Publications by authors named "Adam D Maxwell"

57 Publications

Design and Characterization of an Ultrasound Transducer for Combined Histotripsy-Thrombolytic Therapy.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Sep 17;PP. Epub 2021 Sep 17.

Chronic thrombi of the deep veins of the leg are resistant to dissolution or removal by current interventions and can act as thrombogenic sources. Histotripsy, a focused ultrasound therapy, uses the mechanical activity of bubble clouds to liquefy target tissues. In vitro experiments have shown that histotripsy enhances thrombolytic agent recombinant tissue plasminogen activator in a highly retracted clot model resistant to lytic therapy alone. Although these results are promising, further refinement of the acoustic source is necessary for in vivo studies and clinical translation. The source parameters for use in vivo were defined, and a transducer was fabricated for transcutaneous exposure of porcine and human iliofemoral deep venous thrombosis (DVT) as the target. Based on the design criteria, a 1.5-MHz elliptical source with 6-cm focal length and a focal gain of 60 was selected. The source was characterized by fiber-optic hydrophone and holography. High speed photography showed that the cavitation cloud could be confined to dimensions smaller than the specified vessel lumen. The source was also demonstrated in vitro to create confined lesions within clots. The results support that this design offers an appropriate clinical prototype for combined histotripsy-thrombolytic therapy.
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http://dx.doi.org/10.1109/TUFFC.2021.3113635DOI Listing
September 2021

Factors Affecting Tissue Cavitation during Burst Wave Lithotripsy.

Ultrasound Med Biol 2021 08 31;47(8):2286-2295. Epub 2021 May 31.

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

Burst wave lithotripsy (BWL) is a technology under clinical investigation for non-invasive fragmentation of urinary stones. Under certain ranges of ultrasound exposure parameters, this technology can cause cavitation in tissue leading to renal injury. This study sought to measure the focal pressure amplitude needed to cause cavitation in vivo and determine its consistency in native tissue, in an implanted stone model and under different exposure parameters. The kidneys of eight pigs were exposed to transcutaneous BWL ultrasound pulses. In each kidney, two locations were targeted: the renal sinus and the kidney parenchyma. Each was exposed for 5 min at a set pressure level and parameters, and cavitation was detected using an active cavitation imaging method based on power Doppler ultrasound. The threshold was determined by incrementing the pressure amplitude up or down after each 5-min interval until cavitation occurred/subsided. The pressure thresholds were remeasured postsurgery, targeting an implanted stone or collecting space (in sham). The presence of a stone or sham surgery did not significantly impact the threshold for tissue cavitation. Targeting parenchyma instead of kidney collecting space and lowering the ultrasound pulse repetition frequency both resulted in an increased pressure threshold for cavitation.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259501PMC
August 2021

Mechanical characterization of fibrotic and mineralized tissue in Peyronie's disease.

Int J Impot Res 2021 May 25. Epub 2021 May 25.

VA RR&D Center for Limb Loss and MoBility (CLiMB), VA Puget Sound Health Care System, Seattle, WA, USA.

Peyronie's disease affects penile mechanics, but published research lacks biomechanical characterization of affected tunica albuginea. This work aims to establish mechanical testing methodology and characterize pathological tissue mechanics of Peyronie's disease. Tunica albuginea was obtained from patients (n = 5) undergoing reconstructive surgery for Peyronie's disease, sectioned into test specimens (n = 12), stored frozen at -20 °C, and imaged with micro-computed tomography (µCT). A tensile testing protocol was developed based on similar soft tissues. Correlation of mechanical summary variables (force, displacement, stiffness, work, Young's modulus, ultimate tensile stress, strain at ultimate tensile stress, and toughness) and µCT features were assessed with linear regression. Specimens empirically grouped into hard or soft stress-strain behavior were compared using a Student's t-test. Surface strain and failure patterns were described qualitatively. Specimens displayed high inter- and intra-subject variability. Mineralization volume was not correlated with mechanical parameters. Empirically hard tissue had higher ultimate tensile stress. Failure mechanisms and strain patterns differed between mineralized and non-mineralized specimens. Size, shape, and quantity of mineralization may be more important in determining Peyronie's disease plaque behavior than presence of mineralization alone, and single summary variables like modulus may not fully describe mechanical behavior.
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http://dx.doi.org/10.1038/s41443-021-00439-2DOI Listing
May 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

Clot Degradation Under the Action of Histotripsy Bubble Activity and a Lytic Drug.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Sep 27;68(9):2942-2952. Epub 2021 Aug 27.

Deep vein thrombosis is a major source of morbidity worldwide. For critical obstructions, catheter-directed thrombolytics are the frontline therapy to achieve vessel recanalization. Techniques that aid lytic therapy are under development to improve treatment efficacy and reduce procedure-related complications. Histotripsy is one such adjuvant under development that relies on focused ultrasound for in situ nucleation of bubble clouds. Prior studies have demonstrated synergistic effects for clot dissolution when histotripsy is combined with lytic therapy. The success of this combination approach is hypothesized to promote thrombolytic efficacy via two mechanisms: erythrocyte fractionation (hemolysis) and increased lytic activity (fibrinolysis). In this study, the contributions of hemolysis and fibrinolysis to clot degradation under histotripsy and a lytic were quantified with measurements of hemoglobin and D-dimer, respectively. A linear regression analysis was used to determine the relationship between hemoglobin, D-dimer, and the overall treatment efficacy (clot mass loss). A similar analysis was conducted to gauge the role of bubble activity, which was assessed with passive cavitation imaging, on hemolysis and fibrinolysis. Tabulation of these data demonstrated hemolysis and fibrinolysis contributed equally to clot mass loss. Furthermore, bubble cloud activity promoted the generation of hemoglobin and D-dimer in equal proportion. These studies indicate a multifactorial process for clot degradation under the action of histotripsy and a lytic therapy.
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http://dx.doi.org/10.1109/TUFFC.2021.3052393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445066PMC
September 2021

Treating Porcine Abscesses with Histotripsy: A Pilot Study.

Ultrasound Med Biol 2021 03 26;47(3):603-619. Epub 2020 Nov 26.

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

Infected abscesses are walled-off collections of pus and bacteria. They are a common sequela of complications in the setting of surgery, trauma, systemic infections and other disease states. Current treatment is typically limited to antibiotics with long-term catheter drainage, or surgical washout when inaccessible to percutaneous drainage or unresponsive to initial care efforts. Antibiotic resistance is also a growing concern. Although bacteria can develop drug resistance, they remain susceptible to thermal and mechanical damage. In particular, short pulses of focused ultrasound (i.e., histotripsy) generate mechanical damage through localized cavitation, representing a potential new paradigm for treating abscesses non-invasively, without the need for long-term catheterization and antibiotics. In this pilot study, boiling and cavitation histotripsy treatments were applied to subcutaneous and intramuscular abscesses developed in a novel porcine model. Ultrasound imaging was used to evaluate abscess maturity for treatment monitoring and assessment of post-treatment outcomes. Disinfection was quantified by counting bacteria colonies from samples aspirated before and after treatment. Histopathological evaluation of the abscesses was performed to identify changes resulting from histotripsy treatment and potential collateral damage. Cavitation histotripsy was more successful in reducing the bacterial load while having a smaller treatment volume compared with boiling histotripsy. The results of this pilot study suggest focused ultrasound may lead to a technology for in situ treatment of acoustically accessible abscesses.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855811PMC
March 2021

Effect of Chilled Irrigation on Caliceal Fluid Temperature and Time to Thermal Injury Threshold During Laser Lithotripsy: Model.

J Endourol 2021 05 3;35(5):700-705. Epub 2020 Dec 3.

Department of Urology and University of Michigan, Ann Arbor, Michigan, USA.

High-power lasers (100-120 W) have widely expanded the available settings for laser lithotripsy and facilitated tailoring of treatment for individual cases. Previous and studies have demonstrated that a toxic thermal dose to tissue can result from treatment within a renal calix. The objective of this study was to compare thermal dose and time with tissue injury threshold when using chilled (CH) irrigation and room temperature (RT) irrigation. A glass tube attached to a 19 mm diameter bulb simulating a renal calix was placed in a 37°C water bath. A 242 μm laser fiber was passed through a ureteroscope with its tip in the center of the glass bulb. A wire thermocouple was placed 3 mm proximal to the ureteroscope tip to measure caliceal fluid temperature. RT at 19°C or CH at 1°C irrigation was delivered at 0, 8, 12, 15, or 40 mL/minute. The laser was activated at 0.5 J × 80 Hz (40 W) for 60 seconds. Thermal dose was calculated using the Sapareto and Dewey t43 methodology with thermal dose = 120 equivalent minutes considered the threshold for thermal tissue injury. At each irrigation rate, CH irrigation produced a lower starting temperature, a lower plateau temperature, and less thermal dose compared with RT irrigation. The threshold of thermal injury was reached after 13 seconds of laser activation without irrigation. With 12 mL/minute irrigation, the threshold was reached in 46 seconds with RT irrigation but was not reached with CH irrigation. As higher power laser lithotripsy techniques become further refined, methods to mitigate and control thermal dose are necessary to enhance efficiency. CH irrigation slows temperature rise, decreases plateau temperature, and lowers thermal dose during high-power laser lithotripsy.
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http://dx.doi.org/10.1089/end.2020.0896DOI Listing
May 2021

First In-Human Burst Wave Lithotripsy for Kidney Stone Comminution: Initial Two Case Studies.

J Endourol 2021 04 5;35(4):506-511. Epub 2020 Nov 5.

Department of Urology and University of Washington School of Medicine, Seattle, Washington, USA.

To test the effectiveness (Participant A) and tolerability (Participant B) of urinary stone comminution in the first-in-human trial of a new technology, burst-wave lithotripsy (BWL). An investigational BWL and ultrasonic propulsion system was used to target a 7-mm kidney stone in the operating room before ureteroscopy (Participant A). The same system was used to target a 7.5 mm ureterovesical junction stone in clinic without anesthesia (Participant B). For Participant A, a ureteroscope inserted after 9 minutes of BWL observed fragmentation of the stone to <2 mm fragments. Participant B tolerated the procedure without pain from BWL, required no anesthesia, and passed the stone on day 15. The first-in-human tests of BWL pulses were successful in that a renal stone was comminuted in <10 minutes, and BWL was also tolerated by an awake subject for a distal ureteral stone. Clinical Trial NCT03873259 and NCT02028559.
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http://dx.doi.org/10.1089/end.2020.0725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080914PMC
April 2021

A simulated model for fluid and tissue heating during pediatric laser lithotripsy.

J Pediatr Urol 2020 Oct 17;16(5):626.e1-626.e8. Epub 2020 Jul 17.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, USA; Department of Urology, University of Washington School of Medicine, USA.

Background: Laser lithotripsy (LL) is a common modality for treatment of children and adolescents with nephrolithiasis. Recent introduction of higher-powered lasers may result in more efficacious "dusting" of urinary calculi. However, in vivo animal studies and computational simulations have demonstrated rapid and sustained rise of fluid temperatures with LL, possibly resulting in irreversible tissue damage. How fluid and tissue heating during LL vary with pediatric urinary tract development, however, is unknown. We hypothesize that kidneys of younger children will be more susceptible to changes in fluid temperature and therefore tissue damage than those of older children.

Methods: Computational simulations were developed for LL in children utilizing COMSOL Multiphysics finite-element modeling software. Simulation parameters were varied, including the child's age (3, 8, and 12 years), flow of irrigation fluid (gravity - 5 mL/min or continuous pressure flow - 40 mL/min), treatment location (renal pelvis, ureter, calyx), and power settings (5 W - 40 W). Using a simplified axisymmetric geometry to represent the collecting space, the model accounted for heat transfer via diffusion, convection, perfusion, and heat sourcing as well as tissue properties and blood flow of the urothelium and renal parenchyma. Laminar and heat-induced convection flow were simulated, assuming room-temperature ureteroscopic irrigation. Renal size was varied by age, based on normative values. The maximum fluid temperature after 60 s of simulated LL was captured. Thermal dose was calculated using the t equivalence of 240 min as a threshold for tissue damage, as was tissue volume at risk for irreversible cellular damage.

Results: Simulation with gravity flow irrigation revealed generation of thermal doses sufficient to cause tissue injury for all ages at 20 W and 40 W power settings. Higher temperatures were seen in younger ages across all power settings. Temperature increases were dampened with intermittent laser activity and continuous pressure flow irrigation.

Conclusions: Smaller renal size is more susceptible to thermal changes induced by LL. However, power settings equal to or greater than 20 W can result in temperatures high enough for tissue damage at any age. Continuous pressure flow and intermittent laser activity may mitigate the potential thermal damage from high power LL.
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http://dx.doi.org/10.1016/j.jpurol.2020.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686138PMC
October 2020

Design, fabrication, and characterization of broad beam transducers for fragmenting large renal calculi with burst wave lithotripsy.

J Acoust Soc Am 2020 07;148(1):44

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1606 San Juan Road, Seattle, Washington 98195, USA.

Burst wave lithotripsy (BWL) is a technology for comminuting urinary stones. A BWL transducer's requirements of high-pressure output, limited acoustic window, specific focal depth, and frequency to produce fragments of passable size constrain focal beamwidth. However, BWL is most effective with a beam wider than the stone. To produce a broad-beam, an iterative angular spectrum approach was used to calculate a phase screen that was realized with a rapid prototyped lens. The technique did not accurately replicate a target beam profile when an axisymmetric profile was chosen. Adding asymmetric weighting functions to the target profile achieved appropriate beamwidth. Lenses were designed to create a spherically focused narrow-beam (6 mm) and a broad-beam (11 mm) with a 350-kHz transducer and 84-mm focal depth. Both lenses were used to fragment artificial stones (11 mm long) in a water bath, and fragmentation rates were compared. The linearly simulated and measured broad beamwidths that were 12 mm and 11 mm, respectively, with a 2-mm-wide null at center. The broad-beam and the narrow-beam lenses fragmented 44 ± 9% and 16 ± 4% (p = 0.007, N = 3) of a stone by weight, respectively, in the same duration at the same peak negative pressure. The method broadened the focus and improved the BWL rate of fragmentation of large stones.
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http://dx.doi.org/10.1121/10.0001512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340507PMC
July 2020

Noninvasive acoustic manipulation of objects in a living body.

Proc Natl Acad Sci U S A 2020 07 6;117(29):16848-16855. Epub 2020 Jul 6.

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

In certain medical applications, transmitting an ultrasound beam through the skin to manipulate a solid object within the human body would be beneficial. Such applications include, for example, controlling an ingestible camera or expelling a kidney stone. In this paper, ultrasound beams of specific shapes were designed by numerical modeling and produced using a phased array. These beams were shown to levitate and electronically steer solid objects (3-mm-diameter glass spheres), along preprogrammed paths, in a water bath, and in the urinary bladders of live pigs. Deviation from the intended path was on average <10%. No injury was found on the bladder wall or intervening tissue.
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http://dx.doi.org/10.1073/pnas.2001779117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382215PMC
July 2020

Modeling of photoelastic imaging of mechanical stresses in transparent solids mimicking kidney stones.

J Acoust Soc Am 2020 06;147(6):3819

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

Theoretical and numerical models were developed to calculate the polariscopic integrated light intensity that forms a projection of the dynamic stress within an axisymmetric elastic object. Although the model is general, this paper addressed its application to measurements of stresses in model kidney stones from a burst wave lithotripter for stone fragmentation. The stress was calculated using linear elastic equations, and the light propagation was modeled in the instantaneous case by integrating over the volume of the stone. The numerical model was written in finite differences. The resulting images agreed well with measured images. The measured images corresponded to the maximum shear stress distribution, although other stresses were also plotted. Comparison of the modeled and observed polariscope images enabled refinement of the photoelastic constant by minimizing the error between the calculated and measured fields. These results enable quantification of the stress within the polariscope images, determination of material properties, and the modes and mechanisms of stress production within a kidney stone. Such a model may help in interpreting elastic waves in structures, such as stones, toward improving lithotripsy procedures.
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http://dx.doi.org/10.1121/10.0001386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292679PMC
June 2020

An investigation of elastic waves producing stone fracture in burst wave lithotripsy.

J Acoust Soc Am 2020 03;147(3):1607

Department of Acoustics, Physics Faculty, Lomonosov Moscow State University, Leninskie Gory, Moscow 119992, Russia.

Burst wave lithotripsy is a method to noninvasively fragment urinary stones by short pulses of focused ultrasound. In this study, physical mechanisms of stone fracture during burst wave lithotripsy were investigated. Photoelasticity imaging was used to visualize elastic wave propagation in model stones and compare results to numerical calculations. Epoxy and glass stone models were made into rectangular, cylindrical, or irregular geometries and exposed in a degassed water bath to focused ultrasound bursts at different frequencies. A high-speed camera was used to record images of the stone during exposure through a circular polariscope backlit by a monochromatic flash source. Imaging showed the development of periodic stresses in the stone body with a pattern dependent on frequency. These patterns were identified as guided wave modes in cylinders and plates, which formed standing waves upon reflection from the distal surfaces of the stone model, producing specific locations of stress concentration in the models. Measured phase velocities compared favorably to numerically calculated modes dependent on frequency and material. Artificial stones exposed to bursts produced cracks at positions anticipated by this mechanism. These results support guided wave generation and reflection as a mechanism of stone fracture in burst wave lithotripsy.
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http://dx.doi.org/10.1121/10.0000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069764PMC
March 2020

QUANTIFICATION OF ACOUSTIC RADIATION FORCES ON SOLID OBJECTS IN FLUID.

Phys Rev Appl 2019 Oct 31;12(4). Epub 2019 Oct 31.

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

Theoretical models allow design of acoustic traps to manipulate objects with radiation force. Here, a model of the acoustic radiation force by an arbitrary beam on a solid object was validated against measurement. The lateral force in water of different acoustic beams was measured and calculated for spheres of different diameter (2-6 wavelengths in water) and composition. This is the first effort to validate a general model, to quantify the lateral force on a range of objects, and to electronically steer large or dense objects with a single-sided transducer. Vortex beams and two other beam shapes having a ring-shaped pressure field in the focal plane were synthesized in water by a 1.5-MHz, 256-element focused array. Spherical targets (glass, brass, ceramic, 2-6 mm dia.) were placed on an acoustically transparent plastic plate that was normal to the acoustic beam axis and rigidly attached to the array. Each sphere was trapped in the beam as the array with the attached plate was rotated until the bead fell from the acoustic trap because of gravity. Calculated and measured maximum obtained angles agreed on average to within 22%. The maximum lateral force occurred when the target diameter equaled the beam width; however, objects up to 40% larger than the beam width were trapped. The lateral force was comparable to the gravitation force on spheres up to 90 mg (0.0009 N) at beam powers on the order of 10 W. As a step toward manipulating objects, the beams were used to trap and electronically steer the spheres along a two-dimensional path.
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http://dx.doi.org/10.1103/physrevapplied.12.044076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050195PMC
October 2019

Evaluation of Urinary Stone Comminution with a Clinical Burst Wave Lithotripsy System.

J Endourol 2020 11 20;34(11):1167-1173. Epub 2020 Mar 20.

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

Our goals were to validate stone comminution with an investigational burst wave lithotripsy (BWL) system in patient-relevant conditions and to evaluate the use of ultrasonic propulsion to move a stone or fragments to aid in observing the treatment endpoint. The Propulse-1 system, used in clinical trials of ultrasonic propulsion and upgraded for BWL trials, was used to fragment 46 human stones (5-7 mm) in either a 15-mm or 4-mm diameter calix phantom in water at either 50% or 75% dissolved oxygen level. Stones were paired by size and composition, and exposed to 20-cycle, 390-kHz bursts at 6-MPa peak negative pressure (PNP) and 13-Hz pulse repetition frequency (PRF) or 7-MPa PNP and 6.5-Hz PRF. Stones were exposed in 5-minute increments and sieved, with fragments >2 mm weighed and returned for additional treatment. Effectiveness for pairs of conditions was compared statistically within a framework of survival data analysis for interval censored data. Three reviewers blinded to the experimental conditions scored ultrasound imaging videos for degree of fragmentation based on stone response to ultrasonic propulsion. Overall, 89% (41/46) and 70% (32/46) of human stones were fully comminuted within 30 and 10 minutes, respectively. Fragments remained after 30 minutes in 4% (1/28) of calcium oxalate monohydrate stones and 40% (4/10) of brushite stones. There were no statistically significant differences in comminution time between the two output settings ( = 0.44), the two dissolved oxygen levels ( = 0.65), or the two calyx diameters ( = 0.58). Inter-rater correlation on endpoint detection was substantial (Fleiss' kappa = 0.638,  < 0.0001), with individual reviewer sensitivities of 95%, 86%, and 100%. Eighty-nine percent of human stones were comminuted with a clinical BWL system within 30 minutes under conditions intended to reflect conditions . The results demonstrate the advantage of using ultrasonic propulsion to disperse fragments when making a visual determination of breakage endpoint from the real-time ultrasound image.
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http://dx.doi.org/10.1089/end.2019.0873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698855PMC
November 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

In Vitro Thrombolytic Efficacy of Single- and Five-Cycle Histotripsy Pulses and rt-PA.

Ultrasound Med Biol 2020 02 27;46(2):336-349. Epub 2019 Nov 27.

Department of Radiology, University of Chicago, Chicago, Illinois, USA; Committee on Medical Physics, University of Chicago, Chicago, Illinois, USA. Electronic address:

Although primarily known as an ablative modality, histotripsy can increase the efficacy of lytic therapy in a retracted venous clot model. Bubble cloud oscillations are the primary mechanism of action for histotripsy, and the type of bubble activity is dependent on the pulse duration. A retracted human venous clot model was perfused with and without the thrombolytic recombinant tissue plasminogen activator (rt-PA). The clot was exposed to histotripsy pulses of single- or five-cycle duration and peak negative pressures of 0-30 MPa. Bubble activity within the clot was monitored via passive cavitation imaging. The combination of histotripsy and rt-PA was more efficacious than rt-PA alone for single- and five-cycle pulses with peak negative pressures of 25 and 20 MPa, respectively. For both excitation schemes, the detected acoustic emissions correlated with the degree of thrombolytic efficacy. These results indicate that rt-PA and single- or multicycle histotripsy pulses enhance thrombolytic therapy.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930350PMC
February 2020

Defining Thermally Safe Laser Lithotripsy Power and Irrigation Parameters: Model.

J Endourol 2020 01 19;34(1):76-81. Epub 2019 Nov 19.

Division of Endourology, Department of Urology, University of Michigan, Ann Arbor, Michigan.

High-power laser settings are commonly employed for stone dusting techniques. Previous and studies have demonstrated that a toxic thermal dose can result from treatment within a renal calix without adequate irrigation. Hence, both laser power and irrigation rate must be considered together to determine safe laser lithotripsy parameters. The objective of this study was to map parameter safety boundaries and create guidelines for selection of safe laser and irrigation settings. The experimental system consisted of models simulating ureter, renal calix, and renal pelvis placed in a water bath maintained at 37°C. Temperature was recorded during ureteroscopy with laser activation for 60 seconds. Trials were conducted at strategically selected power levels and irrigation rates. Thermal dose for each trial was calculated based on Sapareto and Dewey t methodology with thermal dose >120 equivalent minutes considered to result in thermal tissue injury. A parameter safety boundary was established by plotting the maximal safe power level for each irrigation rate. The parameter safety boundary was found to be linear for each scenario with the renal pelvis able to tolerate the highest laser power and the renal calix the least power without injury. This study describes the methodology to determine parameter safety boundaries that can be used to guide proper selection of thermally safe laser settings and irrigation rates during ureteroscopy with laser lithotripsy. This work provides a framework to assess the effectiveness of various strategies to control and mitigate thermal dose.
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http://dx.doi.org/10.1089/end.2019.0499DOI Listing
January 2020

Evaluation of Renal Stone Comminution and Injury by Burst Wave Lithotripsy in a Pig Model.

J Endourol 2019 10 27;33(10):787-792. Epub 2019 May 27.

Department of Urology, University of Washington School of Medicine, Seattle, Washington.

Burst wave lithotripsy is an experimental technology to noninvasively fragment kidney stones with focused bursts of ultrasound (US). This study evaluated the safety and effectiveness of specific lithotripsy parameters in a porcine model of nephrolithiasis. A 6- to 7-mm human kidney stone was surgically implanted in each kidney of three pigs. A burst wave lithotripsy US transducer with an inline US imager was coupled to the flank and the lithotripter focus was aligned with the stone. Each stone was exposed to burst wave lithotripsy at 6.5 to 7 MPa focal pressure for 30 minutes under real-time image guidance. After treatment, the kidneys were removed for gross, histologic, and MRI assessment. Stone fragments were retrieved from the kidney to determine the mass comminuted to pieces <2 mm. On average, 87% of the stone mass was reduced to fragments <2 mm. In three of five treatments, stones were completely comminuted to <2-mm fragments. In two of five treatments, stones were partially disintegrated, but larger fragments remained. One stone was not treated because no suitable acoustic window was identified. No injury was detected through gross, histologic, or MRI examination in the parenchymal tissue, although petechial damage and surface erosion were identified on the urothelium of the collecting system limited to the area around the stone. Burst wave lithotripsy can consistently produce stone fragments small enough to spontaneously pass by transcutaneous administration of US pulses. The data suggest that such exposures produce minimal injury to the kidney and urinary tract.
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http://dx.doi.org/10.1089/end.2018.0886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798804PMC
October 2019

PIXUL-ChIP: integrated high-throughput sample preparation and analytical platform for epigenetic studies.

Nucleic Acids Res 2019 07;47(12):e69

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA 98195, USA.

Chromatin immunoprecipitation (ChIP) is the most widely used approach for identification of genome-associated proteins and their modifications. We have previously introduced a microplate-based ChIP platform, Matrix ChIP, where the entire ChIP procedure is done on the same plate without sample transfers. Compared to conventional ChIP protocols, the Matrix ChIP assay is faster and has increased throughput. However, even with microplate ChIP assays, sample preparation and chromatin fragmentation (which is required to map genomic locations) remains a major bottleneck. We have developed a novel technology (termed 'PIXUL') utilizing an array of ultrasound transducers for simultaneous shearing of samples in standard 96-well microplates. We integrated PIXUL with Matrix ChIP ('PIXUL-ChIP'), that allows for fast, reproducible, low-cost and high-throughput sample preparation and ChIP analysis of 96 samples (cell culture or tissues) in one day. Further, we demonstrated that chromatin prepared using PIXUL can be used in an existing ChIP-seq workflow. Thus, the high-throughput capacity of PIXUL-ChIP provides the means to carry out ChIP-qPCR or ChIP-seq experiments involving dozens of samples. Given the complexity of epigenetic processes, the use of PIXUL-ChIP will advance our understanding of these processes in health and disease, as well as facilitate screening of epigenetic drugs.
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http://dx.doi.org/10.1093/nar/gkz222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614803PMC
July 2019

For Whom the Bubble Grows: Physical Principles of Bubble Nucleation and Dynamics in Histotripsy Ultrasound Therapy.

Ultrasound Med Biol 2019 05 26;45(5):1056-1080. Epub 2019 Mar 26.

Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA.

Histotripsy is a focused ultrasound therapy for non-invasive tissue ablation. Unlike thermally ablative forms of therapeutic ultrasound, histotripsy relies on the mechanical action of bubble clouds for tissue destruction. Although acoustic bubble activity is often characterized as chaotic, the short-duration histotripsy pulses produce a unique and consistent type of cavitation for tissue destruction. In this review, the action of histotripsy-induced bubbles is discussed. Sources of bubble nuclei are reviewed, and bubble activity over the course of single and multiple pulses is outlined. Recent innovations in terms of novel acoustic excitations, exogenous nuclei for targeted ablation and histotripsy-enhanced drug delivery and image guidance metrics are discussed. Finally, gaps in knowledge of the histotripsy process are highlighted, along with suggested means to expedite widespread clinical utilization of histotripsy.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524960PMC
May 2019

The Impact of Dust and Confinement on Fragmentation of Kidney Stones by Shockwave Lithotripsy in Tissue Phantoms.

J Endourol 2019 05 1;33(5):400-406. Epub 2019 Feb 1.

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

The goal was to test whether stone composition and kidney phantom configuration affected comminution in extracorporeal shockwave lithotripsy (SWL) laboratory tests. Confinement may enhance the accumulation of dust and associated cavitation bubbles in the fluid surrounding the stone. It is known that high shockwave delivery rates in SWL are less effective because bubbles generated by one shockwave do not have sufficient time to dissolve, thereby shielding the next shockwave. Experiments were conducted with a lithotripter coupled to a water bath. The rate of comminution was measured by weighing fragments over 2 mm at 5-minute time points. First, plaster and crystal stones were broken in four phantoms: a nylon wire mesh, an open polyvinyl chloride (PVC) cup, a closed PVC cup, and an anatomical kidney model-the phantoms have decreasing fluid volumes around the stone. Second, the fluid volume in the kidney model was flushed with water at different rates (0, 7, and 86 mL/min) to remove dust. The efficiency of breakage of stones decreases for the dust emitting plaster stones (percentage of breakage in 5 minutes decreased from 92% ± 2% [ = 3] in wire mesh to 19% ± 3% [ = 3] in model calix) with increasing confinement, but not for the calcite crystal stones that produced little dust (percentage of breakage changed from 87% ± 3% [ = 3] in wire mesh to 81% ± 3% [ = 3] in kidney model). Flushing the kidney phantom at the fastest rate improved comminution of smaller plaster stones by 27%. Phantoms restricting dispersion of dust were found to affect stone breakage in SWL and experiments should replicate kidney environments. The dust around the stone and potential cavitation may shield the stone from shockwaves and reduce efficacy of SWL. Understanding of stone composition and degree of hydronephrosis could be used to adapt patient-specific protocols.
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http://dx.doi.org/10.1089/end.2018.0516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533787PMC
May 2019

Simulation of Laser Lithotripsy-Induced Heating in the Urinary Tract.

J Endourol 2019 02 29;33(2):113-119. Epub 2019 Jan 29.

3 Department of Urology, University of Michigan, Ann Arbor, Michigan.

Purpose: Holmium laser lithotripsy is a common modality used to fragment urinary stones during ureteroscopy. Laser energy deposited during activation produces heat and potentially causes thermal bioeffects. We aimed to characterize laser-induced heating through a computational simulation.

Materials And Methods: A finite-element model was developed and used to estimate temperature in the urinary tract. Axisymmetric models of laser lithotripsy in a renal calyx, the renal pelvis, and proximal ureter were created. Heat generation by laser and heat transfer were simulated under different laser powers between 5 and 40 W. Irrigation fluid flow was introduced at rates between 0 and 40 mL/min. The model was validated by comparison with previous in vitro temperature data in a test tube, then used to calculate heating and thermal dose in the three tissue models.

Results: Simulated temperature rises agreed well with most in vitro experimental measurements. In tissue models, temperature rises depended strongly on laser power and irrigation rate, and to a lesser extent on location. Injurious temperatures were reached for 5-40 W laser power without irrigation, >10 W with 5 mL/min irrigation, 40 W with 15 mL/min irrigation, and were not found at 40 mL/min irrigation. Tissue injury volumes up to 2.3 cm were calculated from thermal dose.

Conclusions: The results suggest a numerical model can accurately simulate the thermal profile of laser lithotripsy. Laser heating is strongly dependent on parameters and may cause a substantial temperature rise in the fluid in the urinary tract and surrounding tissue under clinically relevant conditions.
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http://dx.doi.org/10.1089/end.2018.0485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388709PMC
February 2019

Energy shielding by cavitation bubble clouds in burst wave lithotripsy.

J Acoust Soc Am 2018 11;144(5):2952

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

Combined laboratory experiment and numerical simulation are conducted on bubble clouds nucleated on the surface of a model kidney stone to quantify the energy shielding of the stone caused by cavitation during burst wave lithotripsy (BWL). In the experiment, the bubble clouds are visualized and bubble-scattered acoustics are measured. In the simulation, a compressible, multi-component flow solver is used to capture complex interactions among cavitation bubbles, the stone, and the burst wave. Quantitative agreement is confirmed between results of the experiment and the simulation. In the simulation, a significant shielding of incident wave energy by the bubble clouds is quantified. The magnitude of shielding can reach up to 90% of the energy of the incoming burst wave that otherwise would be transmitted into the stone, suggesting a potential loss of efficacy of stone comminution. There is a strong correlation between the magnitude of the energy shielding and the amplitude of the bubble-scattered acoustics, independent of the initial size and the void fraction of the bubble cloud within a range addressed in the simulation. This correlation could provide for real-time monitoring of cavitation activity in BWL.
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http://dx.doi.org/10.1121/1.5079641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258362PMC
November 2018

DESIGN OF A TRANSDUCER FOR FRAGMENTING LARGE KIDNEY STONES USING BURST WAVE LITHOTRIPSY.

Proc Meet Acoust 2018 Nov 9;35(1). Epub 2019 Jan 9.

Department of Urology, University of Washington School of Medicine, Seattle, WA, USA.

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http://dx.doi.org/10.1121/2.0000954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328968PMC
November 2018

Field Characterization and Compensation of Vibrational Nonuniformity for a 256-Element Focused Ultrasound Phased Array.

IEEE Trans Ultrason Ferroelectr Freq Control 2018 09 27;65(9):1618-1630. Epub 2018 Jun 27.

Multielement focused ultrasound phased arrays have been used in therapeutic applications to treat large tissue volumes by electronic steering of the focus, to target multiple simultaneous foci, and to correct aberration caused by inhomogeneous tissue pathways. There is an increasing interest in using arrays to generate more complex beam shapes and corresponding acoustic radiation force patterns for manipulation of particles such as kidney stones. Toward this end, experimental and computational tools are needed to enable accurate delivery of desired transducer vibrations and corresponding ultrasound fields. The purpose of this paper was to characterize the vibrations of a 256-element array at 1.5 MHz, implement strategies to compensate for variability, and test the ability to generate specified vortex beams that are relevant to particle manipulation. The characterization of the array output was performed in water using both element-by-element measurements at the focus of the array and holography measurements for which all the elements were excited simultaneously. Both methods were used to quantify each element's output so that the power of each element could be equalized. Vortex beams generated using both compensation strategies were measured and compared to the Rayleigh integral simulations of fields generated by an idealized array based on the manufacturer's specifications. Although both approaches improved beam axisymmetry, compensation based on holography measurements had half the error relative to the simulation results in comparison to the element-by-element method.
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http://dx.doi.org/10.1109/TUFFC.2018.2851188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344030PMC
September 2018

Caliceal Fluid Temperature During High-Power Holmium Laser Lithotripsy in an In Vivo Porcine Model.

J Endourol 2018 08 13;32(8):724-729. Epub 2018 Jul 13.

1 Department of Urology, University of Michigan , Ann Arbor, Michigan.

Introduction: With increasing use of high-power laser settings for lithotripsy, the potential exists to induce thermal tissue damage. In vitro studies have demonstrated that temperature elevation sufficient to cause thermal tissue damage can occur with certain laser and irrigation settings. The objective of this pilot study was to measure caliceal fluid temperature during high-power laser lithotripsy in an in vivo porcine model.

Methods: Four female pigs (30-35 kg) were placed under general anesthesia and positioned supine. Retrograde ureteroscopy with entry into upper or middle calices was performed. Thermocouples were placed into the calix by open exposure and puncture of the kidney or retrograde alongside the ureteroscope. A 242 μm laser fiber was positioned in the center of the calix and activated (0.5 J, 80 Hz, 40 W) for 60 seconds with high, medium, or no irrigation delivered in each trial. Finite element simulations of laser-induced heating in a renal calix were also performed.

Results: Peak temperatures of 84.8°C, 63.9°C, and 43.6°C were recorded for no, medium, and high irrigation, respectively. Mean time to reach threshold of thermal injury (t of 120 minutes) was 12.7 and 17.8 seconds for no and medium irrigation. Thermal damage thresholds were not reached in high-irrigation trials. Numerical simulations revealed similar results with peak spatial average fluid temperatures of >100°C, 58.5°C, and 37.5°C during 60 seconds of laser activation for 0.1, 15, and 40 mL/minute irrigation, respectively.

Conclusions: High-power holmium laser settings (40 W) can induce potentially injurious temperatures in the porcine in vivo model, particularly with slower irrigation rates. Characterization of thermal dose across a broader range of laser parameter settings is underway to map out the thermal safety envelope.
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http://dx.doi.org/10.1089/end.2018.0395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096348PMC
August 2018

Combined Burst Wave Lithotripsy and Ultrasonic Propulsion for Improved Urinary Stone Fragmentation.

J Endourol 2018 04 20;32(4):344-349. Epub 2018 Mar 20.

2 Department of Urology, University of Washington School of Medicine , Seattle, Washington.

Purpose: Burst wave lithotripsy (BWL) is a new technology in development to fragment urinary stones. Ultrasonic propulsion (UP) is a separate technology under investigation for displacing stones. We measure the effect of propulsion pulses on stone fragmentation from BWL.

Materials And Methods: Two artificial stone models (crystalline calcite, BegoStone plaster) and human calcium oxalate monohydrate (COM) stones measuring 5 to 8 mm were subjected to ultrasound exposures in a polyvinyl chloride tissue phantom within a water bath. Stones were exposed to BWL with and without propulsion pulses interleaved for set time intervals depending on stone type. Fragmentation was measured as a fraction of the initial stone mass fragmented to pieces smaller than 2 mm.

Results: BegoStone model comminution improved from 6% to 35% (p < 0.001) between BWL and BWL with interleaved propulsion in a 10-minute exposure. Propulsion alone did not fragment stones, whereas addition of propulsion after BWL slightly improved BegoStone model comminution from 6% to 11% (p < 0.001). BegoStone model fragmentation increased with rate of propulsion pulses. Calcite stone fragmentation improved from 24% to 39% in 5 minutes (p = 0.047) and COM stones improved from 17% to 36% (p = 0.01) with interleaved propulsion.

Conclusions: BWL with UP improved stone fragmentation compared with BWL alone in vitro. The improvement was greatest when propulsion pulses are interleaved with BWL treatment and when propulsion pulses are applied at a higher rate. Thus, UP may be a useful adjunct to enhance fragmentation in lithotripsy in vivo.
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http://dx.doi.org/10.1089/end.2017.0675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909083PMC
April 2018

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

Post Hoc Analysis of Passive Cavitation Imaging for Classification of Histotripsy-Induced Liquefaction in Vitro.

IEEE Trans Med Imaging 2018 01 2;37(1):106-115. Epub 2017 Aug 2.

Histotripsy utilizes focused ultrasound to generate bubble clouds for transcutaneous tissue liquefaction. Bubble activity maps are under development to provide image guidance and monitor treatment progress. The aim of this paper was to investigate the feasibility of using plane wave B-mode and passive cavitation images to be used as binary classifiers of histotripsy-induced liquefaction. Prostate tissue phantoms were exposed to histotripsy pulses over a range of pulse durations (5- ) and peak negative pressures (12-23 MPa). Acoustic emissions were recorded during the insonation and beamformed to form passive cavitation images. Plane wave B-mode images were acquired following the insonation to detect the hyperechoic bubble cloud. Phantom samples were sectioned and stained to delineate the liquefaction zone. Correlation between passive cavitation and plane wave B-mode images and the liquefaction zone was assessed using receiver operating characteristic (ROC) curve analysis. Liquefaction of the phantom was observed for all the insonation conditions. The area under the ROC (0.94 versus 0.82), accuracy (0.90 versus 0.83), and sensitivity (0.81 versus 0.49) was greater for passive cavitation images relative to B-mode images ( ) along the azimuth of the liquefaction zone. The specificity was greater than 0.9 for both imaging modalities. These results demonstrate a stronger correlation between histotripsy-induced liquefaction and passive cavitation imaging compared with the plane wave B-mode imaging, albeit with limited passive cavitation image range resolution.
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http://dx.doi.org/10.1109/TMI.2017.2735238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816682PMC
January 2018
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