Publications by authors named "Tatiana D Khokhlova"

29 Publications

  • Page 1 of 1

Ultrastructural Analysis of Volumetric Histotripsy Bio-effects in Large Human Hematomas.

Ultrasound Med Biol 2021 Sep 9;47(9):2608-2621. Epub 2021 Jun 9.

Laboratory for Industrial and Medical Ultrasound, Physics Faculty, M. V. Lomonosov Moscow State University, Moscow, Russian Federation; Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington, USA.

Large-volume soft tissue hematomas are a serious clinical problem, which, if untreated, can have severe consequences. Current treatments are associated with significant pain and discomfort. It has been reported that in an in vitro bovine hematoma model, pulsed high-intensity focused ultrasound (HIFU) ablation, termed histotripsy, can be used to rapidly and non-invasively liquefy the hematoma through localized bubble activity, enabling fine-needle aspiration. The goals of this study were to evaluate the efficiency and speed of volumetric histotripsy liquefaction using a large in vitro human hematoma model. Large human hematoma phantoms (85 cc) were formed by recalcifying blood anticoagulated with citrate phosphate dextrose/saline-adenine-glucose-mannitol solution. Typical boiling histotripsy pulses (10 or 2 ms) or hybrid histotripsy pulses using higher-amplitude and shorter pulses (0.4 ms) were delivered at 1% duty cycle while continuously translating the HIFU focus location. Histotripsy exposures were performed under ultrasound guidance with a 1.5-MHz transducer (8-cm aperture, F# = 0.75). The volume of liquefied lesions was determined by ultrasound imaging and gross inspection. Untreated hematoma samples and samples of the liquefied lesions aspirated using a fine needle were analyzed cytologically and ultrastructurally with scanning electron microscopy. All exposures resulted in uniform liquid-filled voids with sharp edges; liquefaction speed was higher for exposures with shorter pulses and higher shock amplitudes at the focus (up to 0.32, 0.68 and 2.62 mL/min for 10-, 2- and 0.4-ms pulses, respectively). Cytological and ultrastructural observations revealed completely homogenized blood cells and fibrin fragments in the lysate. Most of the fibrin fragments were less than 20 μm in length, but a number of fragments were up to 150 μm. The lysate with residual debris of that size would potentially be amenable to fine-needle aspiration without risk for needle clogging in clinical implementation.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355095PMC
September 2021

Partial Respiratory Motion Compensation for Abdominal Extracorporeal Boiling Histotripsy Treatments With a Robotic Arm.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Sep 27;68(9):2861-2870. Epub 2021 Aug 27.

Extracorporeal boiling histotripsy (BH), a noninvasive method for mechanical tissue disintegration, is getting closer to clinical applications. However, the motion of the targeted organs, mostly resulting from the respiratory motion, reduces the efficiency of the treatment. Here, a practical and affordable unidirectional respiratory motion compensation method for BH is proposed and evaluated in ex vivo tissues. The BH transducer is fixed on a robotic arm following the motion of the skin, which is tracked using an inline ultrasound imaging probe. In order to compensate for system lags and obtain a more accurate compensation, an autoregressive motion prediction model is implemented. BH pulse gating is also implemented to ensure targeting accuracy. The system is then evaluated with ex vivo BH treatments of tissue samples undergoing motion simulating breathing with the movement of amplitudes between 5 and 10 mm, the frequency between 16 and 18 breaths/min, and a maximum speed of 14.2 mm/s. Results show a reduction of at least 89% of the value of the targeting error during treatment while only increasing the treatment time by no more than 1%. The lesions obtained by treating with the motion compensation were close in size and affected area to the no-motion case, whereas lesions obtained without the compensation were often incomplete and had larger affected areas. This approach to motion compensation could benefit extracorporeal BH and other histotripsy methods in clinical translation.
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http://dx.doi.org/10.1109/TUFFC.2021.3075938DOI Listing
September 2021

Inertial Cavitation Behaviors Induced by Nonlinear Focused Ultrasound Pulses.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Sep 27;68(9):2884-2895. Epub 2021 Aug 27.

Inertial cavitation induced by pulsed high-intensity focused ultrasound (pHIFU) has previously been shown to successfully permeabilize tumor tissue and enhance chemotherapeutic drug uptake. In addition to HIFU frequency, peak rarefactional pressure ( p ), and pulse duration, the threshold for cavitation-induced bioeffects has recently been correlated with asymmetric distortion caused by nonlinear propagation, diffraction and formation of shocks in the focal waveform, and therefore with the transducer F -number. To connect previously observed bioeffects with bubble dynamics and their attendant physical mechanisms, the dependence of inertial cavitation behavior on shock formation was investigated in transparent agarose gel phantoms using high-speed photography and passive cavitation detection (PCD). Agarose phantoms with concentrations ranging from 1.5% to 5% were exposed to 1-ms pulses using three transducers of the same aperture but different focal distances ( F -numbers of 0.77, 1.02, and 1.52). Pulses had central frequencies of 1, 1.5, or 1.9 MHz and a range of p at the focus varying within 1-18 MPa. Three distinct categories of bubble behavior were observed as the acoustic power increased: stationary near-spherical oscillation of individual bubbles, proliferation of multiple bubbles along the pHIFU beam axis, and fanned-out proliferation toward the transducer. Proliferating bubbles were only observed under strongly nonlinear or shock-forming conditions regardless of frequency, and only where the bubbles reached a certain threshold size range. In stiffer gels with higher agarose concentrations, the same pattern of cavitation behavior was observed, but the dimensions of proliferating clouds were smaller. These observations suggest mechanisms that may be involved in bubble proliferation: enhanced growth of bubbles under shock-forming conditions, subsequent shock scattering from the gel-bubble interface, causing an increase in the repetitive tension created by the acoustic wave, and the appearance of a new growing bubble in the proximal direction. Different behaviors corresponded to specific spectral characteristics in the PCD signals: broadband noise in all cases, narrow peaks of backscattered harmonics in the case of stationary bubbles, and broadened, shifted harmonic peaks in the case of proliferating bubbles. The shift in harmonic peaks can be interpreted as a Doppler shift from targets moving at speeds of up to 2 m/s, which correspond to the observed bubble proliferation speeds.
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http://dx.doi.org/10.1109/TUFFC.2021.3073347DOI Listing
September 2021

Dual-Use Transducer for Ultrasound Imaging and Pulsed Focused Ultrasound Therapy.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Sep 27;68(9):2930-2941. Epub 2021 Aug 27.

Pulsed focused ultrasound (pFUS) uses short acoustic pulses delivered at low duty cycle and moderate intensity to noninvasively apply mechanical stress or introduce disruption to tissue. Ultrasound-guided pFUS has primarily been used for inducing cavitation at the focus, with or without contrast agents, to promote drug delivery to tumors. When applied in tandem with contrast agents, pFUS is often administered using an ultrasound imaging probe, which has a small footprint and does not require a large acoustic window. The use of nonlinear pFUS without contrast agents was recently shown to be beneficial for localized tissue disruption, but required higher ultrasound pressure levels than a conventional ultrasound imaging probe could produce. In this work, we present the design of a compact dual-use 1-MHz transducer for ultrasound-guided pFUS without contrast agents. Nonlinear pressure fields that could be generated by the probe, under realistic power input, were simulated using the Westervelt equation. In water, fully developed shocks of 42-MPa amplitude and peak negative pressure of 8 MPa were predicted to form at the focus at 458-W acoustic power or 35% of the maximum reachable power of the transducer. In absorptive soft tissue, fully developed shocks formed at higher power (760 W or 58% of the maximum reachable power) with the shock amplitude of 33 MPa and peak negative pressure of 7.5 MPa. The electronic focus-steering capabilities of the array were evaluated and found to be sufficient to cover a target with dimensions of 19 mm in axial direction and 44 mm in transversal direction.
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http://dx.doi.org/10.1109/TUFFC.2021.3070528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443157PMC
September 2021

Bilayer aberration-inducing gel phantom for high intensity focused ultrasound applications.

J Acoust Soc Am 2020 12;148(6):3569

Department of Acoustics, Physics Faculty, Moscow State University, Leninskie Gory, Moscow 119991, Russia.

Aberrations induced by soft tissue inhomogeneities often complicate high-intensity focused ultrasound (HIFU) therapies. In this work, a bilayer phantom made from polyvinyl alcohol hydrogel and ballistic gel was built to mimic alternating layers of water-based and lipid tissues characteristic of an abdominal body wall and to reproducibly distort HIFU fields. The density, sound speed, and attenuation coefficient of each material were measured using a homogeneous gel layer. A surface with random topographical features was designed as an interface between gel layers using a 2D Fourier spectrum approach and replicating different spatial scales of tissue inhomogeneities. Distortion of the field of a 256-element 1.5 MHz HIFU array by the phantom was characterized through hydrophone measurements for linear and nonlinear beam focusing and compared to the corresponding distortion induced by an ex vivo porcine body wall of the same thickness. Both spatial shift and widening of the focal lobe were observed, as well as dramatic reduction in focal pressures caused by aberrations. The results suggest that the phantom produced levels of aberration that are similar to a real body wall and can serve as a research tool for studying HIFU effects as well as for developing algorithms for aberration correction.
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http://dx.doi.org/10.1121/10.0002877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097711PMC
December 2020

A Prototype Therapy System for Boiling Histotripsy in Abdominal Targets Based on a 256-Element Spiral Array.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 May 26;68(5):1496-1510. Epub 2021 Apr 26.

Boiling histotripsy (BH) uses millisecond-long ultrasound (US) pulses with high-amplitude shocks to mechanically fractionate tissue with potential for real-time lesion monitoring by US imaging. For BH treatments of abdominal organs, a high-power multielement phased array system capable of electronic focus steering and aberration correction for body wall inhomogeneities is needed. In this work, a preclinical BH system was built comprising a custom 256-element 1.5-MHz phased array (Imasonic, Besançon, France) with a central opening for mounting an imaging probe. The array was electronically matched to a Verasonics research US system with a 1.2-kW external power source. Driving electronics and software of the system were modified to provide a pulse average acoustic power of 2.2 kW sustained for 10 ms with a 1-2-Hz repetition rate for delivering BH exposures. System performance was characterized by hydrophone measurements in water combined with nonlinear wave simulations based on the Westervelt equation. Fully developed shocks of 100-MPa amplitude are formed at the focus at 275-W acoustic power. Electronic steering capabilities of the array were evaluated for shock-producing conditions to determine power compensation strategies that equalize BH exposures at multiple focal locations across the planned treatment volume. The system was used to produce continuous volumetric BH lesions in ex vivo bovine liver with 1-mm focus spacing, 10-ms pulselength, five pulses/focus, and 1% duty cycle.
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http://dx.doi.org/10.1109/TUFFC.2020.3036580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191454PMC
May 2021

Phase-Aberration Correction for HIFU Therapy Using a Multielement Array and Backscattering of Nonlinear Pulses.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 26;68(4):1040-1050. Epub 2021 Mar 26.

Phase aberrations induced by heterogeneities in body wall tissues introduce a shift and broadening of the high-intensity focused ultrasound (HIFU) focus, associated with decreased focal intensity. This effect is particularly detrimental for HIFU therapies that rely on shock front formation at the focus, such as boiling histotripsy (BH). In this article, an aberration correction method based on the backscattering of nonlinear ultrasound pulses from the focus is proposed and evaluated in tissue-mimicking phantoms. A custom BH system comprising a 1.5-MHz 256-element array connected to a Verasonics V1 engine was used as a pulse/echo probe. Pulse inversion imaging was implemented to visualize the second harmonic of the backscattered signal from the focus inside a phantom when propagating through an aberrating layer. Phase correction for each array element was derived from an aberration-correction method for ultrasound imaging that combines both the beamsum and the nearest neighbor correlation method and adapted it to the unique configuration of the array. The results were confirmed by replacing the target tissue with a fiber-optic hydrophone. Comparing the shock amplitude before and after phase-aberration correction showed that the majority of losses due to tissue heterogeneity were compensated, enabling fully developed shocks to be generated while focusing through aberrating layers. The feasibility of using a HIFU phased-array transducer as a pulse-echo probe in harmonic imaging mode to correct for phase aberrations was demonstrated.
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http://dx.doi.org/10.1109/TUFFC.2020.3030890DOI Listing
April 2021

Effect of Stiffness of Large Extravascular Hematomas on Their Susceptibility to Boiling Histotripsy Liquefaction in Vitro.

Ultrasound Med Biol 2020 08 20;46(8):2007-2016. Epub 2020 May 20.

Department of Radiology, University of Washington, Seattle, Washington, USA.

Large intra-abdominal, retroperitoneal and intramuscular hematomas are common consequences of sharp and blunt trauma and post-surgical bleeds, and often threaten organ failure, compartment syndrome or spontaneous infection. Current therapy options include surgical evacuation and placement of indwelling drains that are not effective because of the viscosity of the organized hematoma. We have previously reported the feasibility of using boiling histotripsy (BH)-a pulsed high-intensity focused ultrasound method-for liquefaction of large volumes of freshly coagulated blood and subsequent fine-needle aspiration. The goal of this work was to evaluate the changes in stiffness of large coagulated blood volumes with aging and retraction in vitro, and to correlate these changes with the size of the BH void and, therefore, the susceptibility of the material to BH liquefaction. Large-volume (55-200 mL) whole-blood clots were fabricated in plastic molds from human and bovine blood, either by natural clotting or by recalcification of anticoagulated blood, with or without addition of thrombin. Retraction of the clots was achieved by incubation for 3 h, 3 d or 8 d. The shear modulus of the samples was measured with a custom-built indentometer and shear wave elasticity (SWE) imaging. Sizes of single liquefied lesions produced with a 1.5-MHz high-intensity focused ultrasound transducer within a 30-s standard BH exposure served as the metric for susceptibility of clot material to this treatment. Neither the shear moduli of naturally clotted human samples (0.52 ± 0.08 kPa), nor their degree of retraction (ratio of expelled fluid to original volume 50%-58%) depended on the length of incubation within 0-8 d, and were significantly lower than those of bovine samples (2.85 ± 0.17 kPa, retraction 5%-38%). In clots made from anticoagulated bovine blood, the variation of calcium chloride concentration within 5-40 mmol/L did not change the stiffness, whereas lower concentrations and the addition of thrombin resulted in significantly softer clots, similar to naturally clotted human samples. Within the achievable shear modulus range (0.4-1.6 kPa), the width of the BH-liquefied lesion was more affected by the changes in stiffness than the length of the lesion. In all cases, however, the lesions were larger compared with any soft tissue liquefied with the same BH parameters, indicating higher susceptibility of hematomas to BH damage. These results suggest that clotted bovine blood with added thrombin is an acceptable in vitro model of both acute and chronic human hematomas for assessing the efficiency of BH liquefaction strategies.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360281PMC
August 2020

Pilot in vivo studies on transcutaneous boiling histotripsy in porcine liver and kidney.

Sci Rep 2019 12 27;9(1):20176. Epub 2019 Dec 27.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA, USA.

Boiling histotripsy (BH) is a High Intensity Focused Ultrasound (HIFU) method for precise mechanical disintegration of target tissue using millisecond-long pulses containing shocks. BH treatments with real-time ultrasound (US) guidance allowed by BH-generated bubbles were previously demonstrated ex vivo and in vivo in exposed porcine liver and small animals. Here, the feasibility of US-guided transabdominal and partially transcostal BH ablation of kidney and liver in an acute in vivo swine model was evaluated for 6 animals. BH parameters were: 1.5 MHz frequency, 5-30 pulses of 1-10 ms duration per focus, 1% duty cycle, peak acoustic powers 0.9-3.8 kW, sonication foci spaced 1-1.5 mm apart in a rectangular grid with 5-15 mm linear dimensions. In kidneys, well-demarcated volumetric BH lesions were generated without respiratory gating and renal medulla and collecting system were more resistant to BH than cortex. The treatment was accelerated 10-fold by using shorter BH pulses of larger peak power without affecting the quality of tissue fractionation. In liver, respiratory motion and aberrations from subcutaneous fat affected the treatment but increasing the peak power provided successful lesion generation. These data indicate BH is a promising technology for transabdominal and transcostal mechanical ablation of tumors in kidney and liver.
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http://dx.doi.org/10.1038/s41598-019-56658-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934604PMC
December 2019

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

Clin Cancer Res 2020 03 15;26(5):1152-1161. Epub 2019 Oct 15.

Department of Surgery, Brown University, Providence, Rhode Island.

Purpose: Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors.

Experimental Design: We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival.

Results: Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4Foxp3, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4, CD8α, and CD8αCD11c cells, CD11c in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, < 0.0001). This combination treatment significantly also induces CD4CD44CD62L and CD8αCD44CD62L population and is adoptively transferable, imparting immunity, slowing subsequent tumor engraftment.

Conclusions: Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1604DOI Listing
March 2020

Mechanical decellularization of tissue volumes using boiling histotripsy.

Phys Med Biol 2018 Dec 4;63(23):235023. Epub 2018 Dec 4.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA, United States of America.

High intensity focused ultrasound (HIFU) is rapidly advancing as an alternative therapy for non-invasively treating specific cancers and other pathological tissues through thermal ablation. A new type of HIFU therapy-boiling histotripsy (BH)-aims at mechanical fractionation of into subcellular fragments, with a range of accompanying thermal effects that can be tuned from none to substantial depending on the requirements of the application. The degree of mechanical tissue damage induced by BH has been shown to depend on the tissue type, with collagenous structures being most resistant, and cellular structures being most sensitive. This has been reported for single BH lesions, but has not been replicated in large volumes. Such tissue selectivity effect has potential uses involving tissue decellularization for biofabrication technologies as well as mechanical ablation by BH while sparing critical structures. The goal of this study was to investigate tissue decellularization effect in larger, clinically relevant liquefied volumes of tissue, and to evaluate the accumulated thermal effect in the volumetric lesions under different exposure parameters. All BH exposures were performed with a 256-element 1.2 MHz array of a magnetic resonance imaging-guided HIFU (MR-HIFU) clinical system (Sonalleve V1, Profound Medical Inc, Mississauga, Canada). The volumetric BH lesions were produced in degassed ex vivo bovine liver using 1-10 ms long pulses with in situ shock amplitudes of 75-100 MPa at the focus and pulse repetition frequencies (PRFs) of 1-10 Hz covering a range of effects from pure mechanical homogenization to thermal ablation. Multimodal analysis of the lesions was then performed, including microstructure (histological), ultrastructure (electron microscopy), and molecular (biochemistry) methods. Results show a range of tissue effects in terms of the degree of tissue selectivity and the amount of heat generated in large BH lesions, thereby demonstrating potential for treatments tailored to different clinical applications.
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http://dx.doi.org/10.1088/1361-6560/aaef16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527100PMC
December 2018

Boiling Histotripsy Ablation of Renal Cell Carcinoma in the Eker Rat Promotes a Systemic Inflammatory Response.

Ultrasound Med Biol 2019 01 16;45(1):137-147. Epub 2018 Oct 16.

Department of Medicine, University of Washington, Seattle, Washington, USA. Electronic address:

Boiling histotripsy (BH) is an experimental focused ultrasound technique that produces non-thermal mechanical ablation. We evaluated the feasibility, short-term histologic effects and the resulting acute inflammatory response to BH ablation of renal cell carcinoma (RCC) in the Eker rat. Genotyped Eker rats were monitored for de novo RCCs with serial ultrasound (US) imaging. When tumors were ≥8 mm, rats underwent ultrasound-guided extracorporeal ablation of the tumor with BH, a pulsed focused US technique that produces non-thermal mechanical ablation of targeted tissues, or a sham US procedure. Treatments targeted approximately 50% of the largest RCC with a margin of normal kidney. BH treated rats were euthanized at 1 (n = 4) or 48 (n = 4) h, and sham patients (n = 4) at 48 h. Circulating plasma cytokine levels were assessed with multiplex assays before and at 0.25, 1, 4, 24 and 48 h following treatment. Kidneys were collected and processed for histologic assessment, immunohistochemistry and intrarenal cytokine concentration measurements. For statistical analysis Student's t-test was used. US-guided BH treatment was successful in all animals, producing hypoechoic regions within the targeted volume consistent with BH treatment effect. Grossly, regions of homogenized tissue were apparent with evidence of focal intra-parenchymal hemorrhage. Histologically, BH produced a sharply demarcated region of homogenized tumor and non-tumor tissue containing acellular debris. BH treatment was associated with significantly increased relative concentration of plasma TNF versus sham treatment (p < 0.05) and transient elevations in high-mobility group box 1 (HMGB1), IL-10 and IL-6 consistent with acute inflammatory response to trauma. Intrarenal cytokine concentrations followed the same trend. At 48 h, enhanced infiltration of CD8 T cells was observed by immunohistochemistry in both the treated and un-treated contralateral RCC/kidneys in BH-treated animals versus sham treatment. BH treatment was well tolerated with transient gross hematuria and a perinephric hematoma developing in one subject each. The study demonstrates the feasibility of BH ablation of de novo RCC and suggests activation of the acute inflammatory cascade following treatment that appears to stimulate CD8+ T cell infiltration of both treated and untreated tumors. Longer duration chronic studies are ongoing to characterize the longevity and robustness of this response.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546431PMC
January 2019

A Prototype Therapy System for Transcutaneous Application of Boiling Histotripsy.

IEEE Trans Ultrason Ferroelectr Freq Control 2017 10 14;64(10):1542-1557. Epub 2017 Aug 14.

Boiling histotripsy (BH) is a method of focused ultrasound surgery that noninvasively applies millisecond-length pulses with high-amplitude shock fronts to generate liquefied lesions in tissue. Such a technique requires unique outputs compared to a focused ultrasound thermal therapy apparatus, particularly to achieve high in situ pressure levels through intervening tissue. This paper describes the design and characterization of a system capable of producing the necessary pressure to transcutaneously administer BH therapy through clinically relevant overlying tissue paths using pulses with duration up to 10 ms. A high-voltage electronic pulser was constructed to drive a 1-MHz focused ultrasound transducer to produce shock waves with amplitude capable of generating boiling within the pulse duration in tissue. The system output was characterized by numerical modeling with the 3-D Westervelt equation using boundary conditions established by acoustic holography measurements of the source field. Such simulations were found to be in agreement with directly measured focal waveforms. An existing derating method for nonlinear therapeutic fields was used to estimate in situ pressure levels at different tissue depths. The system was tested in ex vivo bovine liver samples to create BH lesions at depths up to 7 cm. Lesions were also created through excised porcine body wall (skin, adipose, and muscle) with 3-5 cm thickness. These results indicate that the system is capable of producing the necessary output for transcutaneous ablation with BH.
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http://dx.doi.org/10.1109/TUFFC.2017.2739649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871228PMC
October 2017

Dependence of Boiling Histotripsy Treatment Efficiency on HIFU Frequency and Focal Pressure Levels.

Ultrasound Med Biol 2017 09 20;43(9):1975-1985. Epub 2017 Jun 20.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA, USA; Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, Russia.

Boiling histotripsy (BH) is a high-intensity focused ultrasound (HIFU)-based method of mechanical tissue fractionation that utilizes millisecond-long bursts of HIFU shock waves to cause boiling at the focus in milliseconds. The subsequent interaction of the incoming shocks with the vapor bubble mechanically lyses surrounding tissue and cells. The acoustic parameter space for BH has been investigated previously and an inverse dependence between the HIFU frequency and the dimensions of a BH lesion has been observed. The primary goal of the present study was to investigate in more detail the ablation rate and reliability of BH in the frequency range relevant to treatment of deep abdominal tissue targets (1-2 MHz). The second goal was to investigate the effect of focal peak pressure levels and shock amplitude on BH lesion formation, given a constant duty factor, a constant ratio of the pulse duration to the time to reach boiling and a constant number of BH pulses. A custom-built 12-element sector array HIFU transducer with F-number = 1.05 was used in all experiments. BH pulses at 5 different frequencies (1, 1.2, 1.5, 1.7 and 1.9 MHz) were delivered to optically transparent polyacrylamide gel phantoms and ex vivo bovine liver and myocardium tissue to observe cavitation and boiling bubble activity with high-speed photography and B-mode ultrasound imaging, correspondingly. In gel phantoms, a cavitation bubble cloud was shown to form prefocally and to shield the focus in all exposures at 1 and 1.2 MHz and in the highest amplitude exposures at 1.5-1.7 MHz; shielding was not observed at 1.9 MHz. In ex vivo tissue, this shielding effect was observed in 25% of exposures when peak negative in situ pressure exceeded 10.2 MPa at 1 MHz and 14.5 MPa at 1.5 MHz. When shielding occurred, the exposures resulted in mild tissue disruption in the prefocal region, but not liquefaction. The dimensions of liquefied lesions followed the inverse proportionality trend with frequency; consequently, the frequency range of 1.2-1.5 MHz appeared to be preferable for BH exposures in terms of the compromise between the ablation rate and reliability. The lesion size was independent of the duration of the BH pulses (or the total "HIFU on" time), provided that the number of pulses was constant and boiling was induced within each pulse. Thus, the use of shorter (1 ms vs. 10 ms), higher amplitude BH pulses allowed up to 10-fold reduction in treatment time for a given duty factor.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547902PMC
September 2017

Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy.

Radiology 2017 04 1;283(1):158-167. Epub 2016 Nov 1.

From the Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Wash (J.R.C., E.N.G., M.D.G., M.T.); Institute for Systems Biology, Seattle, Wash (J.R.C., K.W.); Department of Medicine (T.D.K., J.H.H.), Department of Urology (G.R.S.), and Applied Physics Laboratory (F.S., Y.N.W.), University of Washington, Seattle, Wash; and Departments of Internal Medicine (M.D.G., M.T.) and Biomedical Engineering, Center for Computational Medicine and Bioinformatics, and the Biointerfaces Institute (M.T.), University of Michigan, 109 Zina Pitcher Pl, 1502 BSRB, SPC 2200, Ann Arbor, MI 48109.

Purpose To compare the abilities of three pulsed focused ultrasound regimes (that cause tissue liquefaction, permeabilization, or mild heating) to release tumor-derived microRNA into the circulation in vivo and to evaluate release dynamics. Materials and Methods All rat experiments were approved by the University of Washington Institutional Animal Care and Use Committee. Reverse-transcription quantitative polymerase chain reaction array profiling was used to identify candidate microRNA biomarkers in a rat solid tumor cell line. Rats subcutaneously grafted with these cells were randomly assigned among three pulsed focused ultrasound treatment groups: (a) local tissue liquefaction via boiling histotripsy, (b) tissue permeabilization via inertial cavitation, and (c) mild (<10°C) heating of tissue, as well as a sham-treated control group. Blood specimens were drawn immediately prior to treatment and serially over 24 hours afterward. Plasma microRNA was quantified with reverse-transcription quantitative polymerase chain reaction, and statistical significance was determined with one-way analysis of variance (Kruskal-Wallis and Friedman tests), followed by the Dunn multiple-comparisons test. Results After tissue liquefaction and cavitation treatments (but not mild heating), plasma quantities of candidate biomarkers increased significantly (P value range, <.0001 to .04) relative to sham-treated controls. A threefold to 32-fold increase occurred within 15 minutes after initiation of pulsed focused ultrasound tumor treatment, and these increases persisted for 3 hours. Histologic examination confirmed complete liquefaction of the targeted tumor area with boiling histotripsy, in addition to areas of petechial hemorrhage and tissue disruption by means of cavitation-based treatment. Conclusion Mechanical tumor tissue disruption with pulsed focused ultrasound-induced bubble activity significantly increases the plasma abundance of tumor-derived microRNA rapidly after treatment. RSNA, 2016 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016160024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375625PMC
April 2017

Histotripsy Liquefaction of Large Hematomas.

Ultrasound Med Biol 2016 07 25;42(7):1491-8. Epub 2016 Apr 25.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA, USA.

Intra- and extra-muscular hematomas result from repetitive injury as well as sharp and blunt limb trauma. The clinical consequences can be serious, including debilitating pain and functional deficit. There are currently no short-term treatment options for large hematomas, only lengthy conservative treatment. The goal of this work was to evaluate the feasibility of a high intensity focused ultrasound (HIFU)-based technique, termed histotripsy, for rapid (within a clinically relevant timeframe of 15-20 min) liquefaction of large volume (up to 20 mL) extra-vascular hematomas for subsequent fine-needle aspiration. Experiments were performed using in vitro extravascular hematoma phantoms-fresh bovine blood poured into 50 mL molds and allowed to clot. The resulting phantoms were treated by boiling histotripsy (BH), cavitation histotripsy (CH) or a combination in a degassed water tank under ultrasound guidance. Two different transducers operating at 1 MHz and 1.5 MHz with f-number = 1 were used. The liquefied lysate was aspirated and analyzed by histology and sized in a Coulter Counter. The peak instantaneous power to achieve BH was lower than (at 1.5 MHz) or equal to (at 1 MHz) that which was required to initiate CH. Under the same exposure duration, BH-induced cavities were one and a half to two times larger than the CH-induced cavities, but the CH-induced cavities were more regularly shaped, facilitating easier aspiration. The lysates contained a small amount of debris larger than 70 μm, and 99% of particulates were smaller than 10 μm. A combination treatment of BH (for initial debulking) and CH (for liquefaction of small residual fragments) yielded 20 mL of lysate within 17.5 minutes of treatment and was found to be most optimal for liquefaction of large extravascular hematomas.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899253PMC
July 2016

Therapeutic potential of ultrasound microbubbles in gastrointestinal oncology: recent advances and future prospects.

Therap Adv Gastroenterol 2015 Nov;8(6):384-94

Associate Professor of Medicine, Division of Gastroenterology, Department of Medicine, University of Washington, Box 359773, 325 Ninth Avenue, Seattle, WA 98104, USA.

Microbubbles were initially invented as contrast agents for ultrasound imaging. However, lately more and more therapeutic applications of microbubbles are emerging, mostly related to drug and gene delivery. Ultrasound is a safe and noninvasive therapeutic modality which has the unique ability to interact with microbubbles and release their payload in situ in addition to permeabilizing the target tissues. The combination of drug-loaded microbubbles and ultrasound has been used in preclinical studies on blood-brain barrier opening, drug and gene delivery to solid tumors, and ablation of blood vessels. This review covers the basic principles of ultrasound-microbubble interaction, the types of microbubbles and the effect they have on tissue, and the preclinical and clinical experience with this approach to date in the field of gastrointestinal oncology.
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http://dx.doi.org/10.1177/1756283X15592584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622285PMC
November 2015

HIFU for Palliative Treatment of Pancreatic Cancer.

Adv Exp Med Biol 2016 ;880:83-95

Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

Pancreatic cancer is one of the deadliest malignancies, with only a 6 % 5-year survival rate and over 50 % of patients being diagnosed at the advanced stage. Current therapies are ineffective, and the treatment of patients with advanced disease is palliative. In the past decade, HIFU ablation has emerged as a modality for palliative treatment of pancreatic tumors. Multiple preclinical and non-randomized clinical trials have been performed to evaluate the safety and efficacy of this procedure. Substantial tumor-related pain reduction was achieved in most cases after HIFU treatment and few significant side effects were observed. In addition, some studies indicate that combination of HIFU ablation with chemotherapy may provide a survival benefit. This chapter summarizes the pre-clinical and clinical experience obtained to date in HIFU treatment of pancreatic tumors and discusses the challenges, limitations and new approaches in this modality.
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http://dx.doi.org/10.1007/978-3-319-22536-4_5DOI Listing
March 2016

Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.

Cancer Res 2015 09 27;75(18):3738-46. Epub 2015 Jul 27.

Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.

Pancreatic cancer is characterized by extensive stromal desmoplasia, which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity-cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high-intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active vs. passive drug diffusion). For both types, the pHIFU exposures that were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized doxorubicin concentration by up to 4.5-fold compared with controls. Furthermore, normalized doxorubicin concentration was associated with the cavitation metrics (P < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, that is, doxorubicin infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors. .
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629806PMC
September 2015

Histotripsy methods in mechanical disintegration of tissue: towards clinical applications.

Int J Hyperthermia 2015 Mar 24;31(2):145-62. Epub 2015 Feb 24.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington , Seattle, Washington , USA .

In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti-tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery.
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http://dx.doi.org/10.3109/02656736.2015.1007538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448968PMC
March 2015

A new active cavitation mapping technique for pulsed HIFU applications--bubble Doppler.

IEEE Trans Ultrason Ferroelectr Freq Control 2014 Oct;61(10):1698-708

In this work, a new active cavitation mapping technique for pulsed high-intensity focused ultrasound (pHIFU) applications termed bubble Doppler is proposed and its feasibility is tested in tissue-mimicking gel phantoms. pHIFU therapy uses short pulses, delivered at low pulse repetition frequency, to cause transient bubble activity that has been shown to enhance drug and gene delivery to tissues. The current gold standard for detecting and monitoring cavitation activity during pHIFU treatments is passive cavitation detection (PCD), which provides minimal information on the spatial distribution of the bubbles. B-mode imaging can detect hyperecho formation, but has very limited sensitivity, especially to small, transient microbubbles. The bubble Doppler method proposed here is based on a fusion of the adaptations of three Doppler techniques that had been previously developed for imaging of ultrasound contrast agents-color Doppler, pulse-inversion Doppler, and decorrelation Doppler. Doppler ensemble pulses were interleaved with therapeutic pHIFU pulses using three different pulse sequences and standard Doppler processing was applied to the received echoes. The information yielded by each of the techniques on the distribution and characteristics of pHIFU-induced cavitation bubbles was evaluated separately, and found to be complementary. The unified approach-bubble Doppler-was then proposed to both spatially map the presence of transient bubbles and to estimate their sizes and the degree of nonlinearity.
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http://dx.doi.org/10.1109/TUFFC.2014.006502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454370PMC
October 2014

Pulsed focused ultrasound treatment of muscle mitigates paralysis-induced bone loss in the adjacent bone: a study in a mouse model.

Ultrasound Med Biol 2014 Sep 21;40(9):2113-24. Epub 2014 May 21.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington, USA.

Bone loss can result from bed rest, space flight, spinal cord injury or age-related hormonal changes. Current bone loss mitigation techniques include pharmaceutical interventions, exercise, pulsed ultrasound targeted to bone and whole body vibration. In this study, we attempted to mitigate paralysis-induced bone loss by applying focused ultrasound to the midbelly of a paralyzed muscle. We employed a mouse model of disuse that uses onabotulinumtoxinA-induced paralysis, which causes rapid bone loss in 5 d. A focused 2 MHz transducer applied pulsed exposures with pulse repetition frequency mimicking that of motor neuron firing during walking (80 Hz), standing (20 Hz), or the standard pulsed ultrasound frequency used in fracture healing (1 kHz). Exposures were applied daily to calf muscle for 4 consecutive d. Trabecular bone changes were characterized using micro-computed tomography. Our results indicated that application of certain focused pulsed ultrasound parameters was able to mitigate some of the paralysis-induced bone loss.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2014.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410740PMC
September 2014

Ultrasound-guided tissue fractionation by high intensity focused ultrasound in an in vivo porcine liver model.

Proc Natl Acad Sci U S A 2014 Jun 19;111(22):8161-6. Epub 2014 May 19.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA 98105; andDepartment of Acoustics, Physics Faculty, Moscow State University, Leninskie Gory, Moscow 119991, Russia.

The clinical use of high intensity focused ultrasound (HIFU) therapy for noninvasive tissue ablation has been recently gaining momentum. In HIFU, ultrasound energy from an extracorporeal source is focused within the body to ablate tissue at the focus while leaving the surrounding organs and tissues unaffected. Most HIFU therapies are designed to use heating effects resulting from the absorption of ultrasound by tissue to create a thermally coagulated treatment volume. Although this approach is often successful, it has its limitations, such as the heat sink effect caused by the presence of a large blood vessel near the treatment area or heating of the ribs in the transcostal applications. HIFU-induced bubbles provide an alternative means to destroy the target tissue by mechanical disruption or, at its extreme, local fractionation of tissue within the focal region. Here, we demonstrate the feasibility of a recently developed approach to HIFU-induced ultrasound-guided tissue fractionation in an in vivo pig model. In this approach, termed boiling histotripsy, a millimeter-sized boiling bubble is generated by ultrasound and further interacts with the ultrasound field to fractionate porcine liver tissue into subcellular debris without inducing further thermal effects. Tissue selectivity, demonstrated by boiling histotripsy, allows for the treatment of tissue immediately adjacent to major blood vessels and other connective tissue structures. Furthermore, boiling histotripsy would benefit the clinical applications, in which it is important to accelerate resorption or passage of the ablated tissue volume, diminish pressure on the surrounding organs that causes discomfort, or insert openings between tissues.
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http://dx.doi.org/10.1073/pnas.1318355111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050569PMC
June 2014

HIFU for palliative treatment of pancreatic cancer.

J Gastrointest Oncol 2011 Sep;2(3):175-84

Division of Gastroenterology, Department of Medicine, Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington, USA.

High intensity focused ultrasound (HIFU) is a novel non-invasive modality for ablation of various solid tumors including uterine fibroids, prostate cancer, hepatic, renal, breast and pancreatic tumors. HIFU therapy utilizes mechanical energy in the form of a powerful ultrasound wave that is focused inside the body to induce thermal and/or mechanical effects in tissue. Multiple preclinical and non-randomized clinical trials have been performed to evaluate the safety and efficacy of HIFU for palliative treatment of pancreatic tumors. Substantial tumor-related pain reduction was achieved in most cases after HIFU treatment, and no significant side-effects were observed. This review provides a description of different physical mechanisms underlying HIFU therapy, summarizes the clinical experience obtained to date in HIFU treatment of pancreatic tumors, and discusses the challenges, limitations and new approaches in this modality.
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http://dx.doi.org/10.3978/j.issn.2078-6891.2011.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397618PMC
September 2011

Temperature dependence of the optoacoustic transformation efficiency in ex vivo tissues for application in monitoring thermal therapies.

J Biomed Opt 2012 Jun;17(6):061214

International Laser Center, M.V. Lomonosov Moscow State University, Moscow, Russia.

The calibration dependencies of the optoacoustic (OA) transformation efficiency on tissue temperature are obtained for the application in OA temperature monitoring during thermal therapies. Accurate measurement of the OA signal amplitude versus temperature is performed in different ex vivo tissues in the temperature range 25°C to 80°C. The investigated tissues were selected to represent different structural components: chicken breast (skeletal muscle), porcine lard (fatty tissue), and porcine liver (richly perfused tissue). Backward mode of the OA signal detection and a narrow probe laser beam were used in the experiments to avoid the influence of changes in light scattering with tissue coagulation on the OA signal amplitude. Measurements were performed in heating and cooling regimes. Characteristic behavior of the OA signal amplitude temperature dependences in different temperature ranges were described in terms of changes in different structural components of the tissue samples. The accuracy of temperature reconstruction from the obtained calibration dependencies for the investigated tissue types is evaluated.
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http://dx.doi.org/10.1117/1.JBO.17.6.061214DOI Listing
June 2012

Controlled tissue emulsification produced by high intensity focused ultrasound shock waves and millisecond boiling.

J Acoust Soc Am 2011 Nov;130(5):3498-510

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40th Street, Seattle, Washington 98105, USA.

In high intensity focused ultrasound (HIFU) applications, tissue may be thermally necrosed by heating, emulsified by cavitation, or, as was recently discovered, emulsified using repetitive millisecond boiling caused by shock wave heating. Here, this last approach was further investigated. Experiments were performed in transparent gels and ex vivo bovine heart tissue using 1, 2, and 3 MHz focused transducers and different pulsing schemes in which the pressure, duty factor, and pulse duration were varied. A previously developed derating procedure to determine in situ shock amplitudes and the time-to-boil was refined. Treatments were monitored using B-mode ultrasound. Both inertial cavitation and boiling were observed during exposures, but emulsification occurred only when shocks and boiling were present. Emulsified lesions without thermal denaturation were produced with shock amplitudes sufficient to induce boiling in less than 20 ms, duty factors of less than 0.02, and pulse lengths shorter than 30 ms. Higher duty factors or longer pulses produced varying degrees of thermal denaturation combined with mechanical emulsification. Larger lesions were obtained using lower ultrasound frequencies. The results show that shock wave heating and millisecond boiling is an effective and reliable way to emulsify tissue while monitoring the treatment with ultrasound.
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http://dx.doi.org/10.1121/1.3626152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259668PMC
November 2011

Cloud condensation nuclei and ice nucleation activity of hydrophobic and hydrophilic soot particles.

Phys Chem Chem Phys 2009 Sep 28;11(36):7906-20. Epub 2009 Jul 28.

Department of Atmospheric Science, Colorado State University, Fort Collins, CO 80523, USA.

Cloud condensation nuclei (CCN) activity and ice nucleation behavior (for temperatures
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http://dx.doi.org/10.1039/b905334bDOI Listing
September 2009

Magnetic resonance imaging of boiling induced by high intensity focused ultrasound.

J Acoust Soc Am 2009 Apr;125(4):2420-31

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington 98105, USA.

Both mechanically induced acoustic cavitation and thermally induced boiling can occur during high intensity focused ultrasound (HIFU) medical therapy. The goal was to monitor the temperature as boiling was approached using magnetic resonance imaging (MRI). Tissue phantoms were heated for 20 s in a 4.7-T magnet using a 2-MHz HIFU source with an aperture and radius of curvature of 44 mm. The peak focal pressure was 27.5 MPa with corresponding beam width of 0.5 mm. The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73 degrees C after 7 s of continuous HIFU exposure when boiling started. Boiling was detected by visual observation, by appearance on the MR images, and by a marked change in the HIFU source power. Nonlinear modeling of the acoustic field combined with a heat transfer equation predicted 100 degrees C after 7 s of exposure. Averaging of the calculated temperature field over the volume of the MRI voxel (0.3 x 0.5 x 2 mm(3)) yielded a maximum of 73 degrees C that agreed with the MR thermometry measurement. These results have implications for the use of MRI-determined temperature values to guide treatments with clinical HIFU systems.
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http://dx.doi.org/10.1121/1.3081393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736739PMC
April 2009

Optoacoustic imaging of absorbing objects in a turbid medium: ultimate sensitivity and application to breast cancer diagnostics.

Appl Opt 2007 Jan;46(2):262-72

Faculty of Physics, Moscow State University, Moscow, Russia.

One of the major medical applications of optoacoustic (OA) tomography is in the diagnostics of early-stage breast cancer. A numerical approach was developed to characterize the following parameters of an OA imaging system: resolution, maximum depth at which the tumor can be detected, and image contrast. The parameters of the 64-element focused array transducer were obtained. The results of numerical modeling were compared with known analytical solutions and further validated by phantom experiments. The OA images of a 3 mm piece of bovine liver immersed in diluted milk at various depths were obtained. Based on the results of modeling, a signal filtering algorithm for OA image contrast enhancement has been proposed.
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http://dx.doi.org/10.1364/ao.46.000262DOI Listing
January 2007
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