droplets and bubbles with ultrasound has been studied extensively in the last 25 years. Microbubbles are broadly used in diagnostic and therapeutic medical applications, for instance, as ultrasound contrast agents. They have a similar size as red blood cells, and thus are able to circulate within blood vessels. Perfluorocarbon liquid droplets can be a potential new generation of microbubble agents as ultrasound can trigger their conversion into gas bubbles. Prior to activation, they are at least five times smaller in diameter than the resulting bubbles. Together with the violent nature of the phase-transition, the droplets can be used for local drug delivery, embolotherapy, HIFU enhancement and tumor imaging. Here we explain the basics of bubble dynamics, described by the Rayleigh-Plesset equation, bubble resonance frequency, damping and quality factor. We show the elegant calculation of the above characteristics for the case of small amplitude oscillations by linearizing the equations. The effect and importance of a bubble coating and effective surface tension are also discussed. We give the main characteristics of the power spectrum of bubble oscillations. Preceding bubble dynamics, ultrasound propagation is introduced. We explain the speed of sound, nonlinearity and attenuation terms. We examine bubble ultrasound scattering and how it depends on the wave-shape of the incident wave. Finally, we introduce droplet interaction with ultrasound. We elucidate the ultrasound-focusing concept within a droplets sphere, droplet shaking due to media compressibility and droplet phase-conversion dynamics.

Microbubble-based enhancement of radiation effect: Role of cell membrane ceramide metabolism.

Directory of Open Access Journals (Sweden)

Azza Al-Mahrouki

Full Text Available Ultrasound (US stimulated microbubbles (MB is a new treatment approach that sensitizes cancer cells to radiation (XRT. The molecular pathways in this response remain unelucidated, however, previous data has supported a role for cell membrane-metabolism related pathways including an up regulation of UDP glycosyltransferase 8 (UGT8, which catalyzes the transfer of galactose to ceramide, a lipid that is associated with the induction of apoptotic signalling. In this study, the role of UGT8 in responses of prostate tumours to ultrasound-stimulated microbubble radiation enhancement therapy is investigated. Experiments were carried out with cells in vitro and tumours in vivo in which UGT8 levels had been up regulated or down regulated. Genetically modified PC3 cells were treated with XRT, US+MB, or a combination of XRT+US+MB. An increase in the immunolabelling of ceramide was observed in cells where UGT8 was down-regulated as opposed to cells where UGT8 was either not regulated or was up-regulated. Clonogenic assays have revealed a decreased level of cellular survival with the down-regulation of UGT8. Xenograft tumours generated from stably transfected PC3 cells were also treated with US+MB, XRT or US+MB+XRT. Histology demonstrated more cellular damage in tumours with down-regulated UGT8 in comparison with control tumours. In contrast, tumours with up-regulated UGT8 had less damage than control tumours. Power Doppler imaging indicated a reduction in the vascular index with UGT8 down-regulation and photoacoustic imaging revealed a reduction in oxygen saturation. This was contrary to when UGT8 was up regulated. The down regulation of UGT8 led to the accumulation of ceramide resulting in more cell death signalling and therefore, a greater enhancement of radiation effect when vascular disruption takes place through the use of ultrasound-stimulated microbubbles.

Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents

International Nuclear Information System (INIS)

Hohmann, J.; Albrecht, T.; Hoffmann, C.W.; Wolf, K.-J.

2003-01-01

Ultrasonography (US) is the first choice for screening patients with suspected liver lesions. However, due to a lack of contrast agents, US used to be less sensitive and specific compared with computed tomography (CT) and magnet resonance imaging (MRI). The advent of microbubble contrast agents increased both sensitivity and specificity dramatically. Rapid developments of the contrast agents as well as of special imaging techniques were made in recent years. Today numerous different US imaging methods exist which based either on Doppler or on harmonic imaging. They are using the particular behaviour of microbubbles in a sound field which varies depending on the energy of insonation (low/high mechanical index, MI) as well as on the properties of the agent themselves. Apart from just blood pool enhancement some agents have a hepatosplenic specific late phase. US imaging during this late phase using relatively high MI in phase inversion mode (harmonic imaging) or stimulated acoustic emission (SAE; Doppler method) markedly improves the detection of focal liver lesions and is also very helpful for lesion characterisation. With regards to detection, contrast enhanced US performs similarly to CT as shown by recent studies. Early results of studies using low MI imaging and the newer perfluor agents are also showing promising results for lesion detection. Low MI imaging with these agents has the advantage of real time imaging and is particularly helpful for characterisation of focal lesions based on their dynamic contrast behaviour. Apart from the techniques which based on the morphology of liver lesions there were some attempts for the detection of occult metastases or micrometastases by means of liver blood flow changes. Also in this field the use of US contrast agents appears to have advantages over formerly used non contrast-enhanced methods although no conclusive results are available yet

An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro.

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Fix, Samantha M; Novell, Anthony; Yun, Yeoheung; Dayton, Paul A; Arena, Christopher B

2017-01-01

Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro. Parameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125-600 kPa) and pulse lengths (5-50 cycles) using propidium iodide as an indicator molecule. We achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure. We conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo.

Comparison between maximum radial expansion of ultrasound contrast agents and experimental postexcitation signal results.

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King, Daniel A; O'Brien, William D

2011-01-01

Experimental postexcitation signal data of collapsing Definity microbubbles are compared with the Marmottant theoretical model for large amplitude oscillations of ultrasound contrast agents (UCAs). After taking into account the insonifying pulse characteristics and size distribution of the population of UCAs, a good comparison between simulated results and previously measured experimental data is obtained by determining a threshold maximum radial expansion (Rmax) to indicate the onset of postexcitation. This threshold Rmax is found to range from 3.4 to 8.0 times the initial bubble radius, R0, depending on insonification frequency. These values are well above the typical free bubble inertial cavitation threshold commonly chosen at 2R0. The close agreement between the experiment and models suggests that lipid-shelled UCAs behave as unshelled bubbles during most of a large amplitude cavitation cycle, as proposed in the Marmottant equation.

Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

Science.gov (United States)

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-07-01

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will

Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

International Nuclear Information System (INIS)

Arvanitis, Costas D; McDannold, Nathan; Livingstone, Margaret S

2013-01-01

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood–brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood–brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that

Laser-Activated Polymeric Microcapsules for Ultrasound Imaging and Therapy: In Vitro Feasibility

NARCIS (Netherlands)

Lajoinie, Guillaume; van Rooij, Tom; Skachkov, Ilya; Blazejewski, Emilie; Veldhuis, Gert; de Jong, Nico; Kooiman, Klazina; Versluis, Michel

2017-01-01

Polymeric microcapsules with a light-absorbing dye incorporated in their shell can generate vapor microbubbles that can be spatiotemporally controlled by pulsed laser irradiation. These contrast agents of 6–8 μm in diameter can circulate through the vasculature, offering possibilities for ultrasound

Contrast-Enhanced Ultrasound in Vascular Surgery

DEFF Research Database (Denmark)

Bredahl, Kim; Mestre, Xavier Marti; Coll, Ramon Vila

2017-01-01

modalities. Ultrasound has only challenged these methods in assessment of carotid disease, aortic aneurysms, venous insufficiency, and thromboembolism and in surveillance of in situ bypasses. These practice patterns may change with the introduction of second-generation ultrasound contrast agents which...... are easy to use, manageable, and safe. This topical review attempts to summarize and highlight the current evidence and future prospects for contrast-enhanced ultrasound in vascular surgery, with a particular focus on opportunities in carotid and lower limb arteriosclerotic disease and surveillance after...

Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery

Directory of Open Access Journals (Sweden)

Vera ePaefgen

2015-09-01

Full Text Available Ultrasound is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents. There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular contrast agents enable functional analyses, e.g. to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles’ shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by ultrasound pulses to locally release the entrapped agent. Recent studies show that ultrasound contrast agents are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of ultrasound contrast agents and introduces the current clinical applications of contrast-enhanced ultrasound. Additionally, an overview of the recent developments in ultrasound probe design for functional and molecular diagnosis as well as for drug delivery is given.

Are microbubbles free flowing tracers through the Myocardium? Comparison of indicator-dilution curves obtained from dye dilution and echo contrast using harmonic power Doppler imaging.

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Tiemann, K; Schlosser, T; Pohl, C; Bimmel, D; Wietasch, G; Hoeft, A; Likungu, J; Vahlhaus, C; Kuntz, S; Nanda, N C; Becher, H; Lüderitz, B

2000-01-01

Harmonic power Doppler imaging (H-PDI) has been introduced into the field of contrast echocardiography as a contrast-specific imaging modality. However, there has been considerable skepticism as to whether H-PDI would be quantifiable, because it depends on the destruction of microbubbles and has more complex signal processing than gray scale imaging. The aim of the present study was to evaluate the relationship between the concentration of microbubbles and the resulting H-PDI signals even under conditions where bubble destruction is most likely. Furthermore, we evaluated whether microbubbles of Levovist freely pass the microcirculation, which is a prerequisite for the assessment of myocardial blood flow. A strong positive correlation was found between the H-PDI signals and the amount of microbubbles up to the onset of acoustic shadowing (r = 0. 968, Pgreen (ICG) in both a flow phantom and a working heart setup. The mean transit times (MTTs) through the myocardium of both agents were compared after a bolus injection into the left coronary artery. A close correlation was observed between 1/MTT and flow in both setups (r>0.98, Pgreen. We conclude that microbubbles fulfill the prerequisites of free flowing tracers through the myocardium. Furthermore, H-PDI technology allows a reliable assessment of time-concentration curves of air-filled microbubbles up to the onset of acoustic shadowing.

Characterization of hepatic lesions (≤30 mm) with liver-specific contrast agents: A comparison between ultrasound and magnetic resonance imaging

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Takahashi, Masanori, E-mail: machat1215@yahoo.co.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Maruyama, Hitoshi, E-mail: maru-cib@umin.ac.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Shimada, Taro, E-mail: bobtaro51@yahoo.co.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Kamezaki, Hidehiro, E-mail: ugn29814@yahoo.co.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Sekimoto, Tadashi, E-mail: tad_sekimoto@yahoo.co.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Kanai, Fumihiko, E-mail: kanaif@faculty.chiba-u.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Yokosuka, Osamu, E-mail: yokosukao@faculty.chiba-u.jp [Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan)

2013-01-15

Purpose: Imaging-based differentiation of hepatic lesions (≤30 mm) between well-differentiated hepatocellular carcinomas (w-HCC) and regenerative nodules (RN) presents difficulties. The aim was to compare the diagnostic abilities to differentiate w-HCC from RN using contrast-enhanced ultrasound and magnetic resonance imaging (MRI) both with liver-specific contrast agents. Materials and methods: This prospective study included 67 pathologically proven hepatic lesions (17.5 ± 5.4 mm, 54 w-HCCs, 13 RNs) in 56 patients with chronic hepatitis/cirrhosis (male 40, female 16; 29–79y). Hepatic-arterial/liver-specific phase enhancements were assessed quantitatively by ultrasound with perflubutane microbubble agent and MRI with gadolinium-ethoxybenzyl-diethylenetriamine with respect to the histological findings. Results: Sensitivity, specificity and accuracy of hepatic-arterial phase hyper-enhancement for w-HCC were 59.3%, 100% and 67.2% by ultrasound and 46.3%, 100% and 56.7% by MRI without significant difference. Meanwhile, those of liver-specific-phase hypo-enhancement for w-HCC were 44.4%, 100% and 55.2% by ultrasound and 87.0% (p < 0.0001), 46.2% (p = 0.0052) and 79.1% (p = 0.0032) by MRI. Diagnostic accuracies for w-HCC by area under the receiver operating characteristic curves were higher in the hepatic-arterial phase in ultrasound (0.8316) than MRI (0.6659, p = 0.0101) and similar in the liver-specific phase in ultrasound (0.7225) and MRI (0.7347, p = 0.8814). Conclusions: Hypervascularity is a significant feature which distinguishes w-HCC from RN, and ultrasound exerts a beneficial impact better than MRI for such characterization. However, both imaging have comparable abilities in the characterization of non-hypervascular lesions, compensating mutually for the poor sensitivity of ultrasound and the poor specificity of MRI in the liver-specific phase.

Therapeutic response assessment of high intensity focused ultrasound therapy for uterine fibroid: Utility of contrast-enhanced ultrasonography

International Nuclear Information System (INIS)

Zhou Xiaodong; Ren Xiaolong; Zhang Jun; He Guangbin; Zheng Minjuan; Tian Xue; Li Li; Zhu Ting; Zhang Min; Wang Lei; Luo Wen

2007-01-01

Purpose: To assess the utility of contrast-enhanced ultrasonography (ceUS) in the assessment of the therapeutic response to high intensity focused ultrasound (HIFU) ablation in patients with uterine fibroid. Materials and methods: Sixty-four patients with a total of 64 uterine fibroids (mean: 5.3 ± 1.2 cm; range: 3.2-8.9 cm) treated with HIFU ablation under the ultrasound guidance were evaluated with ceUS after receiving an intravenous bolus injection of a microbubble contrast agent (SonoVue) within 1 week after intervention. We obtained serial ceUS images during the time period from beginning to 5 min after the initiation of the bolus contrast injection. All of the patients underwent a contrast enhanced MRI (ceMRI) and ultrasound guided needle puncture biopsy within 1 week after HIFU ablation. And as a follow-up, all of the patients underwent US at 1, 3, 6 and 12 months after HIFU treatment. The volume change was observed and compared to pre- and post-HIFU ablation. The results of the ceUS were compared with those of the ceMRI in terms of the presence or absence of residual unablated tumor and pathologic change in the treated lesions. Results: On ceUS, diagnostic accuracy was 100%, while residual unablated tumors were found in three uterine fibroids (4.7%) and failed treatment was found in eight uterine fibroids (12.5%). All the 11 fibroids were subjected to additional HIFU ablation. Of the 58 ablated fibroids without residual tumors on both the ceUS and ceMRI after the HIFU ablation, the volumes of all the fibroids decreased in different degrees during the 1 year follow-up USs. And histologic examinations confirmed findings of necrotic and viable tumor tissue, respectively. Conclusion: CEUS is potentially useful for evaluating the early therapeutic effect of percutaneous HIFU ablation for uterine fibroids

Combining multi-pulse excitation and chirp coding in contrast-enhanced ultrasound imaging

International Nuclear Information System (INIS)

Crocco, M; Sciallero, C; Trucco, A; Pellegretti, P

2009-01-01

The development of techniques to separate the response of the contrast agent from that of the biological tissues is of great importance in ultrasound medical imaging. In the literature, one can find various solutions involving the use of multiple transmitted signals and the weighted sum of related echoes. In this paper, the combination of one of these multi-pulse techniques with a coded excitation is proposed and assessed. Coded excitation has been used mainly to increase the signal-to-noise ratio (SNR) and the penetration depth, provided that a matched filtering is applied in the reception chain. However, it has been shown that a signal with a long duration time also increases the backscattered echoes produced by the microbubbles and, consequently, the contrast-to-tissue ratio. Therefore, the implementation of a multi-pulse technique using a long coded pulse can yield a better contrast-to-tissue ratio and SNR. This paper investigates the combination of the linear chirp pulse with a multi-pulse technique based on the transmission of three pulses. The performance was evaluated using both simulated and real signals, assessing the improvement in the contrast-to-tissue ratio and SNR, the visual quality of the images obtained and the axial accuracy. A comparison with the same multi-pulse technique implemented using a traditional amplitude-modulated pulse revealed that the deployment of a chirp pulse produces several noticeable advantages and only a minor drawback

Effects of high-fat diet and losartan on renal cortical blood flow using contrast ultrasound imaging.

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Declèves, Anne-Emilie; Rychak, Joshua J; Smith, Dan J; Sharma, Kumar

2013-11-01

Obesity-related kidney disease occurs as a result of complex interactions between metabolic and hemodynamic effects. Changes in microvascular perfusion may play a major role in kidney disease; however, these changes are difficult to assess in vivo. Here, we used perfusion ultrasound imaging to evaluate cortical blood flow in a mouse model of high-fat diet-induced kidney disease. C57BL/6J mice were randomized to a standard diet (STD) or a high-fat diet (HFD) for 30 wk and then treated either with losartan or a placebo for an additional 6 wk. Noninvasive ultrasound perfusion imaging of the kidney was performed during infusion of a microbubble contrast agent. Blood flow within the microvasculature of the renal cortex and medulla was derived from imaging data. An increase in the time required to achieve full cortical perfusion was observed for HFD mice relative to STD. This was reversed following treatment with losartan. These data were concurrent with an increased glomerular filtration rate in HFD mice compared with STD- or HFD-losartan-treated mice. Losartan treatment also abrogated fibro-inflammatory disease, assessed by markers at the protein and messenger level. Finally, a reduction in capillary density was found in HFD mice, and this was reversed upon losartan treatment. This suggests that alterations in vascular density may be responsible for the elevated perfusion time observed by imaging. These data demonstrate that ultrasound contrast imaging is a robust and sensitive method for evaluating changes in renal microvascular perfusion and that cortical perfusion time may be a useful parameter for evaluating obesity-related renal disease.

Extracellular delivery induced by ultrasound and microbubbles in cells

Science.gov (United States)

Hussein, Farah; Antonescu, Costin; Karshafian, Raffi

2017-03-01

Ultrasound and microbubble treatment (USMB) can enhance the intracellular uptake of molecules, which otherwise would be excluded from the cell, through USMB-mediated transient membrane disruption and through enhanced endocytosis. However, the effect of USMB on the outward movement of molecules from cells is not well understood. This study investigates the effects of USMB on the release of molecules from various cellular compartments including cytoplasm, lysosomes, and recycling endosomes. In vitro ARPE-19 (RPE henceforth) cells were loaded with Alexa fluor-labeled transferrin as a marker for recycling endosomes, LAMP-1 antibody was used to detect the fusion of lysosomes with the plasma membrane, GFP-transfected RPE cells were used to examine the release of GFP from the cytoplasm, and 7-AAD was used to assess cell viability. Subsequently, cells were exposed to USMB (106 cells/mL, 300 kPa peak negative pressure, 1 min treatment duration, and 20 µL/mL Definity microbubbles). Following USMB, the release of the fluorescent markers was examined at 1.5, 11.5, and 21.5 minutes from the start of USMB. The mean fluorescent intensity (MFI) of untreated and USMB treated samples were measured using flow cytometry. USMB increased the extracellular delivery of GFP molecules from the cytoplasm; the MFI in USMB treated GFP-transfected RPE cells decreased by 17% in viable cells and this MFI decreased by 70% in non-viable cells. This could be due to diffusion of GFP through the membrane disruptions induced by USMB. Additionally, the MFI of viable cells stained with LAMP-1 antibody increased by 50% and this increase was 15 folds in the non-viable cells indicating lysosome exocytosis as a mechanism for membrane repair. Furthermore, the MFI of cells loaded with fluorescent transferrin decreased by 22% after USMB treatment in viable cells, indicating a significant increase in transferrin recycling to the cell membrane. However, the increased recycling was not statistically significant

Modeling of ultrasound propagation through contrast agents

NARCIS (Netherlands)

Grootens, J.J.F.A.H.; Mischi, M.; Böhmer, M.; Korsten, H.; Aarts, R.M.; Vander Sloten, Jos; Verdonck, Pascal; Nyssen, Marc

2008-01-01

In the past years many advances have been made in the detection of ultrasound contrast agents (UCA) by exploiting their nonlinear behavior. However, little attention has been paid to the nonlinear distortion of ultrasound (US) waves propagating through contrast media. The aim of this study is to

Relaxation behavior of a microbubble under ultrasonic field

International Nuclear Information System (INIS)

Kang, Sarng Woo; Kwak, Ho Young

2000-01-01

Nonlinear oscillation of a microbubble under ultrasound was investigated theoretically. The bubble radius-time curves calculated by the Rayleigh-Plesset equation with a polytropic index and by the Keller-Miksis equation with the analytical solution for the Navier-Stokes equations of the gases were compared with the observed results by the light scattering method. This study has revealed that the bubble behavior such as the expansion ratio and the bouncing motion after the first collapse under ultrasound depends crucially on the retarded time of the bubble motion to the applied ultrasound

Tumor Vessel Compression Hinders Perfusion of Ultrasonographic Contrast Agents

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Mirco Galiè

2005-05-01

Full Text Available Contrast-enhanced ultrasound (CEUS is an advanced approach to in vivo assessment of tumor vascularity and is being increasingly adopted in clinical oncology. It is based on 1- to 10 μm-sized gas microbubbles, which can cross the capillary beds of the lungs and are effective echo enhancers. It is known that high cell density, high transendothelial fluid exchange, and poorly functioning lymphatic circulation all provoke solid stress, which compresses vessels and drastically reduces tumor blood flow. Given their size, we supposed that the perfusion of microbubbles is affected by anatomic features of tumor vessels more than are contrast agents traditionally used in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI. Here, we compared dynamic information obtained from CEUS and DCE-MRI on two experimental tumor models exhibiting notable differences in vessel anatomy. We found that tumors with small, flattened vessels show a much higher resistance to microbubble perfusion than to MRI contrast agents, and appear scarcely vascularized at CEUS examination, despite vessel volume adequate for normal function. Thus, whereas CEUS alone could induce incorrect diagnosis when tumors have small or collapsed vessels, integrated analysis using CEUS and DCE-MRI allows in vivo identification of tumors with a vascular profile frequently associated with malignant phenotypes.

Ultrasonic microbubble contrast agents and the transplant kidney

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Kay, D.H., E-mail: davidhkay@doctors.org.u [Department of Radiology, Western Infirmary, Glasgow (United Kingdom); Mazonakis, M.; Geddes, C. [Department of Renal Medicine, Western Infirmary, Glasgow (United Kingdom); Baxter, G. [Department of Radiology, Western Infirmary, Glasgow (United Kingdom)

2009-11-15

Aim: To evaluate the potential application of microbubble agents in the immediate post-transplant period, by studying contrast uptake and washout, and to correlate these values with clinical indices, and thus, assess the potential prognostic value of this technique. Materials and methods: The study group comprised 20 consecutive renal transplant patients within 7 days of transplantation. Sonovue was administered as an intravenous bolus with continuous imaging of the transplant kidney at low mechanical index (MI) for 1 min post-injection. These data were analysed off-line by two observers, and time intensity curves (TIC) for the upper, mid, and lower poles constructed. Within each pole, a region of interest (5 mm square) was placed over the cortex, medullary pyramid, and interlobar artery, resulting in a total of nine TIC for each patient. TIC parameters included the arrival time (AT), time to peak (TTP), peak intensity (Max), gradient of the slope (M), and the area under curve (AUC). Results: For both observers there was good agreement for all values measured from the cortex and medulla, but poor interobserver correlation for the vascular values. In addition, there was only agreement for these values in the upper and mid-pole of the transplant with poor agreement for the lower pole values. The mid-pole of the transplant kidney was chosen as the point of measurement for subsequent studies. Mid-pole values were correlated with clinical data and outcome over the 3-month post-transplant period. Renal microbubble perfusion correlated with the transplant estimated glomerular filtration rate (eGFR) at 3 months post-transplantation (p = 0.016). Discussion: In conclusion, this is the first study to confirm reproducibility of the Sonovue TIC data in transplant patients and to quantify regional variation and perfusion. The statistically significant estimates of transplant perfusion may be of future benefit to transplant recipients and potentially utilized as a prognostic tool

Transfection of CXCR-4 using microbubble-mediated ultrasound irradiation and liposomes improves the migratory ability of bone marrow stromal cells.

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Wang, Gong; Zhuo, Zhongxiong; Zhang, Qian; Xu, Yali; Wu, Shengzheng; Li, Lu; Xia, Hongmei; Gao, Yunhua

2015-01-01

Bone marrow stromal cells (BMSCs) have proven useful for the treatment of various human diseases and injuries. However, their reparative capacity is limited by their poor migration and homing ability, which are primarily dependent on the SDF-1/CXCR4 axis. Most subcultured BMSCs lack CXCR4 receptor expression on the cell surface and exhibit impaired migratory capacity. To increase responsiveness to SDF-1 and promote cell migration and survival of cultured BMSCs, we used a combination of ultrasound-targeted microbubble destruction (UTMD) and liposomes to increase CXCR4 expression in vitro. We isolated and cultured rat BMSCs to their third passage and transduced them with recombinant plasmid pDsRed-CXCR4 using microbubble-mediated ultrasound irradiation and liposomes. Compared to some viral vectors, the method we employed here resulted in significantly better transfection efficiency, CXCR4 expression, and technical reproducibility. The benefits of this approach are likely due to the combination of "sonoporation" caused by shockwaves and microjet flow resulting from UTMD-generated cavitation. Following transfection, we performed a transwell migration assay and found that the migration ability of CXCR4-modified BMSCs was 9-fold higher than controls. The methods we describe here provide an effective, safe, non-viral means to achieve high levels of CXCR4 expression. This is associated with enhanced migration of subcultured BMSCs and may be useful for clinical application as well.

Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging

Science.gov (United States)

Errico, Claudia; Pierre, Juliette; Pezet, Sophie; Desailly, Yann; Lenkei, Zsolt; Couture, Olivier; Tanter, Mickael

2015-11-01

Non-invasive imaging deep into organs at microscopic scales remains an open quest in biomedical imaging. Although optical microscopy is still limited to surface imaging owing to optical wave diffusion and fast decorrelation in tissue, revolutionary approaches such as fluorescence photo-activated localization microscopy led to a striking increase in resolution by more than an order of magnitude in the last decade. In contrast with optics, ultrasonic waves propagate deep into organs without losing their coherence and are much less affected by in vivo decorrelation processes. However, their resolution is impeded by the fundamental limits of diffraction, which impose a long-standing trade-off between resolution and penetration. This limits clinical and preclinical ultrasound imaging to a sub-millimetre scale. Here we demonstrate in vivo that ultrasound imaging at ultrafast frame rates (more than 500 frames per second) provides an analogue to optical localization microscopy by capturing the transient signal decorrelation of contrast agents—inert gas microbubbles. Ultrafast ultrasound localization microscopy allowed both non-invasive sub-wavelength structural imaging and haemodynamic quantification of rodent cerebral microvessels (less than ten micrometres in diameter) more than ten millimetres below the tissue surface, leading to transcranial whole-brain imaging within short acquisition times (tens of seconds). After intravenous injection, single echoes from individual microbubbles were detected through ultrafast imaging. Their localization, not limited by diffraction, was accumulated over 75,000 images, yielding 1,000,000 events per coronal plane and statistically independent pixels of ten micrometres in size. Precise temporal tracking of microbubble positions allowed us to extract accurately in-plane velocities of the blood flow with a large dynamic range (from one millimetre per second to several centimetres per second). These results pave the way for deep non

Quantitative Differences Between the First and Second Injection of Contrast Agent in Contrast-Enhanced Ultrasonography of Feline Kidneys and Spleen.

Science.gov (United States)

Stock, Emmelie; Vanderperren, Katrien; Haers, Hendrik; Duchateau, Luc; Hesta, Myriam; Saunders, Jimmy H

2017-02-01

Contrast-enhanced ultrasound is a valuable and safe technique for the evaluation of organ perfusion. Repeated injections of ultrasound contrast agent are often administered during the same imaging session. However, it remains unclear if quantitative differences are present between the consecutive microbubble injections. Therefore, the first and second injection of contrast agent for the left renal cortex, renal medulla and the splenic parenchyma in healthy cats were compared. A lower peak intensity and area under the curve were observed for the first injection of contrast agent in the feline kidney, both for the renal cortex and medulla, and spleen. Moreover, for the renal cortex, the time-intensity curve was steeper after the second injection. Findings from the present study demonstrate that a second injection of contrast agent provides stronger enhancement. The exact mechanism behind our findings remains unclear; however, saturation of the lung macrophages is believed to play an important role. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Focal hepatic lesions: contrast-enhancement patterns at pulse-inversion harmonic US using a microbubble contrast agent

Energy Technology Data Exchange (ETDEWEB)

Kim, Eun-A; Yoon, Kwon-Ha; Lee, Young-Hwan; Kim, Hye-Won; Juhng, Seon-Kwan; Won, Jong-Jin [Wonkwang University, Iksan (Korea, Republic of)

2003-12-15

To analyze the contrast-enhancement patterns obtained at pulse-inversion harmonic imaging (PIHI) of focal hepatic lesions, and to thus determine tumor vascularity and the acoustic emission effect. We reviewed pulse-inversion images in 90 consecutive patients with focal hepatic lesions, namely hepatocellular carcinoma (HHC) (n=43), metastases (n=30), and hemangioma (n=17). Vascular and delayed phase images were obtained immediately and five minutes following the injection of a microbubble contrast agent. Tumoral vascularity at vascular phase imaging and the acoustic emission effect at delayed phase imaging were each classified as one of four patterns. Vascular phase images depicted internal vessels in 93% of HCCs, marginal vessels in 83% of metastases, and peripheral enhancement in 71% of hemangiomas. Delayed phase images showed inhomogeneous enhancement in 86% of HCCs; hypoechoic, decreased enhancement in 93% of metastases; and hypoechoic and reversed echogenicity in 65% of hemangiomas. Vascular and delayed phase enhancement patterns were associated with a specificity of 91% or greater, and 92% or greater, respectively, and with positive predictive values of 71% or greater, and 85% or greater, respectively. Contrast-enhancement patterns depicting tumoral vascularity and the acoustic emission effect at PIHI can help differentiate focal hepatic lesions.

Tumor Vessel Compression Hinders Perfusion of Ultrasonographic Contrast Agents1

Science.gov (United States)

Galiè, Mirco; D'Onofrio, Mirko; Montani, Maura; Amici, Augusto; Calderan, Laura; Marzola, Pasquina; Benati, Donatella; Merigo, Flavia; Marchini, Cristina; Sbarbati, Andrea

2005-01-01

Abstract Contrast-enhanced ultrasound (CEUS) is an advanced approach to in vivo assessment of tumor vascularity and is being increasingly adopted in clinical oncology. It is based on 1- to 10 µm-sized gas microbubbles, which can cross the capillary beds of the lungs and are effective echo enhancers. It is known that high cell density, high transendothelial fluid exchange, and poorly functioning lymphatic circulation all provoke solid stress, which compresses vessels and drastically reduces tumor blood flow. Given their size, we supposed that the perfusion of microbubbles is affected by anatomic features of tumor vessels more than are contrast agents traditionally used in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Here, we compared dynamic information obtained from CEUS and DCE-MRI on two experimental tumor models exhibiting notable differences in vessel anatomy. We found that tumors with small, flattened vessels show a much higher resistance to microbubble perfusion than to MRI contrast agents, and appear scarcely vascularized at CEUS examination, despite vessel volume adequate for normal function. Thus, whereas CEUS alone could induce incorrect diagnosis when tumors have small or collapsed vessels, integrated analysis using CEUS and DCE-MRI allows in vivo identification of tumors with a vascular profile frequently associated with malignant phenotypes. PMID:15967105

On the dynamics of StemBells: Microbubble-conjugated stem cells for ultrasound-controlled delivery

Science.gov (United States)

Kokhuis, Tom J. A.; Naaijkens, Benno A.; Juffermans, Lynda J. M.; Kamp, Otto; van der Steen, Antonius F. W.; Versluis, Michel; de Jong, Nico

2017-07-01

The use of stem cells for regenerative tissue repair is promising but hampered by the low number of cells delivered to the site of injury. To increase the delivery, we propose a technique in which stem cells are linked to functionalized microbubbles, creating echogenic complex dubbed StemBells. StemBells are highly susceptible to acoustic radiation force which can be employed after injection to push the StemBells locally to the treatment site. To optimally benefit from the delivery technique, a thorough characterization of the dynamics of StemBells during ultrasound exposure is needed. Using high-speed optical imaging, we study the dynamics of StemBells as a function of the applied frequency from which resonance curves were constructed. A theoretical model, based on a modified Rayleigh-Plesset type equation, captured the experimental resonance characteristics and radial dynamics in detail.

Cavitation microstreaming and stress fields created by microbubbles.

Science.gov (United States)

Collis, James; Manasseh, Richard; Liovic, Petar; Tho, Paul; Ooi, Andrew; Petkovic-Duran, Karolina; Zhu, Yonggang

2010-02-01

Cavitation microstreaming plays a role in the therapeutic action of microbubbles driven by ultrasound, such as the sonoporative and sonothrombolytic phenomena. Microscopic particle-image velocimetry experiments are presented. Results show that many different microstreaming patterns are possible around a microbubble when it is on a surface, albeit for microbubbles much larger than used in clinical practice. Each pattern is associated with a particular oscillation mode of the bubble, and changing between patterns is achieved by changing the sound frequency. Each microstreaming pattern also generates different shear stress and stretch/compression distributions in the vicinity of a bubble on a wall. Analysis of the micro-PIV results also shows that ultrasound-driven microstreaming flows around bubbles are feasible mechanisms for mixing therapeutic agents into the surrounding blood, as well as assisting sonoporative delivery of molecules across cell membranes. Patterns show significant variations around the bubble, suggesting sonoporation may be either enhanced or inhibited in different zones across a cellular surface. Thus, alternating the patterns may result in improved sonoporation and sonothrombolysis. The clear and reproducible delineation of microstreaming patterns based on driving frequency makes frequency-based pattern alternation a feasible alternative to the clinically less desirable practice of increasing sound pressure for equivalent sonoporative or sonothrombolytic effect. Surface divergence is proposed as a measure relevant to sonoporation.

Ultrasound-guided drug delivery in cancer

Energy Technology Data Exchange (ETDEWEB)

Chowdhury, Sayan Mullick; Lee, Tae Hwa; Willmann, Jugen K. [Dept. of Radiology, Stanford University School of Medicine, Stanford (United States)

2017-07-15

Recent advancements in ultrasound and microbubble (USMB) mediated drug delivery technology has shown that this approach can improve spatially confined delivery of drugs and genes to target tissues while reducing systemic dose and toxicity. The mechanism behind enhanced delivery of therapeutics is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. In this review, progress and challenges of USMB mediated drug delivery are summarized, with special focus on cancer therapy.

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.

Science.gov (United States)

Belcik, J Todd; Davidson, Brian P; Xie, Aris; Wu, Melinda D; Yadava, Mrinal; Qi, Yue; Liang, Sherry; Chon, Chae Ryung; Ammi, Azzdine Y; Field, Joshua; Harmann, Leanne; Chilian, William M; Linden, Joel; Lindner, Jonathan R

2017-03-28

Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for 10 minutes after intravenous injection of 2×10 8 lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signaling pathways were assessed by studying interventions that (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or K ATP channels; or (3) inhibited downstream signaling pathways involving endothelial nitric oxide synthase or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease. Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with sickle cell disease. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced an ≈40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of

Microbubble responses to a similar mechanical index with different real-time perfusion imaging techniques.

Science.gov (United States)

Porter, Thomas R; Oberdorfer, Joseph; Rafter, Patrick; Lof, John; Xie, Feng

2003-08-01

The purpose of this study was to determine differences in contrast enhancement and microbubble destruction rates with current commercially available low-mechanical index (MI) real-time perfusion imaging modalities. A tissue-mimicking phantom was developed that had vessels at 3 cm (near field) and 9 cm (far field) from a real-time transducer. Perfluorocarbon-exposed sonicated dextrose albumin microbubbles (PESDA) were injected proximal to a mixing chamber, and then passed through these vessels while the region was insonified with either pulses of alternating polarity with pulse inversion Doppler (PID) or pulses of alternating amplitude by power modulation (PM) at MIs of 0.1, 0.2 and 0.3. Effluent microbubble concentration, contrast intensity and the slope of digital contrast intensity vs. time were measured. Our results demonstrated that microbubble destruction already occurs with PID at an MI of 0.1. Contrast intensity seen with PID was less than with PM. Therefore, differences in contrast enhancement and microbubble destruction rates occur at a similar MI setting when using different real-time pulse sequence schemes.

State-of-the-Art Materials for Ultrasound-Triggered Drug Delivery

Science.gov (United States)

Sirsi, Shashank; Borden, Mark

2014-01-01

Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents. PMID:24389162

Ultrasound contrast-agent improves imaging of lower limb occlusive disease

DEFF Research Database (Denmark)

Eiberg, J P; Hansen, M A; Jensen, F

2003-01-01

to evaluate if ultrasound contrast-agent infusion could improve duplex-ultrasound imaging of peripheral arterial disease (PAD) and increase the agreement with digital subtraction arteriography (DSA).......to evaluate if ultrasound contrast-agent infusion could improve duplex-ultrasound imaging of peripheral arterial disease (PAD) and increase the agreement with digital subtraction arteriography (DSA)....

Contrast enhanced ultrasound of sentinel lymph nodes

Directory of Open Access Journals (Sweden)

XinWu Cui

2013-03-01

Full Text Available Sentinel lymph nodes are the first lymph nodes in the region that receive lymphatic drainage from a primary tumor. The detection or exclusion of sentinel lymph node micrometastases is critical in the staging of cancer, especially breast cancer and melanoma because it directly affects patient’s prognosis and surgical management. Currently, intraoperative sentinel lymph node biopsies using blue dye and radioisotopes are the method of choice for the detection of sentinel lymph node with high identification rate. In contrast, conventional ultrasound is not capable of detecting sentinel lymph nodes in most cases. Contrast enhanced ultrasound with contrast specific imaging modes has been used for the evaluation and diagnostic work-up of peripherally located suspected lymphadenopathy. The method allows for real-time analysis of all vascular phases and the visualization of intranodal focal “avascular” areas that represent necrosis or deposits of neoplastic cells. In recent years, a number of animal and human studies showed that contrast enhanced ultrasound can be also used for the detection of sentinel lymph node, and may become a potential application in clinical routine. Several contrast agents have been used in those studies, including albumin solution, hydroxyethylated starch, SonoVue®, Sonazoid® and Definity®. This review summarizes the current knowledge about the use of ultrasound techniques in detection and evaluation of sentinel lymph node.

Nonlinear Dynamics of a Bubble Contrast Agent Oscillating near an Elastic Wall

Science.gov (United States)

Garashchuk, Ivan R.; Sinelshchikov, Dmitry I.; Kudryashov, Nikolay A.

2018-05-01

Contrast agent microbubbles, which are encapsulated gas bubbles, are widely used to enhance ultrasound imaging. There are also several new promising applications of the contrast agents such as targeted drug delivery and noninvasive therapy. Here we study three models of the microbubble dynamics: a nonencapsulated bubble oscillating close to an elastic wall, a simple coated bubble and a coated bubble near an elastic wall.We demonstrate that complex dynamics can occur in these models. We are particularly interested in the multistability phenomenon of bubble dynamics. We show that coexisting attractors appear in all of these models, but for higher acoustic pressures for the models of an encapsulated bubble.We demonstrate how several tools can be used to localize the coexisting attractors. We provide some considerations why the multistability can be undesirable for applications.

Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug

Directory of Open Access Journals (Sweden)

Lin CY

2012-04-01

Full Text Available Chung-Yin Lin1*, Hsiao-Ching Tseng1*, Heng-Ruei Shiu1, Ming-Fang Wu2, Cheng-Ying Chou3, Win-Li Lin1,41Institute of Biomedical Engineering, 2Laboratory Animal Center, 3Department of Bio-Industrial Mechatronics Engineering, National Taiwan University, Taipei, Taiwan; 4Division of Medical Engineering Research, National Health Research Institutes, Miaoli, Taiwan*These authors contributed equally to this workAbstract: Ultrasound (US sonication with microbubbles (MBs has the potential to disrupt blood vessels and enhance the delivery of drugs into the sonicated tissues. In this study, mouse ear tumors were employed to investigate the therapeutic effects of US, MBs, and pegylated liposomal doxorubicin (PLD on tumors. Tumors started to receive treatments when they grew up to about 15 mm3 (early stage with injection of PLD 10 mg/kg, or up to 50 mm3 (medium stage with PLD 6 (or 4 mg/kg. Experiments included the control, PLD alone, PLD + MBs + US, US alone, and MBs + US groups. The procedure for the PLD + MBs + US group was that PLD was injected first, MB (SonoVue injection followed, and then US was immediately sonicated on the tumor. The results showed that: (1 US sonication with MBs was always able to produce a further hindrance to tumor growth for both early and medium-stage tumors; (2 for the medium-stage tumors, 6 mg/kg PLD alone was able to inhibit their growth, while it did not work for 4 mg/kg PLD alone; (3 with the application of MBs + US, 4 mg/kg PLD was able to inhibit the growth of medium-stage tumors; (4 for early stage tumors after the first treatment with a high dose of PLD alone (10 mg/kg, the tumor size still increased for several days and then decreased (a biphasic pattern; (5 MBs + US alone was able to hinder the growth of early stage tumors, but unable to hinder that of medium stage tumors. The results of histological examinations and blood perfusion measurements indicated that the application of MBs + US disrupts the tumor blood

Ultrasound-guided drug delivery in cancer

Directory of Open Access Journals (Sweden)

Sayan Mullick Chowdhury

2017-07-01

Full Text Available Recent advancements in ultrasound and microbubble (USMB mediated drug delivery technology has shown that this approach can improve spatially confined delivery of drugs and genes to target tissues while reducing systemic dose and toxicity. The mechanism behind enhanced delivery of therapeutics is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. In this review, progress and challenges of USMB mediated drug delivery are summarized, with special focus on cancer therapy.

Results of vardenafil mediated power Doppler ultrasound, contrast enhanced ultrasound and systematic random biopsies to detect prostate cancer.

Science.gov (United States)

Morelli, Girolamo; Pagni, Riccardo; Mariani, Chiara; Minervini, Riccardo; Morelli, Andrea; Gori, Francesco; Ferdeghini, Ezio Maria; Paterni, Marco; Mauro, Eva; Guidi, Elisa; Armillotta, Nicola; Canale, Domenico; Vitti, Paolo; Caramella, Davide; Minervini, Andrea

2011-06-01

We evaluated the ability of the phosphodiesterase-5 inhibitor vardenafil to increase prostate microcirculation during power Doppler ultrasound. We also evaluated the results of contrast and vardenafil enhanced targeted biopsies compared to those of standard 12-core random biopsies to detect cancer. Between May 2008 and January 2010, 150 consecutive patients with prostate specific antigen more than 4 ng/ml at first diagnosis with negative digital rectal examination and transrectal ultrasound, and no clinical history of prostatitis underwent contrast enhanced power Doppler ultrasound (bolus injection of 2.4 ml SonoVue® contrast agent), followed by vardenafil enhanced power Doppler ultrasound (1 hour after oral administration of vardenafil 20 mg). All patients underwent standard 12-core transrectal ultrasound guided random prostate biopsy plus 1 further sampling from each suspected hypervascular lesion detected by contrast and vardenafil enhanced power Doppler ultrasound. Prostate cancer was detected in 44 patients (29.3%). Contrast and vardenafil enhanced power Doppler ultrasound detected suspicious, contrast enhanced and vardenafil enhanced areas in 112 (74.6%) and 110 patients (73.3%), and was diagnostic for cancer in 32 (28.5%) and 42 (38%), respectively. Analysis of standard technique, and contrast and vardenafil enhanced power Doppler ultrasound findings by biopsy core showed significantly higher detection using vardenafil vs contrast enhanced power Doppler ultrasound and standard technique (41.2% vs 22.7% and 8.1%, p power Doppler ultrasound was 10% and 11.7% (p not significant). Vardenafil enhanced power Doppler ultrasound enables excellent visualization of the microvasculature associated with cancer and can improve the detection rate compared to contrast enhanced power Doppler ultrasound and the random technique. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Fluid viscosity affects the fragmentation and inertial cavitation threshold of lipid encapsulated microbubbles

Science.gov (United States)

Helfield, Brandon; Black, John J.; Qin, Bin; Pacella, John; Chen, Xucai; Villanueva, Flordeliza S.

2015-01-01

Ultrasound and microbubble optimization studies for therapeutic applications are often conducted in water/saline, with a fluid viscosity of 1 cP. In an in vivo context, microbubbles are situated in blood, a more viscous fluid (~4 cP). In this study, ultra-high speed microscopy and passive cavitation approaches were employed to investigate the effect of fluid viscosity on microbubble behavior at 1 MHz subject to high pressures (0.25 – 2 MPa). The propensity for individual microbubble (n=220) fragmentation was shown to significantly decrease in 4 cP fluid as compared to 1 cP fluid, despite achieving similar maximum radial excursions. Microbubble populations diluted in 4 cP fluid exhibited decreased wideband emissions (up to 10.2 times), and increasingly distinct harmonic emission peaks (e.g. ultraharmonic) with increasing pressure as compared to 1 cP fluid. These results suggest that in vitro studies should consider an evaluation using physiologic viscosity perfusate before transitioning to in vivo evaluations. PMID:26674676

Effective in vitro and in vivo gene delivery by the combination of liposomal bubbles (bubble liposomes) and ultrasound exposure.

Science.gov (United States)

Suzuki, Ryo; Maruyama, Kazuo

2010-01-01

Gene delivery with a physical mechanism using ultrasound (US) and nano/microbubbles is expected as an ideal system in terms of delivering plasmid DNA noninvasively into a specific target site. We developed novel liposomal bubbles (Bubble liposomes (BLs)) containing the lipid nanobubbles of perfluoropropane which were utilized for contrast enhancement in ultrasonography. BLs were smaller in diameter than conventional microbubbles and induced cavitation upon exposure ultrasound. In addition, when coupled with US exposure, BLs could deliver plasmid DNA into various types of cells in vitro and in vivo. The transfection efficiency with BLs and US was higher than that with conventional lipofection method. Therefore, the combination of BLs and US might be an efficient and novel nonviral gene delivery system.

Magnetic targeting to enhance microbubble delivery in an occluded microarterial bifurcation.

Science.gov (United States)

de Saint Victor, M; Carugo, D; Barnsley, L C; Owen, J; Coussios, C-C; Stride, E

2017-09-05

Ultrasound and microbubbles have been shown to accelerate the breakdown of blood clots both in vitro and in vivo. Clinical translation of this technology is still limited, however, in part by inefficient microbubble delivery to the thrombus. This study examines the obstacles to delivery posed by fluid dynamic conditions in occluded vasculature and investigates whether magnetic targeting can improve microbubble delivery. A 2D computational fluid dynamic model of a fully occluded Y-shaped microarterial bifurcation was developed to determine: (i) the fluid dynamic field in the vessel with inlet velocities from 1-100 mm s -1 (corresponding to Reynolds numbers 0.25-25); (ii) the transport dynamics of fibrinolytic drugs; and (iii) the flow behavior of microbubbles with diameters in the clinically-relevant range (0.6-5 µm). In vitro experiments were carried out in a custom-built microfluidic device. The flow field was characterized using tracer particles, and fibrinolytic drug transport was assessed using fluorescence microscopy. Lipid-shelled magnetic microbubbles were fluorescently labelled to determine their spatial distribution within the microvascular model. In both the simulations and experiments, the formation of laminar vortices and an abrupt reduction of fluid velocity were observed in the occluded branch of the bifurcation, severely limiting drug transport towards the occlusion. In the absence of a magnetic field, no microbubbles reached the occlusion, remaining trapped in the first vortex, within 350 µm from the bifurcation center. The number of microbubbles trapped within the vortex decreased as the inlet velocity increased, but was independent of microbubble size. Application of a magnetic field (magnetic flux density of 76 mT, magnetic flux density gradient of 10.90 T m -1 at the centre of the bifurcation) enabled delivery of microbubbles to the occlusion and the number of microbubbles delivered increased with bubble size and with decreasing inlet

A contrast-enhanced ultrasound study of benign and malignant ...

African Journals Online (AJOL)

A contrast-enhanced ultrasound study of benign and malignant breast tissue. S Barnard, E Leen, T Cooke, W Angerson. Abstract. Objective. To determine the diagnostic value of haemodynamic contrast-enhanced ultrasound assessment in benign and malignant breast tissue, using histological examination as the reference ...

Preparation of Metallochelating Microbubbles and Study on Their Site-Specific Interaction with rGFP-HisTag as a Model Protein

Czech Academy of Sciences Publication Activity Database

Lukáč, R.; Kauerová, Z.; Mašek, J.; Bartheldyová, E.; Kulich, P.; Koudelka, Š.; Korvasová, Z.; Plocková, J.; Papoušek, František; Kolář, František; Schmidt, R.; Turánek, J.

2011-01-01

Roč. 27, č. 8 (2011), s. 4829-4837 ISSN 0743-7463 R&D Projects: GA AV ČR KAN200520703 Grant - others:GA ČR(CZ) GAP304/10/1951; GA AV ČR(CZ) KAN200100801 Program:GA; KA Institutional research plan: CEZ:AV0Z50110509 Keywords : microbubble * ultrasound imaging * metallochelating bond * rGFP * liposome * contrast echocardiography * static light scattering * flow * cytometry * confocal Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.186, year: 2011

Temporal effect of inertial cavitation with and without microbubbles on surface deformation of agarose S gel in the presence of 1-MHz focused ultrasound.

Science.gov (United States)

Tomita, Y; Matsuura, T; Kodama, T

2015-01-01

Sonoporation has the potential to deliver extraneous molecules into a target tissue non-invasively. There have been numerous investigations of cell membrane permeabilization induced by microbubbles, but very few studies have been carried out to investigate sonoporation by inertial cavitation, especially from a temporal perspective. In the present paper, we show the temporal variations in nano/micro-pit formations following the collapse of inertial cavitation bubbles, with and without Sonazoid® microbubbles. Using agarose S gel as a target material, erosion experiments were conducted in the presence of 1-MHz focused ultrasound applied for various exposure times, Tex (0.002-60 s). Conventional microscopy was used to measure temporal variations in micrometer-scale pit numbers, and atomic force microscopy utilized to detect surface roughness on a nanometer scale. The results demonstrated that nanometer-scale erosion was predominantly caused by Sonazoid® microbubbles and C4F10 gas bubbles for 0.002 scavitation bubbles such as C4F10 gas bubbles and vapor bubbles, increased exponentially with increasing Tex in the range 0.1 scavitation-induced sonoporation can produce various pore sizes in membranes, enabling the delivery of external molecules of differing sizes into cells or tissues. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of chirp reversal power modulation sequence for contrast agent imaging

International Nuclear Information System (INIS)

Novell, A; Sennoga, CA; Escoffre, JM; Chaline, J; Bouakaz, A

2014-01-01

Over the last decade, significant research effort has been focused on the use of chirp for contrast agent imaging because chirps are known to significantly increase imaging contrast-to-noise ratio (CNR). New imaging schemes, such as chirp reversal (CR), have been developed to improve contrast detection by increasing non-linear microbubble responses. In this study we evaluated the contrast enhancement efficiency of various chirped imaging sequences in combination with well-established imaging schemes such as power modulation (PM) and pulse inversion (PI). The imaging schemes tested were implemented on a fully programmable open scanner and evaluated by ultrasonically scanning (excitation frequency of 2.5 MHz; amplitude of 350 kPa) a tissue-mimicking flow phantom comprising a 4 mm diameter tube through which aqueous dispersions (dilution fraction of 1/2000) of the commercial ultrasound contrast agent, SonoVue ® were continuously circulated. The recovery of non-linear microbubble responses after chirp compression requires the development and the optimization of a specific filter. A compression filter was therefore designed and used to compress and extract several non-linear components from the received microbubble responses. The results showed that using chirps increased the image CNR by approximately 10 dB, as compared to conventional Gaussian apodized sine burst excitation but degraded the axial resolution by a factor of 1.4, at −3 dB. We demonstrated that the highest CNR and contrast-to-noise ratio (CTR) were achievable when CR was combined with PM as compared to other imaging schemes such as PI. (paper)

Microbubbles combined with ultrasound therapy in ischemic stroke: A systematic review of in-vivo preclinical studies.

Directory of Open Access Journals (Sweden)

Laurent Auboire

Full Text Available Microbubbles (MBs combined with ultrasound sonothrombolysis (STL appears to be an alternative therapeutic strategy for acute ischemic stroke (IS, but clinical results remain controversial.The aim of this systematic review is to identify the parameters tested; to assess evidence on the safety and efficacy on preclinical data on STL; and to assess the validity and publication bias.Pubmed® and Web of ScienceTM databases were systematically searched from January 1995 to April 2017 in French and English. We included studies evaluating STL on animal stroke model. This systematic review was conducted in accordance with the PRISMA guidelines. Data were extracted following a pre-defined schedule by two of the authors. The CAMARADES criteria were used for quality assessment. A narrative synthesis was conducted.Sixteen studies met the inclusion criteria. The result showed that ultrasound parameters and types of MBs were heterogeneous among studies. Numerous positive outcomes on efficacy were found, but only four studies demonstrated superiority of STL versus recombinant tissue-type plasminogen activator on clinical criteria. Data available on safety are limited.Quality assessment of the studies reviewed revealed a number of biases.Further in vivo studies are needed to demonstrate a better efficacy and safety of STL compared to currently approved therapeutic options.http://syrf.org.uk/protocols/.

A REVIEW OF LOW-INTENSITY ULTRASOUND FOR CANCER THERAPY

Science.gov (United States)

WOOD, ANDREW K. W.; SEHGAL, CHANDRA M.

2015-01-01

The literature describing the use of low-intensity ultrasound in four major areas of cancer therapy was reviewed - sonodynamic therapy, ultrasound mediated chemotherapy, ultrasound mediated gene delivery and antivascular ultrasound therapy. Each technique consistently resulted in the death of cancer cells and the bioeffects of ultrasound were primarily attributed to thermal actions and inertial cavitation. In each therapeutic modality, theranostic contrast agents composed of microbubbles played a role in both therapy and vascular imaging. The development of these agents is important as it establishes a therapeutic-diagnostic platform which can monitor the success of anti-cancer therapy. Little attention, however, has been given to either the direct assessment of the underlying mechanisms of the observed bioeffects or to the viability of these therapies in naturally occurring cancers in larger mammals; if such investigations provided encouraging data there could be a prompt application of a therapy technique in treating cancer patients. PMID:25728459

Ultrasound Targeted Microbubble Destruction Stimulates Cellular Endocytosis in Facilitation of Adeno-Associated Virus Delivery

Directory of Open Access Journals (Sweden)

Lian-Fang Du

2013-05-01

Full Text Available The generally accepted mechanism for ultrasound targeted microbubble destruction (UTMD to enhance drug and gene delivery is through sonoporation. However, passive uptake of adeno-associated virus (AAV into cells following sonoporation does not adequately explain observations of enhanced transduction by UTMD. This study investigated alternative mechanisms of UTMD enhancement in AAV delivery. UTMD significantly enhanced transduction efficiency of AAV in a dose-dependent manner. UTMD stimulated a persistent uptake of AAV into the cytoplasm and nucleus. This phenomenon occurred over several hours, suggesting that some viral particles are endocytosed by cells rather than exclusively passing through pores created by sonoporation. Additionally, UTMD enhanced clathrin expression and accumulation at the plasma membrane suggesting greater clathrin-mediated endocytosis following UTMD. Transmission electron microscopy (TEM revealed that UTMD stimulated formation of clathrin-coated pits (CPs and uncoated pits (nCPs. Furthermore, inhibition of clathrin-mediated endocytosis partially blocked the enhancement of AAV uptake following UTMD. The results of this study implicate endocytosis as a mechanism that contributes to UTMD-enhanced AAV delivery.

Lesion Contrast Enhancement in Medical Ultrasound Imaging

DEFF Research Database (Denmark)

Stetson, Paul F.; Sommer, F.G.; Macovski, A.

1997-01-01

Methods for improving the contrast-to-noise ratio (CNR) of low-contrast lesions in medical ultrasound imaging are described. Differences in the frequency spectra and amplitude distributions of the lesion and its surroundings can be used to increase the CNR of the lesion relative to the background...

Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and definity microbubbles: a short-term study.

Science.gov (United States)

Baseri, Babak; Choi, James J; Tung, Yao-Sheng; Konofagou, Elisa E

2010-09-01

As a potentially viable method of brain drug delivery, the safety profile of blood-brain barrier (BBB) opening using focused ultrasound (FUS) and ultrasound contrast agents (UCA) needs to be established. In this study, we provide a short-term (30-min or 5-h survival) histological assessment of murine brains undergoing FUS-induced BBB opening. Forty-nine mice were intravenously injected with Definity microbubbles (0.05 microL/kg) and sonicated under the following parameters: frequency of 1.525 MHz, pulse length of 20 ms, pulse repetition frequency of 10 Hz, peak rarefactional acoustic pressures of 0.15-0.98 MPa and two 30-s sonication intervals with an intermittent 30-s delay. The BBB opening threshold was found to be 0.15-0.3 MPa based on fluorescence and magnetic resonance imaging of systemically injected tracers. Analysis of three histological measures in hematoxylin and eosin-stained sections revealed the safest acoustic pressure to be within the range of 0.3-0.46 MPa in all examined time periods post sonication. Across different pressure amplitudes, only the samples 30 min post opening showed significant difference (p < 0.05) in the average number of distinct damaged sites, microvacuolated sites, dark neurons and sites with extravasated erythrocytes. Enhanced fluorescence around severed microvessels was also noted and found to be associated with the largest tissue effects, whereas mildly diffuse BBB opening with uniform fluorescence in the parenchyma was associated with no or mild tissue injury. Region-specific areas of the sonicated brain (thalamus, hippocampal fissure, dentate gyrus and CA3 area of hippocampus) exhibited variation in fluorescence intensity based on the position, orientation and size of affected vessels. The results of this short-term histological analysis demonstrated the feasibility of a safe FUS-UCA-induced BBB opening under a specific set of sonication parameters and provided new insights on the mechanism of BBB opening.

Modeling complicated rheological behaviors in encapsulating shells of lipid-coated microbubbles accounting for nonlinear changes of both shell viscosity and elasticity.

Science.gov (United States)

Li, Qian; Matula, Thomas J; Tu, Juan; Guo, Xiasheng; Zhang, Dong

2013-02-21

It has been accepted that the dynamic responses of ultrasound contrast agent (UCA) microbubbles will be significantly affected by the encapsulating shell properties (e.g., shell elasticity and viscosity). In this work, a new model is proposed to describe the complicated rheological behaviors in an encapsulating shell of UCA microbubbles by applying the nonlinear 'Cross law' to the shell viscous term in the Marmottant model. The proposed new model was verified by fitting the dynamic responses of UCAs measured with either a high-speed optical imaging system or a light scattering system. The comparison results between the measured radius-time curves and the numerical simulations demonstrate that the 'compression-only' behavior of UCAs can be successfully simulated with the new model. Then, the shell elastic and viscous coefficients of SonoVue microbubbles were evaluated based on the new model simulations, and compared to the results obtained from some existing UCA models. The results confirm the capability of the current model for reducing the dependence of bubble shell parameters on the initial bubble radius, which indicates that the current model might be more comprehensive to describe the complex rheological nature (e.g., 'shear-thinning' and 'strain-softening') in encapsulating shells of UCA microbubbles by taking into account the nonlinear changes of both shell elasticity and shell viscosity.

Modeling complicated rheological behaviors in encapsulating shells of lipid-coated microbubbles accounting for nonlinear changes of both shell viscosity and elasticity

International Nuclear Information System (INIS)

Li Qian; Tu Juan; Guo Xiasheng; Zhang Dong; Matula, Thomas J

2013-01-01

It has been accepted that the dynamic responses of ultrasound contrast agent (UCA) microbubbles will be significantly affected by the encapsulating shell properties (e.g., shell elasticity and viscosity). In this work, a new model is proposed to describe the complicated rheological behaviors in an encapsulating shell of UCA microbubbles by applying the nonlinear ‘Cross law’ to the shell viscous term in the Marmottant model. The proposed new model was verified by fitting the dynamic responses of UCAs measured with either a high-speed optical imaging system or a light scattering system. The comparison results between the measured radius–time curves and the numerical simulations demonstrate that the ‘compression-only’ behavior of UCAs can be successfully simulated with the new model. Then, the shell elastic and viscous coefficients of SonoVue microbubbles were evaluated based on the new model simulations, and compared to the results obtained from some existing UCA models. The results confirm the capability of the current model for reducing the dependence of bubble shell parameters on the initial bubble radius, which indicates that the current model might be more comprehensive to describe the complex rheological nature (e.g., ‘shear-thinning’ and ‘strain-softening’) in encapsulating shells of UCA microbubbles by taking into account the nonlinear changes of both shell elasticity and shell viscosity. (paper)

Magnetic stents retain nanoparticle-bound antirestenotic drugs transported by lipid microbubbles.

Science.gov (United States)

Räthel, T; Mannell, H; Pircher, J; Gleich, B; Pohl, U; Krötz, F

2012-05-01

Coating coronary stents with antirestenotic drugs revolutionized interventional cardiology. We developed a system for post-hoc drug delivery to uncoated stents. We coupled rapamycin or a chemically similar fluorescent dye to superparamagnetic nanoparticles. The antiproliferative activity of rapamycin coupled to nanoparticles was confirmed in vitro in primary porcine vascular cells. The particles were then incorporated into lipid based microbubbles. Commercially available stents were made magnetizable by nickel plating and used to induce strong field gradients in order to capture magnetic microbubbles from flowing liquids when placed in an external magnetic field. Nanoparticle bound Rapamycin dose dependently inhibited cell proliferation in vitro. Magnetic microcbubbles carrying coated nanoparticles were caught by magnets placed external to a flow-through tube. Plating commercial stents with nickel resulted in increased deposition at stent struts and allowed for widely increased distance of external magnets. Deposition depended on circulation time and velocity and distance of magnets. Deposited microbubbles were destroyed by ultrasound and delivered their cargo to targeted sites. Drugs can be incorporated into nanoparticle loaded microbubbles and thus be delivered to magnetizable stents from circulating fluids by applying external magnetic fields. This technology could allow for post-hoc drug coating of already implanted vascular stents.

Ambient pressure sensitivity of microbubbles investigated through a parameter study

DEFF Research Database (Denmark)

Andersen, Klaus Scheldrup; Jensen, Jørgen Arendt

2009-01-01

Measurements on microbubbles clearly indicate a relation between the ambient pressure and the acoustic behavior of the bubble. The purpose of this study was to optimize the sensitivity of ambient pressure measurements, using the subharmonic component, through microbubble response simulations....... The behavior of two microbubbles corresponding to two different contrast agents was investigated as a function of driving pulse and ambient overpressure, pov. Simulations of Levovist using a rectangular driving pulse show an almost linear reduction in the subharmonic component as pov is increased. For a 20...... found, although the reduction is not completely linear as a function of the ambient pressure....

Spatial and temporal profile of cisplatin delivery by ultrasound-assisted intravesical chemotherapy in a bladder cancer model.

Directory of Open Access Journals (Sweden)

Noboru Sasaki

Full Text Available Non-muscle invasive bladder cancer is one of the most common tumors of the urinary tract. Despite the current multimodal therapy, recurrence and progression of disease have been challenging problems. We hereby introduced a new approach, ultrasound-assisted intravesical chemotherapy, intravesical instillation of chemotherapeutic agents and microbubbles followed by ultrasound exposure. We investigated the feasibility of the treatment for non-muscle invasive bladder cancer. In order to evaluate intracellular delivery and cytotoxic effect as a function to the thickness, we performed all experiments using a bladder cancer mimicking 3D culture model. Ultrasound-triggered microbubble cavitation increased both the intracellular platinum concentration and the cytotoxic effect of cisplatin at the thickness of 70 and 122 μm of the culture model. The duration of enhanced cytotoxic effect of cisplatin by ultrasound-triggered microbubble cavitation was approximately 1 hr. Based on the distance and duration of delivery, we further tested the feasibility of repetition of the treatment. Triple treatment increased the effective distance by 1.6-fold. Our results clearly showed spatial and temporal profile of delivery by ultrasound-triggered microbubble cavitation in a tumor-mimicking structure. Furthermore, we demonstrated that the increase in intracellular concentration results in the enhancement of the cytotoxic effect in a structure with the certain thickness. Repetition of ultrasound exposure would be treatment of choice in future clinical application. Our results suggest ultrasound-triggered microbubble cavitation can be repeatable and is promising for the local control of non-muscle invasive bladder cancer.

Ultrasound effects on the electrolytically controlled etching of nuclear track filters (NTFs)

International Nuclear Information System (INIS)

Chakarvarti, S.K.; Mahna, S.K.; Sud, L.V.; Singh, P.

1990-01-01

The mechanical stirring of the etchant creates tremendous changes in the etching properties of SSNTDs. Ultrasound stirring also produces a number of effects in liquids by giving a rapid movement to etchant. Cavitation is the most probable phenomenon caused by ultrasound and responsible for most of the effects observed in chemical reactions. Microbubbles are created in liquid medium and explosion of these microbubbles is responsible for momentarily rise in temperature. The possible effects of ultrasound on etching of particle tracks in plastic track detectors as nuclear track filters has been studied. The ultrasound effects on V t and V b have been studied in this work. (author). 5 re fs

Feasibility of ultrasound-guided intraarticular contrast injection for MR arthrography

International Nuclear Information System (INIS)

Baek, Soo Jin; Lee, Jong Min; Kang, Duck Sick

2005-01-01

To assess the feasibility of ultrasound-guided intraarticular contrast injection using the posterior approach for MR arthrography. Between June 2002 and October 2004, 132 patients (29 female, 103 male: mean age, 33.6 years) underwent ultrasound-guided intraarticular contrast media injection (40 ml saline + 10 ml 2% lidocaine + 0.2 ml gadopentetate dimeglumine + 0.4 ml epinephrine) for MR arthrography. The patients were classified into four groups, viz. the no leakage group, the minor leakage with successful intraarticular injection group, the major leakage with unsuccessful intraarticular injection group, and the injection failure group. The 'no leakage' and 'minor leakage' groups were considered to be technical successes, while the 'major leakage' and 'injection failure' groups were regarded as technical failures. The technical success rate of ultrasound-guided intraarticular contrast injection using the posterior approach for MR Arthrography was 99.2% (131/132 patients) and one patients 0.7% (1/132 patients) was included in the 'major leakage' group. Ultrasound-guided intraarticular contrast injection using the posterior approach for MR arthrography was feasible with a high success rate

Microwave ablation of liver metastases guided by contrast-enhanced ultrasound

DEFF Research Database (Denmark)

Lorentzen, T; Skjoldbye, B O; Nolsoe, C P

2011-01-01

The aim of our study was to evaluate the efficacy of microwave (MW) ablation of liver metastases guided by B-mode ultrasound (US) and contrast-enhanced US (CEUS).......The aim of our study was to evaluate the efficacy of microwave (MW) ablation of liver metastases guided by B-mode ultrasound (US) and contrast-enhanced US (CEUS)....

Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

Science.gov (United States)

Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

2012-02-01

Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

Enhanced cavitation and heating of flowing polymer- and lipid-shelled microbubbles and phase-shift nanodroplets during focused ultrasound exposures

Science.gov (United States)

Zhang, Siyuan; Cui, Zhiwei; Li, Chong; Zhou, Fanyu; Zong, Yujin; Wang, Supin; Wan, Mingxi

2017-03-01

Cavitation and heating are the primary mechanisms of numerous therapeutic applications of ultrasound. Various encapsulated microbubbles (MBs) and phase-shift nanodroplets (NDs) have been used to enhance local cavitation and heating, creating interests in developing ultrasound therapy using these encapsulated MBs and NDs. This work compared the efficiency of flowing polymer- and lipid-shelled MBs and phase-shift NDs in cavitation and heating during focused ultrasound (FUS) exposures. Cavitation activity and temperature were investigated when the solution of polymer- and lipid-shelled MBs and NDs flowed through the vessel in a tissue-mimicking phantom with varying flow velocities when exposed to FUS at various acoustic power levels. The inertial cavitation dose (ICD) for the encapsulated MBs and NDs were higher than those for the saline. Temperature initially increased with increasing flow velocities of the encapsulated MBs, followed by a decrease of the temperature with increasing flow velocities when the velocity was much higher. Meanwhile, ICD showed a trend of increases with increasing flow velocity. For the phase-shift NDs, ICD after the first FUS exposure was lower than those after the second FUS exposure. For the encapsulated MBs, ICD after the first FUS exposure was higher than those after the second FUS exposure. Further studies are necessary to investigate the treatment efficiency of different encapsulated MBs and phase-shift NDs in cavitation and heating.

Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

Science.gov (United States)

Downs, Matthew E.; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

2015-10-01

Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound.

Science.gov (United States)

Sheeran, Paul S; Luois, Samantha; Dayton, Paul A; Matsunaga, Terry O

2011-09-06

Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications. © 2011 American Chemical Society

Estimation of Tumor Angiogenesis With Contrast Enhanced Subharmonic Ultrasound Imaging

National Research Council Canada - National Science Library

Forsberg, Flemming

2002-01-01

.... Hence, the current project proposes to increase the ability of breast ultrasound to differentiate between benign and malignant lesions by combining injection of an ultrasound contrast agent with SHI...

Estimation of Tumor Angiogenesis with Contrast Enhanced Subharmonic Ultrasound Imaging

National Research Council Canada - National Science Library

Forsberg, Flemming

2004-01-01

.... Hence, the current project proposes to increase the ability of breast ultrasound to differentiate between benign and malignant lesions by combining injection of an ultrasound contrast agent with SHI...

Novel fluorescence nanobubbles for contrast-enhanced ultrasound imaging in rabbit VX2 hepatocellular carcinoma model

Science.gov (United States)

Yu, Houqiang; Wang, Wei; He, Xiaoling; Zhou, Qibing; Ding, Mingyue

2017-03-01

Ultrasound contrast agents (UCAs) such as SonoVue or Optison have been used widely in clinic for contrast-enhanced vascular imaging. However, microbubbles UCAs display limitations in tumor-targeted imaging due to the large sizes, nanoscaled UCAs has consequently attracted increasing attentions. In this work, we synthesized nanobubbles (NBs) by ultrasonic cavitation method, then a fluorescent marker of Alexa Fluor 680 was conjugated to the shell in order to observe the localization of NBs in tumor tissue. Measurement of fundamental characteristics showed that the NBs had homogeneous distribution of mean diameter of 267.9 +/- 19.2 nm and polydispersity index of 0.410 +/- 0.056. To assess in vivo tumor-selectivity of NBs, we established the rabbits VX2 hepatocellular carcinoma model though surgical implantation method. After the rabbits were intravenous administered of NBs, contrast-enhanced sonograms was observed in the surrounding of VX2 tumor, which showed there are rich capillaries in the tumor periphery. We additionally investigated the toxic of the NBs by hematoxylin-eosin staining. The results indicated that the NBs is a biocompatible non-toxic lipid system. Furthermore, the VX2 tumors and major organs were analyzed using ex vivo fluorescence imaging to confirm the targeted selectivity of NBs, and the results verified that the NBs were capable of targeting VX2 tumor. Confocal laser scanning microscopy examination showed that the NBs can traverse the VX2 tumor capillaries and target to the hepatocellular carcinoma tumor cells. All these results suggested that the newly prepared NBs have a potential application in molecular imaging and tumor-targeting therapy.

Effects of Microbubble Size on Ultrasound-Mediated Gene Transfection in Auditory Cells

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Ai-Ho Liao

2014-01-01

Full Text Available Gene therapy for sensorineural hearing loss has recently been used to insert genes encoding functional proteins to preserve, protect, or even regenerate hair cells in the inner ear. Our previous study demonstrated a microbubble- (MB-facilitated ultrasound (US technique for delivering therapeutic medication to the inner ear. The present study investigated whether MB-US techniques help to enhance the efficiency of gene transfection by means of cationic liposomes on HEI-OC1 auditory cells and whether MBs of different sizes affect such efficiency. Our results demonstrated that the size of MBs was proportional to the concentration of albumin or dextrose. At a constant US power density, using 0.66, 1.32, and 2.83 μm albumin-shelled MBs increased the transfection rate as compared to the control by 30.6%, 54.1%, and 84.7%, respectively; likewise, using 1.39, 2.12, and 3.47 μm albumin-dextrose-shelled MBs increased the transfection rates by 15.9%, 34.3%, and 82.7%, respectively. The results indicate that MB-US is an effective technique to facilitate gene transfer on auditory cells in vitro. Such size-dependent MB oscillation behavior in the presence of US plays a role in enhancing gene transfer, and by manipulating the concentration of albumin or dextrose, MBs of different sizes can be produced.

The role of contrast-enhanced ultrasound in risk assessment of carotid atheroma

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Silviu Stanciu

2016-07-01

Full Text Available Background and objective: Contrast-enhanced ultrasound, used to assess atherosclerotic carotid plaques, improves visualization of vessel wall irregularities and depicts intraplaque neovascularization. This article illustrates the use of contrast-enhanced ultrasound in the risk assessment of carotid atherosclerotic lesions, especially in challenging plaques evaluation. Materials and methods: For 23 patients with difficult duplex ultrasound examination due to carotid tortuosity or calcifications we assessed plaque morphology (contour, echogenicity and stenosis degree using contrast substance (Sonovue, Braco with dedicated vascular low mechanical index CPC software. Conclusion: Contrast-enhanced ultrasound is a new, noninvasive, and safe procedure for imaging carotid atherosclerotic lesions. It is a valuable tool for evaluating the vulnerable plaque at risk for rupture and for the diagnostic of the development and severity of systemic atherosclerotic disease

Molecular Ultrasound Imaging of Early Vascular Response in Prostate Tumors Irradiated with Carbon Ions

Directory of Open Access Journals (Sweden)

Moritz Palmowski

2009-09-01

Full Text Available Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1 and of αvβ3-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of αvβ3-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of αvβ3-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and αvβ3-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.

Transit of micro-bubbles through the pulmonary circulation of Thoroughbred horses during exercise.

Science.gov (United States)

La Gerche, A; Daffy, J R; Mooney, D J; Forbes, G; Davie, A J

2013-10-01

It has been observed that microbubbles may pass through the pulmonary circulation of dogs and humans during exercise. In humans, this phenomenon has been associated with lower pulmonary artery pressures, enhanced right ventricular function and greater exercise capacity. In the exercising Thoroughbred horse, extraordinarily high cardiac outputs exert significant pulmonary vascular stresses. The aim of this study was to determine, using contrast echocardiography, whether Thoroughbred horses performing strenuous exercise developed pulmonary transit of agitated contrast microbubbles (PTAC). At rest, agitated contrast was observed in the right ventricle, but not in the left ventricle. However, post-exercise microbubbles were observed in the left ventricle, confirming the occurrence of PTAC with exercise but not at rest. Further investigation is warranted to investigate whether this phenomenon may be associated with superior physiology and performance measures as has been implicated in other species. Copyright © 2013 Elsevier Ltd. All rights reserved.

Ultrasound-mediated drug delivery by gas bubbles generated from a chemical reaction.

Science.gov (United States)

Lee, Sungmun; Al-Kaabi, Leena; Mawart, Aurélie; Khandoker, Ahsan; Alsafar, Habiba; Jelinek, Herbert F; Khalaf, Kinda; Park, Ji-Ho; Kim, Yeu-Chun

2018-02-01

Highly echogenic and ultrasound-responsive microbubbles such as nitrogen and perfluorocarbons have been exploited as ultrasound-mediated drug carriers. Here, we propose an innovative method for drug delivery using microbubbles generated from a chemical reaction. In a novel drug delivery system, luminol encapsulated in folate-conjugated bovine serum albumin nanoparticles (Fol-BSAN) can generate nitrogen gas (N 2 ) by chemical reaction when it reacts with hydrogen peroxide (H 2 O 2 ), one of reactive oxygen species (ROS). ROS plays an important role in the initiation and progression of cancer and elevated ROS have been observed in cancer cells both in vitro and in vivo. High-intensity focussed ultrasound (HIFU) is used to burst the N 2 microbubbles, causing site-specific delivery of anticancer drugs such as methotrexate. In this research, the drug delivery system was optimised by using water-soluble luminol and Mobil Composition of Matter-41 (MCM-41), a mesoporous material, so that the delivery system was sensitive to micromolar concentrations of H 2 O 2 . HIFU increased the drug release from Fol-BSAN by 52.9 ± 2.9% in 10 minutes. The cytotoxicity of methotrexate was enhanced when methotrexate is delivered to MDA-MB-231, a metastatic human breast cancer cell line, using Fol-BSAN with HIFU. We anticipate numerous applications of chemically generated microbubbles for ultrasound-mediated drug delivery.

A novel microbubble construct for intracardiac or intravascular MR manometry: a theoretical study

International Nuclear Information System (INIS)

Dharmakumar, Rohan; Plewes, Donald B; Wright, Graham A

2005-01-01

It has been demonstrated that gas-filled microbubble contrast agents, based on their volume changes, can serve as pressure probes in an MR field. It was recently reported that such an MR-based pressure measurement with microbubbles at 1.5 T must make use of microbubbles that have a volumetric magnetic susceptibility difference with the blood of at least 34 ppm in SI units. In this work, we show through analytical approximations and numerical simulations that such a microbubble formulation can be achieved by coating typical lipid-shelled microbubbles with particles of high dipole moment. Through finite-element simulations we demonstrate that the effective volumetric magnetic susceptibility of a coated microbubble is dependent on the radius, the shell volume fraction and the magnetic susceptibility of the particulates on the shell. Our calculations suggest that a suitable microbubble formulation which will be MR-sensitive to small pressure changes at 1.5 T must be 2-3 μm in radius and be uniformly coated with single-domain magnetic nanoparticles, such as magnetite, at shell volume fractions below 5%

Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma.

Directory of Open Access Journals (Sweden)

James K Tsuruta

Full Text Available Secreted frizzled related protein 2 (SFRP2 is a tumor endothelial marker expressed in angiosarcoma. Previously, we showed ultrasound molecular imaging with SFRP2-targeted contrast increased average video pixel intensity (VI of angiosarcoma vessels by 2.2 ± 0.6 VI versus streptavidin contrast. We hypothesized that redesigning our contrast agents would increase imaging performance. Improved molecular imaging reagents were created by combining NeutrAvidin™-functionalized microbubbles with biotinylated SFRP2 or IgY control antibodies. When angiosarcoma tumors in nude mice reached 8 mm, time-intensity, antibody loading, and microbubble dose experiments optimized molecular imaging. 10 minutes after injection, the control-subtracted time-intensity curve (TIC for SFRP2-targeted contrast reached a maximum, after subtracting the contribution of free-flowing contrast. SFRP2 antibody-targeted VI was greater when contrast was formulated with 10-fold molar excess of maleimide-activated NeutrAvidin™ versus 3-fold (4.5 ± 0.18 vs. 0.32 ± 0.15, VI ± SEM, 5 x 106 dose, p < 0.001. Tumor vasculature returned greater average video pixel intensity using 5 x 107 versus 5 x 106 microbubbles (21.2 ± 2.5 vs. 4.5 ± 0.18, p = 0.0011. Specificity for tumor vasculature was confirmed by low VI for SFRP2-targeted, and control contrast in peri-tumoral vasculature (3.2 ± 0.52 vs. 1.6 ± 0.71, p = 0.92. After optimization, average video pixel intensity of tumor vasculature was 14.2 ± 3.0 VI units higher with SFRP2-targeted contrast versus IgY-targeted control (22.1 ± 2.5 vs. 7.9 ± 1.6, p < 0.001. After log decompression, 14.2 ΔVI was equal to ~70% higher signal, in arbitray acoustic units (AU, for SFRP2 versus IgY. This provided ~18- fold higher acoustic signal enhancement than provided previously by 2.2 ΔVI. Basing our targeted contrast on NeutrAvidin™-functionalized microbubbles, using IgY antibodies for our control contrast, and optimizing our imaging protocol

Estimation of Tumor Angiogenesis With Contrast Enhanced Subharmonic Ultrasound Imaging

National Research Council Canada - National Science Library

Forsberg, Flemming

2005-01-01

...) and receiving at the subharmonic (f0). Hence, the current project proposes to increase the ability of breast ultrasound to differentiate between benign and malignant lesions by combining injection of an ultrasound contrast agent with SHI...

Toward in vivo detection of hydrogen peroxide with ultrasound molecular imaging

Science.gov (United States)

Olson, Emilia S.; Orozco, Jahir; Wu, Zhe; Malone, Christopher D.; Yi, Boemha; Gao, Wei; Eghtedari, Mohammad; Wang, Joseph; Mattrey, Robert F.

2013-01-01

We present a new class of ultrasound molecular imaging agents that extend upon the design of micromotors that are designed to move through fluids by catalyzing hydrogen peroxide (H2O2) and propelling forward by escaping oxygen microbubbles. Micromotor converters require 62 mm of H2O2 to move – 1000-fold higher than is expected in vivo. Here, we aim to prove that ultrasound can detect the expelled microbubbles, to determine the minimum H2O2 concentration needed for microbubble detection, explore alternate designs to detect the H2O2 produced by activated neutrophils and perform preliminary in vivo testing. Oxygen microbubbles were detected by ultrasound at 2.5 mm H2O2. Best results were achieved with a 400–500 nm spherical design with alternating surface coatings of catalase and PSS over a silica core. The lowest detection limit of 10–100 µm was achieved when assays were done in plasma. Using this design, we detected the H2O2 produced by freshly isolated PMA-activated neutrophils allowing their distinction from naïve neutrophils. Finally, we were also able to show that direct injection of these nanospheres into an abscess in vivo enhanced ultrasound signal only when they contained catalase, and only when injected into an abscess, likely because of the elevated levels of H2O2 produced by inflammatory mediators. PMID:23958028

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

Science.gov (United States)

Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

2013-07-10

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Noninvasive Ambient Pressure Estimation using Ultrasound Contrast Agents -- Invoking Subharmonics for Cardiac and Hepatic Applications

Science.gov (United States)

Dave, Jaydev K.

Ultrasound contrast agents (UCAs) are encapsulated microbubbles that provide a source for acoustic impedance mismatch with the blood, due to difference in compressibility between the gas contained within these microbubbles and the blood. When insonified by an ultrasound beam, these UCAs act as nonlinear scatterers and enhance the echoes of the incident pulse, resulting in scattering of the incident ultrasound beam and emission of fundamental (f0), subharmonic (f0/2), harmonic (n*f0; n ∈ N) and ultraharmonic (((2n-1)/2)*f0; n ∈ N & n > 1) components in the echo response. A promising approach to monitor in vivo pressures revolves around the fact that the ultrasound transmit and receive parameters can be selected to induce an ambient pressure amplitude dependent subharmonic signal. This subharmonic signal may be used to estimate ambient pressure amplitude; such technique of estimating ambient pressure amplitude is referred to as subharmonic aided pressure estimation or SHAPE. This project develops and evaluates the feasibility of SHAPE to noninvasively monitor cardiac and hepatic pressures (using commercially available ultrasound scanners and UCAs) because invasive catheter based pressure measurements are used currently for these applications. Invasive catheter based pressure measurements pose risk of introducing infection while the catheter is guided towards the region of interest in the body through a percutaneous incision, pose risk of death due to structural or mechanical failure of the catheter (which has also triggered product recalls by the USA Food and Drug Administration) and may potentially modulate the pressures that are being measured. Also, catheterization procedures require fluoroscopic guidance to advance the catheter to the site of pressure measurements and such catheterization procedures are not performed in all clinical centers. Thus, a noninvasive technique to obtain ambient pressure values without the catheterization process is clinically

Real-time 3-dimensional contrast-enhanced ultrasound in detecting hemorrhage of blunt renal trauma.

Science.gov (United States)

Xu, Rui-Xue; Li, Ye-Kuo; Li, Ting; Wang, Sha-Sha; Yuan, Gui-Zhong; Zhou, Qun-Fang; Zheng, Hai-Rong; Yan, Fei

2013-10-01

The objective of this study is to evaluate the diagnostic value of real-time 3-dimensional contrast-enhanced ultrasound in the hemorrhage of blunt renal trauma. Eighteen healthy New Zealand white rabbits were randomly divided into 3 groups. Blunt renal trauma was performed on each group by using minitype striker. Ultrasonography, color Doppler flow imaging, and contrast-enhanced 2-dimensional and real-time 3-dimensional ultrasound were applied before and after the strike. The time to shock and blood pressure were subjected to statistical analysis. Then, a comparative study of ultrasound and pathology was carried out. All the struck kidneys were traumatic. In the ultrasonography, free fluid was found under the renal capsule. In the color Doppler flow imaging, active hemorrhage was not identified. In 2-dimensional contrast-enhanced ultrasound, active hemorrhage of the damaged kidney was characterized. Real-time 3-dimensional contrast-enhanced ultrasound showed a real-time and stereoscopic ongoing bleeding of the injured kidney. The wider the hemorrhage area in 4-dimensional contrast-enhanced ultrasound was, the faster the blood pressure decreased. Real-time 3-dimensional contrast-enhanced ultrasound is a promising noninvasive tool for stereoscopically and vividly detecting ongoing hemorrhage of blunt renal trauma in real time. © 2013.

Simulation of microbubble response to ambient pressure changes

DEFF Research Database (Denmark)

Andersen, Klaus Scheldrup; Jensen, Jørgen Arendt

2008-01-01

The theory on microbubbles clearly indicates a relation between the ambient pressure and the acoustic behavior of the bubble. The purpose of this study was to optimize the sensitivity of ambient pressure measurements, using the subharmonic component, through microbubble response simulations....... The behaviour of two different contrast agents was investigated as a function of driving pulse and ambient overpressure, pov. Simulations of Levovist using a rectangular driving pulse show an almost linear reduction in the subharmonic component as pov is increased. For a 20 cycles driving pulse, a reduction...... is not completely linear as a function of the ambient pressure....

Pretest Score for Predicting Microbubble Contrast Agent Use in Stress Echocardiography: A Method to Increase Efficiency in the Echo Laboratory

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Mathieu Bernier

2009-01-01

contrast. Logistic regression models were used to evaluate the association between individual characteristics and contrast use. An 11-point score was derived from the significant characteristics. Results. Variables associated with microbubble use were age, sex, smoking, presence of multiple risk factors, bodymass index (BMI, referral for dobutamine stress echocardiography, history of coronary artery disease, and abnormal baseline electrocardiogram. All variables except BMI were given a score of 1 if present and 0 if absent; BMI was given a score of 0 to 4 according to its value. An increased score was directly proportional to increased likelihood of contrast use. The score cutoff value to optimize sensitivity and specificity was 5. Conclusions. A pretest score can be computed from information available before imaging. It may facilitate contrast agent use through early identification of patients who are likely to benefit from improved endocardial border definition.

Three-Dimensional Phenomena in Microbubble Acoustic Streaming

Science.gov (United States)

Marin, Alvaro; Rossi, Massimiliano; Rallabandi, Bhargav; Wang, Cheng; Hilgenfeldt, Sascha; Kähler, Christian J.

2015-04-01

Ultrasound-driven oscillating microbubbles are used as active actuators in microfluidic devices to perform manifold tasks such as mixing, sorting, and manipulation of microparticles. A common configuration consists of side bubbles created by trapping air pockets in blind channels perpendicular to the main channel direction. This configuration consists of acoustically excited bubbles with a semicylindrical shape that generate significant streaming flow. Because of the geometry of the channels, such flows are generally considered as quasi-two-dimensional. Similar assumptions are often made in many other microfluidic systems based on flat microchannels. However, in this Letter we show that microparticle trajectories actually present a much richer behavior, with particularly strong out-of-plane dynamics in regions close to the microbubble interface. Using astigmatism particle-tracking velocimetry, we reveal that the apparent planar streamlines are actually projections of a stream surface with a pseudotoroidal shape. We, therefore, show that acoustic streaming cannot generally be assumed as a two-dimensional phenomenon in confined systems. The results have crucial consequences for most of the applications involving acoustic streaming such as particle trapping, sorting, and mixing.

The diagnostic value of small bowel wall vascularity after sulfur hexafluoride-filled microbubble injection in patients with Crohn's disease. Correlation with the therapeutic effectiveness of specific anti-inflammatory treatment

International Nuclear Information System (INIS)

Quaia, Emilio; Migaleddu, Vincenzo; Baratella, Elisa; Pizzolato, Riccardo; Rossi, Alexia; Grotto, Maurizio; Cova, Maria Assunta

2009-01-01

Purpose: To assess the value of small bowel wall vascularity after microbubble contrast agent injection in evaluating the therapeutic effectiveness of specific anti-inflammatory treatment in patients with Crohn's disease. Materials and methods: Fifteen patients (7 male and 8 female; mean age ± SD, 40 years ± 6) with a biopsy-proven diagnosis of Crohn's disease - Crohn's disease activity index (CDAI) > 150 (n = 12 patients) or 5 mm) were included. In each patient the terminal loop was scanned by contrast-enhanced ultrasound (CEUS) after sulfur hexafluoride-filled microbubble injection before and after 6-month anti-inflammatory treatment. The vascularity of the terminal loop was quantified in gray-scale levels (0-255) by a manually drawn ROI encompassing the thickened bowel wall and it was correlated with CDAI. Result: Before the beginning of the specific treatment all patients revealed diffuse transparietal contrast enhancement after microbubble injection, except for 3 patients who revealed contrast enhancement limited to the submucosa. In 13 patients the slope of the first ascending tract and the area under the enhancement curve were significantly lower after anti-inflammatory treatment (P < 0.05; Wilcoxon test) with a significant correlation with the CDAI score (ρ = 0.85, P < 0.05). In 2 patients no significant vascularity changes were found even though a mild reduction of CDAI score was identified (from 200 to 150 gray-scale levels). Conclusion: CEUS is a useful method to assess the therapeutic effectiveness of specific medical anti-inflammatory treatment in patients with Crohn's disease.

Advanced detection strategies for ultrasound contrast agents

NARCIS (Netherlands)

J.M.G. Borsboom (Jerome)

2005-01-01

markdownabstract__Abstract__ Ultrasound contrast agent was discovered serendipitously by Gramiak and Shah in I968 when they injected indocyanine green dye into the heart and observed increased echogenicity of the blood containing the dye. Small cavitation bubbles that were formed upon

Protozoa manipulation by ultrasound

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Yancy Milena Porras Rodríguez

2004-01-01

Full Text Available Microorganism manipulation, considered as controlled motion and positioning, is one of the most important activities in microbiology and medicine. To achieve this goal there are some techniques such as those which and optical forces, among others. These techniques are usually sophisticated, and some of them can induce irreversible alterations on the microorganisms which prevents their use in another tests. Thus, there is justified the study of technological alternatives to manipulate microorganisms in an easy and cost-effective way. This work shows the interaction between protozoa and air microbubbles when they are under the influence of an ultrasonic field of 5.8 mW. At the microbubbles resonant frequencies, microorganisms were attracted toward the bubbles' frontier remaining there while the ultrasonic field was applied. Once the ultrasound disappears, protozoa recover their freedom of movement. The observed effects could be used as the actuation principle of devices capable to trap, hold and release microorganisms of high mobility without any apparent damage. Microbubbles are generated by electrolysis which take place on the surface of an electrode array, while the ultrasound is originated by means of a piezoelectric transducer. As microorganisms there were employed those present in stagnated water, and were observed through an stereomicroscope. Key words: manipulator; protozoa; ultrasonic; transducer; piezoelectric.

Effect of acoustic parameters on the cavitation behavior of SonoVue microbubbles induced by pulsed ultrasound.

Science.gov (United States)

Lin, Yutong; Lin, Lizhou; Cheng, Mouwen; Jin, Lifang; Du, Lianfang; Han, Tao; Xu, Lin; Yu, Alfred C H; Qin, Peng

2017-03-01

SonoVue microbubbles could serve as artificial nuclei for ultrasound-triggered stable and inertial cavitation, resulting in beneficial biological effects for future therapeutic applications. To optimize and control the use of the cavitation of SonoVue bubbles in therapy while ensuring safety, it is important to comprehensively understand the relationship between the acoustic parameters and the cavitation behavior of the SonoVue bubbles. An agarose-gel tissue phantom was fabricated to hold the SonoVue bubble suspension. 1-MHz transmitting transducer calibrated by a hydrophone was used to trigger the cavitation of SonoVue bubbles under different ultrasonic parameters (i.e., peak rarefactional pressure (PRP), pulse repetition frequency (PRF), and pulse duration (PD)). Another 7.5-MHz focused transducer was employed to passively receive acoustic signals from the exposed bubbles. The ultraharmonics and broadband intensities in the acoustic emission spectra were measured to quantify the extent of stable and inertial cavitation of SonoVue bubbles, respectively. We found that the onset of both stable and inertial cavitation exhibited a strong dependence on the PRP and PD and a relatively weak dependence on the PRF. Approximate 0.25MPa PRP with more than 20μs PD was considered to be necessary for ultraharmonics emission of SonoVue bubbles, and obvious broadband signals started to appear when the PRP exceeded 0.40MPa. Moreover, the doses of stable and inertial cavitation varied with the PRP. The stable cavitation dose initially increased with increasing PRP, and then decreased rapidly after 0.5MPa. By contrast, the inertial cavitation dose continuously increased with increasing PRP. Finally, the doses of both stable and inertial cavitation were positively correlated with PRF and PD. These results could provide instructive information for optimizing future therapeutic applications of SonoVue bubbles. Copyright © 2016 Elsevier B.V. All rights reserved.

Reproducibility of contrast-enhanced transrectal ultrasound of the prostate

NARCIS (Netherlands)

Sedelaar, J. P.; Goossen, T. E.; Wijkstra, H.; de la Rosette, J. J.

2001-01-01

Transrectal three-dimensional (3-D) contrast-enhanced power Doppler ultrasound (US) is a novel technique for studying possible prostate malignancy. Before studies can be performed to investigate the clinical validity of the technique, reproducibility of the contrast US studies must be proven.

Cumulative phase delay imaging for contrast-enhanced ultrasound tomography

International Nuclear Information System (INIS)

Demi, Libertario; Van Sloun, Ruud J G; Wijkstra, Hessel; Mischi, Massimo

2015-01-01

Standard dynamic-contrast enhanced ultrasound (DCE-US) imaging detects and estimates ultrasound-contrast-agent (UCA) concentration based on the amplitude of the nonlinear (harmonic) components generated during ultrasound (US) propagation through UCAs. However, harmonic components generation is not specific to UCAs, as it also occurs for US propagating through tissue. Moreover, nonlinear artifacts affect standard DCE-US imaging, causing contrast to tissue ratio reduction, and resulting in possible misclassification of tissue and misinterpretation of UCA concentration. Furthermore, no contrast-specific modality exists for DCE-US tomography; in particular speed-of-sound changes due to UCAs are well within those caused by different tissue types. Recently, a new marker for UCAs has been introduced. A cumulative phase delay (CPD) between the second harmonic and fundamental component is in fact observable for US propagating through UCAs, and is absent in tissue. In this paper, tomographic US images based on CPD are for the first time presented and compared to speed-of-sound US tomography. Results show the applicability of this marker for contrast specific US imaging, with cumulative phase delay imaging (CPDI) showing superior capabilities in detecting and localizing UCA, as compared to speed-of-sound US tomography. Cavities (filled with UCA) which were down to 1 mm in diameter were clearly detectable. Moreover, CPDI is free of the above mentioned nonlinear artifacts. These results open important possibilities to DCE-US tomography, with potential applications to breast imaging for cancer localization. (fast track communication)

PLGA Nanoparticles for Ultrasound-Mediated Gene Delivery to Solid Tumors

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Marxa Figueiredo

2012-01-01

Full Text Available This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to spatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid (PLGA or other polymers. We specifically discuss the potential for gene delivery by particles that are echogenic (amenable to destruction by ultrasound composed either of polymers (PLGA, polystyrene or other contrast agent materials (Optison, SonoVue microbubbles. The use of ultrasound is an efficient tool to further enhance gene delivery by PLGA or other echogenic particles in vivo. Echogenic PLGA nanoparticles are an attractive strategy for ultrasound-mediated gene delivery since this polymer is currently approved by the US Food and Drug Administration for drug delivery and diagnostics in cancer, cardiovascular disease, and also other applications such as vaccines and tissue engineering. This paper will review recent successes and the potential of applying PLGA nanoparticles for gene delivery, which include (a echogenic PLGA used with ultrasound to enhance local gene delivery in tumors or muscle and (b PLGA nanoparticles currently under development, which could benefit in the future from ultrasound-enhanced tumor targeted gene delivery.

An experimental system for the study of ultrasound exposure of isolated blood vessels

International Nuclear Information System (INIS)

Tokarczyk, Anna; Rivens, Ian; Symonds-Tayler, Richard; Ter Haar, Gail; Van Bavel, E

2013-01-01

An experimental system designed for the study of the effects of diagnostic or therapeutic ultrasound exposure on isolated blood vessels in the presence or absence of intraluminal contrast agent is described. The system comprised several components. A microscope was used to monitor vessel size (and thus vessel functionality), and potential leakage of intraluminal 70 kDa FITC-dextran fluorescence marker. A vessel chamber allowed the mounting of an isolated vessel whilst maintaining its viability, with pressure regulation for the control of intraluminal pressure and induction of flow for the infusion of contrast microbubbles. A fibre-optic hydrophone sensor mounted on the vessel chamber using a micromanipulator allowed pre-exposure targeting of the vessel to within 150 µm, and monitoring of acoustic cavitation emissions during exposures. Acoustic cavitation was also detected using changes in the ultrasound drive voltage and by detection of audible emissions using a submerged microphone. The suitability of this system for studying effects in the isolated vessel model has been demonstrated using a pilot study of 6 sham exposed and 18 high intensity focused ultrasound exposed vessels, with or without intraluminal contrast agent (SonoVue) within the vessels. (paper)

Contrast Materials

Science.gov (United States)

... is mixed with water before administration liquid paste tablet When iodine-based and barium-sulfate contrast materials ... for patients with kidney failure or allergies to MRI and/or computed tomography (CT) contrast material. Microbubble ...

Vascular Structure Identification in Intraoperative 3D Contrast-Enhanced Ultrasound Data

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Elisee Ilunga-Mbuyamba

2016-04-01

Full Text Available In this paper, a method of vascular structure identification in intraoperative 3D Contrast-Enhanced Ultrasound (CEUS data is presented. Ultrasound imaging is commonly used in brain tumor surgery to investigate in real time the current status of cerebral structures. The use of an ultrasound contrast agent enables to highlight tumor tissue, but also surrounding blood vessels. However, these structures can be used as landmarks to estimate and correct the brain shift. This work proposes an alternative method for extracting small vascular segments close to the tumor as landmark. The patient image dataset involved in brain tumor operations includes preoperative contrast T1MR (cT1MR data and 3D intraoperative contrast enhanced ultrasound data acquired before (3D-iCEUS s t a r t and after (3D-iCEUS e n d tumor resection. Based on rigid registration techniques, a preselected vascular segment in cT1MR is searched in 3D-iCEUS s t a r t and 3D-iCEUS e n d data. The method was validated by using three similarity measures (Normalized Gradient Field, Normalized Mutual Information and Normalized Cross Correlation. Tests were performed on data obtained from ten patients overcoming a brain tumor operation and it succeeded in nine cases. Despite the small size of the vascular structures, the artifacts in the ultrasound images and the brain tissue deformations, blood vessels were successfully identified.

The forgotten organ: Contrast enhanced sonography of the spleen

International Nuclear Information System (INIS)

Goerg, Christian

2007-01-01

Objective: Ultrasound contrast agents in conjunction with contrast specific imaging techniques, are increasingly accepted in clinical use for diagnostic imaging in several organs. Contrast enhanced sonography (CES) of second-generation contrast media have shown a spleen-specific uptake of the microbubble contrast agent. The aim of this review is to illustrate indications for the use of CES in patients with suspected (peri-)splenic pathology. Methods: This review based on the experience of transcutaneous CES in 200 patients with (peri-)splenic pathology diagnosed by B-mode sonography at an internal medicine center. CES studies were performed with a contrast-devoted unit (Acuson, Sequoia, Siemens medical solution) that had contrast-specific, continuous-mode software. A low mechanical index was used. A sulfur hexafluoride-based microbubble contrast medium (Sonovue, Bracco SpA, Milan, Italy) was injected. Results: On our experience, there are several clinical conditions which may show an diagnostic advantage of CES in comparison to B-mode US. CES should be performed to investigate: (1) the perisplenic tumor to diagnose or exclude accessory spleen, (2) the small-sized spleen to diagnose functional asplenia/hyposplenia, (3) the inhomogenous spleen of unknown cause to diagnose focal lesions within the spleen, (4) the incidentally found hypoechoic splenic tumor to diagnose high vascular splenic hemangioma, (5) focal lesions suspect for splenic abscess, hematoma, infarction to confirme diagnosis, and (6) patients with abdominal trauma to diagnose or exclude splenic injuriy. Conclusion: CES is of diagnostic value in several clinical circumstances to diagnose accessory spleen, functional asplenia, small-sized splenic involvement, high vascular splenic hemangioma, and vascular splenic pathology like splenic infarction, splenic abscess, and splenic laceration

The forgotten organ: Contrast enhanced sonography of the spleen

Energy Technology Data Exchange (ETDEWEB)

Goerg, Christian [Medizinische Universitaetsklinik, Baldingerstrasse, 35043 Marburg/Lahn (Germany)], E-mail: goergc@med.uni-marburg.de

2007-11-15

Objective: Ultrasound contrast agents in conjunction with contrast specific imaging techniques, are increasingly accepted in clinical use for diagnostic imaging in several organs. Contrast enhanced sonography (CES) of second-generation contrast media have shown a spleen-specific uptake of the microbubble contrast agent. The aim of this review is to illustrate indications for the use of CES in patients with suspected (peri-)splenic pathology. Methods: This review based on the experience of transcutaneous CES in 200 patients with (peri-)splenic pathology diagnosed by B-mode sonography at an internal medicine center. CES studies were performed with a contrast-devoted unit (Acuson, Sequoia, Siemens medical solution) that had contrast-specific, continuous-mode software. A low mechanical index was used. A sulfur hexafluoride-based microbubble contrast medium (Sonovue, Bracco SpA, Milan, Italy) was injected. Results: On our experience, there are several clinical conditions which may show an diagnostic advantage of CES in comparison to B-mode US. CES should be performed to investigate: (1) the perisplenic tumor to diagnose or exclude accessory spleen, (2) the small-sized spleen to diagnose functional asplenia/hyposplenia, (3) the inhomogenous spleen of unknown cause to diagnose focal lesions within the spleen, (4) the incidentally found hypoechoic splenic tumor to diagnose high vascular splenic hemangioma, (5) focal lesions suspect for splenic abscess, hematoma, infarction to confirme diagnosis, and (6) patients with abdominal trauma to diagnose or exclude splenic injuriy. Conclusion: CES is of diagnostic value in several clinical circumstances to diagnose accessory spleen, functional asplenia, small-sized splenic involvement, high vascular splenic hemangioma, and vascular splenic pathology like splenic infarction, splenic abscess, and splenic laceration.

Fluorescence monitoring of ultrasound degradation processes

International Nuclear Information System (INIS)

Hassoon, Salah; Bulatov, Valery; Yasman, Yakov; Schechter, Israel

2004-01-01

Ultrasound-based water treatment is often applied for degradation of stable organic pollutants, such as polycyclic aromatic hydrocarbons and halogenated compounds. Monitoring the degradation process, during the application of ultrasound radiation, is of considerable economical interest. In this work, the possibility of performing on-line spectral analysis during sonication was examined and it was found that direct absorption or fluorescence readings are misleading. Optical monitoring is strongly affected by the absorption and scattering of light by cavitation micro-bubbles and ultrasound induced particulates. A model was developed to account for these effects and to allow for on-line fluorescence analysis. The model takes into account the absorption and scattering coefficients of the micro-bubbles and particulates, as well as their time dependent concentration. The model parameters are found from independent measurements where the pollutants are added to already sonicated pure water. Then, the model is tested for predicting the actual fluorescence behavior during the sonication process. It has been shown that the model allows for recovery of the true degradation data, as obtained by off-line HPLC measurements

Clinical utility of a microbubble-enhancing contrast (“SonoVue”) in treatment of uterine fibroids with high intensity focused ultrasound: A retrospective study

International Nuclear Information System (INIS)

Peng, Song; Xiong, Yu; Li, Kequan; He, Min; Deng, Yongbin; Chen, Li; Zou, Min; Chen, Wenzhi; Wang, Zhibiao; He, Jia

2012-01-01

Purpose: To evaluate the clinical value of the contrast agent SonoVue in the treatment of uterine fibroids with ultrasound-guided high intensity focused ultrasound (HIFU) therapeutic ablation. Materials and Methods: A total of 291 patients with solitary uterine fibroid from three centers were treated with ultrasound-guided HIFU. Among them, 129 patients from Suining Central Hospital of Sichuan were treated without using SonoVue. 162 patients from the First Hospital of Chongqing Medical University and Chongqing Haifu Hospital were treated with using SonoVue before, during and after HIFU procedure to assess the extent of HIFU. Results: The non-perfused volume (indicative of successful ablation) was observed in all treated uterine fibroids immediately after HIFU ablation; median fractional ablation, defined as non-perfused volume divided by the fibroid volume immediately after HIFU treatment, was 86.0% (range, 28.8–100.0%) in the group with using SonoVue, and 83.0% (8.7–100.0%) without SonoVue. The rate of massive gray scale changes was higher with SonoVue than without the agent. The sonication time to achieve massive gray scale changes was shorter with SonoVue than without. The sonication time for ablating 1 cm 3 of fibroid volume was significantly shorter with using SonoVue than without. No major complications were observed in any patients. Conclusions: Based on our results, SonoVue may enhance the outcome of HIFU ablation and can be used to assess the extent of treatment.

Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent.

Science.gov (United States)

Unger, E C; McCreery, T P; Sweitzer, R H; Caldwell, V E; Wu, Y

1998-12-01

Paclitaxel-carrying lipospheres (MRX-552) were developed and evaluated as a new ultrasound contrast agent for chemotherapeutic drug delivery. Paclitaxel was suspended in soybean oil and added to an aqueous suspension of phospholipids in vials. The headspace of the vials was replaced with perfluorobutane gas; the vials were sealed, and they were agitated at 4200 rpm on a shaking device. The resulting lipospheres containing paclitaxel were studied for concentration, size, acute toxicity in mice, and acoustic activity and drug release with ultrasound. Lipospheres containing sudan black dye were produced to demonstrate the acoustically active liposphere (AAL)-ultrasound release concept. Acoustically active lipospheres containing paclitaxel had a mean particle count of approximately 1 x 10(9) particles per mL and a mean size of 2.9 microns. Acute toxicity studies in mice showed a 10-fold reduction in toxicity for paclitaxel in AALs compared with free paclitaxel. The AALs reflected ultrasound as a contrast agent. Increasing amounts of ultrasound energy selectively ruptured the AALs and released the paclitaxel. Acoustically active lipospheres represent a new class of acoustically active drug delivery vehicles. Future studies will assess efficacy of AALs for ultrasound-mediated drug delivery.

Contrast-enhanced ultrasound for extrahepatic lesions: preliminary experience

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Thorelius, Lars E-mail: lars@thorelius.com

2004-06-01

Ultrasound imaging (US) is a convenient, inexpensive and non-invasive investigation. Its use is limited by low sensitivity in the detection of a number of parenchymal lesions, especially those produced by trauma, such as infarctions. Contrast enhancement with SonoVue{sup [reg]} improves the sensitivity of ultrasound in the detection and characterization of focal liver lesions to such an extent, that it may replace computed tomography (CT) and magnetic resonance imaging (MRI). Preliminary experience suggests that SonoVue-enhanced sonography may be useful in the detection of lesions in which blood flow is severely reduced as compared to surrounding parenchyma, such as infarctions, lacerations, hematomas, necrotic tissue and non-vascular cysts, especially in the spleen, kidney and pancreas. This technique can also rule out occlusion of the superior mesenteric, splenic and portal veins, and dilation of the biliary tree. Clinical trials comparing contrast-enhanced sonography with contrast-enhanced computed tomography are warranted to establish the role of this inexpensive and non-invasive technique in the routine work-up of patients with abdominal trauma or presenting with sudden flank pain.

Inertial Cavitation Ultrasound with Microbubbles Improves Reperfusion Efficacy When Combined with Tissue Plasminogen Activator in an In Vitro Model of Microvascular Obstruction.

Science.gov (United States)

Goyal, Akash; Yu, Francois T H; Tenwalde, Mathea G; Chen, Xucai; Althouse, Andrew; Villanueva, Flordeliza S; Pacella, John J

2017-07-01

We have previously reported that long-tone-burst, high-mechanical-index ultrasound (US) and microbubble (MB) therapy can restore perfusion in both in vitro and in vivo models of microvascular obstruction (MVO). Addition of MBs to US has been found to potentiate the efficacy of thrombolytics on large venous thrombi; however, the optimal US parameters for achieving microvascular reperfusion of MVO caused by microthrombi, when combined with tissue plasminogen activator (tPA), are unknown. We sought to elucidate the specific effects of US, with and without tPA, for effective reperfusion of MVO in an in vitro model using both venous and arterial microthrombi. Venous- and arterial-type microthrombi were infused onto a mesh with 40-μm pores to simulate MVO. Pulsed US (1 MHz) was delivered with inertial cavitation (IC) (1.0 MPa, 1000 cycles, 0.33 Hz) and stable cavitation (SC) US (0.23 MPa, 20% duty cycle, 0.33 Hz) regimes while MB suspension (2 × 10 6  MBs/mL) was infused. The efficacy of sonoreperfusion with these parameters was tested with and without tPA. Sonoreperfusion efficacy was significantly greater for IC + tPA compared with tPA alone, IC, SC and SC + tPA, suggesting lytic synergism between tPA and US for both venous- and arterial-type microthrombi. In contrast to our previous in vitro studies using 1.5 MPa at 5000 US cycles without tPA, the IC regime employed herein used 90% less US energy. These findings suggest an IC regime can be used with tPA synergistically to achieve a high degree of fibrinolysis for both thrombus types. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

The role of contrast-enhanced endoscopic ultrasound in pancreatic adenocarcinoma

DEFF Research Database (Denmark)

Saftoiu, Adrian; Vilmann, Peter; Bhutani, Manoop S

2016-01-01

contrast agents for early detection, tridimensional and fusion techniques for enhanced staging and resectability assessment but also novel applications of perfusion imaging for monitoring ablative therapy, improved local detection through EUS-guided sampling of portal vein flow or enhanced drug delivery......Contrast-enhanced endoscopic ultrasound (CE-EUS) allows characterization, differentiation, and staging of focal pancreatic masses. The method has a high sensitivity and specificity for the diagnosis of pancreatic adenocarcinoma which is visualized as hypo-enhanced as compared to the rest...... of the parenchyma while chronic pancreatitis and neuroendocrine tumors are generally either iso-enhanced or hyper-enhanced. The development of contrast-enhanced low mechanical index harmonic imaging techniques used in real time during endoscopic ultrasound (EUS) allowed perfusion imaging and the quantification...

Effect of ultrasound on herpes simplex virus infection in cell culture

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Iwai Soichi

2011-09-01

Full Text Available Abstract Background Ultrasound has been shown to increase the efficiency of gene expression from retroviruses, adenoviruses and adeno-associated viruses. The effect of ultrasound to stimulate cell membrane permeabilization on infection with an oncolytic herpes simplex virus type 1 (HSV-1 was examined. Results Vero monkey kidney cells were infected with HSV-1 and exposed to 1 MHz ultrasound after an adsorption period. The number of plaques was significantly greater than that of the untreated control. A combination of ultrasound and microbubbles further increased the plaque number. Similar results were obtained using a different type of HSV-1 and oral squamous cell carcinoma (SCC cells. The appropriate intensity, duty cycle and time of ultrasound to increase the plaque number were 0.5 W/cm2, 20% duty cycle and 10 sec, respectively. Ultrasound with microbubbles at an intensity of 2.0 W/cm2, at 50% duty cycle, or for 40 sec reduced cell viability. Conclusion These results indicate that ultrasound promotes the entry of oncolytic HSV-1 into cells. It may be useful to enhance the efficiency of HSV-1 infection in oncolytic virotherapy.

Ultrasound-mediated gene delivery of naked plasmid DNA in skeletal muscles: a case for bolus injections.

Science.gov (United States)

Sanches, Pedro Gomes; Mühlmeister, Mareike; Seip, Ralf; Kaijzel, Eric; Löwik, Clemens; Böhmer, Marcel; Tiemann, Klaus; Grüll, Holger

2014-12-10

Localized gene delivery has many potential clinical applications. However, the nucleic acids (e.g. pDNA and siRNA) are incapable of passively crossing the endothelium, cell membranes and other biological barriers which must be crossed to reach their intracellular targets. A possible solution is the use of ultrasound to burst circulating microbubbles inducing transient permeabilization of surrounding tissues which mediates nucleic acid extravasation and cellular uptake. In this study we report on an optimization of the ultrasound gene delivery technique. Naked pDNA (200 μg) encoding luciferase and SonoVue® microbubbles were co-injected intravenously in mice. The hindlimb skeletal muscles were exposed to ultrasound from a non-focused transducer (1 MHz, 1.25 MPa, PRI 30s) and injection protocols and total amounts as well as ultrasound parameters were systemically varied. Gene expression was quantified relative to a control using a bioluminescence camera system at day 7 after sonication. Bioluminescence ratios in sonicated/control muscles of up to 101× were obtained. In conclusion, we were able to specifically deliver genetic material to the selected skeletal muscles and overall, the use of bolus injections and high microbubble numbers resulted in increased gene expression reflected by stronger bioluminescence signals. Based on our data, bolus injections seem to be required in order to achieve transient highly concentrated levels of nucleic acids and microbubbles at the tissue of interest which upon ultrasound exposure should lead to increased levels of gene delivery. Thus, ultrasound mediated gene delivery is a promising technique for the clinical translation of localized drug delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

The feasibility of a targeted ultrasound contrast agent carrying genes and cell-penetrating peptides to hypoxic HUVEC

International Nuclear Information System (INIS)

Tian Ju; Wang Zhigang; Ren Jianli; Zhang Qingfeng; Liu Li

2012-01-01

Objective: To prepare an anti-P-selectin targeted ultrasound contrast agent carrying genes and cell-penetrating peptides (CPP) and to investigate its feasibility of delivery to hypoxic human umbilical vein endothelial cells (HUVEC). Methods: Anti-P-selectin targeted ultrasound contrast agent carrying a green fluorescent protein gene (pEGFP-N1) and CPP was prepared by mechanical vibration and carbodiimide techniques. The appearance, distribution, concentration and diameter of the ultrasound contrast agent were measured. The gene and CPP distribution on the agent was investigated using confocal laser scanning microscopy (CLSM). The efficiency of the ultrasound contrast agent to carry the gene and CPP was investigated by fluorospectrophotometry. HUVEC were cultured in vitro and hypoxic HUVEC were prepared using hydrogen peroxide (H 2 O 2 ). Hypoxic HUVEC were randomly assigned targeted ultrasound contrast agents and non-targeted ultrasound contrast agents for transfection. The transfection effect of green fluorescent protein in the two groups was observed using fluorescence microscopy and flow cytometry. T-test and linear correlation analysis were used for statistical analysis. Results: The average diameter of anti-P-selectin targeted ultrasound contrast agents carrying gene and CPP was (2.15 ±0.36) μm and the concentration was (1.58 ± 0.23) × 10 7 /ml.The results of CLSM showed that gene and CPP were distributed on the shell of the agent. The gene encapsulation efficiency was 28% (y=0.932x-0.09, r=0.993, P<0.05), and the CPP encapsulation efficiency was 25% (y=5.875x-0.81, r=0.987, P<0.05). EGFP expression was observed using fluorescence microscopy in targeted ultrasound contrast agents and non-targeted ultrasound contrast agents. The average transfection efficiencies of targeted ultrasound contrast agents and non-targeted ultrasound contrast agents were (18.74 ± 0.47) % and (15.34 ± 0.22) % after 24 h (t=10.923, P<0.001). Conclusions: The in vitro studies

Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring.

Directory of Open Access Journals (Sweden)

Costas D Arvanitis

Full Text Available The ability of ultrasonically-induced oscillations of circulating microbubbles to permeabilize vascular barriers such as the blood-brain barrier (BBB holds great promise for noninvasive targeted drug delivery. A major issue has been a lack of control over the procedure to ensure both safe and effective treatment. Here, we evaluated the use of passively-recorded acoustic emissions as a means to achieve this control. An acoustic emissions monitoring system was constructed and integrated into a clinical transcranial MRI-guided focused ultrasound system. Recordings were analyzed using a spectroscopic method that isolates the acoustic emissions caused by the microbubbles during sonication. This analysis characterized and quantified harmonic oscillations that occur when the BBB is disrupted, and broadband emissions that occur when tissue damage occurs. After validating the system's performance in pilot studies that explored a wide range of exposure levels, the measurements were used to control the ultrasound exposure level during transcranial sonications at 104 volumes over 22 weekly sessions in four macaques. We found that increasing the exposure level until a large harmonic emissions signal was observed was an effective means to ensure BBB disruption without broadband emissions. We had a success rate of 96% in inducing BBB disruption as measured by in contrast-enhanced MRI, and we detected broadband emissions in less than 0.2% of the applied bursts. The magnitude of the harmonic emissions signals was significantly (P<0.001 larger for sonications where BBB disruption was detected, and it correlated with BBB permeabilization as indicated by the magnitude of the MRI signal enhancement after MRI contrast administration (R(2 = 0.78. Overall, the results indicate that harmonic emissions can be a used to control focused ultrasound-induced BBB disruption. These results are promising for clinical translation of this technology.

THE EXPERIENCE OF USING ULTRASOUND WITH CONTRAST ENHANCEMENT IN THE DIAGNOSIS OF CERVICAL CANCER

Directory of Open Access Journals (Sweden)

M. A. Chekalova

2017-01-01

Full Text Available The purpose of the study was to evaluate the value of contrast-enhanced ultrasound in detecting local spread, regional and distant metastases from cervical cancer. Materials and methods. The findings of contrast-enhanced ultrasound examination of 4 cervical cancer patients (IB1–IVB treated at N.N. Blokhin Russian Cancer Research Center from September to October 2016 were evaluated. The HI VISION Ascendus device was used. Ultrasound patterns in different phases of contrast-enhanced accumulation and excretion were analyzed. Results. Our first experience in using contrast-enhanced ultrasound in the detection of local spread, regional and distant metastases from cervical cancer allowed us to study the structure of the tumor and its spread in greater detail. Conclusion. A small number of observations do not yet allow us to draw serious conclusions about the capabilities of this modern technology. 

Closed-Loop Noninvasive Ultrasound Glucose Sensing and Insulin Delivery

Science.gov (United States)

2007-09-01

mechanism suggests that ultrasound interacts with the structured lipids within the intracellular channels of the stratum corneum to permeabilize the...R. Prausnitz, “Mechanism of intracellular delivery by acoustic cavitation ,” Ultrasound Med. Biol. 32, 915–924 2006. 14E. Maione, K. K. Shung, R. J...result of cavitation (11– 14). Low frequency ultrasound is capable of generating microbubbles in the water and tissue. These bubbles allow water

Feasibility of contrast-enhanced ultrasound-guided biopsy of sentinel lymph nodes in dogs.

Science.gov (United States)

Gelb, Hylton R; Freeman, Lynetta J; Rohleder, Jacob J; Snyder, Paul W

2010-01-01

Our goal was to develop and validate a technique to identify the sentinel lymph nodes of the mammary glands of healthy dogs with contrast-enhanced ultrasound, and evaluate the feasibility of obtaining representative samples of a sentinel lymph node under ultrasound guidance using a new biopsy device. Three healthy intact female adult hounds were anesthetized and each received an injection of octafluoropropane-filled lipid microspheres and a separate subcutaneous injection of methylene blue dye around a mammary gland. Ultrasound was then used to follow the contrast agent through the lymphatic channel to the sentinel lymph node. Lymph node biopsy was performed under ultrasound guidance, followed by an excisional biopsy of the lymph nodes and a regional mastectomy procedure. Excised tissues were submitted for histopathologic examination and evaluated as to whether they were representative of the node. The ultrasound contrast agent was easily visualized with ultrasound leading up to the sentinel lymph nodes. Eight normal lymph nodes (two inguinal, one axillary in two dogs; two inguinal in one dog) were identified and biopsied. Lymphoid tissue was obtained from all biopsy specimens. Samples from four of eight lymph nodes contained both cortical and medullary lymphoid tissue. Contrast-enhanced ultrasound can be successfully used to image and guide minimally invasive biopsy of the normal sentinel lymph nodes draining the mammary glands in healthy dogs. Further work is needed to evaluate whether this technique may be applicable in patients with breast cancer or other conditions warranting evaluation of sentinel lymph nodes in animals.

Usefulness of contrast-enhanced transabdominal ultrasound for tumor classification and tumor staging in the pancreatic head

DEFF Research Database (Denmark)

Grossjohann, Hanne Sønder; Rappeport, Eli David; Jensen, Claus Verner

2010-01-01

To evaluate contrast-enhanced ultrasound (CEUS) and compare it to ultrasound (US) and 64-slice-CT (64-CT) for diagnosing, staging and evaluation of resectability of pancreatic cancer.......To evaluate contrast-enhanced ultrasound (CEUS) and compare it to ultrasound (US) and 64-slice-CT (64-CT) for diagnosing, staging and evaluation of resectability of pancreatic cancer....

Value of contrast-enhanced ultrasound in rheumatoid arthritis

International Nuclear Information System (INIS)

Zordo, Tobias de; Mlekusch, Sabine P.; Feuchtner, Gudrun M.; Mur, Erich; Schirmer, Michael; Klauser, Andrea S.

2007-01-01

The purpose of this review is to describe the spectrum of sonographic findings in rheumatic diseases with respect to the diagnostic potential using US contrast media which prove activity or inactivity in synovial tissue where new treatment regimes target. Synovial activity can be found in non-erosive and erosive forms of primary and secondary osteoarthritis, and in inflammatory forms of joint diseases like rheumatoid arthritis and peripheral manifestations of spondyloarthritis including, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis and enteropathic arthritis. It can also be present in metabolic and endocrine forms of arthritis, in connective tissue arthropathies like systemic lupus erythematosus or scleroderma and in infectious arthritis. Ultrasound should be used as first-line imaging modality in suspected early cases of RA and other forms of arthritis, whereas contrast-enhanced ultrasound (CEUS) can further enable for sensitive assessment of vascularity which correlates with disease activity

Value of contrast-enhanced ultrasound in rheumatoid arthritis

Energy Technology Data Exchange (ETDEWEB)

Zordo, Tobias de; Mlekusch, Sabine P.; Feuchtner, Gudrun M. [Department of Radiology II, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck (Austria); Mur, Erich [Department of Internal Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck (Austria); Schirmer, Michael [Department of Internal Medicine, Hospital of the Elisabethines Klagenfurt, Voelkermarkter Strasse 15-19, 9020 Klagenfurt (Austria); Klauser, Andrea S. [Department of Radiology II, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck (Austria)], E-mail: andrea.klauser@i-med.ac.at

2007-11-15

The purpose of this review is to describe the spectrum of sonographic findings in rheumatic diseases with respect to the diagnostic potential using US contrast media which prove activity or inactivity in synovial tissue where new treatment regimes target. Synovial activity can be found in non-erosive and erosive forms of primary and secondary osteoarthritis, and in inflammatory forms of joint diseases like rheumatoid arthritis and peripheral manifestations of spondyloarthritis including, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis and enteropathic arthritis. It can also be present in metabolic and endocrine forms of arthritis, in connective tissue arthropathies like systemic lupus erythematosus or scleroderma and in infectious arthritis. Ultrasound should be used as first-line imaging modality in suspected early cases of RA and other forms of arthritis, whereas contrast-enhanced ultrasound (CEUS) can further enable for sensitive assessment of vascularity which correlates with disease activity.

EFFECT OF SEDATION ON CONTRAST-ENHANCED ULTRASONOGRAPHY OF THE SPLEEN IN HEALTHY DOGS.

Science.gov (United States)

Rossi, Federica; Fina, Caroline; Stock, Emmelie; Vanderperren, Katrien; Duchateau, Luc; Saunders, Jimmy H

2016-05-01

Contrast-enhanced ultrasound of the spleen enables the dynamic assessment of the perfusion of this organ, however, both subjective and quantitative evaluation can be strongly influenced by sedative agent administration. The purpose of this prospective, experimental study was to test effects of two sedative agents on splenic perfusion during contrast-enhanced ultrasound of the spleen in a sample of healthy dogs. Contrast-enhanced ultrasound of the spleen was repeated in six healthy Beagles following a cross-over study design comparing three protocols: awake, butorphanol 0.2 mg/Kg intramuscular (IM), and dexmedetomidine 500 μg/m(2) IM. After intravenous injection of a phospholipid stabilized sulfur hexafluoride microbubble solution (SonoVue®, Bracco Imaging, Milano, Italy), the enhancement intensity and perfusion pattern of the splenic parenchyma were assessed and perfusion parameters were calculated. Normal spleen was slightly heterogeneous in the early phase, but the parenchyma was homogeneous at a later phase. Sedation with butorphanol did not modify perfusion of the spleen. Dexmedetomidine significantly reduced splenic enhancement, providing diffuse parenchymal hypoechogenicity during the entire examination. Measured parameters were significantly modified, with increased arrival time (AT; (dogs. Short-term and diffuse heterogeneity of the spleen in the early venous phase was determined to be a normal finding. © 2016 American College of Veterinary Radiology.

The contribution of contrast enhanced ultrasound for the characterization of benign liver lesions in clinical practice - a monocentric experience.

Science.gov (United States)

Martie, Alina; Bota, Simona; Sporea, Ioan; Sirli, Roxana; Popescu, Alina; Danila, Mirela

2012-12-01

Contrast-enhanced ultrasound (CEUS) uses second generation microbubble contrast agents and is considered to be a useful imaging method for focal liver lesions (FLLs) characterization. To observe if CEUS increases the diagnostic performance of benign FLLs as compared with standard ultrasonography examination (US). This is a single centre study developed during September 2009- December 2011 in the Department of Gastroenterology and Hepatology, in Timisoara. We evaluated 386 benign FLLs diagnosed by means of CEUS. Before performing CEUS, all FLLs were examined by US and Power Doppler techniques. At CEUS, the benign nature of a lesion was established by the absence of washout in the portal and late phase. The typical features observed using contrast, allowed their classification in a particular type of pathology, according to the 2008 EFSUMB Guidelines. From 386 benign FLLs, 81 (20.9%) of them were diagnosed in patients with chronic liver disease, while 305 (79.1%) were in patients without chronic hepatopathy. In 355 (92%) cases CEUS established a particular type of pathology. The most frequent lesions were: hemangiomas (37.5%), focal fatty alterations (24.8%), complex cysts (10.7%) and regenerative nodules (11.8%). Based on US we correctly estimated the positive diagnosis in 55.7% cases and using CEUS, the diagnostic performance increased up to 92%. In our study, by means of US the estimate positive diagnosis was made in 55.7% of cases. CEUS properly characterized 92% of benign FLLs and increased the diagnostic performance of these lesions, as compared with US.

Drug perfusion enhancement in tissue model by steady streaming induced by oscillating microbubbles.

Science.gov (United States)

Oh, Jin Sun; Kwon, Yong Seok; Lee, Kyung Ho; Jeong, Woowon; Chung, Sang Kug; Rhee, Kyehan

2014-01-01

Drug delivery into neurological tissue is challenging because of the low tissue permeability. Ultrasound incorporating microbubbles has been applied to enhance drug delivery into these tissues, but the effects of a streaming flow by microbubble oscillation on drug perfusion have not been elucidated. In order to clarify the physical effects of steady streaming on drug delivery, an experimental study on dye perfusion into a tissue model was performed using microbubbles excited by acoustic waves. The surface concentration and penetration length of the drug were increased by 12% and 13%, respectively, with streaming flow. The mass of dye perfused into a tissue phantom for 30s was increased by about 20% in the phantom with oscillating bubbles. A computational model that considers fluid structure interaction for streaming flow fields induced by oscillating bubbles was developed, and mass transfer of the drug into the porous tissue model was analyzed. The computed flow fields agreed with the theoretical solutions, and the dye concentration distribution in the tissue agreed well with the experimental data. The computational results showed that steady streaming with a streaming velocity of a few millimeters per second promotes mass transfer into a tissue. © 2013 Published by Elsevier Ltd.

Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques.

Science.gov (United States)

McDannold, Nathan; Arvanitis, Costas D; Vykhodtseva, Natalia; Livingstone, Margaret S

2012-07-15

The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method.

Experimental investigation of the penetration of ultrasound nanobubbles in a gastric cancer xenograft

Science.gov (United States)

Fan, Xiaozhou; Wang, Luofu; Guo, Yanli; Tong, Haipeng; Li, Lang; Ding, Jun; Huang, Haiyun

2013-08-01

Nanobubbles as a type of ultrasound contrast agent have attracted much interest in recent years due to their many advantages, such as strong penetrating power and high stability. However, there is still insufficient morphological evidence concerning gas-filled nanobubbles in tumor tissue spaces and tumor angiogenesis. We used a gastric cancer xenograft as an example to study this question. Nanobubbles with a particle size of 435.2 ± 60.53 nm were prepared and compared with SonoVue® microbubbles in vitro and in vivo, and they exhibited a superior contrast imaging effect. After excluding the impact of the nanobubbles in blood vessels through saline flush, we used an ultrasound burst and frozen sectioning to investigate the distribution of nanobubbles in the gastric cancer xenografts and confirmed this by transmission electron microscopy. Preliminary results showed that the nanobubbles were able to pass through the gaps between the endothelial cells in the tumor vascular system to enter the tissue space. These findings could provide morphological evidence for extravascular ultrasound imaging of tumors and serve as a foundation for the application of nanobubbles in extravascular tumor-targeted ultrasonic diagnostics and therapy.

Experimental investigation of the penetration of ultrasound nanobubbles in a gastric cancer xenograft

International Nuclear Information System (INIS)

Fan Xiaozhou; Guo Yanli; Tong Haipeng; Li Lang; Ding Jun; Huang Haiyun; Wang Luofu

2013-01-01

Nanobubbles as a type of ultrasound contrast agent have attracted much interest in recent years due to their many advantages, such as strong penetrating power and high stability. However, there is still insufficient morphological evidence concerning gas-filled nanobubbles in tumor tissue spaces and tumor angiogenesis. We used a gastric cancer xenograft as an example to study this question. Nanobubbles with a particle size of 435.2 ± 60.53 nm were prepared and compared with SonoVue ® microbubbles in vitro and in vivo, and they exhibited a superior contrast imaging effect. After excluding the impact of the nanobubbles in blood vessels through saline flush, we used an ultrasound burst and frozen sectioning to investigate the distribution of nanobubbles in the gastric cancer xenografts and confirmed this by transmission electron microscopy. Preliminary results showed that the nanobubbles were able to pass through the gaps between the endothelial cells in the tumor vascular system to enter the tissue space. These findings could provide morphological evidence for extravascular ultrasound imaging of tumors and serve as a foundation for the application of nanobubbles in extravascular tumor-targeted ultrasonic diagnostics and therapy. (paper)

Counterbalancing the use of ultrasound contrast agents by a cavitation-regulated system.

Science.gov (United States)

Desjouy, C; Fouqueray, M; Lo, C W; Muleki Seya, P; Lee, J L; Bera, J C; Chen, W S; Inserra, C

2015-09-01

The stochastic behavior of cavitation can lead to major problems of initiation and maintenance of cavitation during sonication, responsible of poor reproducibility of US-induced bioeffects in the context of sonoporation for instance. To overcome these disadvantages, the injection of ultrasound contrast agents as cavitation nuclei ensures fast initiation and lower acoustic intensities required for cavitation activity. More recently, regulated-cavitation devices based on the real-time modulation of the applied acoustic intensity have shown their potential to maintain a stable cavitation state during an ultrasonic shot, in continuous or pulsed wave conditions. In this paper is investigated the interest, in terms of cavitation activity, of using such regulated-cavitation device or injecting ultrasound contrast agents in the sonicated medium. When using fixed applied acoustic intensity, results showed that introducing ultrasound contrast agents increases reproducibility of cavitation activity (coefficient of variation 62% and 22% without and with UCA, respectively). Moreover, the use of the regulated-cavitation device ensures a given cavitation activity (coefficient of variation less 0.4% in presence of UCAs or not). This highlights the interest of controlling cavitation over time to free cavitation-based application from the use of UCAs. Interestingly, during a one minute sonication, while ultrasound contrast agents progressively disappear, the regulated-cavitation device counterbalance their destruction to sustain a stable inertial cavitation activity. Copyright © 2015 Elsevier B.V. All rights reserved.

Clinical utility of three-dimensional contrast-enhanced ultrasound in the differentiation between noninvasive and invasive neoplasms of urinary bladder.

Science.gov (United States)

Li, Qiu-yang; Tang, Jie; He, En-hui; Li, Yan-mi; Zhou, Yun; Zhang, Xu; Chen, Guangfu

2012-11-01

The purpose of this study was to evaluate the effectiveness of three-dimensional contrast-enhanced ultrasound in differentiating invasive and noninvasive neoplasms of urinary bladder. A total of 60 lesions in 60 consecutive patients with bladder tumors received three dimensional ultrasonography, low acoustic power contrast enhanced ultrasonography and low acoustic power three-dimensional contrast-enhanced ultrasound examination. The IU22 ultrasound scanner and a volume transducer were used and the ultrasound contrast agent was SonoVue. The contrast-specific sonographic imaging modes were PI (pulse inversion) and PM (power modulation). The three dimensional ultrasonography, contrast enhanced ultrasonography, and three-dimensional contrast-enhanced ultrasound images were independently reviewed by two readers who were not in the images acquisition. Images were analyzed off-site. A level of confidence in the diagnosis of tumor invasion of the muscle layer was assigned on a 5° scale. Receiver operating characteristic analysis was used to assess overall confidence in the diagnosis of muscle invasion by tumor. Kappa values were used to assess inter-readers agreement. Histologic diagnosis was obtained for all patients. Final pathologic staging revealed 44 noninvasive tumors and 16 invasive tumors. Three-dimensional contrast-enhanced ultrasound depicted all 16 muscle-invasive tumors. The diagnostic performance of three-dimensional contrast-enhanced ultrasound was better than those of three dimensional ultrasonography and contrast enhanced ultrasonography. The receiver operating characteristic curves were 0.976 and 0.967 for three-dimensional contrast-enhanced ultrasound, those for three dimensional ultrasonography were 0.881 and 0.869, those for contrast enhanced ultrasonography were 0.927 and 0.929. The kappa values in the three dimensional ultrasonography, contrast enhanced ultrasonography and three-dimensional contrast-enhanced ultrasound for inter-reader agreements

Clinical utility of three-dimensional contrast-enhanced ultrasound in the differentiation between noninvasive and invasive neoplasms of urinary bladder

International Nuclear Information System (INIS)

Li, Qiu-yang; Tang, Jie; He, En-hui; Li, Yan-mi; Zhou, Yun; Zhang, Xu; Chen, Guangfu

2012-01-01

Objectives: The purpose of this study was to evaluate the effectiveness of three-dimensional contrast-enhanced ultrasound in differentiating invasive and noninvasive neoplasms of urinary bladder. Methods: A total of 60 lesions in 60 consecutive patients with bladder tumors received three dimensional ultrasonography, low acoustic power contrast enhanced ultrasonography and low acoustic power three-dimensional contrast-enhanced ultrasound examination. The IU22 ultrasound scanner and a volume transducer were used and the ultrasound contrast agent was SonoVue. The contrast-specific sonographic imaging modes were PI (pulse inversion) and PM (power modulation). The three dimensional ultrasonography, contrast enhanced ultrasonography, and three-dimensional contrast-enhanced ultrasound images were independently reviewed by two readers who were not in the images acquisition. Images were analyzed off-site. A level of confidence in the diagnosis of tumor invasion of the muscle layer was assigned on a 5° scale. Receiver operating characteristic analysis was used to assess overall confidence in the diagnosis of muscle invasion by tumor. Kappa values were used to assess inter-readers agreement. Histologic diagnosis was obtained for all patients. Results: Final pathologic staging revealed 44 noninvasive tumors and 16 invasive tumors. Three-dimensional contrast-enhanced ultrasound depicted all 16 muscle-invasive tumors. The diagnostic performance of three-dimensional contrast-enhanced ultrasound was better than those of three dimensional ultrasonography and contrast enhanced ultrasonography. The receiver operating characteristic curves were 0.976 and 0.967 for three-dimensional contrast-enhanced ultrasound, those for three dimensional ultrasonography were 0.881 and 0.869, those for contrast enhanced ultrasonography were 0.927 and 0.929. The kappa values in the three dimensional ultrasonography, contrast enhanced ultrasonography and three-dimensional contrast-enhanced ultrasound

Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012

DEFF Research Database (Denmark)

Claudon, Michel; Dietrich, Christoph F; Choi, Byung Ihn

2013-01-01

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some...... Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications...... non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging...

Evaluation of the diagnosis on staging of the bladder cancers by contrast-enhanced ultrasound

International Nuclear Information System (INIS)

Gao Yong; Xu Haiyan; Huan Haiming; Chen Yane

2010-01-01

Objective: To study the value of the staging of the bladder cancers with the contrast-enhanced ultrasound. Methods: After rapid injection of the contrast agent SonoVue through the elbow vein, the staging of images was completed in 18 cases of bladder cancer. Results: The results of contrast-enhanced ultrasound were compared with post-operative pathological analysis, the rate of accuracy of diagnosis on T1, T2, T3 and T4 stage was 100%, 80%, 83% and 100% respectively. The accuracy made by new methods higher than those of other imaging examinations in T1 stage; the other stages were similar to those of other imaging examinations. Conclusion: The evaluation of Contrast-enhanced ultrasound on the staging of the bladder cancer is higher than that of the conventional ultrasound examination, while the observation of blood flow in the tumor can make accurate diagnosis and differential diagnosis, this method can be complement each other with CT and MRI to improve the rate of accuracy on the staging of bladder cancer. (authors)

Dynamic contrast-enhanced ultrasound and transient arterial occlusion for quantification of arterial perfusion reserve in peripheral arterial disease

International Nuclear Information System (INIS)

Amarteifio, E.; Wormsbecher, S.; Krix, M.; Demirel, S.; Braun, S.; Delorme, S.; Böckler, D.; Kauczor, H.-U.; Weber, M.-A.

2012-01-01

Objective: To quantify muscular micro-perfusion and arterial perfusion reserve in peripheral arterial disease (PAD) with dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion. Materials and methods: This study had local institutional review board approval and written informed consent was obtained from all subjects. We examined the dominant lower leg of 40 PAD Fontaine stage IIb patients (mean age, 65 years) and 40 healthy volunteers (mean age, 54 years) with CEUS (7 MHz; MI, 0.28) during continuous intravenous infusion of 4.8 mL microbubbles. Transient arterial occlusion at mid-thigh level simulated physical exercise. With time–CEUS–intensity curves obtained from regions of interest within calf muscles, we derived the maximum CEUS signal after occlusion (max) and its time (t max ), slope to maximum (m), vascular response after occlusion (AUC post ), and analysed accuracy, receiver operating characteristic (ROC) curves, and correlations with ankle-brachial index (ABI) and walking distance. Results: All parameters differed in PAD and volunteers (p max was delayed (31.2 ± 13.6 vs. 16.7 ± 8.5 s, p post as optimal parameter combination for diagnosing PAD and therefore impaired arterial perfusion reserve. Conclusions: Dynamic CEUS with transient arterial occlusion quantifies muscular micro-perfusion and arterial perfusion reserve. The technique is accurate to diagnose PAD.

Ultrasound-triggered local release of lipophilic drugs from a novel polymeric ultrasound contrast agent

NARCIS (Netherlands)

Kooiman, K.; Böhmer, M.R.; Emmer, M.; Vos, Hendrik J.; Chlon, C.; Foppen-Harteveld, M.; Versluis, Michel; de Jong, N.; van Wamel, A.; Hennink, W.E.; Feijen, J.; Sam, A.P.

2008-01-01

The advantage of ultrasound contrast agents (UCAs) as drug delivery systems is the ability to non-invasively control the local and triggered release of a drug or gene. In this study we designed and characterized a novel UCA-based drug delivery system, based on polymer-shelled microcapsules filled

Optimization of ultrasound parameters of myocardial cavitation microlesions for therapeutic application.

Science.gov (United States)

Miller, Douglas L; Dou, Chunyan; Owens, Gabe E; Kripfgans, Oliver D

2014-06-01

Intermittent high intensity ultrasound scanning with contrast microbubbles can induce scattered cavitation microlesions in the myocardium, which may be of value for tissue reduction therapy. Anesthetized rats were treated in a heated water bath with 1.5 MHz focused ultrasound pulses, guided by an 8 MHz imaging transducer. The relative efficacy with 2 or 4 MPa pulses, 1:4 or 1:8 trigger intervals and 5 or 10 cycle pulses was explored in six groups. Electrocardiogram premature complexes (PCs) induced by the triggered pulse bursts were counted, and Evans blue stained cardiomyocyte scores (SCSs) were obtained. The increase from 2 to 4 MPa produced significant increases in PCs and SCSs and eliminated an anticipated decline in the rate of PC induction with time, which might hinder therapeutic efficacy. Increased intervals and pulse durations did not yield significant increases in the effects. The results suggest that cavitation microlesion production can be refined and potentially lead to a clinically robust therapeutic method. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

Science.gov (United States)

Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying; Olumolade, Oluyemi O; Dayton, Paul A; Konofagou, Elisa E

2013-12-28

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. © 2013.

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

Science.gov (United States)

Cao, Yang; Chen, Yuli; Yu, Tao; Guo, Yuan; Liu, Fengqiu; Yao, Yuanzhi; Li, Pan; Wang, Dong; Wang, Zhigang; Chen, Yu; Ran, Haitao

2018-01-01

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release. PMID:29507623

Size-based sorting of micro-particles using microbubble streaming

Science.gov (United States)

Wang, Cheng; Jalikop, Shreyas; Hilgenfeldt, Sascha

2009-11-01

Oscillating microbubbles driven by ultrasound have shown great potential in microfluidic applications, such as transporting particles and promoting mixing [1-3]. The oscillations generate secondary steady streaming that can also trap particles. We use the streaming to develop a method of sorting particles of different sizes in an initially well-mixed solution. The solution is fed into a channel consisting of bubbles placed periodically along a side wall. When the bubbles are excited by an ultrasound piezo-electric transducer to produce steady streaming, the flow field is altered by the presence of the particles. This effect is dependent on particle size and results in size-based sorting of the particles. The effectiveness of the separation depends on the dimensions of the bubbles and particles as well as on the ultrasound frequency. Our experimental studies are aimed at a better understanding of the design and control of effective microfluidic separating devices. Ref: [1] P. Marmottant and S. Hilgenfeldt, Nature 423, 153 (2003). [2] P. Marmottant and S. Hilgenfeldt, Proc. Natl. Acad. Science USA, 101, 9523 (2004). [3] P. Marmottant, J.-P. Raven, H. Gardeniers, J. G. Bomer, and S. Hilgenfeldt, J. Fluid Mech., vol.568, 109 (2006).

Contrast Enhanced Ultrasound of the Kidneys: What Is It Capable of?

Directory of Open Access Journals (Sweden)

Demosthenes D. Cokkinos

2013-01-01

Full Text Available One of the many imaging uses of contrast enhanced ultrasound (CEUS is studying a wide variety of kidney pathology, due to its ability to detect microvascular blood flow in real time without affecting renal function. CEUS enables dynamic assessment and quantification of microvascularisation up to capillary perfusion. The objective of this paper is to briefly refresh basic knowledge of ultrasound (US contrast agents’ physical properties, to study technical details of CEUS scanning in the kidneys, and to review the commonest renal indications for CEUS, with imaging examples in comparison to baseline unenhanced US and computed tomography when performed. Safety matters and limitations of CEUS of the kidneys are also discussed.

Dynamics of micro-bubble sonication inside a phantom vessel

KAUST Repository

Qamar, Adnan; Samtaney, Ravi; Bull, Joseph L.

2013-01-01

A model for sonicated micro-bubble oscillations inside a phantom vessel is proposed. The model is not a variant of conventional Rayleigh-Plesset equation and is obtained from reduced Navier-Stokes equations. The model relates the micro-bubble oscillation dynamics with geometric and acoustic parameters in a consistent manner. It predicts micro-bubble oscillation dynamics as well as micro-bubble fragmentation when compared to the experimental data. For large micro-bubble radius to vessel diameter ratios, predictions are damped, suggesting breakdown of inherent modeling assumptions for these cases. Micro-bubble response with acoustic parameters is consistent with experiments and provides physical insight to the micro-bubble oscillation dynamics.

Dynamics of micro-bubble sonication inside a phantom vessel

KAUST Repository

Qamar, Adnan

2013-01-10

A model for sonicated micro-bubble oscillations inside a phantom vessel is proposed. The model is not a variant of conventional Rayleigh-Plesset equation and is obtained from reduced Navier-Stokes equations. The model relates the micro-bubble oscillation dynamics with geometric and acoustic parameters in a consistent manner. It predicts micro-bubble oscillation dynamics as well as micro-bubble fragmentation when compared to the experimental data. For large micro-bubble radius to vessel diameter ratios, predictions are damped, suggesting breakdown of inherent modeling assumptions for these cases. Micro-bubble response with acoustic parameters is consistent with experiments and provides physical insight to the micro-bubble oscillation dynamics.

Microultrasound Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 in a Mouse Model of Tumor Angiogenesis

Directory of Open Access Journals (Sweden)

Joshua J. Rychak

2007-09-01

Full Text Available High-frequency microultrasound imaging of tumor progression in mice enables noninvasive anatomic and functional imaging at excellent spatial and temporal resolution, although microultrasonography alone does not offer molecular scale data. In the current study, we investigated the use of microbubble ultrasound contrast agents bearing targeting ligands specific for molecular markers of tumor angiogenesis using high-frequency microultrasound imaging. A xenograft tumor model in the mouse was used to image vascular endothelial growth factor receptor 2 (VEGFR-2 expression with microbubbles conjugated to an anti-VEGFR-2 monoclonal antibody or an isotype control. Microultrasound imaging was accomplished at a center frequency of 40 MHz, which provided lateral and axial resolutions of 40 and 90 μm, respectively. The B-mode (two-dimensional mode acoustic signal from microbubbles bound to the molecular target was determined by an ultrasound-based destruction-subtraction scheme. Quantification of the adherent microbubble fraction in nine tumor-bearing mice revealed significant retention of VEGFR-2-targeted microbubbles relative to control-targeted microbubbles. These data demonstrate that contrast-enhanced microultrasound imaging is a useful method for assessing molecular expression of tumor angiogenesis in mice at high resolution.

Spark channel propagation in a microbubble liquid

Energy Technology Data Exchange (ETDEWEB)

Panov, V. A.; Vasilyak, L. M., E-mail: vasilyak@ihed.ras.ru; Vetchinin, S. P.; Pecherkin, V. Ya.; Son, E. E. [Russian Academy of Sciences, Joint Institute for High Temperatures (Russian Federation)

2016-11-15

Experimental study on the development of the spark channel from the anode needle under pulsed electrical breakdown of isopropyl alcohol solution in water with air microbubbles has been performed. The presence of the microbubbles increases the velocity of the spark channel propagation and increases the current in the discharge gap circuit. The observed rate of spark channel propagation in microbubble liquid ranges from 4 to 12 m/s, indicating the thermal mechanism of the spark channel development in a microbubble liquid.

A model for ultrasound contrast agent in a phantom vessel

KAUST Repository

Qamar, Adnan; Samtaney, Ravi

2014-01-01

A theoretical framework to model the dynamics of Ultrasound Contrast Agent (UCA) inside a phantom vessel is presented. The model is derived from the reduced Navier-Stokes equation and is coupled with the evolving flow field solution inside

Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity

International Nuclear Information System (INIS)

McDannold, N; Vykhodtseva, N; Hynynen, K

2006-01-01

Acoustic emission was monitored during focused ultrasound exposures in conjunction with an ultrasound contrast agent (Optison (registered) ) in order to determine if cavitation activity is associated with the induction of blood-brain barrier disruption (BBBD). Thirty-four locations were sonicated (frequency: 260 kHz) at targets 10 mm deep in rabbit brain (N = 9). The sonications were applied at peak pressure amplitudes ranging from 0.11 to 0.57 MPa (burst length: 10 ms; repetition frequency of 1 Hz; duration: 20 s). Acoustic emission was recorded with a focused passive cavitation detector. This emission was recorded at each location during sonications with and without Optison (registered) . Detectable wideband acoustic emission was observed only at 0.40 and 0.57 MPa. BBBD was observed in contrast MRI after sonication at 0.29-0.57 MPa. The appearance of small regions of extravasated erythrocytes appeared to be associated with this wideband emission signal. The results thus suggest that BBBD resulting from focused ultrasound pulses in the presence of Optison (registered) can occur without indicators for inertial cavitation in vivo, wideband emission and extravasation. If inertial cavitation is not responsible for the BBBD, other ultrasound/microbubble interactions are likely the source. A significant increase in the emission signal due to Optison (registered) at the second and third harmonics of the ultrasound driving frequency was found to correlate with BBBD and might be useful as an online method to indicate when the disruption occurs

Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

Science.gov (United States)

Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini; Zhang, Yongzhi; McDannold, Nathan

2016-02-01

The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Acoustically excited encapsulated microbubbles and mitigation of biofouling

KAUST Repository

Qamar, Adnan

2017-08-31

Provided herein is a universally applicable biofouling mitigation technology using acoustically excited encapsulated microbubbles that disrupt biofilm or biofilm formation. For example, a method of reducing biofilm formation or removing biofilm in a membrane filtration system is provided in which a feed solution comprising encapsulated microbubbles is provided to the membrane under conditions that allow the encapsulated microbubbles to embed in a biofilm. Sonication of the embedded, encapsulated microbubbles disrupts the biofilm. Thus, provided herein is a membrane filtration system for performing the methods and encapsulated microbubbles specifically selected for binding to extracellular polymeric substances (EFS) in a biofilm.

Ultrasound-triggered drug release from vibrating microbubbles

NARCIS (Netherlands)

Y. Luan (Ying)

2014-01-01

markdownabstract__Abstract__ Diagnostic medical ultrasound may have a slightly longer history than what you expected. Its root dates back to 1930s and 1940s, when Theodore Dussik, a psychiatrist and neurologist, and his brother Friederich used a 1.5 MHz source to record signal variations after

Rectal water contrast transvaginal ultrasound versus double-contrast barium enema in the diagnosis of bowel endometriosis

OpenAIRE

Jiang, Jipeng; Liu, Ying; Wang, Kun; Wu, Xixiang; Tang, Ying

2017-01-01

Objectives The aim of study was to compare the accuracy between rectal water contrast transvaginal ultrasound (RWC-TVS) and double-contrast barium enema (DCBE) in evaluating the bowel endometriosis presence as well as its extent. Design and setting 198 patients at reproductive age with suspicious bowel endometriosis were included. Physicians in two groups specialised at endometriosis performed RWC-TVS as well as DCBE before laparoscopy and both groups were blinded to other groups’ results. Fi...

Lead-silicate glass optical microbubble resonator

Energy Technology Data Exchange (ETDEWEB)

Wang, Pengfei, E-mail: pengfei.wang@dit.ie [Photonics Research Centre, Dublin Institute of Technology, Kevin Street, Dublin 8 (Ireland); Optoelectronics Research Centre, University of Southampton, Southampton SO17 1BJ (United Kingdom); Ward, Jonathan; Yang, Yong; Chormaic, Síle Nic [Light-Matter Interactions Unit, OIST Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495 (Japan); Feng, Xian; Brambilla, Gilberto [Optoelectronics Research Centre, University of Southampton, Southampton SO17 1BJ (United Kingdom); Farrell, Gerald [Photonics Research Centre, Dublin Institute of Technology, Kevin Street, Dublin 8 (Ireland)

2015-02-09

Microbubble whispering gallery resonators have the potential to become key components in a variety of active and passive photonic circuit devices by offering a range of significant functionalities. Here, we report on the fabrication, optical characterization, and theoretical analysis of lead-silicate glass and optical microbubble resonators. Evanescent field coupling to the microbubbles was achieved using a 1 μm diameter, silica microfiber at a wavelength of circa 775 nm. High Q-factor modes were efficiently excited in both single-stem and two-stem, lead-silicate glass, and microbubble resonators, with bubble diameters of 38 μm (single-stem) and 48 μm (two-stem). Whispering gallery mode resonances with Q-factors as high as 2.3 × 10{sup 5} (single-stem) and 7 × 10{sup 6} (two-stem) were observed. By exploiting the high-nonlinearity of the lead-silicate glass, this work will act as a catalyst for studying a range of nonlinear optical effects in microbubbles, such as Raman scattering and four-wave mixing, at low optical powers.

The Effect of Docetaxel-Loaded Micro-Bubbles Combined with Low-Frequency Ultrasound in H22 Hepatocellular Carcinoma-Bearing Mice.

Science.gov (United States)

Ren, Shu-Ting; Shen, Shu; He, Xin-Ying; Liao, Yi-Ran; Sun, Peng-Fei; Wang, Bing; Zhao, Wen-Bao; Han, Shui-Ping; Wang, Yi-Li; Tian, Tian

2016-02-01

A novel lipid micro-bubble (MB) loaded with docetaxel (DOC-MB) was investigated in a previous study. However, its anti-tumor effects and mechanism of action in combination with low-frequency ultrasound (LFUS) in vivo are still unclear. DOC-MBs containing 5.0 mg of DOC were prepared by lyophilization with modification via ultrasonic emulsification. Then, the effects of DOC-MBs combined with LFUS on tumor growth, proliferating cell nuclear antigen (PCNA) expression and cell apoptosis, as well as local DOC delivery, were investigated in H22 hepatocellular carcinoma (HCC)-bearing mice. Compared with the previously prepared DOC-MBs (1.6 mg of DOC loaded), the encapsulation efficiency (81.2% ± 3.89%) and concentration ([7.94 ± 0.04] × 10(9) bubbles/mL) of the DOC-MBs containing 5.0 mg of DOC were higher, but the bubble size (1.368 ± 0.004 μm) was smaller. After treatment with the DOC-MBs and LFUS, the H22 HCC growth inhibition rate was significantly increased, PCNA expression in tumor tissue was significantly inhibited and local release of DOC was induced. In conclusion, new DOC-MBs containing 5.0 mg of DOC were successfully prepared with a high encapsulation efficiency and superior bubble size and concentration, and their combination with LFUS significantly enhanced the anti-tumor effect of DOC in H22 HCC-bearing mice by inhibiting tumor cell proliferation and increasing local drug delivery. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Focused ultrasound-modulated glomerular ultrafiltration assessed by functional changes in renal arteries.

Directory of Open Access Journals (Sweden)

Feng-Yi Yang

Full Text Available This study demonstrates the feasibility of using focused ultrasound (FUS to modulate glomerular ultrafiltration by renal artery sonication and determine if protein-creatinine ratios are estimated through vascular parameters. All animal experiments were approved by our Animal Care and Use Committee. The renal arteries of Sprague-Dawley rats were surgically exposed and sonicated at various acoustic power levels using a FUS transducer with a resonant frequency of 1 MHz. The mean peak systolic velocity (PSV of the blood flow was measured by Doppler ultrasound imaging. Urinary protein-creatinine ratios were calculated during the experiments. Histological examination of renal arteries and whole kidneys was performed. The PSV, pulsatility index, and resistance index of blood flow significantly increased in the arteries after FUS sonication without microbubbles (p<0.05. The change in normalized protein-creatinine ratios significantly increased with increasing acoustic power, but such was not observed when microbubbles were administered. Furthermore, no histological changes were observed in the hematoxylin- and eosin-stained sections. Glomerular ultrafiltration is regulated temporarily by renal artery sonication without microbubbles. Monitoring vascular parameters are useful in estimating the normalized change in protein-creatinine ratios.

Real-Time Measurements and Modelling on Dynamic Behaviour of SonoVue Bubbles Based on Light Scattering Technology

International Nuclear Information System (INIS)

Juan, Tu; Rongjue, Wei; Guan, J. F.; Matula, T. J.; Crum, L. A.

2008-01-01

The dynamic behaviour of SonoVue microbubbles, a new generation ultrasound contrast agent, is investigated in real time with light scattering method. Highly diluted SonoVue microbubbles are injected into a diluted gel made of xanthan gum and water. The responses of individual SonoVue bubbles to driven ultrasound pulses are measured. Both linear and nonlinear bubble oscillations are observed and the results suggest that SonoVue microbubbles can generate strong nonlinear responses. By fitting the experimental data of individual bubble responses with Sarkar's model, the shell coating parameter of the bubbles and dilatational viscosity is estimated to be 7.0 nm·s·Pa

Radiographic, MR or ultrasound contrast media in pregnant or breast-feeding women. What are the key issues?

International Nuclear Information System (INIS)

Froehlich, J.M.; Kubik-Huch, Rahel A.

2013-01-01

The use and the safety of radiographic, MR- or ultrasound contrast media in the diagnostic work-up of pregnant or lactating patients is a frequently discussed question. As only sparse clinical data is available, a careful benefit-risk assessment must contain physico-chemical properties, preclinical data including teratogeneity and embryotoxicity, as well as maternal and foetal exposure. With consideration to the individual risks, iodinated contrast media, macrocyclic MR contrast media with increased stability or sulphur hexafluoride ultrasound contrast media may, if clinically justified, be administered in the smallest possible doses throughout pregnancy. After parental administration of an iodinated contrast medium after the 12th week of pregnancy, the neonate's thyroidal function should be checked during the first week after birth. After parental administration of iodinated, stable macrocyclic, gadolinium or ultrasound contrast media, lactation can be continued normally. In any case, contrast media should be used with caution and only if the benefits outweigh the risk. (orig.)

[Radiographic, MR or ultrasound contrast media in pregnant or breast-feeding women: what are the key issues?].

Science.gov (United States)

Fröhlich, J M; Kubik-Huch, R A

2013-01-01

The use and the safety of radiographic, MR- or ultrasound contrast media in the diagnostic work-up of pregnant or lactating patients is a frequently discussed question. As only sparse clinical data is available, a careful benefit-risk assessment must contain physico-chemical properties, preclinical data including teratogeneity and embryotoxicity, as well as maternal and foetal exposure. With consideration to the individual risks, iodinated contrast media, macrocyclic MR contrast media with increased stability or sulphur hexafluoride ultrasound contrast media may, if clinically justified, be administered in the smallest possible doses throughout pregnancy. After parental administration of an iodinated contrast medium after the 12th week of pregnancy, the neonate's thyroidal function should be checked during the first week after birth. After parental administration of iodinated, stable macrocyclic, gadolinium or ultrasound contrast media, lactation can be continued normally. In any case, contrast media should be used with caution and only if the benefits outweigh the risk. © Georg Thieme Verlag KG Stuttgart · New York.

Cavitation thresholds of contrast agents in an in vitro human clot model exposed to 120-kHz ultrasound.

Science.gov (United States)

Gruber, Matthew J; Bader, Kenneth B; Holland, Christy K

2014-02-01

Ultrasound contrast agents (UCAs) can be employed to nucleate cavitation to achieve desired bioeffects, such as thrombolysis, in therapeutic ultrasound applications. Effective methods of enhancing thrombolysis with ultrasound have been examined at low frequencies (cavitation thresholds for two UCAs exposed to 120-kHz ultrasound. A commercial ultrasound contrast agent (Definity(®)) and echogenic liposomes were investigated to determine the acoustic pressure threshold for ultraharmonic (UH) and broadband (BB) generation using an in vitro flow model perfused with human plasma. Cavitation emissions were detected using two passive receivers over a narrow frequency bandwidth (540-900 kHz) and a broad frequency bandwidth (0.54-1.74 MHz). UH and BB cavitation thresholds occurred at the same acoustic pressure (0.3 ± 0.1 MPa, peak to peak) and were found to depend on the sensitivity of the cavitation detector but not on the nucleating contrast agent or ultrasound duty cycle.

Dependence of the subharmonic signal from contrast agent microbubbles on ambient pressure: A theoretical analysis.

Science.gov (United States)

Jiménez-Fernández, J

2018-01-01

This paper investigates the dependence of the subharmonic response in a signal scattered by contrast agent microbubbles on ambient pressure to provide quantitative estimations of local blood pressure. The problem is formulated by assuming a gas bubble encapsulated by a shell of finite thickness with dynamic behavior modeled by a nonlinear viscoelastic constitutive equation. For ambient overpressure compatible with the clinical range, the acoustic pressure intervals where the subharmonic signal may be detected (above the threshold for the onset and below the limit value for the first chaotic transition) are determined. The analysis shows that as the overpressure is increased, all harmonic components are displaced to higher frequencies. This displacement is significant for the subharmonic of order 1/2 and explains the increase or decrease in the subharmonic amplitude with ambient pressure described in previous works. Thus, some questions related to the monotonic dependence of the subharmonic amplitude on ambient pressure are clarified. For different acoustic pressures, quantitative conditions for determining the intervals where the subharmonic amplitude is a monotonic or non-monotonic function of the ambient pressure are provided. Finally, the influence of the ambient pressure on the subharmonic resonance frequency is analyzed.

Characterization of Definity™ Ultrasound Contrast Agent at Frequency Range of 5–15 MHz

NARCIS (Netherlands)

Faez, Telli; Goertz, David; de Jong, N.

2011-01-01

The status of vasa vasorum, which can be imaged using ultrasound contrast agents, is an indication for the progression of atherosclerosis. The preferred ultrasound frequency for this purpose is between 5 and 15 MHz. Therefore, it is essential to have knowledge about the acoustic properties of

Age-related differences in skeletal muscle microvascular response to exercise as detected by contrast-enhanced ultrasound (CEUS).

Science.gov (United States)

Hildebrandt, Wulf; Schwarzbach, Hans; Pardun, Anita; Hannemann, Lena; Bogs, Björn; König, Alexander M; Mahnken, Andreas H; Hildebrandt, Olaf; Koehler, Ulrich; Kinscherf, Ralf

2017-01-01

Aging involves reductions in exercise total limb blood flow and exercise capacity. We hypothesized that this may involve early age-related impairments of skeletal muscle microvascular responsiveness as previously reported for insulin but not for exercise stimuli in humans. Using an isometric exercise model, we studied the effect of age on contrast-enhanced ultrasound (CEUS) parameters, i.e. microvascular blood volume (MBV), flow velocity (MFV) and blood flow (MBF) calculated from replenishment of Sonovue contrast-agent microbubbles after their destruction. CEUS was applied to the vastus lateralis (VLat) and intermedius (VInt) muscle in 15 middle-aged (MA, 43.6±1.5 years) and 11 young (YG, 24.1±0.6 years) healthy males before, during, and after 2 min of isometric knee extension at 15% of peak torque (PT). In addition, total leg blood flow as recorded by femoral artery Doppler-flow. Moreover, fiber-type-specific and overall capillarisation as well as fiber composition were additionally assessed in Vlat biopsies obtained from CEUS site. MA and YG had similar quadriceps muscle MRT-volume or PT and maximal oxygen uptake as well as a normal cardiovascular risk factors and intima-media-thickness. During isometric exercise MA compared to YG reached significantly lower levels in MFV (0.123±0.016 vs. 0.208±0.036 a.u.) and MBF (0.007±0.001 vs. 0.012±0.002 a.u.). In the VInt the (post-occlusive hyperemia) post-exercise peaks in MBV and MBF were significantly lower in MA vs. YG. Capillary density, capillary fiber contacts and femoral artery Doppler were similar between MA and YG. In the absence of significant age-related reductions in capillarisation, total leg blood flow or muscle mass, healthy middle-aged males reveal impaired skeletal muscle microcirculatory responses to isometric exercise. Whether this limits isometric muscle performance remains to be assessed.

An automatic respiratory gating method for the improvement of microcirculation evaluation: application to contrast-enhanced ultrasound studies of focal liver lesions

Energy Technology Data Exchange (ETDEWEB)

Mule, S; Kachenoura, N; Lucidarme, O; De Oliveira, A; Pellot-Barakat, C; Herment, A; Frouin, F, E-mail: Sebastien.Mule@gmail.com [INSERM UMR-S 678, 75634 Paris Cedex 13 (France)

2011-08-21

Contrast-enhanced ultrasound (CEUS), with the recent development of both contrast-specific imaging modalities and microbubble-based contrast agents, allows noninvasive quantification of microcirculation in vivo. Nevertheless, functional parameters obtained by modeling contrast uptake kinetics could be impaired by respiratory motion. Accordingly, we developed an automatic respiratory gating method and tested it on 35 CEUS hepatic datasets with focal lesions. Each dataset included fundamental mode and cadence contrast pulse sequencing (CPS) mode sequences acquired simultaneously. The developed method consisted in (1) the estimation of the respiratory kinetics as a linear combination of the first components provided by a principal components analysis constrained by a prior knowledge on the respiratory rate in the frequency domain, (2) the automated generation of two respiratory-gated subsequences from the CPS mode sequence by detecting end-of-inspiration and end-of-expiration phases from the respiratory kinetics. The fundamental mode enabled a more reliable estimation of the respiratory kinetics than the CPS mode. The k-means algorithm was applied on both the original CPS mode sequences and the respiratory-gated subsequences resulting in clustering maps and associated mean kinetics. Our respiratory gating process allowed better superimposition of manually drawn lesion contours on k-means clustering maps as well as substantial improvement of the quality of contrast uptake kinetics. While the quality of maps and kinetics was satisfactory in only 11/35 datasets before gating, it was satisfactory in 34/35 datasets after gating. Moreover, noise amplitude estimated within the delineated lesions was reduced from 62 {+-} 21 to 40 {+-} 10 (p < 0.01) after gating. These findings were supported by the low residual horizontal (0.44 {+-} 0.29 mm) and vertical (0.15 {+-} 0.16 mm) shifts found during manual motion correction of each respiratory-gated subsequence. The developed

Clinical Applications of Contrast-Enhanced Ultrasound in the Pediatric Work-Up of Focal Liver Lesions and Blunt Abdominal Trauma

DEFF Research Database (Denmark)

Laugesen, Nicolaj Grønbæk; Nolsoe, Christian Pallson; Rosenberg, Jacob

2017-01-01

of CEUS is indeed promising. However, no ultrasound contrast agent manufactured today is registered for pediatric use in Europe. The contrast agent SonoVue(®) has recently been approved by the FDA under the name of Lumason(®) to be used in hepatic investigations in adults and children. This article...... help reduce radiation exposure and use of iodinated contrast agents in pediatrics, thereby potentially reducing complications in routine imaging.......In pediatrics ultrasound has long been viewed more favorably than imaging that exposes patients to radiation and iodinated contrast or requires sedation. It is child-friendly and diagnostic capabilities have been improved with the advent of contrast-enhanced ultrasound (CEUS). The application...

Detection of vascularity in wrist tenosynovitis: power doppler ultrasound compared with contrast-enhanced grey-scale ultrasound.

Science.gov (United States)

Klauser, Andrea S; Franz, Magdalena; Arora, Rohit; Feuchtner, Gudrun M; Gruber, Johann; Schirmer, Michael; Jaschke, Werner R; Gabl, Markus F

2010-01-01

We sought to assess vascularity in wrist tenosynovitis by using power Doppler ultrasound (PDUS) and to compare detection of intra- and peritendinous vascularity with that of contrast-enhanced grey-scale ultrasound (CEUS). Twenty-six tendons of 24 patients (nine men, 15 women; mean age ± SD, 54.4 ± 11.8 years) with a clinical diagnosis of tenosynovitis were examined with B-mode ultrasonography, PDUS, and CEUS by using a second-generation contrast agent, SonoVue (Bracco Diagnostics, Milan, Italy) and a low-mechanical-index ultrasound technique. Thickness of synovitis, extent of vascularized pannus, intensity of peritendinous vascularisation, and detection of intratendinous vessels was incorporated in a 3-score grading system (grade 0 to 2). Interobserver variability was calculated. With CEUS, a significantly greater extent of vascularity could be detected than by using PDUS (P < 0.001). In terms of peri- and intratendinous vessels, CEUS was significantly more sensitive in the detection of vascularization compared with PDUS (P < 0.001). No significant correlation between synovial thickening and extent of vascularity could be found (P = 0.089 to 0.097). Interobserver reliability was calculated to be excellent when evaluating the grading score (κ = 0.811 to 1.00). CEUS is a promising tool to detect tendon vascularity with higher sensitivity than PDUS by improved detection of intra- and peritendinous vascularity.

Ultrasound-mediated drug delivery to the brain: principles, progress and prospects

NARCIS (Netherlands)

Dasgupta, I.; Liu, M.; Ojha, T.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

2016-01-01

The blood–brain barrier (BBB) limits drug delivery to the central nervous system. When combined with microbubbles, ultrasound can transiently permeate blood vessels in the brain. This approach, which can be referred to as sonoporation or sonopermeabilization, holds significant promise for shuttling

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model.

Directory of Open Access Journals (Sweden)

Habib Baghirov

Full Text Available The treatment of brain diseases is hindered by the blood-brain barrier (BBB preventing most drugs from entering the brain. Focused ultrasound (FUS with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma.

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

Science.gov (United States)

Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

2018-01-01

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

Interaction of a high-order Bessel beam with a submerged spherical ultrasound contrast agent shell - Scattering theory.

Science.gov (United States)

Mitri, F G

2010-03-01

Acoustic scattering properties of ultrasound contrast agents are useful in extending existing or developing new techniques for biomedical imaging applications. A useful first step in this direction is to investigate the acoustic scattering of a new class of acoustic beams, known as helicoidal high-order Bessel beams, to improve the understanding of their scattering characteristics by an ultrasound contrast agent, which at present is very limited. The transverse acoustic scattering of a commercially available albuminoidal ultrasound contrast agent shell filled with air or a denser gas such as perfluoropropane and placed in a helicoidal Bessel beam of any order is examined numerically. The shell is assumed to possess an outer radius a=3.5 microns and a thickness of approximately 105 nm. Moduli of the total and resonance transverse acoustic scattering form functions are numerically evaluated in the bandwidth 0scattering of a helicoidal Bessel beam of order m1 so that the dynamics of contrast agents would be significantly altered. The main finding of the present theory is the suppression or enhancement for a particular resonance that may be used to advantage in imaging with ultrasound contrast agents for clinical applications. 2009 Elsevier B.V. All rights reserved.

Safety of ultrasound contrast agents in stress echocardiography.

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Gabriel, Ruvin S; Smyth, Yvonne M; Menon, Venu; Klein, Allan L; Grimm, Richard A; Thomas, James D; Sabik, Ellen Mayer

2008-11-01

Definity and Optison are perflutren-based ultrasound contrast agents used in echocardiography. United States Food and Drug Administration warnings regarding serious cardiopulmonary reactions and death after Definity administration highlighted the limited safety data in patients who undergo contrast stress echocardiography. From 1998 and 2007, 2,022 patients underwent dobutamine stress echocardiography and 2,764 underwent exercise stress echocardiography with contrast at the Cleveland Clinic. The echocardiographic database, patient records, and the Social Security Death Index were reviewed for the timing and cause of death, severe adverse events, arrhythmias, and symptoms. Complication rates for contrast dobutamine stress echocardiography and exercise stress echocardiography were compared with those in a control group of 5,012 patients matched for test year and type who did not receive contrast. Ninety-five percent of studies were performed in outpatients. There were no differences in the rates of severe adverse events (0.19% vs 0.17%, p = 0.7), death within 24 hours (0% vs 0.04%, p = 0.1), cardiac arrest (0.04% vs 0.04%, p = 0.96), and sustained ventricular tachycardia (0.2% vs 0.1%, p = 0.32) between patients receiving and not receiving intravenous contrast, respectively. In conclusion, severe adverse reactions to intravenous contrast agents during stress echocardiography are uncommon. Contrast use does not add to the baseline risk for severe adverse events in patients who undergo stress echocardiography.

Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

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Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

2009-04-01

Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

Ultrasound-enhanced thrombolysis using Definity as a cavitation nucleation agent.

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Datta, Saurabh; Coussios, Constantin-C; Ammi, Azzdine Y; Mast, T Douglas; de Courten-Myers, Gabrielle M; Holland, Christy K

2008-09-01

Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment.

Association schemes perspective of microbubble cluster in ultrasonic fields.

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Behnia, S; Yahyavi, M; Habibpourbisafar, R

2018-06-01

Dynamics of a cluster of chaotic oscillators on a network are studied using coupled maps. By introducing the association schemes, we obtain coupling strength in the adjacency matrices form, which satisfies Markov matrices property. We remark that in general, the stability region of the cluster of oscillators at the synchronization state is characterized by Lyapunov exponent which can be defined based on the N-coupled map. As a detailed physical example, dynamics of microbubble cluster in an ultrasonic field are studied using coupled maps. Microbubble cluster dynamics have an indicative highly active nonlinear phenomenon, were not easy to be explained. In this paper, a cluster of microbubbles with a thin elastic shell based on the modified Keller-Herring equation in an ultrasonic field is demonstrated in the framework of the globally coupled map. On the other hand, a relation between the microbubble elements is replaced by a relation between the vertices. Based on this method, the stability region of microbubbles pulsations at complete synchronization state has been obtained analytically. In this way, distances between microbubbles as coupling strength play the crucial role. In the stability region, we thus observe that the problem of study of dynamics of N-microbubble oscillators reduce to that of a single microbubble. Therefore, the important parameters of the isolated microbubble such as applied pressure, driving frequency and the initial radius have effective behavior on the synchronization state. Copyright © 2018 Elsevier B.V. All rights reserved.

Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

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Farnaz Fekri

Full Text Available Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR, and distinct mechanism(s that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may

Gene delivery systems by the combination of lipid bubbles and ultrasound.

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Negishi, Yoichi; Endo-Takahashi, Yoko; Maruyama, Kazuo

2016-11-28

Gene therapy is promising for the treatment of many diseases including cancers and genetic diseases. From the viewpoint of safety, ultrasound (US)-mediated gene delivery with nano/ microbubbles was recently developed as a novel non-viral vector system. US-mediated gene delivery using nano/microbubbles are able to produce transient changes in the permeability of the cell membrane after US-induced cavitation while reducing cellular damage and enables the tissue-specific or the site-specific intracellular delivery of gene both in vitro and in vivo. We have recently developed novel lipid nanobubbles (Lipid Bubbles). These nanobubbles can also be used to enhance the efficacy of the US-mediated genes (plasmid DNA, siRNA, and miRNA etc.) delivery. In this review, we describe US-mediated delivery systems combined with nano/microbubbles and discuss their feasibility as non-viral vector systems.

Analysis of achilles tendon vascularity with second-generation contrast-enhanced ultrasound.

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Genovese, Eugenio; Ronga, Mario; Recaldini, Chiara; Fontana, Federico; Callegari, Leonardo; Maffulli, Nicola; Fugazzola, Carlo

2011-01-01

To compare morphological, power Doppler, and contrast-enhanced ultrasound (CEUS) features of the Achilles tendon between asymptomatic athletes and athletes who had undergone surgical repair of a previous rupture. Twenty-four athletes were divided in two groups (A and B). Group A included 14 patients with a median age of 32 years (range 27 to 47 years) who had undergone surgical repair for unilateral Achilles tendon rupture. Group B (control group) included 10 subjects with a median age of 34 years (range 27 to 40 years) with no previous or present history of tendinopathy. All patients were evaluated with ultrasound, power Doppler, and CEUS with second-generation contrast agent. We studied the uninjured Achilles tendon in athletes of group A and either the left or the right Achilles tendon of the athletes in group B. CEUS showed a significantly greater ability to detect a greater number of vascular spots within the uninjured tendon of group A compared to group B (power Doppler ultrasound in the uninjured contralateral Achilles tendon. CEUS is useful to evaluate vascularity not detected by other imaging techniques. Vascularity in the uninjured tendon seems to be increased in patients who had a previous rupture. Copyright © 2011 Wiley Periodicals, Inc.

Prospective study of ultrasound with perflutrene contrast compared to magnetic resonance imaging in the diagnosis of hepatic hemangiomas

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Joel Schmillevitch

2011-06-01

Full Text Available CONTEXT:The incidence of hepatic hemangiomas ranges from 0.4% to 20% in the general population. Conventional ultrasound is usually the first diagnostic method to identify these hemangiomas, typically as an incidental finding. Ultrasonography with second generation contrast materials is being used in various areas of hepatology, yielding similar results to those obtained with computerized tomography and magnetic resonance imaging in the diagnosis of hepatic hemangiomas. OBJECTIVE: To evaluate the agreement between ultrasound with perflutrene contrast and magnetic resonance imaging in the diagnosis of hepatic hemangiomas. METHODS: A total of 37 patients were prospectively examined between January 2006 and August 2008. A total of 57 hepatic nodules were documented in this group as incidental findings on routine ultrasound exams. The 37 patients were administered perflutrene contrast without adverse reactions, and were all submitted to magnetic resonance exams. RESULTS: Conventional ultrasound identified 15 patients with nodules typical of hemangiomas and 22 patients with other nodules. In 35 patients, the contrast characteristics were consistent with hepatic hemangiomas. CONCLUSION: Agreement between the data obtained from ultrasound with contrast and magnetic resonance was 94.5%. In discordant cases, the magnetic resonance diagnosis prevailed. In the case which presented indeterminate findings on contrast ultrasonography, magnetic resonance was repeated after 3 months, confirming the diagnosis of a hepatic hemangioma. A biopsy was performed on the suspected malignant nodule which also confirmed the presence of a hepatic hemangioma. Ultrasonography with contrast has the advantages of being more accessible to the public at large and lower cost than magnetic resonance. The results of our study highlight the need for a new protocol in hepatic nodules incidentally identified on conventional ultrasonography. In the case of typical hemangiomas

PIV measurement of a contraction flow using micro-bubble tracer

International Nuclear Information System (INIS)

Ishikawa, Masaaki; Irabu, Kunio; Teruya, Isao; Nitta, Munehiro

2009-01-01

Recently, a technique using the micro-bubbles is focused. It was applied to many fields such as purification of rivers and lakes, washing the industrial parts, growth of plants and marine products. The characteristics of micro-bubbles are small size, wide surface area, low terminal velocity, and so on. If this micro-bubble is available as tracer of PIV (Particle Image Velocimetry), environment load would become lower because it doesn't need to discard particle. In this paper, we make a micro-bubble generator with Venturi type mechanism. The generated micro-bubbles are applied to a vertical channel flow with contraction. We validate about traceability of the micro-bubble tracer in comparison with the particle tracer.

[Destruction of synovial pannus of antigen-induced arthritis by ultrasonic cavitation in rabbits].

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Zhang, Ling-yan; Qiu, Li; Wang, Lei; Lin, Ling; Wen, Xiao-rong

2011-11-01

To optimize the conditions of ultrasonic irradiation and microbubble of ultrasound cavitation on destruction of synovial pannus of antigen-induced arthritis (AIA) in rabbits. Antigen-induced arthritis was successfully induced on bilateral knee joints of 85 rabbits. Each 10 AIA rabbits were divided into two groups to compare various peak negative pressures, different ultrasonic pulse durations, various pulse repetition frequencies, different irradiance duration, different dosages of microbubble contrast agents, different ultrasonic irradiance times. With intravenous infusion of Sonovue to the rabbits, ultrasonic irradiance was performed on the right knee joint using the above condition of ultrasound cavitation. At the day 1 after ultrasonic irradiance, MRI and pathological examination were employed to evaluate the optimal conditions. The optimal parameters and conditions for ultrasonic irradiance included intermittent ultrasonic application (in 6 s intervals), 0.6 mL/kg of microbubble contrast agent, 4.6 MPa of ultrasonic peak negative pressure, 100 cycles of pulse duration, 50 Hz of pulse repetition frequency, 5 min of ultrasonic duration, 0.6 mL/kg of dosages of microbubble contrast agents and multi-sessional ultrasonic irradiance. After the ultrasonic irradiance, the thickness of right knee synovium measured by MRI was thinner than that of left knee and synovial necrosis was confirmed by the pathological finding. Under optimal ultrasonic irradiation and microbubble conditions, ultrasonic cavitation could destroy synovial pannus of AIA in rabbits.

Use of Ultrasound Contrast Agents in Relation to Percutaneous Interventional Procedures

DEFF Research Database (Denmark)

Nolsøe, Christian Pállson; Nolsøe, Alexander Bjørneboe; Klubien, Jeanett

2018-01-01

The aim of this article is to provide an inventory of the use of contrast-enhanced ultrasound (CEUS) in relation to percutaneous interventional procedures. The article is structured into a systematic literature review followed by a clinical part relating to percutaneous CEUS-guided procedures...

Non-invasive ambient pressure estimation using non-linear ultrasound contrast agents

DEFF Research Database (Denmark)

Andersen, Klaus Scheldrup

Many attempts to find a non-invasive procedure to measure the blood pressure locally in the body have been made. This dissertation focuses on the approaches which utilize highly compressible ultrasound contrast agents as ambient pressure sensors. The literature within the topic has been reviewed...

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.

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Downs, Matthew E; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Teichert, Tobias; Chen, Shangshang; Konofagou, Elisa E; Ferrera, Vincent P

2015-01-01

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500 kHz, 200-400 kPa, 4-5 μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

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Chen, Shuyuan [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Chen, Jiaxi [The University of Texas Southwestern Medical Center at Dallas, Medical School, 5235 Harry Hine Blvd., Dallas, TX (United States); Huang, Pintong [Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province (China); Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Grayburn, Paul A., E-mail: paulgr@baylorhealth.edu [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall St, Suite H030, Dallas, TX (United States)

2015-03-20

Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation.

Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

International Nuclear Information System (INIS)

Chen, Shuyuan; Chen, Jiaxi; Huang, Pintong; Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song; Grayburn, Paul A.

2015-01-01

Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation

Microbubble Distillation for Ethanol-Water Separation

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Atheer Al-yaqoobi

2016-01-01

Full Text Available In the current study, a novel approach for separating ethanol-water mixture by microbubble distillation technology was investigated. Traditional distillation processes require large amounts of energy to raise the liquid to its boiling point to effect removal of volatile components. The concept of microbubble distillation by comparison is to heat the gas phase rather than the liquid phase to achieve separation. The removal of ethanol from the thermally sensitive fermentation broths was taken as a case of study. Consequently the results were then compared with those which could be obtained under equilibrium conditions expected in an “ideal” distillation unit. Microbubble distillation has achieved vapour compositions higher than that which could be obtained under traditional equilibrium conditions. The separation was achieved at liquid temperature significantly less than the boiling point of the mixture. In addition, it was observed that the separation efficiency of the microbubble distillation could be increased by raising the injected air temperature, while the temperature of the liquid mixture increased only moderately. The separation efficiency of microbubble distillation was compared with that of pervaporation for the recovery of bioethanol from the thermally sensitive fermentation broths. The technology could be controlled to give high separation and energy efficiency. This could contribute to improving commercial viability of biofuel production and other coproducts of biorefinery processing.

Feasibility and usefulness of using swallow contrast-enhanced ultrasound to diagnose Zenker's diverticulum: preliminary results.

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Cui, Xin-Wu; Ignee, Andre; Baum, Ulrich; Dietrich, Christoph F

2015-04-01

Zenker's diverticulum (ZD) may be misdiagnosed on conventional ultrasound as a thyroid nodule or other lesion. A barium esophagram is usually used to confirm the diagnosis; however, this procedure exposes the patient to radiation. The aim of this study was to evaluate the feasibility of using swallow contrast-enhanced ultrasound (swallow-CEUS) to diagnose ZD. Ten consecutive patients with ZD (7 men and 3 women, aged 67 ± 11 y) were included in the study. In 4 patients, ZD was incidentally found on head and neck ultrasound, and in 6 patients, ZD was suspected because of dysphagia. All lesions could be detected on conventional ultrasound before swallow-CEUS. Ten healthy volunteers (8 men and 2 women, aged 60 ± 12 y) were chosen as a control group. Written informed consent was obtained. With the patient in the sitting or upright position, conventional ultrasound was performed first to image the lesion, then the patient was asked to swallow ultrasound contrast agent (UCA) (2-4 drops of SonoVue diluted with about 200 mL of tap water). Transity of the contrast agent in the esophagus was imaged with CEUS. Retention of the UCA in the diverticulum was monitored for at least 3 min. All patients underwent a barium esophagram as the gold standard. Swallow-CEUS revealed that in all patients (100%), the UCA was transported from the pharynx to the esophagus while the patient swallowed. ZD appeared as a pouch-shaped structure at the posterior pharyngo-esophageal junction that retained UCA longer than 3 min. The barium esophagram confirmed the diagnosis of ZD in all patients. For the 10 volunteers, no abnormal structure (retaining UCA) was detected during or after swallowing of UCA. With the advantages of no radiation and bedside availability, swallow-CEUS may become a method of choice in confirmation of the diagnosis of ZD, especially when ZD is suspected on conventional ultrasound. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier

Pharmacokinetic changes induced by focused ultrasound in glioma-bearing rats as measured by dynamic contrast-enhanced MRI.

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Feng-Yi Yang

Full Text Available Focused ultrasound (FUS combined with microbubbles has been shown to be a noninvasive and targeted drug delivery technique for brain tumor treatment. The purpose of this study was to measure the kinetics of Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA in glioma-bearing rats in the presence of FUS-induced blood-brain barrier disruption (BBB-D by magnetic resonance imaging (MRI. A total of ten glioma-bearing rats (9-12 weeks, 290-340 g were used in this study. Using dynamic contrast-enhanced (DCE-MRI, the spatial permeability of FUS-induced BBB-D was evaluated and the kinetic parameters were calculated by a general kinetic model (GKM. The results demonstrate that the mean Ktrans of the sonicated tumor (0.128±0.019 at 20 min and 0.103±0.023 at 24 h after sonication, respectively was significantly higher than (2.46-fold at 20 min and 1.78-fold at 24 h that of the contralateral (non-sonicated tumor (0.052±0.019 at 20 min and 0.058±0.012 at 24 h after sonication, respectively. In addition, the transfer constant Ktrans in the sonicated tumor correlated strongly with tissue EB extravasation (R = 0.95, which suggests that DCE-MRI may reflect drug accumulation in the brain. Histological observations showed no macroscopic damage except for a few small erythrocyte extravasations. The current study demonstrates that DCE-MRI can monitor the dynamics of the FUS-induced BBB-D process and constitutes a useful tool for quantifying BBB permeability in tumors.

Inverse effects of flowing phase-shift nanodroplets and lipid-shelled microbubbles on subsequent cavitation during focused ultrasound exposures.

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Zhang, Siyuan; Cui, Zhiwei; Xu, Tianqi; Liu, Pan; Li, Dapeng; Shang, Shaoqiang; Xu, Ranxiang; Zong, Yujin; Niu, Gang; Wang, Supin; He, Xijing; Wan, Mingxi

2017-01-01

This paper compared the effects of flowing phase-shift nanodroplets (NDs) and lipid-shelled microbubbles (MBs) on subsequent cavitation during focused ultrasound (FUS) exposures. The cavitation activity was monitored using a passive cavitation detection method as solutions of either phase-shift NDs or lipid-shelled MBs flowed at varying velocities through a 5-mm diameter wall-less vessel in a transparent tissue-mimicking phantom when exposed to FUS. The intensity of cavitation for the phase-shift NDs showed an upward trend with time and cavitation for the lipid-shelled MBs grew to a maximum at the outset of the FUS exposure followed by a trend of decreases when they were static in the vessel. Meanwhile, the increase of cavitation for the phase-shift NDs and decrease of cavitation for the lipid-shelled MBs had slowed down when they flowed through the vessel. During two discrete identical FUS exposures, while the normalized inertial cavitation dose (ICD) value for the lipid-shelled MB solution was higher than that for the saline in the first exposure (p-value 0.95). Meanwhile, the normalized ICD value for the phase-shift NDs was 0.182 at a flow velocity of 5cm/s and increased to 0.188 at a flow velocity of 15cm/s. As the flow velocity increased to 20cm/s, the normalized ICD was 0.185 and decreased to 0.178 at a flow velocity of 30cm/s. At high acoustic power, the normalized ICD values for both the lipid-shelled MBs and the phase-shift NDs increased with increasing flow velocities from 5 to 30cm/s (r>0.95). The effects of the flowing phase-shift NDs vaporized into gas bubbles as cavitation nuclei on the subsequent cavitation were inverse to those of the flowing lipid-shelled MBs destroyed after focused ultrasound exposures. Copyright © 2016 Elsevier B.V. All rights reserved.

Buoyancy-activated cell sorting using targeted biotinylated albumin microbubbles.

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Yu-Ren Liou

Full Text Available Cell analysis often requires the isolation of certain cell types. Various isolation methods have been applied to cell sorting, including fluorescence-activated cell sorting and magnetic-activated cell sorting. However, these conventional approaches involve exerting mechanical forces on the cells, thus risking cell damage. In this study we applied a novel isolation method called buoyancy-activated cell sorting, which involves using biotinylated albumin microbubbles (biotin-MBs conjugated with antibodies (i.e., targeted biotin-MBs. Albumin MBs are widely used as contrast agents in ultrasound imaging due to their good biocompatibility and stability. For conjugating antibodies, biotin is conjugated onto the albumin MB shell via covalent bonds and the biotinylated antibodies are conjugated using an avidin-biotin system. The albumin microbubbles had a mean diameter of 2 μm with a polydispersity index of 0.16. For cell separation, the MDA-MB-231 cells are incubated with the targeted biotin-MBs conjugated with anti-CD44 for 10 min, centrifuged at 10 g for 1 min, and then allowed 1 hour at 4 °C for separation. The results indicate that targeted biotin-MBs conjugated with anti-CD44 antibodies can be used to separate MDA-MB-231 breast cancer cells; more than 90% of the cells were collected in the MB layer when the ratio of the MBs to cells was higher than 70:1. Furthermore, we found that the separating efficiency was higher for targeted biotin-MBs than for targeted avidin-incorporated albumin MBs (avidin-MBs, which is the most common way to make targeted albumin MBs. We also demonstrated that the recovery rate of targeted biotin-MBs was up to 88% and the sorting purity was higher than 84% for a a heterogenous cell population containing MDA-MB-231 cells (CD44(+ and MDA-MB-453 cells (CD44-, which are classified as basal-like breast cancer cells and luminal breast cancer cells, respectively. Knowing that the CD44(+ is a commonly used cancer

Bioeffects of albumin-encapsulated microbubbles and real-time myocardial contrast echocardiography in an experimental canine model

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P.M.M. Dourado

2006-06-01

Full Text Available Myocardial contrast echocardiography has been used for assessing myocardial perfusion. Some concerns regarding its safety still remain, mainly regarding the induction of microvascular alterations. We sought to determine the bioeffects of microbubbles and real-time myocardial contrast echocardiography (RTMCE in a closed-chest canine model. Eighteen mongrel dogs were randomly assigned to two groups. Nine were submitted to continuous intravenous infusion of perfluorocarbon-exposed sonicated dextrose albumin (PESDA plus continuous imaging using power pulse inversion RTMCE for 180 min, associated with manually deflagrated high-mechanical index impulses. The control group consisted of 3 dogs submitted to continuous imaging using RTMCE without PESDA, 3 dogs received PESDA alone, and 3 dogs were sham-operated. Hemodynamics and cardiac rhythm were monitored continuously. Histological analysis was performed on cardiac and pulmonary tissues. No hemodynamic changes or cardiac arrhythmias were observed in any group. Normal left ventricular ejection fraction and myocardial perfusion were maintained throughout the protocol. Frequency of mild and focal microhemorrhage areas in myocardial and pulmonary tissue was similar in PESDA plus RTMCE and control groups. The percentages of positive microscopical fields in the myocardium were 0.4 and 0.7% (P = NS in the PESDA plus RTMCE and control groups, respectively, and in the lungs they were 2.1 and 1.1%, respectively (P = NS. In this canine model, myocardial perfusion imaging obtained with PESDA and RTMCE was safe, with no alteration in cardiac rhythm or left ventricular function. Mild and focal myocardial and pulmonary microhemorrhages were observed in both groups, and may be attributed to surgical tissue manipulation.

The Role of Breast Ultrasound in Early Cancer Detection

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Huay-Ben Pan

2016-12-01

Full Text Available Ultrasonography (US is currently considered the first-line examination in the detection and characterization of breast lesions including the evaluation of breast cancer. Yet only few single-center cohort studies analyzing breast US in the framework of screening could be identified. In spite of mammography consider as the primary method for screening especially the noteworthy ability of microcalcifications detection. US is good in mass or mass- like lesion detection, especially in the dense breast population that proved by the study of ACRIN 6666. A lobular hypoechoic area; lesion with ductal extension and dilatation; and a hypoechoic nodular lesion with a dilated lactiferous duct leading to the retroareolar region, that were the common ultrasound findings in Ductal carcinoma in situ (DCIS and probably related to nuclear grade of cancer. Computer programs have been developed and approved for use in clinical practice, the application including CAD (computer aided/assisted detection/diagnosis, ABUS (automated breast US, elastography and microbubbles in contrast-enhanced ultrasound. Furthermore the standardized scanning; improving with computer technology implementation and familiar to the picture of DCIS is necessary for progress the competence of early breast cancer detection.

Magnetic resonance imaging-guided focused ultrasound to increase localized blood-spinal cord barrier permeability.

Science.gov (United States)

Payne, Allison H; Hawryluk, Gregory W; Anzai, Yoshimi; Odéen, Henrik; Ostlie, Megan A; Reichert, Ethan C; Stump, Amanda J; Minoshima, Satoshi; Cross, Donna J

2017-12-01

Spinal cord injury (SCI) affects thousands of people every year in the USA, and most patients are left with some permanent paralysis. Therapeutic options are limited and only modestly affect outcome. To address this issue, we used magnetic resonance imaging-guided focused ultrasound (MRgFUS) as a non-invasive approach to increase permeability in the blood-spinal cord barrier (BSCB). We hypothesize that localized, controlled sonoporation of the BSCB by MRgFUS will aid delivery of therapeutics to the injury. Here, we report our preliminary findings for the ability of MRgFUS to increase BSCB permeability in the thoracic spinal cord of a normal rat model. First, an excised portion of normal rat spinal column was used to characterize the acoustic field and to estimate the insertion losses that could be expected in an MRgFUS blood spinal cord barrier opening. Then, in normal rats, MRgFUS was applied in combination with intravenously administered microbubbles to the spinal cord region. Permeability of the BSCB was indicated as signal enhancement by contrast administered prior to T1-weighted magnetic resonance imaging and verified by Evans blue dye. Neurological testing using the Basso, Beattie, and Breshnahan scale and the ladder walk was normal in 8 of 10 rats tested. Two rats showed minor impairment indicating need for further refinement of parameters. No gross tissue damage was evident by histology. In this study, we have opened successfully the blood spinal cord barrier in the thoracic region of the normal rat spine using magnetic resonance-guided focused ultrasound combined with microbubbles.

Enhancement pattern of hilar cholangiocarcinoma: Contrast-enhanced ultrasound versus contrast-enhanced computed tomography