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The Silver Medal is presented to individuals, without age limitation, for contributions to the advancement of science, engineering, or human welfare through the application of acoustic principles, or through research accomplishment in acoustics.

Boiling histotripsy (BH) is a mechanical tissue liquefaction method that uses sequences of millisecond-long high intensity focused ultrasound (HIFU) pulses with shock fronts. The BH treatment generates bubbles that move within the sonicated volume due to acoustic radiation force. Since the velocity of the bubbles and tissue debris is expected to depend on the lesion size and liquefaction completeness, it could provide a quantitative metric of the treatment progression. In this study, the motion of bubble remnants and tissue debris immediately following BH pulses was investigated using high-pulse repetition frequency (PRF) plane-wave color Doppler ultrasound in ex vivo myocardium tissue. A 256-element 1.5 MHz spiral HIFU array with a coaxially integrated ultrasound imaging probe (ATL P4-2) produced 10 ms BH pulses to form volumetric lesions with electronic beam steering. Prior to performing volumetric BH treatments, the motion of intact myocardium tissue and anticoagulated bovine blood following isolated BH pulses was assessed as two limiting cases. In the liquid blood the velocity of BH-induced streaming at the focus reached over 200 cm/s, whereas the intact tissue was observed to move toward the HIFU array consistent with elastic rebound of tissue. Over the course of volumetric BH treatments tissue motion at the focus locations was dependent on the axial size of the forming lesion relative to the corresponding size of the HIFU focal area. For axially small lesions, the maximum velocity after the BH pulse was directed toward the HIFU transducer and monotonically increased over time from about 20-100 cm/s as liquefaction progressed, then saturated when tissue was fully liquefied. For larger lesions obtained by merging multiple smaller lesions in the axial direction, the high-speed streaming away from the HIFU transducer was observed at the point of full liquefaction. Based on these observations, the maximum directional velocity and its location along the HIFU propagation axis were proposed and evaluated as candidate metrics of BH treatment completeness.

One of the challenges of transcutaneous high-intensity focused ultrasound (HIFU) therapies, especially ones relying heavily on shock formation, such as boiling histotripsy (BH), is the loss of focusing from aberration induced by the heterogeneities of the body wall. Here, a methodology to execute aberration correction in vivo is proposed. A custom BH system consisting of a 1.5-MHz phased array of 256 elements connected to a Verasonics V1 system is used in pulse/echo mode on a porcine model under general anesthesia. Estimation of the time shifts needed to correct for aberration in the liver and kidney is done by maximizing the value of the coherence factor on the acquired backscattered signals. As this process requires multiple pulse/echo sequences on a moving target to converge to a solution, tracking is also implemented to ensure that the same target is used between each iteration. The method was validated by comparing the acoustic power needed to generate a boiling bubble at one target with aberration correction and at another target within a 5-mm radius without aberration correction. Results show that the aberration correction effectively lowers the acoustic power required to reach boiling by up to 45%, confirming that it indeed restored formation of the nonlinear shock front at the focus.

Phase aberration induced by soft tissue inhomogeneities often complicates high-intensity focused ultrasound (HIFU) therapies by distorting the field and, previously, we designed and fabricated a bilayer gel phantom to reproducibly mimic that effect. A surface pattern containing size scales relevant to inhomogeneities of a porcine body wall was introduced between gel materials with fat- and muscle-like acoustic properties—ballistic and polyvinyl alcohol gels. Here, the phantom design was refined to achieve relevant values of ultrasound absorption and scattering and make it more robust, facilitating frequent handling and use in various experimental arrangements. The fidelity of the interfacial surface of the fabricated phantom to the design was confirmed by three-dimensional ultrasound imaging. The HIFU field distortions—displacement of the focus, enlargement of the focal region, and reduction of focal pressure—produced by the phantom were characterized using hydrophone measurements with a 1.5 MHz 256-element HIFU array and found to be similar to those induced by an ex vivo porcine body wall. A phase correction approach was used to mitigate the aberration effect on nonlinear focal waveforms and enable boiling histotripsy treatments through the phantom or body wall. The refined phantom represents a practical tool to explore HIFU therapy systems capabilities.

The problem of accelerating algorithms is considered for calculating the effects of diffraction, nonlinearity, and absorption in modeling high-intensity ultrasonic beams using the nonlinear Westervelt equation. The results from calculations using graphics accelerators (graphical processing units) are compared to ones obtained with a central processing unit. The performance of the algorithm is analyzed as a function of the parameters of the input data.

A study is performed of the effect acoustic inhomogeneities of the abdominal wall have on the focusing of a powerful ultrasonic beam at different positions of a transducer. A focused beam generated by a 1 MHz transducer is modeled numerically using an acoustic model of the human body created via computer-aided tomography. It is found that the focal maximum of the field of intensity shifts in space, and the maximum achievable intensity in the beam when focusing through the acoustically inhomogeneous abdominal wall is reduced. The best location of the transducer is selected to minimize distortions.

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 wash-out 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.

Histotripsy is a therapeutic ultrasound technology to liquefy tissue into acellular debris using sequences of high-power focused ultrasound pulses. Research on histotripsy has been rapidly growing in the past decade; newer applications are being proposed and evaluated for clinical use. In contrast to conventional high-intensity focused ultrasound (HIFU) thermal therapy, the major mechanism of histotripsy is mechanical, which enables localized tissue disintegration at the target sites without thermal damage to overlying and surrounding tissues. Two major approaches, cavitational histotripsy and boiling histotripsy, with two different mechanisms, have been extensively explored lately. Histotripsy therapy is being evaluated for treating cancer, thrombosis, hematomas, abscess, neurological diseases, for inducing an enhanced immune response and performing noninvasive biopsy in preclinical studies with small and large animal models. The first clinical trials using histotripsy for benign prostatic hyperplasia, liver cancer, and calcified aortic stenosis have been undertaken.

Soniс boom propagation in the atmospheric turbulent layer, represented by a model of homogeneous isotropic turbulence, is investigated numerically in two-dimensional geometry using a KZK-type nonlinear parabolic equation for an inhomogeneous moving medium with relaxation. The mean value, standard deviation, and cumulative probabilities of the sonic boom amplitude, shock front steepness, and the Perceived Loudness Mark VII metric of subjective loudness of an impulse noise are analyzed at different propagation distances traveled by the sonic boom wave in the turbulent layer and for different initial amplitudes of the wave.

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.

When designing phased antenna arrays for use in noninvasive ultrasound surgery, it is desirable to provide the highest possible power for a given array dimensions. At the same time, it is necessary to take into account the limitations on the maximum allowable ultrasound intensity at the array elements and to ensure suppression of spurious diffraction maxima in the spatial structure of the emitted field. The problem can be solved by designing an irregular arrangement combined with the densest filling of the array surface with elements. This paper presents a modification of such a method for creating fully populated arrays with nonperiodic tessellation distribution of elements, based on the restriction of the relaxation mechanism in an iterative array design algorithm. A computer model that allows for controlling the degree of irregularity in distribution of the array elements was developed. The stability of maintaining the low level of acoustic intensity in unwanted grating lobes was tested for various random realizations of the element arrangements by analyzing a statistical ensemble of 500 model arrays. The advantages of the considered arrays in comparison with existing models of fully populated arrays are demonstrated.

Boiling histotripsy (BH) is a focused ultrasound technology that uses millisecond-long pulses with shock fronts to induce mechanical tissue ablation. The pulsing scheme and mechanisms of BH differ from those of cavitation cloud histotripsy, which was previously developed for benign prostatic hyperplasia. The goal of the work described here was to evaluate the feasibility of using BH to ablate fresh ex vivo human prostate tissue as a proof of principle for developing BH for prostate applications. Fresh human prostate samples (N = 24) were obtained via rapid autopsy (24 h after death, institutional review board exempt). Samples were analyzed using shear wave elastography to ensure that mechanical properties of autopsy tissue were clinically representative. Samples were exposed to BH using 10- or 1-ms pulses with 1% duty cycle under real-time B-mode and Doppler imaging. Volumetric lesions were created by sonicating 1-4 rectangular planes spaced 1 mm apart, containing a grid of foci spaced 1-2 mm apart. Tissue then was evaluated grossly and histologically, and the lesion content was analyzed using transmission electron microscopy and scanning electron microscopy. Observed shear wave elastography characterization of ex vivo prostate tissue (37.9 ± 22.2 kPa) was within the typical range observed clinically. During BH, hyperechoic regions were visualized at the focus on B-mode, and BH-induced bubbles were also detected using power Doppler. As treatment progressed, hypoechoic regions of tissue appeared, suggesting successful tissue fractionation. BH treatment was twofold faster using shorter pulses (1 ms vs. 10 ms). Histological analysis revealed lesions containing completely homogenized cell debris, consistent with histotripsy-induced mechanical ablation. It was therefore determined that BH is feasible in fresh ex vivo human prostate tissue producing desired mechanical ablation. The study supports further work aimed at translating BH technology as a clinical option for prostate ablation.

For therapeutic ultrasound applications, design and planning of treatments often involve simulations to predict the in situ acoustic field, and these simulations rely on estimates of the acoustic properties of soft tissues. As defined in simulation models, these properties describe how a plane wave propagates in a homogeneous medium. However, because soft tissues inherently contain inhomogeneities, measurements are most appropriately performed on small, relatively homogeneous samples. In addition, mostly small samples of human tissue, either autopsy or post-surgical, are typically available for characterization. As published in a recent paper [J. Acoust. Soc. Am. 2021, 149(1): 386–404], we have proposed a holography-based technique to extract plane-wave measurements from ultrasound beams passing through small (cm-sized) material samples. Here, we seek to adapt this technique for measuring small samples of deformable materials using an apparatus that holds such samples with two plane, parallel surfaces that can be interrogated by an incident ultrasound beam having a diameter smaller than that of the sample. Initial testing over a range of frequencies from 0.5 to 10MHz is performed utilizing well characterized materials, such as hydrogels and silicone rubber. [Work supported by NIH grant R01EB025187.]

“HIFU beam” is a freely available software tool that comprises a MATLAB toolbox combined with a user-friendly interface and binary executable compiled from FORTRAN source code ( HIFU beam . (2021). Available: http://limu.msu.ru/node/3555?language=en ). It is designed for simulating high-intensity focused ultrasound (HIFU) fields generated by single-element transducers and annular arrays with propagation in flat-layered media that mimic biological tissues. Numerical models incorporated in the simulator include evolution-type equations, either the Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation or one-way Westervelt equation, for radially symmetric ultrasound beams in homogeneous and layered media with thermoviscous or power-law acoustic absorption. The software uses shock-capturing methods that allow for simulating strongly nonlinear acoustic fields with high-amplitude shocks. In this article, a general description of the software is given along with three representative simulation cases of ultrasound transducers and focusing conditions typical for therapeutic applications. The examples illustrate major nonlinear wave effects in HIFU fields including shock formation. Two examples simulate propagation in water, involving a single-element source (1-MHz frequency, 100-mm diameter, 90-mm radius of curvature) and a 16-element annular array (3-MHz frequency, 48-mm diameter, and 35-mm radius of curvature). The third example mimics the scenario of a HIFU treatment in a “water-muscle-kidney” layered medium using a source typical for abdominal HIFU applications (1.2-MHz frequency, 120-mm diameter, and radius of curvature). Linear, quasi-linear, and shock-wave exposure protocols are considered. It is intended that “HIFU beam” can be useful in teaching nonlinear acoustics; designing and characterizing high-power transducers; and developing exposure protocols for a wide range of therapeutic applications such as shock-based HIFU, boiling histotripsy, drug delivery, immunotherapy, and others.

Pulsed focused ultrasound (pFUS) uses short acoustic pulses delivered at low duty cycle and moderate intensity to non-invasively 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.

Liquid atomization and fountain formation by focused ultrasound was first published by Wood and Loomis [1]. Since then, the cavitation-wave hypothesis emerged to explain atomization in a fountain, which states atomization arises from a combination of surface capillary waves and the collapse of cavitation bubbles. More recently, high intensity focused ultrasound (HIFU) has been shown to fractionate tissue through either pulsed-cavitation or millisecond boiling histotripsy therapies; however it is unclear how millimeter-size boiling bubbles or cavitation bubble clouds fractionate tissue into submicron-size fragments. The objective of this work is to test the hypothesis experimentally that atomization and fountain formation occurs similarly in liquids and tissues and results in tissue erosion. A 2-MHz HIFU transducer operating at peak in situ pressures of 50 MPa and −11 MPa (linear intensity = 14,000 W/cm(2)) was focused at the interface between a liquid or tissue and air. A high-speed camera was used to monitor atomization and fountain formation in water, ethanol, glycerol, bovine liver, and porcine blood clots. The in situ linear intensity threshold for consistent atomization in one 10-ms pulse increased in the order: ethanol (180 W/cm(2)) < blood clot (250 W/cm(2)) < water (350 W/cm(2)) < liver (6200 W/cm(2)); glycerol did not atomize. Average jet velocities for the initial spray at the maximum acoustic intensity were similar for all materials and on the order of 20 m/s. The tissue erosion rate of liver approached saturation at around 300 10-ms pulses repeated at 1 Hz, which had an average erosion volume of 25.7±10.9 mm(3). While tissue atomization and fountain formation does not completely mimic what is observed in liquids, atomization provides a plausible explanation of how tissue is fractionated in millisecond boiling and possibly even cavitation cloud histotrispy therapies.

Aim of the study: demonstrate the feasibility of non-invasive mechanical disintegration of human prostate tissue using pulsed high-intensity focused ultrasound (pHIFU), a method termed boiling histotripsy. Materials and methods An ultrasound experimental system was developed for producing localized mechanical lesions in ex vivo biological tissue samples under ultrasound guidance. A series of experiments was carried out to create small single-focus lesions (volume 50 mm3) in ex vivo prostate tissue samples. After irradiation, two samples were bisected to visualize the region of destruction; the other tissue samples were examined histologically. Results During pHIFU irradiation under B-mode ultrasound guidance, a region of increased echogenicity caused by formation of vapor-gas bubbles was visualized in the target region. After exposure, small and large lesions filled with a suspension of liquefied tissue were observed. Histological examination confirmed that the prostate tissue in the focal region was disintegrated into subcellular fragments. Conclusion A pilot study showed the feasibility of using boiling histotripsy as a non-invasive method for treating prostate diseases.

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.

Multi-element high-intensity focused ultrasound phased arrays in the shape of hemispheres are currently used in clinics for thermal lesioning in deep brain structures. Certain side effects of overheating non-targeted tissues and skull bones have been revealed. Here, an approach is developed to mitigate these effects. A specific design of a fully populated 256-element 1-MHz array shaped as a spherical segment (F-number, F(#) = 1) and filled by randomly distributed equal-area polygonal elements is proposed. Capability of the array to generate high-amplitude shock fronts at the focus is tested in simulations by combining three numerical algorithms for linear and nonlinear field modeling and aberration correction. The algorithms are based on the combination of the Rayleigh integral, a linear pseudo-spectral time domain Kelvin–Voigt model, and nonlinear Westervelt model to account for the effects of inhomogeneities, aberrations, reflections, absorption, nonlinearity, and shear waves in the skull. It is shown that the proposed array can generate nonlinear waveforms with shock amplitudes >60 MPa at the focus deep inside the brain without exceeding the existing technical limitation on the intensity of 40 W/cm(2) at the array elements. Such shock amplitudes are sufficient for mechanical ablation of brain tissues using the boiling histotripsy approach and implementation of other shock-based therapies.

The paper presents the results of a numerical experiment comparing the rates of volumetric thermal ablation of bovine liver tissue ex vivo, generated by a multielement ultrasound array Sonalleve V1 3.0T (Philips Healthcare) using various exposure protocols. Pulsed sonications with the same time-average, but different peak power and duty cycle were modeled. The treatment trajectory consisted of a discrete set of single foci located at the center and along two concentric circles. Beam focusing in tissue was modeled using the Westervelt equation, the temperature field was calculated using the bioheat equation, and the threshold of tissue damage was determined according to the thermal dose formulation. It is shown that pulsed shock-wave exposures can provide up to three times faster volumetric ablation of tissue as compared to continuous quasi-harmonic wave treatments.

Objective. Boiling histotripsy (BH) is a novel high intensity focused ultrasound (HIFU) application currently being developed for non-invasive mechanical fractionation of soft tissues and large hematomas. In the context of development of BH treatment planning approaches for ablating targets adjacent to gas-containing organs, this study aimed at investigation of the ultrasound pressure thresholds of atomization-induced damage to the tissue-air interface and correlation of the danger zone dimensions with spatial structure of nonlinear HIFU field parameters. Approach. A flat interface with air of freshly clotted bovine blood was used as an ex vivo model due to its homogenous structure and higher susceptibility to ultrasound-induced mechanical damage compared to soft tissues. Three 1.5 MHz transducers of different F-numbers (0.77, 1 and 1.5) were focused at various distances before or beyond a flat clot surface, and a BH exposure was delivered either at constant, high-amplitude output level, or at gradually increasing level until a visible damage to the clot surface occurred. The HIFU pressure field parameters at the clot surface were determined through a combination of hydrophone measurements in water, forward wave propagation simulation using ‘HIFU beam’ software and an image source method to account for the wave reflection from the clot surface and formation of a standing wave. The iso-levels of peak negative pressure in the resulting HIFU field were correlated to the outlines of surface erosion to identify the danger zone around the BH focus. Main results. The outline of the danger zone was shown to differ from that of a typical BH lesion produced in a volume of clot material. In the prefocal area, the zone was confined within the 4 MPa contour of the incident peak-to-peak pressure; within the main focal lobe it was determined by the maximum BH lesion width, and in the postfocal area—by the transverse size of the focal lobe and position of the first postfocal pressure axial null. Significance. The incident HIFU pressure-based danger zone boundaries were outlined around the BH focus and can be superimposed onto in-treatment ultrasound image to avoid damage to adjacent gas-containing bodies.

Boiling histotripsy (BH) is a pulsed high intensity focused ultrasound (HIFU) method relying on the generation of high amplitude shocks and bubble activity to induce tissues liquefaction. A sequence of pulses, 1–20 ms long, generates boiling bubbles at the focus of the HIFU transducer within each pulse, and the remainder of the pulse then interacts with those bubbles. One effect is the creation of a prefocal bubble cloud due to shock scattering: the shock is inverted when reflected from the bubble wall resulting in sufficient negative pressure to reach intrinsic cavitation threshold immediately proximally to these bubbles. Here, a methodology is proposed to extend the length of this prefocal bubble cloud by steering the focus toward the transducer during the BH pulse and thus accelerate treatment. A BH system comprising a 1.5 MHz 256-element phased array connected to a Verasonics V1 system was used. High-speed imaging in transparent gels was performed to observe the extension of the bubble cloud resulting from shock scattering. Volumetric BH lesions were generated in ex vivo tissue. Results showed a threefold increase of the volumetric ablation rate with focus steering compared to standard BH. [Work supported by NIH R01EB007643, R01GM122859, and R01EB25187.]

Acoustic holography is frequently used for the characterization of fields generated by ultrasound transducers. For arrays with electronic focusing and beam steering, separate holograms are needed to represent the 3D field for each combination of array parameters. In this paper, we show that holograms for the field generated by each individual element in an ultrasound array can be recorded in a single hydrophone scan, by interleaving a series of excitations at each measurement location in which each element is driven separately. Such holograms were recorded for a 64-element diagnostic-therapeutic linear array with a nominal focal length of 50 mm and pitch of 0.8 mm, which is smaller than the wavelength at the operating frequency of 1.05 MHz. The resulting holograms reveal aspects of crosstalk and variations between array elements. By summing the elemental holograms with the appropriate phase shifts, holograms are synthesized representing source conditions for cases where the entire array is used to generate different beam configurations, with focal lengths between 35 mm and 60 mm, and steering angles of up to 20°. These synthetic holograms are shown to accurately characterize non-ideal steering behavior of the transducer, confirmed through direct hydrophone measurements. [Work supported by NIH grants R01EB023910 and R01EB025187.]

Previous studies have shown that the Sonalleve MR-HIFU clinical system can generate shocks of 80–105 MPa at the focus, which is sufficient for boiling histotripsy. Two versions of the system (V1 and V2) have therapeutic transducers that differ in focusing angle, arrangement of elements, and the size of a central opening. The goal here was to reveal the impact of different array geometries on shock amplitudes at the focus. Nonlinear modeling of the array’s field in water using boundary conditions reconstructed from holography shows that at the same power output, the V2 array generates 10–15 MPa lower shock amplitudes at the focus. Although this difference is mainly caused by the smaller focusing angle of the V2 array, the larger central opening of the V2 array has a nontrivial impact. By suppressing a direct wave, the central opening produces a somewhat higher shock amplitude. Axisymmetric equivalent source models were constructed for both arrays and the importance of including the central opening was demonstrated. These models can be used in the “HIFU beam” software for simulating nonlinear fields of the Sonalleve V1 and V2 systems in water and flat-layered biological tissues. [Work supported by RSF-22-72-00047 and NIH R01EB025187.]

Pulsed high-intensity focused ultrasound (pHIFU) is capable of inducing cavitation in tissue without the need for contrast agents, thereby enhancing permeability and passive drug penetration in tissue with poor perfusion. We have developed and characterized the performance of a 64-element linear ultrasound array for image-guided therapy, capable of generating sufficient levels of inertial cavitation at 1 MHz, along with B-mode and Doppler imaging for targeting and cavitation assessment, respectively. Cavitation behaviors induced by different pHIFU exposures were investigated using high-speed imaging in agarose and polyacrylamide phantoms in conjunction with passive cavitation detection (PCD) and plane wave Doppler imaging. Image quality assessment was performed on in vivo porcine models, and cavitation monitoring was demonstrated on ex vivo tissues. High-speed images of the induced cavitation behavior while steering the beam focus both axially and laterally (within ±1.2 cm) were in agreement with Doppler power distributions and broadband noise emissions from PCD. Destructive cavitation behaviors in both gels and tissue were induced at relatively low peak-negative pressures (3–4 MPa), provided that the pHIFU focal waveform was nonlinearly distorted. B-mode image quality is sufficient for recognizing the relative position of anatomic landmarks and targeting cm-sized regions. [Work supported by NIH grants R01EB023910 and R01EB025187.]

Acoustic holography has been successfully applied for accurate characterization of ultrasound sources. However, its direct use for multi-element phased arrays with many possible field configurations is not feasible. Here, two methods based on transient acoustic holography are proposed allowing reconstruction of all field configurations over a range of frequencies. The methods were tested using a 2 MHz piezocomposite 12-element annular array. First, the holography measurement was performed with all array elements excited in phase. After field reconstruction on the array surface, each element was separated spatially. Second, the array elements were excited individually in sequence for each measurement location. After separating the measured signals in time, 12 separate holograms were obtained to representing each array element individually. For both methods, the array performance was predicted by numerically defining the phase of each element. To evaluate these predictions, a hologram for a specific case of focus steering toward the array was measured independently. Although both characterization methods captured the array performance with focus steering, the approach that extracts elements from time sequences provided higher accuracy and thus can be used for sources with stronger electrical and mechanical crosstalk between the elements. [Work supported by RSF-20-12-00145 and NIH R01EB025187.]

Boiling histotripsy (BH) uses millisecond-long ultrasound pulses with high amplitude shocks to mechanically fractionate tissue with potential for real-time lesion monitoring by ultrasound imaging. For BH treatments of abdominal organs, a high-power multi-element 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, Besanson, France) with a central opening for mounting an imaging probe. The array was electronically matched to a Verasonics research ultrasound 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 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 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 pulse length, 5 pulses/focus, and 1 % duty cycle.

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.

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.

For the acoustic characterization of materials, a method is proposed for interpreting experiments with finite-sized transducers and test samples in terms of the idealized situation in which plane waves are transmitted through an infinite plane-parallel layer. The method uses acoustic holography, which experimentally provides complete knowledge of the wave field by recording pressure waveforms at points on a surface intersected by the acoustic beam. The measured hologram makes it possible to calculate the angular spectrum of the beam to decompose the field into a superposition of plane waves propagating in different directions. Because these waves cancel one another outside the beam, the idealized geometry of an infinite layer can be represented by a sample of finite size if its lateral dimensions exceed the width of the acoustic beam. The proposed method relies on holograms that represent the acoustic beam with and without the test sample in the transmission path. The method is described theoretically, and its capabilities are demonstrated experimentally for silicone rubber samples by measuring their frequency-dependent phase velocities and absorption coefficients in the megahertz frequency range.

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.

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 demonstrated in an in vitro bovine hematoma model that 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 (CPD) - saline-adenine-glucose-mannitol solution (SAGM). Typical boiling histotripsy (BH) pulses (10-ms 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 (SEM). 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.

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 wash-out 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.

The phenomenon of acoustic radiation force acting on solid spherical scatterers inside the field of a focused ultrasonic beam is experimentally studied. Nylon and glass beads are used as scatterers; the acoustic field is generated by a piezoceramic transducer of the megahertz frequency range in water. The angular spectrum of the ultrasonic beam, obtained from the measured transverse distribution of the amplitude and phase of the acoustic pressure, is used to calculate the theoretical value of the radiation force. The results from these calculations are in agreement with the experimentally determined value of the radiation force.

Boiling histotripsy (BH) is a high intensity focused ultrasound method that induces mechanical tissue liquefaction and relies on the formation of a mm-sized vapor bubble at the focus. One challenge of transcutaneous BH is to confirm the presence of such bubble and to differentiate it from prefocal cavitation. Strong prefocal cavitation can shield the focus, prevent initiation of boiling, and lead to unsuccessful treatment, although an echogenic region would still be present on B-mode ultrasound images. Here, a methodology for real-time monitoring of different bubble activity during BH treatment is proposed. Custom BH systems of 1 and 1.5 MHz with inline ultrasound imaging probes connected to a Verasonics V1 system were used for BH treatments in pigs in vivo and in ex vivo tissues. Backscattered signals arriving to the imaging probe were recorded during the 10 ms BH pulses delivered at 1 Hz and passive cavitation imaging (PCI) reconstruction was performed and displayed on top of the B-mode images to identify and classify the regions of bubble activity. Spectral analysis of the PCI signals promoting prefocal cavitation and lack thereof was performed to identify the spectral features corresponding to prefocal cavitation and vapor bubble formation. [Work supported by NIH R01EB007643, R01GM122859, and R01EB25187.]

Pulsed high intensity focused ultrasound was shown to enhance chemotherapeutic drug uptake in tumor tissue through inertial cavitation, which is commonly assumed to require peak rarefactional pressures to exceed a certain threshold. However, recent studies have indicated that inertial cavitation activity also correlates with the presence of shocks at the focus. The shock front amplitude and corresponding peak negative pressure (p−) in the focal waveform are primarily determined by the transducer F-number: less focused transducers produce shocks at lower p−. Here, the dependence of inertial cavitation activity on the transducer F-number was investigated in agarose gel by monitoring broadband noise emissions with a coaxial passive cavitation detector (PCD) during pulsed exposures (pulse duration 1 ms, pulse repetition frequency 1 Hz) with p− varying within 1–15 MPa. Three 1.5 MHz transducers with the same aperture, but different focal distances (F-numbers 0.77, 1.02, 1.52) were used. PCD signals were processed to extract cavitation probability, persistence, and mean noise level. At the same p−, all metrics indicated enhanced cavitation activity at higher F-numbers; specifically, cavitation probability reached 100% when shocks formed at the focus. These results provide further evidence supporting the excitation of inertial cavitation at reduced p− by waveforms with nonlinear distortion and shocks.

A novel numerical algorithm based on the wide-angle parabolic approximation is developed for modeling linear and nonlinear fields generated by axially symmetric ultrasound transducers. An example of a strongly focused single-element transducer is used to compare the results of ultrasound field simulations based on the Westervelt equation, Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation with differently modified boundary condition, and nonlinear wide-angle parabolic equation. It is demonstrated that having a computational speed comparable to modeling the KZK equation, the use of wide-angle parabolic approximation makes it possible to obtain solutions for highly focused ultrasound beams that are closer in accuracy to solutions based on the Westervelt equation.

The results are presented from computer simulations of acoustic pulse propagation in heterogenous media mimicking the human head in two-dimensional and three-dimensional geometries. In the three-dimensional experiment, the cranial bone is presented as a liquid layer with a speed of sound corresponding to that of longitudinal waves in the bone. In the two-dimensional experiment, both longitudinal and transverse waves are considered. Based on data obtained in the numerical experiments, the possibility of obtaining ultrasound images of point scatterers by compensating for aberrations introduced by cranial bones is studied. It is shown that even a simple time delay correction along straight rays greatly improves the quality of an ultrasound image obtained through a nonuniform-thickness solid layer.

The goal of this introductory talk is to present an overview of the software termed “HIFU beam” that has been designed for simulating HIFU fields generated by axially symmetric single-element transducers and annular arrays in flat-layered media that mimic biological tissues. Numerical models include the Khokhlov–Zabolotskaya–Kuznetsov (KZK) and one-way Westervelt equations with thermoviscous absorption as well as power-law absorption to capture frequency-dependent effects. The numerical algorithms include combinations of time- and frequency-domain finite-difference schemes to simulate formation of high-amplitude shocks at the focus. The software comprises a MATLAB toolbox combined with a user-friendly graphical interface and binary executable compiled from FORTRAN source code; it is available for Windows operating systems only. Simulation examples representing typical cases of ultrasound transducers, focusing conditions, and propagation in layered media are presented to illustrate software features for High Intensity Focused Ultrasound (HIFU) applications. The software tool “HIFU beam” is freely available and can be downloaded, along with a detailed help file, from the website http://limu.msu.ru. The software can help to predict nonlinear HIFU pressures generated by existing transducers and help in the design of transducers for achieving specified acoustic outputs. [Work supported by RSF 20-12-00145, NIH R01EB7643, and R01EB25187.]

Acoustic radiation forces can trap and manipulate objects in three-dimensional space (3D). The state of the art in acoustic trapping has demonstrated the ability to move small or lightweight objects using single or multiple transducers. For certain medical applications, acoustic manipulation can be utilized to control foreign objects in the body, such as kidney stones. However, difficulties from these applications include the ability to control large solid objects, transmitting robust acoustic beams through the skin, and the use of a single source due to limited acoustic window in the body. The goal of this work was to use a 1.5 MHz, focused, multi-element array to synthesize specific acoustic beams to trap, levitate, and steer kidney stone models (glass spheres) in a water bath and urinary bladders of live pigs. Stable acoustic traps were investigated numerically and experimentally in water bath to design a protocol for the 3D manipulation strategies used invivo . Three programmed path were used to levitate and manipulate glass spheres in live pigs. The motion was recorded using a camera and a synchronized ultrasound imaging probe. Deviation from the intended paths was on average

Aberrations induced by soft tissue inhomogeneities distort acoustic fields and often complicate HIFU therapies. An aberration-generating phantom was designed and fabricated to mimic the acoustic effects of a porcine body wall. A rippled surface pattern replicating inhomogeneities of size scales relevant to the porcine body wall was transferred to a large phantom made of fat-like and muscle-like gel materials. The acoustic distortions produced by the phantom and an ex vivo porcine body wall were characterized by hydrophone measurements with a 256-element 1.5 MHz focused ultrasound array (diameter = 144 mm, F# = 0.83). Insertion of the phantom generated large distortions for both linear and nonlinear beam focusing including displacement of the focus (up to 0.3 mm transversely), enlargement of the focal region, and reduction in focal pressures due to aberration (up to 2.5-fold peak positive pressure reduction). The phantom and porcine body wall produced similar levels of aberration and attenuation effects. An aberration correction approach was leveraged to isolate the quantitative effect of aberration and to restore shocks in nonlinear waveforms in the focus. Boiling histotripsy treatments through the phantom or body wall were subsequently demonstrated in a hematoma sample. [This work was supported by NIH R01EB7643 and R01EB25187, and RSF 20-12-00145.]

Pulsed high-intensity focused ultrasound (pHIFU) is capable of inducing cavitation without the need for contrast agents, which can enhance drug transport in tissues with poor perfusion. We report on the experimental characterization of cavitation induced by a new dual-mode ultrasound arraydesigned for image-guided pHIFU therapies. The 64-element array (1.071 MHz, aperture of 14.8 × 51.2 mm2 and pitch of 0.8 mm) is driven by the Verasonics V1 ultrasound system, configured for pHIFU excitation. Acoustic properties of the beam in the focal region were characterized through hydrophone measurements in the linear and nonlinear operating regimes while steering the beam azimuthally and axially. A high-speed camera was used to observe the cavitation behaviors induced in tissue-mimicking gel phantoms near the focus of the beam for different pHIFU exposure parameters. As the focal pressure increases, a change in cavitation behavior occurs, from the appearance of single, stationary bubbles, to groups of proliferating bubbles. The pressure at which the transition from stationary to proliferating cavitation was observed corresponds to the onset of shocks in the focal region. Beams with larger F-numbers were shown to induce cavitation at lower pressures than beams with lower F-numbers. [Work supported by NIH R01EB023910 and RSF 20-12-00145.]