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Andrew Brayman

Principal Physicist

Email

brayman@apl.washington.edu

Phone

206-543-9825

Research Interests

Acoustic Cavitation, Ultrasonic Drug Delivery, Microbubble Dynamics

Biosketch

Dr. Brayman's research interests include acoustic cavitation, ultrasonic delivery of non-viral gene vectors and drugs, acoustically-activated microbubble interactions with cells and tissues, non-thermal therapeutic application of ultrasound, and thermal ablation of tissues with high-frequency focused ultrasound.

Topics of his current research projects include:

- Image-guided HIFU for tumor ablation
- Dynamics of contrast agent microbubbles in intravascular environments
- Ultrasound- and microbubble-enhanced non-viral gene delivery for the treatment of hemophilia A and B
- The influence of microbubble shell loading on acoustically-induced bubble dynamics

Dr. Brayman joined APL-UW's Center for Industrial and Medical Ultrasound in 1999.

Education

B.S. Biology, SUNY, Fredonia, 1976

M.S. Plant Physiology, SUNY, College of Environ. Sci. & Forestry/Syracuse University, 1980

Ph.D. Plant Physiology & Biophysics, SUNY, College of Environ. Sci. & Forestry/Syracuse University, 1985

Videos

Non-invasive Treatment of Abscesses with Ultrasound

Abscesses are walled-off collections of fluid and bacteria within the body. They are common complications of surgery, trauma, and systemic infections. Typical treatment is the surgical placement of a drainage catheter to drain the abscess fluid over several days. Dr. Keith Chan and researchers at APL-UW's Center for Industrial + Medical Ultrasound are exploring how to treat abscesses non-invasively, that is, from outside the body, with high-intensity focused ultrasound (HIFU). This experimental therapy could reduce pain, radiation exposure, antibiotic use, and costs for patients with abscesses. Therapeutic ultrasound could also treat abscesses too small or inaccessible for conventional drainage.

20 Jun 2016

Flow Cytometry Techniques Advance Microbubble Science

Researchers at the Center for Industrial and Medical Ultrasound (CIMU) are measuring the physical properties of ultrasound contrast agents — tiny gas bubbles several microns in diameter used to increase sonogram imaging efficiency in the body. When injected to the general circulation they can act as probes and beacons within the body, and can carry and deploy chemotherapeutic payloads.

CIMU researchers have developed a hybrid instrument that combines an off-the-shelf flow cytometer with an acoustic transducer. The cytometer's laser interrogation counts and measures the bubbles while the acoustic interrogation reveals the bubbles' viscosity and elasticity at megahertz frequencies.

5 Dec 2013

Publications

2000-present and while at APL-UW

Preliminary observations on the spatial correlation between short-burst microbubble oscillations and vascular bioeffects

Chen, H., A.A. Brayman, A.P. Evan, and T.J. Matula, "Preliminary observations on the spatial correlation between short-burst microbubble oscillations and vascular bioeffects," Ultrasound Med. Biol., 12, 2151-2162, doi:10.1016/j.ultrasmedbio.2012.08.014, 2012.

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1 Dec 2012

The objective of this preliminary study was to examine the spatial correlation between microbubble (MB)-induced vessel wall displacements and resultant microvascular bioeffects. MBs were injected into venules in ex vivo rat mesenteries and insonated by a single short ultrasound pulse with a center frequency of 1 MHz and peak negative pressures spanning the range of 1.5%u20135.6 MPa. MB and vessel dynamics were observed under ultra-high speed photomicrography. The tissue was examined by histology or transmission electron microscopy for vascular bioeffects. Image registration allowed for spatial correlation of MB-induced vessel wall motion to corresponding vascular bioeffects, if any. In cases in which damage was observed, the vessel wall had been pulled inward by more than 50% of the its initial radius. The observed damage was characterized by the separation of the endothelium from the vessel wall. Although the study is limited to a small number of observations, analytic statistical results suggest that vessel invagination comprises a principal mechanism for bioeffects in venules by microbubbles.

Characteristic microvessel relaxation timescales associated with ultrasound-activated microbubbles

Chen, H., A.A. Brayman, and T.J. Matula, "Characteristic microvessel relaxation timescales associated with ultrasound-activated microbubbles," Appl. Phys. Lett., 101, 163704, doi:10.1063/1.4761937, 2012.

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15 Oct 2012

Ultrasound-activated microbubbles were used as actuators to deform microvessels for quantifying microvessel relaxation timescales at megahertz frequencies. Venules containing ultrasound contrast microbubbles were insonified by short 1 MHz ultrasound pulses. Vessel wall forced-deformations were on the same microsecond timescale as microbubble oscillations. The subsequent relaxation of the vessel was recorded by high-speed photomicrography. The tissue was modeled as a simple Voigt solid. Relaxation time constants were measured to be on the order of ~10 µs. The correlation coefficients between the model and 38 data sets were never lower than 0.85, suggesting this model is sufficient for modeling tissue relaxation at these frequencies. The results place a bound on potential numerical values for viscosity and elasticity of venules.

Acoustic and optical characterization of ultrasound contrast agents via flow cytometry

Perez, C., A. Brayman, J. Tu, J. Swalwell, H. Chen, and T. Matula, "Acoustic and optical characterization of ultrasound contrast agents via flow cytometry," J. Acoust. Soc. Am., 132, 1906, 2012.

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1 Sep 2012

Characterizing ultrasound contrast agents (UCAs) involve measuring the size and population distribution. However, these instruments do not allow for characterization of shell properties, which are important for (1) stability to administration and circulation throughout the vasculature; (2) UCA response to ultrasound; and (3) conjugating ligands for molecular imaging. Thus it is critical to understand the physical and rheological properties of shells. We previously developed a light scattering technique to characterize the shell properties of UCAs [Guan and Matula, JASA, vol. 116(5), 2004; Tu, et al., IEEE Trans. Ultrason., Ferroelec., and Freq. Control, vol. 58(5), 2011]. The most recent manifestation involves a flow cytometer modified with a custom square quartz flow cell in place of the standard nozzle and fluid jet. Acoustic coupling to the carrier sheath fluid and UCA samples occurred through a PZT bonded to one side of the flow cell. The PZT-driven UCA oscillations were processed and fitted to the Marmottant UCA model. Shell properties for UCAs (including Definity, Optison, SonoVue, and even homemade bubbles) were determined. The focus of this talk will be on pressure calibration and additional measurements of unpublished data from Optison and homemade bubbles.

More Publications

Observations of translation and jetting of ultrasound-activated microbubbles in mesenteric microvessels

Chen, H., A.A. Brayman, W. Kreider, M.R. Bailey, and T.J. Matula, "Observations of translation and jetting of ultrasound-activated microbubbles in mesenteric microvessels," Ultrasound Med. Biol., 37, 2139-2148, doi:10.1016/j.ultrasmedbio.2011.09.013, 2011.

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1 Dec 2011

High-speed photomicrography was used to study the translational dynamics of single microbubbles in microvessels of ex vivo rat mesenteries. The microbubbles were insonated by a single 2 microsecond ultrasound pulse with a center frequency of 1 MHz and peak negative pressures spanning the range of 0.8-4 MPa. The microvessel diameters ranged from 10-80 micrometers. The high-speed image sequences show evidence of ultrasound-activated microbubble translation away from the nearest vessel wall; no microbubble showed a net translation toward the nearest vessel wall. Microbubble maximum translation displacements exceeded 20 micrometers. Microjets with the direction of the jets identifiable were also observed; all microjets appear to have been directed away from the nearest vessel wall. These observations appear to be characteristic of a strong coupling between ultrasound-driven microbubbles and compliant microvessels. Although limited to mesenteric tissues, these observations provide an important step in understanding the physical interactions between microbubbles and microvessels.

Explorations of high-intensity therapeutic ultrasound and microbubble-mediated gene delivery in mouse liver

Song, S., Z. Shen, L. Chen, A. A. Brayman, and C.H. Miao, "Explorations of high-intensity therapeutic ultrasound and microbubble-mediated gene delivery in mouse liver," Gene Ther., 18, 1006-1014, doi: 10.1038/gt.2011.34, 2011.

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1 Oct 2011

Ultrasound (US) combined with microbubbles (MBs) is a promising technology for non-viral gene delivery. Significant enhancements of gene expression have been obtained in our previous studies. To optimize and prepare for application to larger animal models, the luciferase reporter gene transfer efficacy of lipid-based Definity MBs of various concentrations, pressure amplitudes and a novel unfocused high-intensity therapeutic US (HITU) system were explored. Luciferase expression exhibited a dependence on MB dose over the range of 0-25 vol%, and a strong dependence on acoustic peak negative pressure at over the range of 0-3.2 MPa. Gene expression reached an apparent plateau at MB concentration >2.5 vol% or at negative pressures >1.8 MPa. Maximum gene expression in treated animals was 700-fold greater than in negative controls. Pulse train US exposure protocols produced an upward trend of gene expression with increasing quiescent time. The hyperbolic correlation of gene expression and transaminase levels suggested that an optimum gene delivery effect can be achieved by maximizing acoustic cavitation-induced enhancement of DNA uptake and minimizing unproductive tissue damage. This study validated the new HITU system equipped with an unfocused transducer with a larger footprint capable of scanning large tissue areas to effectively enhance gene transfer efficiencies.

Targeted long-term venous occlusion using pulsed high-intensity focused ultrasound combined with a pro-inflammatory agent

Zhou, Y., J. Zia, C. Warren, F.L. Starr, A.A. Brayman, L.A. Crum, and J.H. Hwang, "Targeted long-term venous occlusion using pulsed high-intensity focused ultrasound combined with a pro-inflammatory agent," Ultrasound Med. Biol., 37, 10, 1653-1658, doi:10.1016/j.ultrasmedbio.2011.06.007, 2011.

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1 Oct 2011

Esophageal and gastric varices are associated with significant morbidity and mortality for cirrhotic patients. The current modalities available for treating bleeding esophageal and gastric varices, namely endoscopic band ligation and sclerotherapy, require frequent sessions to obtain effective thrombosis and are associated with significant adverse effects. A more effective therapy that results in long-term vascular occlusion has the potential to improve patient outcomes. In this study, we investigated a new potential method for inducing long-term vascular occlusion by targeting segments of a rabbit's auricular vein in vivo with low-duty-cycle, high-peak-rarefaction pressure (9 MPa), pulsed high-intensity focused ultrasound in the presence of intravenously administered ultrasound microbubbles followed by local injection of fibrinogen and a pro-inflammatory agent (ethanol, cyanoacrylate or morrhuate sodium). The novel method introduced in this study resulted in acute and long-term complete vascular occlusions when injecting a pro-inflammatory agent with fibrinogen. Future investigation and translational studies are needed to assess its clinical applicability.

Mechanisms for microvascular damage induced by ultrasound-activated microbubbles

Chen, H., A. Brayman, A. Evan, and T. Matula,"Mechanisms for microvascular damage induced by ultrasound-activated microbubbles," Proceedings, International Society for Therapeutic Ultrasound Symposium 1481, New York, New York, U.S.A., 11-13 April, 41-46, doi:http://dx.doi.org/10.1063/1.4757308 (AIP, 2011).

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11 Apr 2011

To provide insight into the mechanisms of microvascular damage induced by ultrasound-activated microbubbles, experimental studies were performed to correlate microvascular damage to the dynamics of bubble-vessel interactions. High-speed photomicrography was used to record single microbubbles interacting with microvessels in ex vivo tissue, under the exposure of short ultrasound pulses with a center frequency of 1 MHz and peak negative pressures (PNP) ranging from 0.8%u20134 MPa. Vascular damage associated with observed bubble-vessel interactions was either indicated directly by microbubble extravasation or examined by transmission electron microscopy (TEM) analyses. As observed previously, the high-speed images revealed that ultrasound-activated microbubbles could cause distention and invagination of adjacent vessel walls, and could form liquid jets in microvessels. Vessel distention, invagination, and liquid jets were associated with the damage of microvessels whose diameters were smaller than those of maximally expanded microbubbles. However, vessel invagination appeared to be the dominant mechanism for the damage of relative large microvessels.

Heat diffusion constrained inversion of backscattered ultrasound data to image temperature rise during high intensity focused ultrasound therapy

Kaczkowski, P.J., G. Speyer, A.A. Brayman, L.A. Crum, and A. Anand, "Heat diffusion constrained inversion of backscattered ultrasound data to image temperature rise during high intensity focused ultrasound therapy," J. Acoust. Soc. Am., 129, 2439, doi:10.1121/1.3587982, 2011.

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1 Apr 2011

Noninvasive ablative high intensity focused ultrasound (HIFU) therapy must be guided with precision, and monitored in real time. Magnetic resonance imaging (MRI) can provide both high resolution tissue-specific images and temperature maps, but even the most recently developed MRI methods cannot do so in less than a few seconds. Ultrasonic imaging techniques using a sequence of rf frames to measure heating-induced apparent strain have been developed to produce heating maps, but the approach is challenging due to lack of sensitivity and substantial variability in tissue properties. To improve estimates of temperature rise, constraints based on heat diffusion modeling are imposed, thus minimizing the effects of noise and nonmonotonicity of the speed of sound with respect to temperature throughout the therapeutic range. Furthermore, noninvasive protocols for measuring relevant HIFU field and tissue properties in the region of interest enable patient-calibrated mapping of temperature rise during HIFU, at ultrasonic imaging frame rates. Further analysis of the heat-induced apparent strain leads to a modal decomposition of the strain, greatly reducing the computational load for use in real-time feedback and therapy control. Finally, a Rytov approximation applied to the problem leads to further improvement in computational efficiency and physical understanding.

High speed imaging of shockwave-induced dynamics of cavitation bubbles and vessel wall

Chen, H., C. Perez, A.A. Brayman, and T.J. Matula, "High speed imaging of shockwave-induced dynamics of cavitation bubbles and vessel wall," J. Acoust. Soc. Am., 129, 2374, doi: 10.1121/1.3587689, 2011.

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1 Apr 2011

High speed optical imaging under a microscope (high speed photomicrography) was used to observe shockwave-induced bubble dynamics and bubble-induced vascular dynamics. Ultrasound contrast agent microbubbles, serving as cavitation nuclei, were injected into the vessels of ex vivo rat mesentery. The bubbles were then insonated by focused shock wave pulses with peak positive pressures of 42 MPa and peak negative pressures of 10 MPa, generated by an electromagnetic shockwave source (Storz Duolith). The recorded images were analyzed to obtain bubble radius-time curves, vessel wall displacement, as well as their corresponding velocities. In general, bubble dynamics induces vessel distention (outward displacement of vessel wall) and invagination (displacement of vessel wall into the lumen). Comparisons of shockwave-induced dynamics with HIFU-induced dynamics will also be presented.

Phase propagation in ultrasonic backscatter monitoring of high-intensity focused ultrasound therapy

Speyer, G., P. Kaczkowski, A. Brayman, and L. Crum, "Phase propagation in ultrasonic backscatter monitoring of high-intensity focused ultrasound therapy," J. Acoust. Soc. Am., 129, 2439, doi:10.1121/1.3587983, 2011.

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1 Apr 2011

Phase propagation using the Rytov method has recently been proposed as a means for modeling the time-of-flight changes induced by thermal therapy [Speyer et al., J. Acoust. Am. 127]. These results are extended to measurements from a linear array, under which the general problem of imaging material changes is cast. The linear array offers several design components, which can be exploited for therapy monitoring, including the apodization and probing frequency. Phase propagation models are shown to be consistent with many aspects of conventional modeling, linearizing material changes around the same operating points as have been proposed by other researchers, and providing time-of-flight changes linearly related to the temperature distribution under these conditions. Beyond expanding on model properties, experimental evidence is presented, which indicates that phase propagation modeling is significantly more consistent with backscattered ultrasound data than conventional ray approaches

Blood vessel deformations on microsecond time scales by ultrasonic cavitation

Chen, H., W. Kreider, A.A. Brayman, M.R. Bailey, and T.J. Matula, "Blood vessel deformations on microsecond time scales by ultrasonic cavitation," Phys. Rev. Lett., 106, 034301, doi:10.1103/PhysRevLett.106.034301, 2011.

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18 Jan 2011

Transient interactions among ultrasound, microbubbles, and microvessels were studied using high-speed photomicrography. We observed liquid jets, vessel distention (motion outward against the surrounding tissue), and vessel invagination (motion inward toward the lumen). Contrary to current paradigms, liquid jets were directed away from the nearest vessel wall and invagination exceeded distention. These observations provide insight into the mechanics of bubble-vessel interactions, which appear to depend qualitatively upon the mechanical properties of biological tissues.

Vascular damage by ultrasound-activated microbubble induced vessel invagination

Chen, H., A. Brayman, A. Evan, and T. Matula, "Vascular damage by ultrasound-activated microbubble induced vessel invagination," Proceedings, IEEE International Ultrasonics Symposium, San Diego, USA, 11-14 October, 678-681, doi:10.1109/ULTSYM.2010.5935994 (IEEE, 2010).

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11 Oct 2010

Vascular bioeffects produced by ultrasound contrast agent microbubbles are primarily manifested as damage to microvessels. The objective of this work is to directly observe the transient dynamics of bubble-vessel interactions and correlate the observed interactions with associated vascular damage. Microbubbles were perfused into microvessels in ex vivo rat mesenteries and then excited by a single 2 us long ultrasound pulse at 1 MHz. Meanwhile, 14 high-speed photomicrographic images were acquired using 50 ns shutter speeds. The targeted region was then examined by histology and transmission electron microscopy (TEM). Image registration was used to identify the specific vessels that the corresponding high-speed images were captured. The recorded high-speed images revealed that bubble-vessel interactions caused vessel wall distention (motion outward against the surrounding tissue) and invagination (motion inward toward the lumen). Invagination exceeding distention was observed in 60 out of 70 cases. Significant vessel invagination was correlated with vascular damage that was characterized by a separation of the endothelium from the surrounding tissue as revealed by both the histology and TEM analyses. The separation of the endothelium from the surrounding tissue is consistent with damage caused by tensile stresses at the vessel walls that lead to vessel invagination. This suggests that invagination may be an important mechanism by which microbubbles cause vascular damage.

The peculiar interactions of microbubbles and microvessels

Chen, H., A. Brayman, and T. Matula, "The peculiar interactions of microbubbles and microvessels," Proceedings, 20th International Congress on Acoustics, Sydney, Australia, 23-27 August, 1-5, (ICA, 2010).

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23 Aug 2010

The application of microbubbles for both diagnostic macro- and molecular imaging and therapeudic ultrasound requires an understanding of the coupled interactions involving microbubble dynamics with the surrounding compliant microvessel. In this study, ultra-high speed microphotography was used to directly observe transient behaviors of microbubbles in microvessels of ex vivo rat mesenteries. Definity® microbubbles were perfused through the vasculature, and then excited by a 2-µs long ultrasound pulse with a center frequency of 1 MHz with peak negative pressures between 0.8-7.2 MPa. These amplitudes span the diagnostic to therapeutic pressure levels. During insonation, ultrahigh speed images were captured with 50-ns exposure time and 150-ns or 300-ns interframe time. The recorded images show a wonderful assortment of microbubble dynamics, including oscillation, translation, jetting, coalescence and fragmentation. These microbubble behaviors were coupled with the dynamic responses of the vessel wall, which showed distention, invagination, and even rupture.

Blood vessel rupture by cavitation

Chen, H., A.A. Brayman, M.R. Bailey, and T.J. Matula, "Blood vessel rupture by cavitation," Urol. Res., 38, 321-326, doi:10.1007/s00240-010-0302-5, 2010.

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2 Aug 2010

Cavitation is thought to be one mechanism for vessel rupture during shock wave lithotripsy treatment. However, just how cavitation induces vessel rupture remains unknown. In this work, a high-speed photomicrography system was set up to directly observe the dynamics of bubbles inside blood vessels in ex vivo rat mesenteries. Vascular rupture correlating to observed bubble dynamics were examined by imaging bubble extravasation and dye leakage. The high-speed images show that bubble expansion can cause vessel distention, and bubble collapse can lead to vessel invagination. Liquid jets were also observed to form. Our results suggest that all three mechanisms, vessel distention, invagination and liquid jets, can contribute to vessel rupture.

Displacement analysis of diagnostic ultrasound backscatter: A methodology for characterizing, modeling, and monitoring high intensity focused ultrasound therapy

Speyer, G., P.J. Kaczkowski, A.A. Brayman, and L.A. Crum, "Displacement analysis of diagnostic ultrasound backscatter: A methodology for characterizing, modeling, and monitoring high intensity focused ultrasound therapy," J. Acoust. Soc. Am., 128, 104-120, 2010.

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1 Jul 2010

Accurate monitoring of high intensity focused ultrasound (HIFU) therapy is critical for widespread clinical use. Pulse-echo diagnostic ultrasound (DU) is known to exhibit temperature sensitivity through relative changes in time-of-flight between two sets of radio frequency (RF) backscatter measurements, one acquired before and one after therapy. These relative displacements, combined with knowledge of the exposure protocol, material properties, heat transfer, and measurement noise statistics, provide a natural framework for estimating the administered heating, and thereby therapy.

The proposed method, termed displacement analysis, identifies the relative displacements using linearly independent displacement patterns, or modes, each induced by a particular time-varying heating applied during the exposure interval. These heating modes are themselves linearly independent. This relationship implies that a linear combination of displacement modes aligning the DU measurements is the response to an identical linear combination of heating modes, providing the heating estimate. Furthermore, the accuracy of coefficient estimates in this approximation is determined a priori, characterizing heating, thermal dose, and temperature estimates for any given protocol. Predicted performance is validated using simulations and experiments in alginate gel phantoms. Evidence for a spatially distributed interaction between temperature and time-of-flight changes is presented.

Backscatter monitoring of high intensity focused ultrasound therapy using a parametric treatment model

Speyer, G., P. Kaczkowski, A. Brayman, and L. Crum, "Backscatter monitoring of high intensity focused ultrasound therapy using a parametric treatment model," In Proceedings, Ninth International Symposium on Therapeutic Ultrasound, Aix-en-Provence, 24-26 September 2009, K. Hynynen and J. Souquet, eds.,62-65 (AIP, 2010).

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9 Mar 2010

Accurate monitoring of high intensity focused ultrasound (HIFU) surgery is critical to ensuring proper treatment. Pulse-echo diagnostic ultrasound (DU) is a recognized modality for identifying temperature differentials using speckle tracking between two DU radio frequency (RF) frames [2], [4]. This observation has motivated non-parametric temperature estimation, which associates temperature changes directly with the displacement estimates.

We present an estimation paradigm termed displacement mode analysis (DMA), which uses physical modeling to associate particular patterns of observed displacement, called displacement modes, with corresponding modes of variation in the administered therapy. This correspondence allows DMA to estimate therapy directly using a linear combination of displacement modes, imbuing these displacement estimates into the reference using interpolation, and by aligning with the treatment frame, providing a therapy estimate with the heating modes. Since DMA is maximum likelihood estimation (MLE), the accuracy of its estimates can be assessed a priori, providing error bounds for estimates of applied heating, temperature, and thermal dose. Predicted performance is verified using both simulation and experiment for a point exposure of 4.2 Watts of electrical power in alginate, a tissue mimicking phantom.

Targeted venous occlusion using pulsed high-intensity focused ultrasound

Hwang, J.H., Y. Zhou, C. Warren, A.A. Brayman, and L.A. Crum, "Targeted venous occlusion using pulsed high-intensity focused ultrasound," IEEE Trans. Biomed. Eng., 57, 37-40, doi:10.1109/TBME.2009.2029865, 2010.

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4 Jan 2010

Targeted vascular occlusion is desirable for clinical therapies such as in the treatment of esophageal and gastric varices and varicose veins. The feasibility of ultrasound-mediated endothelial damage for vascular occlusion was studied. A segment of a rabbit auricular vein was treated in vivo with low duty cycle, high peak rarefaction pressure (9 MPa) high-intensity focused ultrasound pulses in the presence of intravenously administered circulating microbubbles, followed by fibrinogen injection, which resulted in the formation of an acute occlusive intravascular thrombus. Further investigation and refinements of treatment protocols are necessary for producing durable vascular occlusion.

Observations of bubble-vessel interaction in ultrasound fields

Chen, H., J. Kucewicz, W. Kreider, A. Brayman, M. Bailey, and T. Matula, "Observations of bubble-vessel interaction in ultrasound fields," Proceedings, IEEE International Ultrasonics Symposium, Rome, Italy, 20-23 September, 23-26, doi:10.1109/ULTSYM.2009.5441512 (IEEE, 2009).

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20 Sep 2009

Interactions between bubbles and nearby boundaries have been studied for some time; however, the direct interactions between bubbles and tissue boundaries, especially blood vessel walls, have not been studied to a large extent. In this work highspeed microscopy was used to study the dynamical interaction between microbubbles and microvessels of ex vivo rat mesentery subjected to a single pulse of ultrasound. Ultrasound contrast agent microbubbles were injected into the blood vessels of rat mesentery subsequent to having the blood flushed out. India ink was used to increase the contrast between microvessels and surrounding tissues. Tissue samples were aligned at the focus of both an ultrasound transducer with a center frequency of 1 MHz and an inverted microscope coupled to a high speed camera. Fourteen high-speed microphotographic images were acquired for each experiment using 50 ns shutter speeds. Observations of the coupled dynamics between bubbles and vessels ranging from 10 micrometer to 100 micrometer diameters under the exposure of ultrasound of peak negative pressure within the range of 1 MPa to 7.8 MPa suggest that the vessel wall dilates during bubble expansion, and invaginates during bubble contraction. A significant finding is that the ratio of invagination to distension is usually >1 and large circumferential strains can be imposed on the vessel wall during vessel invagination. In addition, the surrounding tissue response was also quantified. Based on these studies, we hypothesize that vessel invagination is the dominant mechanism for the initial induction of vascular damage via cavitation.

Potential mechanisms for vessel invagination caused by bubble oscillations

Kreider, W., H. Chen, M.R. Bailey, A.A. Brayman, and T.J. Matula, "Potential mechanisms for vessel invagination caused by bubble oscillations," In Proceedings, IEEE International Ultrasonics Symposium, Rome, Italy, 20-23 September, 353-356, doi:10.1109/ULTSYM.2009.5441744 (IEEE, 2009).

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20 Sep 2009

In medical ultrasound, acoustically excited bubbles are relevant to both imaging and therapeutic applications and have been implicated in causing vascular damage. A current paradigm for understanding interactions between bubbles and vessels considers the distention of small vessels and the impingement of bubble jets on vessel walls to be the most likely damage mechanisms. However, recent high-speed photographs suggest a type of interaction that is characterized by a prominent invagination of the vessel wall (i.e., an inward deflection toward the lumen) that appears to exceed any accompanying distention.

To elucidate mechanisms for such behavior, a confined flow geometry between an oscillating bubble and a nearby boundary is modeled and compared to fully spherical flow. From a Bernoulli-type equation for an incompressible and inviscid liquid, the pressure attributable to a bubble at a nearby boundary is found to become biased toward negative values as the flow becomes more confined and less spherical. Such negative values are consistent with invagination. Using radial bubble dynamics inferred from a high-speed photographic sequence of a bubble in a vessel, the aforementioned model was used to simulate the pressure radiated by the bubble at the vessel wall. At the 1 MHz acoustic frequency, the simulated negative pressure is 2.5 times the positive pressure; in turn, the observed vessel displacement inward was about 6 times the corresponding outward displacement.

Bounds on thermal dose estimates using ultrasonic backscatter monitoring of heating

Speyer, G., P. Kaczkowski, A. Brayman, M. Andrew, and L. Crum, "Bounds on thermal dose estimates using ultrasonic backscatter monitoring of heating," Proceedings, 8th International Symposium on Therapeutic Ultrasound, Minneapolis, MN, 10-13 September 2008, 251-255, doi:10.1063/1.3131424 (AIP, 2009).

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14 Apr 2009

Diagnostic ultrasound provides a means for estimating the spatial distribution of temperature in tissue in response to HIFU therapy. One approach to estimating the temperature is to distort backscattered ultrasound between two frames, one preceding and one following the treatment, in a manner consistent with the heat equation, the exposure protocol, the beam pattern, and the specific material properties of the tissue. Ascribing a probability distribution to the measurements taken after treatment, the Cramer Rao bound may be determined for coefficient estimates in a functional expansion for the applied heating during therapy. This formulation also identifies the function with coefficient estimates having least variance, providing the lower bound. We study the implications of this characterization for heat deposition from a linear scan, examining how estimation accuracy is influenced by the lesion length and the delay following treatment and preceding acquisition. It is shown that for these studies, temperature estimates with accuracy well below 1°C are possible. In addition, the thermal dose can be estimated to tens of equivalent minutes, referenced to 43°C.

Direct observation of microbubble interactions with ex vivo microvessels

Chen, H., A.A. Brayman, M.R. Bailey, and T.J. Matula, "Direct observation of microbubble interactions with ex vivo microvessels," J. Acoust. Soc. Am., 125, 2680, 2009.

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1 Apr 2009

The interaction between microbubbles with tissue is poorly understood. Experimental evidence, supported by numerical simulations, suggests that bubble dynamics is highly constrained within blood vessels. To investigate this further, a high-speed microimaging system was set up to study the effects of acoustically activated microbubbles on microvessels in ex vivo rat mesentery tissues. The microbubble-perfused tissues were placed under a microscope and insonified with MHz ultrasound. A variety of interactions was observed by a high-speed camera: arterioles, venules, and capillaries were all recorded to dilate and invaginate by activated microbubbles.

For small diameter microvessels, dilation and invagination were nearly symmetric, and bubble-induced rupture of the vessel was observed at high pressure. For larger microvessels, the portion of the vessel nearest the bubble coupled the strongest to the bubble dynamics, and the extent of dilation was smaller than invagination. Tissue jetting toward the bubble was recorded in many cases. The interaction of multiple bubbles inside microvessels was also observed. Bubble oscillation, vessel wall velocity, and tissue jet velocity were quantitatively measured. Invagination of vessel walls, especially tissue jetting, may be the major mechanism for tissue injury by a bubble.

Microbubble dynamics in microvessels: Observations of microvessel dilation, invagination and rupture

Chen, H., A. Brayman, and T. Matula, "Microbubble dynamics in microvessels: Observations of microvessel dilation, invagination and rupture," IEEE International Ultrasonics Symposium, Beijing, China, 2-5 November, 1163-1166, doi:10.1109/ULTSYM.2008.0280 (IEEE, 2008).

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2 Nov 2008

Understanding the interaction of acoustically activated microbubbles with small blood vessels is important for designing better imaging schemes, and for targeting and drug delivery applications. To understand the fundamental mechanisms of this interaction, high-speed microscopy was used to observe microbubble dynamics in microvessels of ex vivo rat mesenteries exposed to a single pulse of ultrasound with a center frequency of 1 MHz and peak negative pressure (PNP) of 1.2 MPa or 11 MPa. It was found that microbubble oscillation caused adjacent microvessel dilation, invagination and even rupture on a microsecond time scale. In small microvessels, microbubble contacted with the vessel wall during expansion under both low and high pressure levels, and microvessel dilation generated by microbubble expansion was larger than invagination induced by bubble collapse. Specifically, under 11 MPa PNP insonation, a small microvessel (17 mum) dilated to 2.7times, and then invaginated to 0.4times of its original diameter, followed by extravasation of re-expanding daughter microbubbles indicating that the microvessel had been ruptured. For large microvessels, microbubbles did not contact with the vessel wall during expansion, and generated much less dilation than invagination at both pressure levels. In one case, a large microbubble caused the wall of a 100 mum microvessel to form a jet-like structure during invagination.

Quantitative assessment of thermal dose using photographic measurements of tissue discoloration

Speyer, G., P. Kaczkowski, A. Brayman, M. Andrew, S. Kargl, and L.A. Crum, "Quantitative assessment of thermal dose using photographic measurements of tissue discoloration," J. Acoust. Soc. Am., 123, 3223, 2008.

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1 May 2008

High Intensity Focused Ultrasound (HIFU) is rapidly gaining widespread clinical use in China, and is undergoing regulatory evaluation in Europe and the US for many target diseases. Nevertheless, tools for therapy planning, monitoring, and assessment remain at a rudimentary level. In particular, measurement of thermal dose in tissues exposed with HIFU has not been sufficiently quantitative to make detailed comparisons with numerical simulations, required for validation of therapy planning models. Indeed, model validation is complicated by high sensitivity of the results to small changes in parameter values and by the general difficulty of performing geometrical registration with sufficient precision to meaningfully compare millimeter scale features typical of HIFU lesions. Our work uses photographic measurement of visible tissue discoloration so that it can be used to accurately and rapidly quantify HIFU-induced bioeffects at scales of several centimeters for comparison with the prior therapy plan. Precise comparison between nonlinear acoustic simulation and macroscopic lesion data indicates that a newly defined "blanching index" is nearly linearly proportional to the logarithm of predicted thermal dose over a very wide range of exposure, including well below the 240 minute (at 43 degrees) necrotic threshold up to about 10,000 minutes.

Therapeutic ultrasound induced cell death from a histological perspective

Brayman, A., P. Kaczkowski, Y.-N. Wang, M. Andrew, L.A. Crum, S. Kargl, and G. Speyer, "Therapeutic ultrasound induced cell death from a histological perspective," J. Acoust. Soc. Am., 123, 2996, doi:10.1121/1.2932547, 2008.

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1 May 2008

High-power, short-exposure time, High Intensity Focused Ultrasound (HIFU) treatment protocols are under development that offer the potential to increase procedure throughput and optimize individual therapies. Histological examination and optical image analysis of tissues following dynamic HIFU exposure in ex vivo bovine liver have revealed that cells undergo a fundamentally different form of cell death. The rapid temperature rise due to the HIFU exposure leaves the cells structurally intact but no longer viable, similar to the cell "fixation" induced by snap-freezing. These results suggest that careful choice of both staining technique and metric for determining cell death are important in quantifying type and morphology of cell ablation, and more broadly, safety and efficacy of treatment. This finding is similar to those obtained and under discussion in the laser and RF ablation communities. Specifically, the NADH staining technique is superior to H&E for assessing cell viability, and an alternative measure of cell death may be preferable to the binary thermal dose threshold currently the standard for HIFU treatment.

Use of a bovine eye lens for observation of HIFU-induced lesions in real-time

Lafon, C., V.A. Khokhlova, O.A. Sapozhnikov, P.J. Kaczkowski, A.A. Brayman, M.R. Bailey, and L.A. Crum, "Use of a bovine eye lens for observation of HIFU-induced lesions in real-time," Ultrasound Med. Biol. 32, 1731-1741, 2006.

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1 Nov 2006

Study of coagulative lesion formation by high intensity focused ultrasound (HIFU) in tissue usually requires performing a sequence of experiments under different exposure conditions followed by tissue sectioning. This paper, inspired by the pioneering work of Frederic L. Lizzi, reports on the use of the bovine eye lens as a laboratory model to observe visually the development of HIFU-induced lesions. The first part of this work describes the measurement of the lens shape, density, sound speed and attenuation. The measured values were within the range of previously published values. In the second part, HIFU-induced lesion development was observed in real-time and compared with good agreement with theoretical simulation. Theoretical modeling included acoustic propagation, absorptive heating and thermal dose, as well as the experimentally measured lens characteristics. Thus, the transparent eye lens can be used as a laboratory phantom to facilitate the understanding of HIFU treatment in other tissues.

Intravascular inertial cavitation activity detection and quantification in vivo with Optison

Tu, J., J.H. Hwang, T.J. Matula, A.A. Brayman, and L.A. Crum, "Intravascular inertial cavitation activity detection and quantification in vivo with Optison," Ultrasound Med. Biol., 32, 1601-1609, 2006.

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1 Oct 2006

Inertial cavitation (IC) is an important mechanism by which ultrasound (US)-induced bioeffects can be produced. It has been reported that US-induced in vitro mechanical bioeffects with the presence of ultrasound contrast agents (UCAs) are highly correlated with quantified IC "dose" (ICD: cumulated root-mean-squared broadband noise amplitude in the frequency domain). The ICD has also been used to quantify IC activity in ex vivo perfused rabbit ear vessels. The in vivo experiments reported here using a rabbit ear vessel model were designed to: (1) detect and quantify IC activity in vivo within the constrained environment of rabbit auricular veins with the presence of Optison and (2) measure the temporal evolution of microbubble IC activity and the ICD generated during insonation treatment, as a function of acoustic parameters. Preselected regions-of-interest (ROI) in the rabbit ear vein were exposed to pulsed focused US (1.17 MHz, 1 Hz PRF). Experimental acoustic variables included peak rarefaction pressure amplitude ([PRPA]: 1.1, 3.0, 6.5 or 9.0 MPa) and pulse length (20, 100, 500 or 1000 cycles). ICD was quantified based on passive cavitation detection (PCD) measurements. The results show that: (1) after Optison injection, the time to onset of measurable microbubble IC activity was relatively consistent, approximately 20 s; (2) after reaching its peak value, the IC activity decayed exponentially and the half-life decay coefficient (t(1/2)) increased with increasing PRPA and pulse length; and (3) the normalized ICD generated by pulsed US exposure increased significantly with increasing PRPA and pulse length.

Inertial cavitation dose produced in ex vivo rabbit ear arteries with Optison by 1-MHz pulsed ultrasound

Tu, J., T.J. Matula, A.A. Brayman, and L.A. Crum, "Inertial cavitation dose produced in ex vivo rabbit ear arteries with Optison by 1-MHz pulsed ultrasound," Ultrasound Med. Biol., 32, 281-288, 2006.

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1 Feb 2006

Previous in vitro studies have shown that ultrasound-induced mechanical bioeffects with contrast agents present are highly correlated with inertial cavitation (IC) "dose" (Chen et al. 2003a, 2003c). The ex vivo experiments conducted here addressed the following hypotheses: 1. IC activity can be generated by insonating perfused rabbit ear blood vessel, and 2. the IC "dose" developed during insonation treatment can be reliably measured and will vary with varying acoustic parameters and Optison concentration. Ex vivo rabbit auricular arteries were perfused with Optison suspensions and then exposed to 1.1-MHz pulsed focused ultrasound. Experimental variables included peak negative acoustic pressure (0.2 MPa to 5.2 MPa), pulse-repetition frequency (5, 50 or 500 Hz), pulse length (50, 100, 500 or 1000 cycles), and Optison volume concentration (0, 0.2, 0.5 or 1%). Cavitation activity was quantified as IC dose, based on passive cavitation detection measurements. The results show that: 1. The IC pressure threshold decreases with higher concentrations of Optison, and 2. IC dose increases significantly with increasing acoustic pressure, Optison concentration, pulse length or with decreasing pulse-repetition frequency.

Ultrasound enhances gene delivery of human factor IX plasmid

Miao, C.H., A.A. Brayman, K.R. Loeb, P.Q. Ye, L. Zhou, P. Mourad, L.A. Crum, "Ultrasound enhances gene delivery of human factor IX plasmid," Hum. Gene Ther., 16, 893-905, 2005

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6 Jul 2005

Delivery of plasmid DNA can be enhanced by treatment with ultrasound (US); acoustic cavitation appears to play an important role in the process. Ultrasound contrast agents (UCAs; stabilized microbubbles) nucleate acoustic cavitation, and lower the acoustic pressure threshold for inertial cavitation occurrence. Fifty micrograms of a liver-specific, high-expressing human factor IX plasmid, pBS-HCRHP-FIXIA, mixed with UCA or phosphate-buffered saline was delivered to mouse livers by intrahepatic injection, with simultaneous exposure to 1 MHz-pulsed US using various acoustic protocols. Variable pulse duration (PD) at constant treatment time, pulse repetition frequency, and an acoustic peak negative pressure amplitude of 1.8 MPa produced 2- to 13-fold enhancements in hFIX gene expression, but PD was not a strong determinant.

In contrast, a dose–response relationship was demonstrated for the peak negative pressure (P ), with significant enhancement of gene transduction at P ≥ 2 MPa. Up to 63 ng/ml (approaching the therapeutic range for treating hemophilia patients) could be achieved by transducing one liver lobe at 4-MPa P , corresponding to a 66- fold increment relative to treatment with naked DNA alone. Under the same conditions, mouse livers could also be transduced with a GFP plasmid. Histology showed transient liver damage caused by intrahepatic injection and US exposure at 4-MPa P ; however, the damage was repaired in a few days. We conclude that therapeutic US in combination with UCA has the potential to promote safe and efficient nonviral gene transfer of hFIX for the treatment of hemophilia.

Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo

Hwang, J.H., A.A. Brayman, M.A. Reidy, T.J. Matula, M.B. Kimmey, and L.A. Crum, "Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo," Ultrasound Med. Biol., 31, 553-564, doi:10.1016/j.ultrasmedbio.2004.12.014, 2005

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11 Apr 2005

Previous in vivo studies have demonstrated that microvessel hemorrhages and alterations of endothelial permeability can be produced in tissues containing microbubble-based ultrasound contrast agents when those tissues are exposed to MHz-frequency pulsed ultrasound of sufficient pressure amplitudes. The general hypothesis guiding this research was that acoustic (viz., inertial) cavitation, rather than thermal insult, is the dominant mechanism by which such effects arise. We report the results of testing five specific hypotheses in an in vivo rabbit auricular blood vessel model: (1) acoustic cavitation nucleated by microbubble contrast agent can damage the endothelia of veins at relatively low spatial-peak temporal-average intensities, (2) such damage will be proportional to the peak negative pressure amplitude of the insonifying pulses, (3) damage will be confined largely to the intimal surface, with sparing of perivascular tissues, (4) greater damage will occur to the endothelial cells on the side of the vessel distal to the source transducer than on the proximal side and (5) ultrasound/contrast agent-induced endothelial damage can be inherently thrombogenic, or can aid sclerotherapeutic thrombogenesis through the application of otherwise subtherapeutic doses of thrombogenic drugs. Auricular vessels were exposed to 1-MHz focused ultrasound of variable peak pressure amplitude using low duty factor, fixed pulse parameters, with or without infusion of a shelled microbubble contrast agent. Extravasation of Evans blue dye and erythrocytes was assessed at the macroscopic level. Endothelial damage was assessed via scanning electron microscopy (SEM) image analysis. The hypotheses were supported by the data. We discuss potential therapeutic applications of vessel occlusion, e.g., occlusion of at-risk gastric varices.

Occlusive thrombosis in the rabbit auricular vein in vivo targeted by induction of intralumenal cavitation using HIFU and ultrasound contrast agent

Brayman, A.A., J. Tu, T. Matula, L.A. Crum, J.H. Hwang, and M.B. Kimmey, "Occlusive thrombosis in the rabbit auricular vein in vivo targeted by induction of intralumenal cavitation using HIFU and ultrasound contrast agent," J. Acoust. Soc. Am., 117, 2558, 2005

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2 Apr 2005

Hypotheses tested: (1) inertial cavitation [IC] could be induced in the venous lumen in vivo by combined use of intravascular microbubble contrast agent and transcutaneous application of 1-MHz high intensity focused ultrasound [HIFU] of very low duty factor, and that IC activity could be detected and quantified in vivo as in earlier in vitro studies via passive cavitation detection methods; (2) robust IC activity would damage the venous endothelium in treated regions; (3) endothelial damage would be proportional to the IC dose developed in the region; (4) severe local endothelial damage alone may be sufficient to induce occlusive thrombosis, or may sensitize the region to low systemic doses of prothrombotic agents, and (5) biologically significant temperature rises and attendant thermal bioeffects in the vessel and perivascular tissues would not occur, even under the highest amplitude acoustic conditions applied. Each hypothesis was supported by the data. The principal result was that under treatment conditions involving very high peak negative acoustic pressures and contrast agent, treated areas thrombosed acutely but non-occlusively. When fibrinogen was administered locally after such treatment, occlusive thrombi formed acutely and only in the treated region, a response observed with none of the other treatments.

Vector-Doppler ultrasound for the detection of internal bleeding

Cunitz, B.W., P.J. Kaczkowski, and A.A. Brayman, "Vector-Doppler ultrasound for the detection of internal bleeding," J. Acoust. Soc. Am., 117, 2584, 2005

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2 Apr 2005

A vector Doppler (VDop) ultrasound system uses a transmitter and a spatially separated pair of receivers to measure bistatic scattering from blood. VDop has two principal advantages over color-flow Doppler in identifying internal bleeding: (1) measures flow direction, and thus absolute magnitude of flow velocity (2) does not require special orientation to detect and measure flow, thus can measure flows perpendicular to the transmitter. Our hypothesis is that real-time flow direction and magnitude can be used to detect and characterize internal bleeding. A real-time vector Doppler system has been built and tested in vitro. The system is capable of measuring flow magnitude and direction up to 145 cm/s at a depth of 3.6 cm at a processing rate of 10 Hz. Accuracy was measured using a calibrated moving string phantom and the system performs well within a useful range. A blood flow phantom was developed to mimic arterial flow into an open cavity as well as into tissue and replicate both pulsatile flow as well as the energy storage due to vascular elasticity. Flow signature data is gathered under conditions of normal branching flow, and vessel breach. The talk will describe the VDop system and the flow phantom and summarize results.

Ultrasound contrast agents for bleeding detection and acoustic hemostasis

Zderic, V., W. Luo, A. Brayman, L. Crum, and S. Vaezy, "Ultrasound contrast agents for bleeding detection and acoustic hemostasis," J. Acoust. Soc. Am., 117, 2475, 2005.

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1 Apr 2005

Objective: To investigate the application of ultrasound contrast agents (UCA) in improving both therapeutic and diagnostic aspects of ultrasound-guided High Intensity Focused Ultrasound (HIFU) therapy. Methods: Incisions (3 cm long, 0.5 cm deep) were made in rabbit livers (in anterior surface for HIFU treatment, or posterior surface for bleeding detection). UCA Optison ~0.1 ml/kg) was injected into mesenteric vein or ear vein. A HIFU applicator (5.5 MHz, 6400 W/cm2) was scanned manually over the incision until hemostasis was achieved. Occult bleeding was monitored with Doppler ultrasound. Results: The presence of Optison produced 37% reduction in hemostasis times normalized to initial bleeding rates. Gross and histological observations showed similar appearance of HIFU lesions produced in the presence of Optison and control HIFU lesions. The temperature reached 100°C in both HIFU only and HIFU UCA treatments. Tension strength of hemostatic liver incisions was 0.9±0.5 N. Almost no bleeding could be detected before Optison injection. First appearance of contrast enhancement localized at the bleeding site was 15 s after Optison injection, and lasted for ~50 s. Conclusion: The presence of UCA during HIFU treatment of liver incisions resulted in shortening of HIFU application times and better visualization of bleeding sites.

Design and evaluation of complex moving HIFU treatment protocols

Kargl, S.G., M.A. Andrew, P.J. Kaczkowski, A.A. Brayman, and L.A. Crum, "Design and evaluation of complex moving HIFU treatment protocols," Proceedings, American Institute of Physics Conference, number 754, 140-142, doi:10.1063/1.1901621 (2005).

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28 Mar 2005

The use of moving high-intensity focused ultrasound (HIFU) treatment protocols is of interest in achieving efficient formation of large-volume thermal lesions in tissue. Judicious protocol design is critical in order to avoid collateral damage to healthy tissues outside the treatment zone. A KZK–BHTE model, extended to simulate multiple, moving scans in tissue, is used to investigate protocol design considerations. Prediction and experimental observations are presented which 1) validate the model, 2) illustrate how to assess the effects of acoustic nonlinearity, and 3) demonstrate how to assess and control collateral damage such as prefocal lesion formation and lesion formation resulting from thermal conduction without direct HIFU exposure. Experimental data consist of linear and circular scan protocols delivered over a range of exposure regimes in ex vivo bovine liver.

HIFU hemostasis of liver injuries enhanced by ultrasound contrast agents

Zderic, V., S. Vaezy, A.A. Brayman, T.J. Matula, G.E. O'Keefe, and L.A. Crum, "HIFU hemostasis of liver injuries enhanced by ultrasound contrast agents," Proceedings, American Institute of Physics Conference, number 754, 55-57 (2005).

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28 Mar 2005

Our objective was to investigate whether High-Intensity Focused Ultrasound (HIFU) hemostasis can be achieved faster in the presence of ultrasound contrast agents (UCA). Incisions (3 cm long and 0.5 cm deep) were made in surgically exposed rabbit liver. Optison at a concentration of 0.18 ml/kg was injected into the mesenteric vein, immediately before the incision was made. The HIFU applicator (frequency of 5.5 MHz, and intensity of 3,700 W/cm2) was scanned manually over the incision (at an approximate rate of 1 mm/s) until hemostasis was achieved. The times to complete hemostasis were measured and normalized with the initial blood loss. The hemostasis times were 59±23 s in the presence of Optison and 70±23 s without Optison. The presence of Optison produced a 37% reduction in the normalized hemostasis times (p<0.05). Optison also provided faster (by 34%) formation of the coagulum seal over the lesion. Gross observations showed that the lesion size did not change due to the presence of Optison. Histological analysis showed that lesions consisted of an area of coagulation necrosis in vicinity of the incision, occasionally surrounded by a congestion zone filled with blood. Our results suggest the potential utility of microbubble contrast agents for increasing efficiency of HIFU hemostasis of internal organ injuries.

Circular scanned thermal lesions in ex vivo bovine liver

Andrew, M., S. Kargl, P. Kaczkowski, B. Cunitz, and A. Brayman, "Circular scanned thermal lesions in ex vivo bovine liver," Proceedings of the 3rd International Symposium on Therapeutic Ultrasound, edited by J.Y. Chapelon and C. Lafon, 359-364 (Lyon, France, INSERM, 2004).

15 Sep 2004

A comparison of the fragmentation thresholds and inertial cavitation doses of different ultrasound contrast agents

Chen, W.-S., T.J. Matula, A.A. Brayman, and L.A. Crum, "A comparison of the fragmentation thresholds and inertial cavitation doses of different ultrasound contrast agents," J. Acoust. Soc. Am., 113, 643-651, 2003.

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1 Dec 2003

Contrast bubble destruction is important in several new diagnostic and therapeutic applications. The pressure threshold of destruction is determined by the shell material, while the propensity for of the bubbles to undergo inertial cavitation (IC) depends both on the gas and shell properties of the ultrasound contrast agent (UCA). The ultrasonic fragmentation thresholds of three specific UCAs (Optison, Sonazoid, and biSpheres), each with different shell and gas properties, were determined under various acoustic conditions. The acoustic emissions generated by the agents, or their derivatives, characteristic of IC after fragmentation, was also compared, using cumulated broadband-noise emissions (IC "dose"). Albumin-shelled Optison and surfactant-shelled Sonazoid had low fragmentation thresholds (mean = 0.13 and 0.15 MPa at 1.1 MHz, 0.48 and 0.58 MPa at 3.5 MHz, respectively), while polymer-shelled biSpheres had a significant higher threshold (mean = 0.19 and 0.23 MPa at 1.1 MHz, 0.73 and 0.96 MPa for thin- and thick-shell biSpheres at 3.5 MHz, respectively, p<0.01). At comparable initial concentrations, surfactant-shelled Sonazoid produced a much larger IC dose after shell destruction than did either biSpheres or Optison (p<0.01). Thick-shelled biSpheres had the highest fragmentation threshold and produced the lowest IC dose. More than two and five acoustic cycles, respectively, were necessary for the thin- and thick-shell biSpheres to reach a steady-state fragmentation threshold.

Acoustic hemostasis

Crum, L., M. Andrew, M. Bailey, K. Beach, A. Brayman, F. Curra, P. Kaczkowski, S. Kargl, R. Martin, and S. Vaezy, "Acoustic hemostasis," J. Acoust. Soc. Am., 113, 2280, 2003.

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1 Oct 2003

Over the past several years, the Center for Industrial and Medical Ultrasound (CIMU) at the Applied Physics Laboratory in the University of Washington has undertaken a broad research program in the general area of High Intensity Focused Ultrasound (HIFU). Our principal emphasis has been on the use of HIFU to induce hemostasis; in particular, CIMU has sought to develop a small, lightweight, portable device that would use ultrasound for both imaging and therapy. Such a technology is needed because nearly 50% of combat casualty mortality results from exsanguinations, or uncontrolled bleeding. A similar percentage occurs for civilian death due to trauma. In this general review, a presentation of the general problem will be given, as well as our recent approaches to the development of an image-guided, transcutaneous, acoustic hemostasis device.

Study of a scanning HIFU therapy protocol, Part II: Experiment and results

Andrew, M.A., P.J. Kaczkowski, B.W. Cunitz, A.A. Brayman, and S.G. Kargl, "Study of a scanning HIFU therapy protocol, Part II: Experiment and results," J. Acoust. Soc. Am., 113, 2309, 2003.

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1 Oct 2003

Instrumentation and protocols for creating scanned HIFU lesions in freshly excised bovine liver were developed in order to study the in vitro HIFU dose response and validate models. Computer control of the HIFU transducer and 3-axis positioning system provided precise spatial placement of the thermal lesions. Scan speeds were selected in the range of 1 to 8 mm/s, and the applied electrical power was varied from 20 to 60 W. These parameters were chosen to hold the thermal dose constant. A total of six valid scans of 15 mm length were created in each sample; a 3.5 MHz single-element, spherically focused transducer was used. Treated samples were frozen, then sliced in 1.27 mm increments. Digital photographs of slices were downloaded to computer for image processing and analysis. Lesion characteristics, including the depth within the tissue, axial length, and radial width, were computed. Results were compared with those generated from modified KZK and BHTE models, and include a comparison of the statistical variation in the across-scan lesion radial width.

Enhancement of gene delivery of naked human factor IX plasmid into mouse liver by ultrasound exposure

Miao, C.H., A.A. Brayman, P. Ye, P. Mourad, and L.A. Crum, "Enhancement of gene delivery of naked human factor IX plasmid into mouse liver by ultrasound exposure," in Therapeutic Ultrasound, Proceedings of the 2nd International symposium, M.A. Andrew, L.A. Crum, and S. Vaezy, eds., 71-75 (American Institute of Physics Press, 2003).

1 Jun 2003

Experimental apparatus and methods for in vitro HIFU dose response studies

Andrew, M., P. Kaczkowski, A Brayman, B. Cunitz, A. Anand, C. Lafon, and L. Crum, "Experimental apparatus and methods for in vitro HIFU dose response studies," in Therapeutic Ultrasound, Proceedings of the 2nd International Symposium, M.A. Andrew, L.A. Crum and S. Vaezy, eds., 330-340 (American Institute of Physics Press, 2003).

1 Jun 2003

In vitro examination of nonlinear heat deposition in HIFU lesion formation

Kackzkowski, P., M. Andrew, A. Brayman, S. Kargl, B. Cunitz, C. Lafon, V. Khokhlova, and L.A. Crum, "In vitro examination of nonlinear heat deposition in HIFU lesion formation," in Therapeutic Ultrasound, Proceedings of the 2nd International symposium, M.A. Andrew, L.A. Crum, and S. Vaezy, eds., 341-352 (American Institute of Physics Press, 2003).

1 Jun 2003

Mechanisms of lesion formation in HIFU therapy

Chen W.-S., C. Lafon, T.J. Matula, S. Vaezy, A. Brayman, and L.A. Crum, "Mechanisms of lesion formation in HIFU therapy," in Therapeutic Ultrasound, Proceedings of the 2nd International symposium, M.A. Andrew, L.A. Crum, and S. Vaezy, eds., 400-409 (American Institute of Physics Press, 2003).

1 Jun 2003

Pulsed high-intensity focused ultrasound-induced endothelial cell injury in vessels infused with ultrasound contrast agent

Hwang, J.H., A.A. Brayman, and S. Vaezy, "Pulsed high-intensity focused ultrasound-induced endothelial cell injury in vessels infused with ultrasound contrast agent," in Therapeutic Ultrasound, Proceedings of the 2nd International symposium, M.A. Andrew, L.A. Crum, and S. Vaezy, eds., 275-281 (American Institute of Physics Press, 2003).

1 Jun 2003

Inertial cavitation dose and hemolysis produced in vitro with or without Optison®

Chen, W.-S., A.A. Brayman, T.J. Matula, and L.A. Crum, "Inertial cavitation dose and hemolysis produced in vitro with or without Optison®," Ultrasound Med. Biol., 29), 725-737, doi:10.1016/S0301-5629(03)00013-9, 2003.

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9 May 2003

Gas-based contrast agents (CAs) increase ultrasound (US)-induced bioeffects, presumably via an inertial cavitation (IC) mechanism. The relationship between IC dose (ICD) (cumulated root mean squared [RMS] broadband noise amplitude; frequency domain) and 1.1-MHz US-induced hemolysis in whole human blood was explored with Optison®; the hypothesis was that hemolysis would correlate with ICD. Four experimental series were conducted, with variable: 1. peak negative acoustic pressure (P–), 2. Optison® concentration, 3. pulse duration and 4. total exposure duration and Optison® concentration. P– thresholds for hemolysis and ICD were ~0.5 MPa. ICD and hemolysis were detected at Optison® concentrations ≥ 0.01 V%, and with pulse durations as low as four or two cycles, respectively. Hemolysis and ICD evolved as functions of time and Optison® concentration; final hemolysis and ICD values depended on initial Optison® concentration, but initial rates of change did not. Within series, hemolysis was significantly correlated with ICD; across series, the correlation was significant at p < 0.001.

The pulse length-dependence of inertial cavitation dose and hemolysis

Chen, W.-S., A.A. Brayman, T.J. Matula, L.A. Crum, and M.W. Miller, "The pulse length-dependence of inertial cavitation dose and hemolysis," Ultrasound Med. Biol., 29, 739-748, doi:10.1016/S0301-5629(03)00029-2, 2003.

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9 May 2003

Gas-based ultrasound (US) contrast agents increase erythrocyte sonolysis, presumably via enhancing inertial cavitation (IC) activity. The amount of IC activity (IC "dose") and hemolysis generated by exposure to 1.15 MHz US were examined with different US pulse lengths, but with the same delivered acoustic energy, for Optison® and Albunex®. The hypotheses were that 1. at longer pulse lengths, IC would generate more bubbles that could nucleate additional IC activity; 2. if the interval between pulse pairs were short enough for the next pulse to hit derivative bubbles before their dissolution, more IC could be induced; and 3. hemolysis would be proportional to IC activity. Two types of studies were performed. In the first, bubble generation after each burst of IC activity was quantified using an active cavitation detector (ACD), for different pulse lengths (5, 10, 20, 30, 50, 100 or 200 cycles), but the same pressure level (3 MPa) and total "on" time (173.16 ms). Low concentrations of either Optison® or Albunex® were added into the tank with high-intensity and interrogating transducers orthogonal to each other. For pulse lengths > 100 cycles, and pulse repetition intervals < 5 ms, a "cascade" effect (explosive bubble generation) was observed. In the second, IC was measured by passive detection methods. IC dose and hemolysis were determined in whole blood samples at a pressure level (3 MPa) and interpulse interval (5 ms) that induced the "cascade" effect. Each blood sample was mixed with the same number of contrast microbubbles (Optison® ~ 0.3 v/v % and Albunex® ~ 0.5 v/v %), but exposed to different pulse lengths (5, 10, 20, 30, 50, 100 or 200 cycles). With Optison®, up to 60% hemolysis was produced with long pulses (100 and 200 cycles), compared with < 10% with short pulses (5 and 10 cycles). Albunex® generated considerably less IC activity and hemolysis. The r2 value was 0.99 for the correlation between hemolysis and IC dose. High pulse-repetition frequency (PRF) (500 Hz) generated more hemolysis than the low PRF (200 Hz) at 3 MPa. All experimental results could be explained by the dissolution times of IC-generated bubbles.

Broadband noise emissions produced by pulsed 1-MHz ultrasound exposures in the presence or absence of Optison, and their relationship to the hemolytic bioeffect

Brayman, A.A., W.S. Chen, T.J. Matula, and L.A. Crum, "Broadband noise emissions produced by pulsed 1-MHz ultrasound exposures in the presence or absence of Optison, and their relationship to the hemolytic bioeffect," J. Acoust. Soc. Am., 111, 2462, 2002.

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1 Oct 2002

Gas-based contrast agents are known to increase ultrasound-induced bioeffects, presumably via an inertial cavitation (IC) mechanism. The relationship between IC "dose" (ICD) (cumulated rms broadband noise amplitude in the frequency domain) and 1.1-MHz ultrasound-induced hemolysis in whole human blood was explored with additions of Optison or degassed saline; the hypothesis was that hemolysis would correlate with ICD. Four experimental series were conducted, with variable: (1) peak negative acoustic pressure [P–]; (2) Optison concentration; (3) pulse duration; and (4) total exposure duration and variable Optison concentration. The P– thresholds for hemolysis and ICD above noise levels were ~0.5 MPa. Enhancement of ICD and hemolysis was detected even at the lowest Optison concentration tested (0.1%) at P–=3 MPa. At 2 MPa P–(0.3% Optison), significant hemolysis and ICD were detected with pulse durations as brief as 2 and 4 cycles, respectively. At 3 MPa P–, hemolysis and ICD evolved as functions of time and Optison concentration; ultimate levels of hemolysis and ICD depended strongly on initial Optison concentration, but initial rates of change did not. Within experimental series, hemolysis was significantly correlated with ICD; across series, the correlation was significant at p less than 0.001.

Hyperthermic teratogenicity, thermal dose and diagnostic ultrasound during pregnancy: implications of new standards on tissue heating

Miller, M.W., W.L. Nyborg, W.L. Dewey, M.J. Edwards, J.S. Abramowicz, and A.A. Brayman, "Hyperthermic teratogenicity, thermal dose and diagnostic ultrasound during pregnancy: implications of new standards on tissue heating," Int. J. Hyperth., 18, 361-384, 2002.

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1 Sep 2002

Hyperthermia is a recognized teratogen in mammalian laboratory animals and is a suspected teratogen for humans. The purpose of this synopsis is to reanalyse existing data on hyperthermia-induced teratogenic effects in experimental mammalian systems in terms of a thermal dose (temperature:time) concept, and then to illustrate the utility of this concept to human situations involving potential thermal increments to post-implantation embryos and foetuses. For example, the threshold temperature elevation for hyperthermia-induced teratogenic effects in experimental mammals is estimated (but not rigorously tested) to be approximately 1.5 degrees C above core values for exposures of long duration, possibly with a thermal dose of approximately 5 min duration or more at 4 degrees C. This level of tissue temperature increment is within the capability of some modern diagnostic ultrasound (DUS) devices sold within the USA and abroad. Epidemiological studies have not indicated any hazard from the use of DUS, but such studies are limited in sensitivity and were conducted with DUS devices whose acoustic outputs were relatively low compared to those presently available. After a regulatory change that allowed for substantially increased acoustic outputs, modern DUS devices were mandated to provide the user with on-screen information (the Thermal Index, or 'TI') about ultrasound-induced temperature increments in the target tissue. The TI is generally accurate to within a factor of 2, but the factor may be as high as 6 in certain obstetric settings. Thus, informed use of and attention to the TI is strongly advised, with this admonition gaining increased emphasis if the present regulations regarding allowable acoustic outputs of DUS devices were to be further relaxed or eliminated.

A comparison of the hemolystic potential of Optison and Albunex in whole human blood in vitro: acoustic pressure, ultrasound frequency, donor and passive cavitation detection considerations

Miller, M.W., E.C. Everbach, C. Cox, R. Knapp, A.A. Brayman, and T.S. Sherman, "A comparison of the hemolystic potential of Optison and Albunex in whole human blood in vitro: acoustic pressure, ultrasound frequency, donor and passive cavitation detection considerations," Ultrasound Med. Biol., 27, 709-721, 2001.

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1 May 2001

This project tested the hypothesis that a "second-generation" ultrasound (US) contrast agent (Optison), offering extended echogenicity over that of its "first-generation" predecessor (Albunex), would have the greater potential for sonolysis of human erythrocytes in vitro. Whole human blood, obtained from apparently healthy donors, was anticoagulated and subsequently exposed in vitro to US in the presence of one of each or neither of the two US contrast agents. The US exposures were for 30 s and involved frequency (1.0, 2.2 and 3.4 MHz) and amplitude (approximately 2.8 to 0.38 MPa P(-)) regimens; pulse duration (200 micros) and interpulse interval (20 ms) were held constant. The data supported the hypothesis, with an overall ratio of approximately 2.5 for relative extent of background-corrected US-induced hemolysis of the Optison/Albunex regimens. Passive cavitation detection analyses corroborated the results obtained with hemolysis.

Real-time observation of inception and growth of HIFU-induced tissue lesions

Lafon, C., M.R. Bailey, L.N. Couret, P.J. Kaczkowski, A.A. Brayman, L.A. Crum, and O.A. Sapozhnikov, "Real-time observation of inception and growth of HIFU-induced tissue lesions," J. Acoust. Soc. Am., 108, 2546, 2000.

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1 Nov 2000

To study the biological effects of high-intensity focused ultrasound (HIFU), experiments are usually performed on isolated or perfused tissues. Indeed, the complex phenomena occurring in tissue during HIFU-induced coagulation necrosis is difficult to mimic with synthetic phantoms. A good phantom should first match the acoustical and thermal properties of tissues. Furthermore, heating above a thermal threshold should induce a permanent, localized and observable change corresponding to protein denaturing in tissue. Lastly, the choice of a transparent material makes possible real-time examination of the development of coagulation necroses. We have used bovine eye lenses in this aim. The density, sound speed, attenuation, and thermal threshold for irreversible damage to the bovine lens were measured and found to be similar to those for liver or muscle, common tissues for HIFU experiments, although acoustic attenuation is slightly higher in the lens. Transparency of the lens allowed us to observe HIFU-induced lesion evolution in real time. The shape and size of the lesions obtained in the lens agreed well with results obtained in liver. In conclusion, the transparent bovine eye lens is a useful model for visualization of thermal lesions.

Comparative sensitivity of human and bovine erthrocytes to sonolysis by 1 MHz ultrasound

Miller, M.W., T.S. Sherman, and A.A. Brayman, "Comparative sensitivity of human and bovine erthrocytes to sonolysis by 1 MHz ultrasound," Ultrasound Med. Biol., 26, 1317-1326, 2000.

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1 Oct 2000

This project tested the hypothesis that human erythrocytes, being larger than bovine erythrocytes, would be the more sensitive to sonolysis induced by inertial cavitation. The rationale behind this hypothesis was an earlier demonstration that, among sized populations of erythrocytes, an inverse relation existed between erythrocyte volume and mechanically-induced shear forces in the surrounding medium; viz, the larger the cell, the less shear force required to rupture the cell's membrane. At low erythrocyte densities (i.e., approximately 5% hematocrit) the hypothesis was supported; at high cell densities (i.e., approximately 35% hematocrit) it was not supported. The data are consistent with an ultrasound (US)-induced symmetric implosion of affected gas nuclei as causing the effect at low cell densities; under such conditions there is ample spacing among cells for US-induced symmetric growth and collapse of gas nuclei and the concomitant production of radially-expanding shock waves (which lyse the cells); at high cell densities there is not sufficient spacing among cells for US-induced symmetric growth and collapse of bubbles and an alternative mechanism, possibly asymmetric bubble collapse, becomes operational.

Mechanical bioeffects in presence of gas-carrier, ultrasound contrast agents

Brayman, A.A., D. Dalecki, J.H. Wible, J. Wu, J.S. Abramowicz, R.S. Meltzer, and T.R. Porter, "Mechanical bioeffects in presence of gas-carrier, ultrasound contrast agents," in Mechanical Bioeffects From Diagnostic Ultrasound: Consensus Statements, edited by J.B. Fowlkes and C.K. Holland CK, J.Ultrasound Med., 19, 120-142, 2000.

1 Feb 2000

Inventions

Systems, Devices, and Methods for Separating, Concentrating, and/or Differentiating Between Cells from a Cell Sample

Embodiments are generally related to differentiating and/or separating portions of a sample that are of interest from the remainder of the sample. Embodiments may be directed towards separating cells of interest from a cell sample. In some embodiments, acoustic impedances of the cells of interest may be modified. For example, the acoustic properties of the cells of interest may be modified by attaching bubbles to the cells of interest. The cell sample may then be subjected to an acoustic wave. The cells of interest may be differentiated and/or separated from the remainder of the sample based on relative displacements and/or volumetric changes experienced by the cells of interest in response thereto. The cells of interest may be separated using a standing wave and sorted into separate channels of a flow cell. Optionally, the cells may be interrogated by a light source and differentiated by signals generated in response thereto.

Patent Number: 9,645,080

Tom Matula, Andrew Brayman, Oleg Sapozhnikov, Brian MacConaghy, Jarred Swalwell, Camilo Perez

Patent

9 May 2017

Ultrasonic Persistence Imaging of Tissues in Which Acoustic Microbubble Destruction has Occurred

Record of Invention Number: 46066

Andrew Brayman

Disclosure

3 May 2012

Ultrasound Target Vessel Occlusion Using Microbubbles

Patent Number: US 7,591,996 B2

Joo Ha Hwang, Andrew Brayman

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Patent

22 Sep 2009

Selective occlusion of a blood vessel is achieved by selectively damaging endothelial cells at a target location in the blood vessel, resulting in the formation of a fibrin clot proximate to the damaged endothelial cells. Additional fibrinogen can then be introduced into the blood vessel if occlusion is not achieved, as the fibrinogen is converted to fibrin by enzymes released by the exposed thrombogenic tissue and activated platelets. Endothelial cells are selectively damaged using thermal effects induced by ultrasound, by mechanical effects induced by ultrasound, or by mechanical effects produced by a tool introduced into the blood vessel (such as catheter-based tool). A particularly preferred technique for selectively damaging endothelial cells involves introducing an ultrasound activatable agent into the blood vessel, and causing cavitation in that agent using pulses of high-intensity focused ultrasound having a duration insufficient to induce thermal damage in adjacent perivascular tissue.

More Inventions

Method for Diagnostic Ultrasound-based Monitoring of High Intensity Focused Ultrasound Therapy

Record of Invention Number: 8309D

Andrew Brayman, Larry Crum, Peter Kaczkowski, Gavriel Speyer

Disclosure

9 Mar 2009

Acoustics Air-Sea Interaction & Remote Sensing Center for Environmental & Information Systems Center for Industrial & Medical Ultrasound Electronic & Photonic Systems Ocean Engineering Ocean Physics Polar Science Center
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