Acoustic radiation forces can remotely manipulate particles. Forces from a standing wave field align microscale particles along the nodal or anti-nodal locations of the field to form three-dimensional (3D) patterns. These patterns can be used to form 3D microstructures for tissue engineering applications. However, standing wave generation requires more than one transducer or a reflector, which is challenging to implement in vivo. Here, a method is developed and validated to manipulate microspheres using a travelling wave from a single transducer. Diffraction theory and an iterative angular spectrum approach are employed to design phase holograms to shape the acoustic field. The field replicates a standing wave and aligns polyethylene microspheres in water, which are analogous to cells in vivo, at pressure nodes. Using Gor'kov potential to calculate the radiation forces on the microspheres, axial forces are minimized, and transverse forces are maximized to create stable particle patterns. Pressure fields from the phase holograms and resulting particle aggregation patterns match predictions with a feature similarity index > 0.92, where 1 is a perfect match. The resulting radiation forces are comparable to those produced from a standing wave, which suggests opportunities for in vivo implementation of cell patterning toward tissue engineering applications.

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.

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.

Introduction and Objective: In clinical trial NCT03873259, a 2.6-mm lower pole stone was treated transcutaneously and ex vivo with 390-kHz burst wave lithotripsy (BWL) for 40 minutes and failed to break. The stone was subsequently fragmented with 650-kHz BWL after a 4-minute exposure. This study investigated how to fragment small stones and why varying the BWL frequency may more effectively fragment stones to dust.

Methods: A linear elastic theoretical model was used to calculate the stress created inside stones from shock wave lithotripsy (SWL) and different BWL frequencies mimicking the stone's size, shape, lamellar structure, and composition. To test model predictions about the impact of BWL frequency, matched pairs of stones (1–5 mm) were treated at (1) 390 kHz, (2) 830 kHz, and (3) 390 kHz followed by 830 kHz. The mass of fragments > 1 and 2 mm was measured over 10 minutes of exposure.

Results: The linear elastic model predicts that the maximum principal stress inside a stone increases to more than 5.5 times the pressure applied by the ultrasound wave as frequency is increased, regardless of the composition tested. The threshold frequency for stress amplification is proportionate to the wave speed divided by the stone diameter. Thus, smaller stones may be likely to fragment at a higher frequency, but not at a lower frequency below a limit. Unlike with SWL, this amplification in BWL occurs consistently with spherical and irregularly shaped stones. In water tank experiments, stones smaller than the threshold size broke fastest at high frequency (p = 0.0003), whereas larger stones broke equally well to submillimeter dust at high, low, or mixed frequencies.

Conclusions: For small stones and fragments, increasing frequency of BWL may produce amplified stress in the stone causing the stone to break. Using the strategies outlined here, stones of all sizes may be turned to dust efficiently with BWL.

The acoustic parameter of non-linearity B/A has been found capable of discriminating some types of pathological tissue from healthy tissue. The literature on the utility of B/A for cancer diagnostics is very limited, with measurements on the human breast and liver. This work expands the current research on cancer diagnostics by B/A assessment of eight slices of human clear cell renal cell carcinoma (ccRCC) from two patients and four slices of healthy kidney tissue from two healthy kidney samples. The Wilcoxon test identified the B/A distribution of malignant tissue as not significantly different from that of healthy tissue. An alternative way of defining outliers resulted in median B/A values of 8.1 for ccRCC and 6.8 for healthy tissue (p < 0.05). Acoustic attenuation at 2.1 MHz was significantly greater (p < 0.05) for ccRCC (1.7 dB/cm) than for healthy tissue (1.0 dB/cm). The observed differences in the measured values suggest that B/A and acoustic attenuation may represent potential diagnostic markers of ccRCC. More data and an improved experimental design are required to provide a definitive conclusion on the utility of B/A for cancer diagnostics.

Unlike shock wave lithotripsy, burst wave lithotripsy (BWL) uses tone bursts, consisting of many periods of a sinusoidal wave. In this work, an analytical theoretical approach to modeling mechanical stresses in a spherical stone was developed to assess the dependence of frequency and stone size on stress generated in the stone. The analytical model for spherical stones is compared against a finite-difference model used to calculate stress in nonspherical stones. It is shown that at low frequencies, when the wavelength is much greater than the diameter of the stone, the maximum principal stress is approximately equal to the pressure amplitude of the incident wave. With increasing frequency, when the diameter of the stone begins to exceed about half the wavelength in the surrounding liquid (the exact condition depends on the material of the stone), the maximum stress increases and can be more than six times greater than the incident pressure. These results suggest that the BWL frequency should be elevated for small stones to improve the likelihood and rate of fragmentation.

'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.

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, 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 peak rarefactional pressure 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.

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

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

The nonlinear parameter of ultrasound B/A has shown to be a useful diagnostic parameter, reflecting medium content, structure, and temperature. Despite its recognized values, B/A is not yet used as a diagnostic tool in the clinic due to the limitations of current measurement and imaging techniques. This review presents an extensive and comprehensive overview of the techniques developed for B/A measurement of liquid and liquid-like media (e.g., tissue), identifying the methods that are most promising from a clinical perspective. This work summarizes the progress made in the field and the typical challenges on the way to B/A estimation. Limitations and problems with the current techniques are identified, suggesting directions that may lead to further improvement. Since the basic theory of the physics behind the measurement strategies is presented, it is also suited for a reader who is new to nonlinear ultrasound.

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.

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.

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.

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.

Theoretical models allow design of acoustic traps to manipulate objects with radiation force. A model of the acoustic radiation force by an arbitrary beam on a solid object is validated against measurement. The lateral force in water of different acoustic beams is measured and calculated for spheres of different diameters (2–6 wavelengths λ in water) and compositions. 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 are synthesized in water by a 1.5-MHz, 256-element focused array. Spherical targets (glass, brass, ceramic, 2–6 mm dia.) are placed on an acoustically transparent plastic plate that is normal to the acoustic beam axis and rigidly attached to the array. Each sphere is trapped in the beam as the array with the attached plate is rotated until the sphere falls from the acoustic trap because of gravity. Calculated and measured maximum obtained angles agree on average to within 22%. The maximum lateral force occurs when the target diameter equals the beam width; however, objects up to 40% larger than the beam width are trapped. The lateral force is 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 are used to trap and electronically steer the spheres along a two-dimensional path.

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/cm² 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.

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.

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.

The isolation and sorting of cells is an important process in research and hospital labs. Most large research and commercial labs incorporate fluorescently or magnetically labeled antibodies adherent to cell surface antigens for cell identification and separation. In this paper, a process is described that merges biochemical labeling with ultrasound-based separation. Instead of lasers and fluorophore tags, or magnets and magnetic particle tags, the technique uses ultrasound and microbubble tags. Streptavidin-labeled microbubbles were mixed with a human acute lymphoblastic leukemia cell line, CCL 119, conjugated with biotinylated anti-CD7 antibodies. Tagged cells were forced under ultrasound, and their displacement and velocity quantified. Differential displacement in a flow stream was quantified against erythrocytes, which showed almost no displacement under ultrasound. A model for the acoustic radiation force on the conjugated pairs compares favorably with observations. This technology may improve on current time-consuming and costly purification procedures.

Nonlinear evolution of a standing acoustic wave in a spherical resonator with a perfectly soft surface is analyzed. Quadratic approximation of nonlinear acoustics is used to analyze oscillations in the resonator by the slowly varying amplitude method for the standing wave harmonics and slowly varying profile method for the standing wave profile. It is demonstrated that nonlinear effects may lead to considerable increase in peak pressure at the center of the resonator. The proposed theoretical model is used to analyze the acoustic field in liquid drops of an acoustic fountain. It is shown that, as a result of nonlinear evolution, the peak negative pressure may exceed the mechanical strength of the liquid, which may account for the explosive instability of drops observed in experiments.

Maximizing the power of multi-element phased arrays is a critical factor for high intensity focused ultrasound (HIFU) applications such as histotripsy and transcostal sonications. This can be achieved by a tight packing of the array elements. Good electronic focusing capabilities are also required. Currently used quasi-random arrays with a relatively low filling factor of about 60% have this focusing ability. Here, a novel method of designing random HIFU arrays with the maximum possible filling factor (100% if no gaps between elements needed in practice are introduced) and polygonal elements of equal area and slightly different shape based on the capacity-constrained tessellation is described. The method is validated by comparing designs of two arrays with the same geometric and physical parameters: an existing 256-element array with a compact 16-spirals layout of circular elements and the proposed array with the maximum possible filling factor. Introduction of a 0.5 mm gap between the elements of the new array resulted in a reduction of its filling factor to 86% as compared with 61% for the spiral array. It is shown that for the same intensity at the elements, the proposed array provides two times higher total power while maintaining the same electronic focusing capabilities as compared to the spiral one. Furthermore, the surface of the capacity-constrained tessellation array, its boundary, and a central opening can have arbitrary shapes.

The color Doppler ultrasound twinkling artifact, which highlights kidney stones with rapidly changing color, has the potential to improve stone detection; however, its inconsistent appearance has limited its clinical utility. Recently, it was proposed stable crevice bubbles on the kidney stone surface cause twinkling; however, the hypothesis is not fully accepted because the bubbles have not been directly observed. In this paper, the micron or submicron-sized bubbles predicted by the crevice bubble hypothesis are enlarged in kidney stones of five primary compositions by exposure to acoustic rarefaction pulses or hypobaric static pressures in order to simultaneously capture their appearance by high-speed photography and ultrasound imaging. On filming stones that twinkle, consecutive rarefaction pulses from a lithotripter caused some bubbles to reproducibly grow from specific locations on the stone surface, suggesting the presence of pre-existing crevice bubbles. Hyperbaric and hypobaric static pressures were found to modify the twinkling artifact; however, the simple expectation that hyperbaric exposures reduce and hypobaric pressures increase twinkling by shrinking and enlarging bubbles, respectively, largely held for rough-surfaced stones but was inadequate for smoother stones. Twinkling was found to increase or decrease in response to elevated static pressure on smooth stones, perhaps because of the compression of internal voids. These results support the crevice bubble hypothesis of twinkling and suggest the kidney stone crevices that give rise to the twinkling phenomenon may be internal as well as external.

Multi-element ultrasound arrays are increasingly used in clinical practice for both imaging and therapy. In therapy, they allow electronic steering, aberration correction, and focusing. To avoid grating lobes, an important requirement for such an array is the absence of periodicity in the arrangement of the elements. A convenient solution is the arrangement of the elements along spirals. The objective of this work was to design, fabricate, and characterize an array for boiling histotripsy applications that is capable of generating shock waves in the focus of up to 100 MPa peak pressure while having a reasonable electronic steering range.

The use of shock waves for enhancing thermal effects and mechanically ablating tissue is gaining increased attention in high intensity focused ultrasound (HIFU) applications such as tumor treatment, drug delivery, noninvasive biopsy, and immunotherapy. For abdominal targets, the presence of ribs and inhomogeneous adipose tissue can affect shock formation through aberration, absorption, and diffraction. The goal of this study was to design and validate a phantom for investigating the impact of different tissue structures on shock formation in situ. A transducer with driving electronics was developed to operate at 1.2 MHz with the ability to deliver either short pulses at high powers (up to 5 kW electric power) or continuous output at moderate powers (up to 700 W). Fat and muscle layers were represented by phantoms made from polyvinyl alcohol. Ribs were 3D-printed from a photopolymer material based on 3D CT scan images. Representative targeted tissue was comprised of optically transparent alginate or polyacrylamide gels. The system was characterized by hydrophone measurements free-field in water and in the presence of a body wall or rib phantoms. Shocked waveforms with peak positive/negative pressures of +100 / –20 MPa were measured at the focus in a free field at 1 kW electric source power. When ribs were present, shocks formed at about 50% amplitude at the same power, and higher pressures were measured with ribs positioned closer to the transducer. A uniform body wall structure attenuated shock amplitudes by a smaller amount than non-uniform, and the measurements were insensitive to the axial position of the phantom. Signal magnitude loss at the focus for both the rib phantoms and abdominal wall tissue were consistent with results from real tissues. In addition, boiling histotripsy lesions were generated and visualized in the target gels. The results demonstrate that the presence of ribs and absorptive tissue-mimicking layers do not prevent shock formation at the focus. With real-time lesion visualization, the phantom is suitable for adaptation as a training tool.

Hyperbaric pressures of 3–100 atmospheres absolute (ATA) have been shown to reduce the color Doppler ultrasound twinkling artifact on ex vivo human kidney stones, leading to the hypothesis that surface crevice microbubbles cause twinkling. Similarly supportive for the crevice bubble hypothesis is the suppression of kidney stone twinkling in animals breathing elevated levels of carbon dioxide. However, it is unclear whether stable microbubbles can exist on the surface of kidney stones in the human body. For the first time, we investigate the effect of hyperbaric pressure on in situ human kidney stones to determine whether stable microbubbles exist as measured by the color Doppler ultrasound twinkling artifact.

Burst wave lithotripsy (BWL) is an experimental method to noninvasively fragment urinary calculi using low-frequency focused bursts of ultrasound. To optimize many of the acoustic parameters for this technology, it is necessary to understand the physical interactions between ultrasound bursts and stones. In this study, the interaction of elastic waves with model stones was simulated and experimentally visualized by photoelastography, a technique using polarized light to spatially and temporally visualize stress patterns.

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.

Elastography is a non-invasive imaging technique that can assess in vivo tissue stiffness. In shear wave elastography imaging, the acoustic radiation force (ARF) produced by focused ultrasound generates a local force that produces shear waves. The authors compare three existing formulations for the ARF: its full expression in the second-order approximation and two simplified formulations using a quasi-plane wave and an attenuated plane wave approximation. Analytical expressions for the ARF are derived for the special cases of a concave spherical source and a quasi-Gaussian beam. They provide expressions for the resulting ARF and show discrepancies between the different formulations. For strongly divergent or highly focused beams the ARF expressed by the second-order approximation significantly differs from both simplified formulations. However, despite those differences the second-order and quasi-plane wave approximations create identical shear displacements in tissue. To compute the ARF and the displacements produced by a conventional ultrasound probe, the three formulations were incorporated into the k-Wave simulation package. The second-order and quasi-plane wave approximations give different forces but nearly identical displacements while the plane wave approximation significantly differs. It is concluded that to properly take into account the ultrasound field structure, the second-order or quasi-plane wave approximations should be preferably used.

Newer imaging and therapeutic ultrasound technologies may benefit from in situ pressure levels higher than conventional diagnostic ultrasound. One example is the recently developed use of ultrasonic radiation force to move kidney stones and residual fragments out of the urinary collecting system. A commercial diagnostic 2.3 MHz C5-2 array probe has been used to deliver the acoustic pushing pulses. The probe is a curvilinear array comprising 128 elements equally spaced along a convex cylindrical surface. The effectiveness of the treatment can be increased by using higher transducer output to provide a stronger pushing force; however nonlinear acoustic saturation can be a limiting factor. In this work nonlinear propagation effects were analyzed for the C5-2 transducer using a combined measurement and modeling approach. Simulations were based on the three-dimensional Westervelt equation with the boundary condition set to match low power measurements of the acoustic pressure field. Nonlinear focal waveforms simulated for different numbers of operating elements of the array at several output power levels were compared to fiber-optic hydrophone measurements and were found to be in good agreement. It was shown that saturation effects do limit the acoustic pressure in the focal region of a diagnostic imaging probe.

Various clinical applications of high-intensity focused ultrasound have different requirements for the pressure levels and degree of nonlinear waveform distortion at the focus. The goal of this paper is to determine transducer design parameters that produce either a specified shock amplitude in the focal waveform or specified peak pressures while still maintaining quasi-linear conditions at the focus. Multiparametric nonlinear modeling based on the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation with an equivalent source boundary condition was employed. Peak pressures, shock amplitudes at the focus, and corresponding source outputs were determined for different transducer geometries and levels of nonlinear distortion. The results are presented in terms of the parameters of an equivalent single-element spherically shaped transducer. The accuracy of the method and its applicability to cases of strongly focused transducers were validated by comparing the KZK modeling data with measurements and nonlinear full diffraction simulations for a single-element source and arrays with 7 and 256 elements. The results provide look-up data for evaluating nonlinear distortions at the focus of existing therapeutic systems as well as for guiding the design of new transducers that generate specified nonlinear fields.

A theoretical study of the growth of a spherical vapor bubble in a spherically symmetric superheated region is described. The modeling of bubble dynamics is based on considering the hydrodynamic and thermal processes inside a bubble and the surrounding liquid.

Ultrasonic atomization has been used in air humidifiers and is also involved in therapeutic applications of intense ultrasound such as boiling histotripsy. An as-yet unexplained phenomenon occurs when a focused ultrasound beam in water creates an acoustic fountain in the form of a drop chain, which explodes in less than a millisecond. In the present paper, we seek to develop a nonlinear theory to explain this phenomenon. We hypothesize that standing wave harmonics are generated inside the water drops due to acoustic nonlinearities, which, along with localized heat deposition in the drop center, may generate a superheated vapor bubble that causes the explosion.

Acoustic radiation force has many applications. One of the related technologies is the ability to noninvasively expel stones from the kidney. To optimize the procedure it is important to develop theoretical approaches that can provide rapid calculations of the radiation force depending in stone size and elastic properties, together with ultrasound beam diameter, intensity, and frequency. We hypothesize that the radiation force nonmonotonically depends on the ratio between the acoustic beam width and stone diameter because of coupling between the acoustic wave in the fluid and shear waves in the stone. Testing this hypothesis by considering a spherical stone and a quasi-Gaussian beam was performed in the current work. The calculation of the radiation force was conducted for elastic spheres of two types. Dependence of the magnitude of the radiation force on the beam diameter at various fixed values of stone diameters was modeled. In addition to using real material properties, speed of shear wave in the stone was varied to reveal the importance of shear waves in the stone. It was found that the radiation force reaches its maximum at the beamwidth comparable to the stone diameter; the gain in the force magnitude can reach 40% in comparison with the case of a narrow beam.

In this work, an effective transcranial imaging technique is proposed to compensate for distortions of ultrasound (US) field caused by skull bone. The results of an experimental study using skull phantoms and 2D synthetic array are presented. The method was used to visualize mm-sized spherical scatterers made from styrofoam as well as a soft silicone tube mimicking a blood vessel. It is shown that the proposed technique is capable to compensate for field distortion and results in improved imaging through the skull.

In medical and industrial ultrasound, it is often necessary to measure the acoustic properties of a material. A specific medical application requires measurements of sound speed, attenuation, and nonlinearity to characterize livers being evaluated for transplantation. For this application, a transmission-mode caliper device is proposed in which both transmit and receive transducers are directly coupled to a test sample, the propagation distance is measured with an indicator gage, and receive waveforms are recorded for analysis. In this configuration, accurate measurements of nonlinearity present particular challenges: diffraction effects can be considerable while nonlinear distortions over short distances typically remain small. To enable simple estimates of the nonlinearity coeffcient from a quasi-linear approximation to the lossless Burgers’ equation, the calipers utilize a large transmitter and plane waves are measured at distances of 15–50 mm. Waves at 667 kHz and pressures between 0.1 and 1 MPa were generated and measured in water at different distances; the nonlinearity coeffcient of water was estimated from these measurements with a variability of approximately 10%. Ongoing efforts seek to test caliper performance in other media and improve accuracy via additional transducer calibrations.

Various clinical applications of high intensity focused ultrasound (HIFU) have different requirements on the pressure level and degree of nonlinear waveform distortion at the focus. Applications that utilize nonlinear waves with developed shocks are of growing interest, for example, for mechanical disintegration as well as for accelerated thermal ablation of tissue. In this work, an inverse problem of determining transducer parameters to enable formation of shocks with desired amplitude at the focus is solved. The solution was obtained by performing multiple direct simulations of the parabolic Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation for various parameters of the source. It is shown that results obtained within the parabolic approximation can be used to describe the focal region of single element spherical sources as well as complex transducer arrays. It is also demonstrated that the focal pressure level at which fully developed shocks are formed mainly depends on the focusing angle of the source and only slightly depends on its aperture and operating frequency. Using the simulation results, a 256-element HIFU array operating at 1.5 MHz frequency was designed for a specific application of boiling-histotripsy that relies on the presence of 90–100 MPa shocks at the focus. The size of the array elements and focusing angle of the array were chosen to satisfy technical limitations on the intensity at the array elements and desired shock amplitudes in the focal waveform. Focus steering capabilities of the array were analysed using an open-source T-Array software developed at Moscow State University.

The paper considers specific features of ultrasonic visualization of gas bubbles in a liquid or a medium of like soft biological tissue type under conditions when the size of scatterers is comparable to the acoustic wavelength. It was proposed to use styrofoam specimens as the experimental model of stationary gas bubbles. Patterns of ultrasound scattering by a styrofoam sphere in water were obtained experimentally. It was shown that the measurement results agree well with the prediction of the classical theoretical model of scattering of a plane wave by a perfectly soft sphere. Several experiments were performed illustrating the specific features of visualizing millimeter-sized bubbles. A Terason commercial ultrasonic scanner was used; gelatin specimens with embedded styrofoam spheres served as the objects of study. The simulation and experimental results showed that when bubbles with diameters of <1 mm are visualized, it is impossible to measure the diameter of scatterers because bubbles of different diameters are imaged as bright spots of identical diameter, which is equal to the scanner resolution. To eliminate this difficulty, it is recommended to use the results of theoretical simulation performed in this study, which revealed a monotonic increase in the backscattered signal intensity with an increase in bubble radius. An ultrasonic visualization mode is proposed in which the brightness of scattered signals is used to differentiate between bubbles of different size.

The paper considers the problem of precise measurement of the acoustic radiation force of an ultrasonic beam on targets in the form of solid spherical scatterers. Using known analytic relations, a numerical model is developed to perform calculations for different sizes of spherical scatterers and arbitrary frequencies of the incident acoustic wave. A novel method is proposed for measuring the radiation force, which is based on the principle of acoustic echolocation. The radiation force is measured experimentally in a wide range of incident wave intensities using two chosen methods differing in the way the location of the target is controlled.

Acoustic holography is a powerful technique for characterizing ultrasound sources and the fields they radiate, with the ability to quantify source vibrations and reduce the number of required measurements. These capabilities are increasingly appealing for meeting measurement standards in medical ultrasound; however, associated uncertainties have not been investigated systematically. Here errors associated with holographic representations of a linear, continuous-wave ultrasound field are studied. To facilitate the analysis, error metrics are defined explicitly, and a detailed description of a holography formulation based on the Rayleigh integral is provided. Errors are evaluated both for simulations of a typical therapeutic ultrasound source and for physical experiments with three different ultrasound sources. Simulated experiments explore sampling errors introduced by the use of a finite number of measurements, geometric uncertainties in the actual positions of acquired measurements, and uncertainties in the properties of the propagation medium. Results demonstrate the theoretical feasibility of keeping errors less than about 1%. Typical errors in physical experiments were somewhat larger, on the order of a few percent; comparison with simulations provides specific guidelines for improving the experimental implementation to reduce these errors. Overall, results suggest that holography can be implemented successfully as a metrological tool with small, quantifiable errors.

Ultrasonic atomization, or the emission of a fog of droplets, was recently proposed to explain tissue fractionation in boiling histotripsy. However, even though liquid atomization has been studied extensively, the mechanisms underlying tissue atomization remain unclear. In the work described here, high-speed photography and overpressure were used to evaluate the role of bubbles in tissue atomization. As static pressure increased, the degree of fractionation decreased, and the ex vivo tissue became thermally denatured. The effect of surface wetness on atomization was also evaluated in vivo and in tissue-mimicking gels, where surface wetness was found to enhance atomization by forming surface instabilities that augment cavitation. In addition, experimental results indicated that wetting collagenous tissues, such as the liver capsule, allowed atomization to breach such barriers. These results highlight the importance of bubbles and surface instabilities in atomization and could be used to enhance boiling histotripsy for transition to clinical use.

We propose and experimentally demonstrate a method for measuring the phase velocities of Lamb waves in concave piezoelectric plates submerged in a fluid. The method is based on the optical shadowgraphy method of visualizing the ultrasound field that occurs in a fluid when Lamb modes are excited in the plate under study. According to the condition of wave resonance, the propagation direction of the waves radiated into the fluid is determined by the phase velocity of a Lamb wave in the plate, which makes it possible to measure the indicated velocity. Proceeding from this, we demonstrate that when spherical concave piezoelectric plates are used, the phase velocities of Lamb waves can be determined by the position of the caustics%u2014areas of acoustic wave focusing in the fluid. We have experimentally measured the dispersion curves of several Lamb modes for a concave piezoelectric plate with a diameter of 100 mm and thickness of around 2 mm, which was submerged in water. Ultrasound waves were optically visualized in the fluid by the schlieren method on a specially designed setup, in which off-axis parabolic mirrors were used to implement the dark-field method. We demonstrated that the measured dispersion curves for low-order Lamb modes are well described by the theoretical dependences calculated using the Rayleigh-Lamb equation.

When focused ultrasound waves of moderate intensity in liquid encounter an air interface, a chain of drops emerges from the liquid surface to form what is known as a drop-chain fountain. Atomization, or the emission of micro-droplets, occurs when the acoustic intensity exceeds a liquid-dependent threshold. While the cavitation-wave hypothesis, which states that atomization arises from a combination of capillary-wave instabilities and cavitation bubble oscillations, is currently the most accepted theory of atomization, more data on the roles of cavitation, capillary waves, and even heat deposition or boiling would be valuable. In this paper, we experimentally test whether bubbles are a significant mechanism of atomization in drop-chain fountains. High-speed photography was used to observe the formation and atomization of drop-chain fountains composed of water and other liquids. For a range of ultrasonic frequencies and liquid sound speeds, it was found that the drop diameters approximately equalled the ultrasonic wavelengths. When water was exchanged for other liquids, it was observed that the atomization threshold increased with shear viscosity. Upon heating water, it was found that the time to commence atomization decreased with increasing temperature. Finally, water was atomized in an overpressure chamber where it was found that atomization was significantly diminished when the static pressure was increased. These results indicate that bubbles, generated by either acoustic cavitation or boiling, contribute significantly to atomization in the drop-chain fountain.

Purpose
We have developed a new method of lithotripsy that uses short, broadly focused bursts of ultrasound rather than shock waves to fragment stones. This study investigated the characteristics of stone comminution by burst wave lithotripsy in vitro.

Materials and Methods
Artificial and natural stones (mean 8.2±3.0 mm, range 5–15 mm) were treated with ultrasound bursts using a focused transducer in a water bath. Stones were exposed to bursts with focal pressure amplitude 𕟮.5 MPa at 200 Hz burst repetition rate until completely fragmented. Ultrasound frequencies of 170 kHz, 285 kHz, and 800 kHz were applied using 3 different transducers. The time to achieve fragmentation for each stone type was recorded, and fragment size distribution was measured by sieving.

Results
Stones exposed to ultrasound bursts were fragmented at focal pressure amplitudes 𕟴.8 MPa at 170 kHz. Fractures appeared along the stone surface, resulting in fragments separating at the surface nearest to the transducer until the stone was disintegrated. All natural and artificial stones were fragmented at the highest focal pressure of 6.5 MPa with treatment durations between a mean of 36 seconds for uric acid to 14.7 minutes for cystine stones. At a frequency of 170 kHz, the largest artificial stone fragments were <4 mm. Exposures at 285 kHz produced only fragments <2 mm, and 800 kHz produced only fragments <1 mm.

Conclusions
Stone comminution with burst wave lithotripsy is feasible as a potential noninvasive treatment method for nephrolithiasis. Adjusting the fundamental ultrasound frequency allows control of stone fragment size.

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

Burst wave lithotripsy is a novel technology that uses focused, sinusoidal bursts of ultrasound to fragment kidney stones. Prior research laid the groundwork to design an extracorporeal, image-guided probe for in-vivo testing and potentially human clinical testing. Toward this end, a 12-element 330 kHz array transducer was designed and built. The probe frequency, geometry, and shape were designed to break stones up to 1 cm in diameter into fragments <2 mm. A custom amplifier capable of generating output bursts up to 3 kV was built to drive the array. To facilitate image guidance, the transducer array was designed with a central hole to accommodate co-axial attachment of an HDI P4-2 probe. Custom B-mode and Doppler imaging sequences were developed and synchronized on a Verasonics ultrasound engine to enable real-time stone targeting and cavitation detection, Preliminary data suggest that natural stones will exhibit Doppler %u201Ctwinkling%u201D artifact in the BWL focus and that the Doppler power increases as the stone begins to fragment. This feedback allows accurate stone targeting while both types of imaging sequences can also detect cavitation in bulk tissue that may lead to injury.

Nonlinear propagation effects are present in most fields generated by high intensity focused ultrasound (HIFU) sources. In some newer HIFU applications, these effects are strong enough to result in the formation of high amplitude shocks that actually determine the therapy and provide a means for imaging. However, there is no standard approach yet accepted to address these effects. Here, a set of combined measurement and modeling methods to characterize nonlinear HIFU fields in water and predict acoustic pressures in tissue is presented. A characterization method includes linear acoustic holography measurements to set a boundary condition to the model and nonlinear acoustic simulations in water for increasing pressure levels at the source. A derating method to determine nonlinear focal fields with shocks in situ is based on the scaling of the source pressure for data obtained in water to compensate for attenuation losses in tissue. The accuracy of the methods is verified by comparing the results with hydrophone and time-to-boil measurements. Major effects associated with the formation of shocks are overviewed. A set of metrics for determining thermal and mechanical bioeffects is introduced and application of the proposed tools to strongly nonlinear HIFU applications is discussed.

Ultrasound imaging has tissue and blood imaging modes. This report describes development of a kidney stone imaging mode. Two plane pulses generate a B-mode image. Overlaid in color are regions of high decorrelation between the pulses. Our previous data [UMB, 39, 1026-1038 (2013)] indicate the pulses excite bubbles on the stone surface, which causes the decorrelation. As such this mode automatically identifies stones in the image while scanning at a high frame rate. Further in a control box placed on the stone, highly focused beams are scanned across the stone and a harmonic B-mode image is produced to sharpen the lateral resolution. This mode is used to refine the size and shape of the stone. The first mode is used to aid visualization of stones. Our team is also using it to target and track stones that move with respiration during shock wave lithotripsy (SWL) and as an indicator of stone susceptibility to SWL since surface bubbles contribute to comminution. Improved stone sizing by the second mode aids treatment planning, and resolution of surface roughness is another indicator of stone fragility.

Shock wave lithotripsy (SWL) is the most common procedure for treatment of kidney stones. SWL noninvasively delivers high-energy focused shocks to fracture stones into passable fragments. We have recently observed that lower-amplitude, sinusoidal bursts of ultrasound can generate similar fracture of stones. This work investigated the characteristics of stone fragmentation for natural (uric acid, struvite, calcium oxalate, and cystine) and artificial stones treated by ultrasound bursts. Stones were fixed in position in a degassed water tank and exposed to 10-cycle bursts from a 200-kHz transducer with a pressure amplitude of p ≤ 6.5 MPa, delivered at a rate of 40–200 Hz. Exposures caused progressive fractures in the stone surface leading to fragments up to 3 mm. Treatment of artificial stones at different frequencies exhibited an inverse relationship between the resulting fragment sizes and ultrasound frequency. All artificial and natural types of stones tested could be fragmented, but the comminution rate varied significantly with stone composition over a range of 12–630 mg/min. These data suggest that stones can be controllably fragmented by sinusoidal ultrasound bursts, which may offer an alternative treatment strategy to SWL.

The use of projection methods is increasingly accepted as a standard way of characterizing the 3D fields generated by medical ultrasound sources. When combined with hydrophone measurements of pressure amplitude and phase over a surface transverse to the wave propagation, numerical projection can be used to reconstruct 3D fields that account for operational details and imperfections of the source. Here, we use holography measurements to characterize the fields generated by two array transducers with different geometries and modes of operation. First, a seven-element, high-power therapy transducer is characterized in the continuous-wave regime using holography measurements and nonlinear forward-projection calculations. Second, a C5-2 imaging probe (Philips Healthcare) with 128 elements is characterized in the transient regime using holography measurements and linear projection calculations. Results from the numerical projections for both sources are compared with independent hydrophone measurements of select waveforms, including shocked focal waveforms for the therapy transducer. Accurate 3D field representations have been confirmed, though a notable sensitivity to hydrophone calibrations is revealed. Uncertainties associated with this approach are discussed toward the development of holography measurements combined with numerical projections as a standard metrological tool.

Previous studies have provided insight into the physical mechanisms of stone fracture in shock wave lithotripsy. Broadly focused shocks efficiently generate shear waves in the stone leading to internal tensile stresses, which in concert with cavitation at the stone surface, cause cracks to form and propagate. Here, we propose a separate mechanism by which stones may fragment from sinusoidal ultrasound bursts without shocks. A numerical elastic wave model was used to simulate propagation of tone bursts through a cylindrical stone at a frequency between 0.15 and 2 MHz. Results suggest that bursts undergo mode conversion into surface waves on the stone that continually create significant stresses well after the exposure is terminated. Experimental exposures of artificial cylindrical stones to focused burst waves in vitro produced periodic fractures along the stone surface. The fracture spacing and resulting fragment sizes corresponded well with the spacing of stresses caused by surface waves in simulation at different frequencies. These results indicate surface waves may be an important factor in fragmentation of stones by focused tone bursts and suggest that the resulting stone fragment sizes may be controlled by ultrasound frequency.

High-intensity focused ultrasound (HIFU) is a treatment modality that relies on the delivery of acoustic energy to remote tissue sites to induce thermal and/or mechanical tissue ablation. To ensure the safety and efficacy of this medical technology, standard approaches are needed for accurately characterizing the acoustic pressures generated by clinical ultrasound sources under operating conditions. Characterization of HIFU fields is complicated by nonlinear wave propagation and the complexity of phased-array transducers. Previous work has described aspects of an approach that combines measurements and modeling, and here we demonstrate this approach for a clinical phased-array transducer. First, low amplitude hydrophone measurements were performed in water over a scan plane between the array and the focus. Second, these measurements were used to holographically reconstruct the surface vibrations of the transducer and to set a boundary condition for a 3-D acoustic propagation model. Finally, nonlinear simulations of the acoustic field were carried out over a range of source power levels. Simulation results were compared with pressure waveforms measured directly by hydrophone at both low and high power levels, demonstrating that details of the acoustic field, including shock formation, are quantitatively predicted.

Histotripsy treatments use high-amplitude shock waves to fractionate tissue. Such treatments have been demonstrated using both cavitation bubbles excited with microsecond-long pulses and boiling bubbles excited for milliseconds. A common feature of both approaches is the need for bubble growth, where at 1 MHz cavitation bubbles reach maximum radii on the order of 100 microns and boiling bubbles grow to about 1 mm. To explore how histotripsy bubbles grow, a model of a single, spherical bubble that accounts for heat and mass transport was used to simulate the bubble dynamics. Results suggest that the asymmetry inherent in nonlinearly distorted waveforms can lead to rectified bubble growth, which is enhanced at elevated temperatures. Moreover, the rate of this growth is sensitive to the waveform shape, in particular the transition from the peak negative pressure to the shock front. Current efforts are focused on elucidating this behavior by obtaining an improved calibration of measured histotripsy waveforms with a fiber-optic hydrophone, using a nonlinear propagation model to assess the impact on the focal waveform of higher harmonics present at the source's surface, and photographically observing bubble growth rates.

The mechanism of the twinkling artifact (TA) that occurs during Doppler ultrasound imaging of kidney stones was investigated. The TA expresses itself in Doppler images as time-varying color. To define the TA quantitatively, beam-forming and Doppler processing were performed on raw per channel radio-frequency data collected when imaging human kidney stones in vitro. Suppression of twinkling by an ensemble of computer-generated replicas of a single radio frequency signal demonstrated that the TA arises from variability among the acoustic signals and not from electronic signal capture or processing. This variability was found to be random, and its suppression by elevated static pressure and return when the pressure was released suggest that the presence of bubbles on the stone surface is the mechanism that gives rise to the TA.

The goal of this study was to investigate theoretically the effects of nonlinear propagation in a high-intensity focused ultrasound (HIFU) field produced by a therapeutic phased array and the resultant heating of tissue behind a rib cage. Three configurations of focusing were simulated: in water, in water with ribs in the beam path and in water with ribs backed by a layer of soft tissue. The Westervelt equation was used to model the nonlinear HIFU field, and a 1 MHz phased array consisting of 254 circular elements was used as a boundary condition to the model. The temperature rise in tissue was modelled using the bioheat equation, and thermally necrosed volumes were calculated using the thermal dose formulation. The shapes of lesions predicted by the modelling were compared with those previously obtained in in vitro experiments at low-power sonications. Intensity levels at the face of the array elements that corresponded to the formation of high-amplitude shock fronts in the focal region were determined as 10 W cm^-2 in the free field in water and 40 W cm^-2 in the presence of ribs. It was shown that exposures with shocks provided a substantial increase in tissue heating, and its better spatial localization in the main focal region only. The relative effects of overheating ribs and splitting of the focus due to the periodic structure of the ribs were therefore reduced. These results suggest that utilizing nonlinear propagation and shock formation effects can be beneficial for inducing confined HIFU lesions when irradiating through obstructions such as ribs. Design of compact therapeutic arrays to provide maximum power outputs with lower intensity levels at the elements is necessary to achieve shock wave regimes for clinically relevant sonication depths in tissue.

A theoretical approach is developed to calculate the radiation force of an arbitrary acoustic beam on an elastic sphere in a liquid or gas medium. First, the incident beam is described as a sum of plane waves by employing conventional angular spectrum decomposition. Then, the classical solution for the scattering of a plane wave from an elastic sphere is applied for each plane-wave component of the incident field. The net scattered field is expressed as a superposition of the scattered fields from all angular spectrum components of the incident beam. With this formulation, the incident and scattered waves are superposed in the far field to derive expressions for components of the radiation stress tensor. These expressions are then integrated over a spherical surface to analytically describe the radiation force on an elastic sphere. Limiting cases for particular types of incident beams are presented and are shown to agree with known results. Finally, the analytical expressions are used to calculate radiation forces associated with two specific focusing transducers.

Atomization and fountain formation is a well-known phenomenon that occurs when a focused ultrasound wave in liquid encounters an air interface. High intensity focused ultrasound (HIFU) has been shown to fractionate a tissue into submicron-sized fragments in a process termed boiling histotripsy, wherein the focused ultrasound wave superheats the tissue at the focus, producing a millimetre-sized boiling or vapour bubble in several milliseconds. Yet the question of how this millimetre-sized boiling bubble creates submicron-sized tissue fragments remains. The hypothesis of this work is that the tissue can behave as a liquid such that it atomizes and forms a fountain within the vapour bubble produced in boiling histotripsy. We describe an experiment, in which a 2 MHz HIFU transducer (maximum in situ intensity of 24,000 W cm^-2) was aligned with an air–tissue interface meant to simulate the boiling bubble. Atomization and fountain formation was observed with high-speed photography and resulted in tissue erosion. Histological examination of the atomized tissue showed whole and fragmented cells and nuclei. Air–liquid interfaces were also filmed. Our conclusion was that HIFU can fountain and atomize tissue. Although this process does not entirely mimic what was observed in liquids, it does explain many aspects of tissue fractionation in boiling histotripsy.

Surgery is moving more and more toward minimally-invasive procedures — using laparoscopic approaches with instruments inserted through tiny incisions or catheters placed in blood vessels through puncture sites. These techniques minimize the risks to the patient such as bleeding complications or infection during surgery. Taken a step further, high-intensity focused ultrasound (HIFU) can provide a tool to accomplish many of the same procedures without any incision at all. This article discusses the acoustics of histotripsy — including the processes of generation and focusing of intense ultrasound, the formation of cavitation clouds and rapid boiling in tissue, and the interactions of ultrasound shock waves with bubbles leading to tissue disintegration.

High intensity focused ultrasound (HIFU) is a rapidly growing medical technology with many clinical applications. The safety and efficacy of these applications require accurate characterization of ultrasound fields produced by HIFU systems. Current nonlinear numerical models based on the KZK and Westervelt wave equations have been shown to serve as quantitatively accurate tools for HIFU metrology. One of the critical parts of the modeling is to set a boundary condition at the source. In previous studies we proposed using measurements of low-amplitude fields to determine the source parameters. In this paper, two approaches of setting the boundary condition are reviewed: The acoustic holography method utilizes two-dimensional scanning of pressure amplitude and phase and numerical back-propagation to the transducer surface. An equivalent source method utilizes one-dimensional pressure measurements on the beam axis and in the focal plane. The dimensions and surface velocity of a uniformly vibrating transducer then are determined to match the one-dimensional measurements in the focal region. Nonlinear simulations are performed for increasing pressure levels at the source for both approaches. Several examples showing the accuracy and capabilities of the proposed methods are presented for typical HIFU transducers with different geometries.

We study finite-amplitude shear waves in one-dimensional resonator represented by a layer of rubber-like medium with inhomogeneities in the form of through holes made on the side face. The holes are parallel to the bases and perpendicular to the direction of vibrations. Two different configurations of the resonator: with holes at the bottom and at the top are studied. A rigid plate of finite mass is fixed on the upper surface. The lower boundary of the layer oscillates harmonically with a given acceleration. The equation of motion of particles in the resonator was found using the model of medium with one relaxation time, and a cubic dependence of the shear modulus of deformation. The measurements were performed in a resonator in the form of a rectangular parallelepiped of 15 mm thickness made of a rubber-like polymer plastisol. The linear shear modulus and shear viscosity of the polymer at the first resonant frequency were determined using the finite element method. The amplitudes of the oscillations in the resonator reached a point where the maximum shear strain in the resonator is 0.4 - 0.6, making it possible to observe nonlinear effects. The evolution of the resonance curves at different amplitudes of acceleration was investigated. A harmonic analysis of the acceleration profiles of the upper boundary was performed. The dependence of nonlinear effects on the holes position was studied.

An exact solution to the Helmholtz equation is proposed. The solution describes a quasi-Gaussian beam with an arbitrary width and has the form of a superposition of sources and sinks with complex coordinates. It is shown that such a beam always lacks a component that propagates against the principal propagation direction. In addition, when the diameter of the beam exceeds the wavelength, the beam becomes directional in the broad sense: the radiation condition is satisfied with respect to the beam waist plane. For the beam under study, expressions for the angular spectrum and the spherical harmonic expansion coefficients are derived.

Acoustic fields of powerful ultrasound sources with Gaussian spatial apodization and initial excitation in the form of a periodic wave or single pulse are examined based on the numerical solution of the Khokhlov-Zabolotskaya-Kuznetsov equation. The influence of nonlinear effects on the spatial structure of focused beams, as well as on the limiting values of the acoustic field parameters is compared. It is demonstrated that pressure saturation in periodic fields is mainly due to the effect of nonlinear absorption at a shock front, while in pulsed fields is due to the effect of nonlinear refraction. The limiting attainable values for the peak positive pressure in periodic fields turned out to be higher than the analogous values in pulsed acoustic fields. The total energy in a beam of periodic waves decreases with the distance from the source faster than in the case of a pulsed field, but it becomes concentrated within much smaller spatial region in the vicinity of the focus. These special features of nonlinear effect manifestation provide an opportunity to use pulsed beams for more efficient delivery of wave energy to the focus and to use periodic beams for attaining higher values of pressure in the focal region.

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

Histotripsy describes treatments in which high-amplitude acoustic pulses are used to excite bubbles and erode tissue. Though tissue erosion can be directly attributed to bubble activity, the genesis and dynamics of bubbles remain unclear. Histotripsy lesions that show no signs of thermal coagulative damage have been generated with two different acoustic protocols: relatively long acoustic pulses that produce local boiling within milliseconds and relatively short pulses that are higher in amplitude but likely do not produce boiling. While these two approaches are often distinguished as 'boiling' versus 'cavitation', such labels can obscure similarities. In both cases, a bubble undergoes large changes in radius and vapor is transported into and out of the bubble as it oscillates. Moreover, observations from both approaches suggest that bubbles grow to a size at which they cease to collapse violently. In order to better understand the dynamics of histotripsy bubbles, a single-bubble model has been developed that couples acoustically excited bubble motions to the thermodynamic state of the surrounding liquid. Using this model for bubbles exposed to histotripsy sound fields, simulations suggest that two mechanisms can act separately or in concert to lead to the typically observed bubble growth. First, nonlinear acoustic propagation leads to the evolution of shocks and an asymmetry in the positive and negative pressures that drive bubble motion. This asymmetry can have a rectifying effect on bubble oscillations whereby the bubble grows on average during each acoustic cycle. Second, vapor transport to/from the bubble tends to produce larger bubbles, especially at elevated temperatures. Vapor transport by itself can lead to rectified bubble growth when the ambient temperature exceeds 100C ('boiling') or local heating in the vicinity of the bubble leads to a superheated boundary layer.

The fiber-optic probe hydrophone (FOPH) (RP Acoustics, Leutenbach, Germany) is the standard for shock wave measurement, as it is omnidirectional with a flat frequency response ranging from static pressure to several megahertz. The FOPH calibration is determined from the equation of state of water, the optical refractive index of the glass/water interface, and the dc level of reflected light. We tested the accuracy of this calibration by placing the sensitive tip of the FOPH under static pressure up to 140 MPa. The FOPH gave accurate readings of applied static pressures provided there were no defects in the fiber. Defects (cracks and chips) in the glass fiber were difficult to control and could occur during routine handling: stripping, cleaving, or mounting. Such defects led to spurious spikes in measured waveforms. Defects were also caused by cavitation damage to the fiber. In addition, cavitation bubbles on the fiber compressed the fiber and resulted in distorted waveform measurement. Thus, although the FOPH is omnidirectional and accurate from zero to tens of megahertz, it is also susceptible to minute defects in the fiber and to cavitation bubble collapse along the fiber.

Laser vibrometry is a practical method to detect surface displacement. The method enables a direct measurement of acoustic field parameters such as acoustic particle displacement or acoustic particle velocity. Unlike other sensors, e.g., hydrophones, laser vibrometers are completely non-contact. Such devices are capable of measuring displacements from centimeters to sub nanometers at frequencies from near dc to 10 s of megahertz and have been proven to establish a primary standard for calibrating hydrophones [Bacon, IEEE Trans. UFFC, 35 (1988)]. In this technique, an ultrasonic transducer radiates an acoustic wave which is detected by a thin plastic membrane - a pellicle. The pellicle is effectively transparent to the acoustic beam so that the vibration of the pellicle follows the particle motion in the sound wave, but is reflective to the optical beam of the vibrometer allowing for a measurement. The present talk will report on measurements of nonlinearly distorted sawtooth waves in water performed with two commercial Polytec laser vibrometers: a scanning 24 MHz bandwidth system and a non-scanning 600 MHz bandwidth system. It is shown that appropriately chosen optical targets - pellicle or thick glass block with flat sides - allow resolution of both shock front and the smooth part of the waveform.

Numerical modeling has been shown to be an effective tool to characterize nonlinear pressure fields for single-element HIFU transducers, but it has not yet been applied for the much more complex three-dimensional (3-D) fields generated by therapeutic phased arrays. In this work, two approaches are presented to simulate nonlinear effects in the field of a 256-element focused array. A new full-diffraction approach includes rigorous 3-D simulations of the nonlinear wave equation with a boundary condition given at the elements of the array. A second simpler approach is based on the KZK model and a focused piston source as the boundary condition. The effective aperture and initial pressure of the piston source are set by matching linear simulations of the two models in the focal region. It is shown that as output power is increased, agreement in the focal waveforms of the two simulations, even when shocks were present, is maintained up to very high power outputs of the array. These results demonstrate the feasibility of using the simplified KZK model to evaluate the role of nonlinear effects in the fields of two-dimensional (2-D) phased arrays of clinical devices.

Clinical therapeutic ultrasound systems rely on the delivery of known acoustic pressures to treatment sites. Assessing the safety and efficacy of these systems relies upon characterization of ultrasound sources in order to determine the acoustic fields they produce and to understand performance changes over time. While direct hydrophone measurements of intense acoustic fields are possible, data acquisition throughout a treatment volume can be time-consuming and is only applicable to the specific source conditions tested. Moreover, measuring intense acoustic fields poses challenges for the hydrophone. An alternate approach combines low-amplitude pressure measurements with modeling of the nonlinear pressure field at various transducer power levels. In this work, low-intensity measurements were acquired for several therapeutic transducers. Pressure amplitude and phase were measured on a plane near the test transducer; the Rayleigh integral was used to back-propagate the acoustic field and mathematically reconstruct relative vibrations of the transducer surface. Such holographic reconstructions identified the vibratory characteristics of different types of transducers, including a 256-element clinical array. These reconstructions can be used to define boundary conditions for modeling and to record characteristics of transducer performance.

Twinkling artifact on color Doppler ultrasound is the color labeling of hard objects, such as kidney stones, in the image. The origin of the artifact is unknown, but clinical studies have shown that twinkling artifact can improve the sensitivity of detection of stones by ultrasound. Although Doppler detection normally correlates changes in phase with moving blood, here the effect of amplitude on the artifact is investigated. Radio-frequency and in-phase and quadrature (IQ) data were recorded by pulse-echo ensembles using a software-programmable ultrasound system. Various hard targets in water and in tissue were insonified with a linear probe, and rectilinear pixel-based imaging was used to minimize beam-forming complexity. In addition, synthesized radio-frequency signals were sent directly into the ultrasound system to separate acoustic and signal processing effects. Artifact was observed both in onscreen and post-processed images, and as high statistical variance within the ensemble IQ data. Results showed that twinkling artifact could be obtained from most solid objects by changing the Doppler gain, yet signal amplitude did not have to be sufficiently high to saturate the receive circuits. In addition, low signal but high time gain compensation created the largest variance.

Feasibility of soft tissue emulsification using shock wave heating and millisecond boiling induced by high intensity focused ultrasound was demonstrated recently. However, the mechanism by which the bubbles emulsify tissue is not well understood. High-speed photography of such exposures in transparent gel phantoms shows a milimeter-sized boiling bubble, and histological analysis in tissue samples reveals sub-micron-sized fragments. Here, a novel mechanism of tissue emulsification by the formation of a miniature acoustic fountain within the boiling bubble is tested experimentally using a 2 MHz transducer generating up to 70 MPa positive and 15 MPa negative peak pressures at the focus. The focus was positioned at or 1-2 mm off the plane interface between air and various materials including degassed water, transparent gel, thin sliced muscle tissue phantom, and ex-vivo tissue. Pulsing schemes with duty factors 0.001-0.1, and pulse durations 0.05-500 ms were used. Violent removal of micron-sized fragments and substantial displacement of the phantom surface were observed through high-speed filming. At the end of each exposure, the resulting erosion of the phantom surface and subsurface area was photographed and related to the exposure parameters.

The radiation force created by an acoustic wave incident on an elastic sphere is studied theoretically. Elastic spheres with properties similar to kidney stones are considered. An acoustic wave is taken in the form of a high-intensity focused ultrasound beam of megahertz frequency, which is typical for transducers proposed for stone therapy. To study radiation force of beams with arbitrary structure, the source excitation is modeled as a sum of plane waves of various inclinations (angular spectrum representation). First, a plane acoustic wave scattering at the stone is modeled using the known solution in the form of a spherical harmonics series. Then superposition of such solutions is used to calculate the scattered field from a focused beam. Once the acoustic field is known, the radiation stress tensor is calculated on a surface surrounding the sphere. Finally, the net force acting on the sphere is calculated by integrating the radiation stress along the surface. Numerical calculations show that the direction and value of the radiation force acting on the sphere depend on the pressure field structure in the region where the scatterer is positioned.

Lithotripsy shockwaves are particularly difficult to measure because of their wide signal bandwidth and large pressures. A polyvinylidene fluoride (PVDF) membrane hydrophone and preamplifier were built and tested. A broad-focus electromagnetic lithotripter was used to calibrate the PVDF hydrophone. A fiber optic probe hydrophone (FOPH) with known impulse response was used as a measurement standard for secondary calibration. A low-frequency circuit model for the PVDF membrane electrodes in an infinite conductive medium was developed. The model response was compared with signals recorded by the FOPH and PVDF hydrophone at different levels of water conductivity ranging from 1 to 1300 microseconds/cm. Measured waveforms were distorted by high-pass filtering effects of the water conductivity. The model results showed good agreement with the measured waveforms and provided a correction for the system. When the input impedance was altered appropriately or the hydrophone was submerged in a nonconductive fluid, the PVDF and FOPH waveforms appeared nearly identical. The PVDF hydrophone is capable of measuring lithotripsy shockwaves accurately when the low-frequency response is properly taken into account.

When an intense ultrasound beam is directed at a free surface of a liquid, an acoustic fountain is produced that is typically accompanied by ejection of tiny droplets, i.e., liquid atomization. This phenomenon is usually attributed to instability of cavitation-produced capillary waves on the surface. In addition to capillary effects, a process called spallation may also contribute. Although the acoustic fountain is typically observed at a flat liquid surface, nothing prohibits the atomization from occurring at a curved surface. This brings about the possibility to create an acoustic fountain and droplet emission at the surface of a gas cavity in liquid or, similarly, in the bulk of soft biological tissue. The appropriate condition occurs when high-intensity ultrasound is focused in tissue and creates large (0.1 - 1 mm in diameter) bubbles due to acoustic cavitation or rapid boiling. To test this hypothesis, acoustic pressure distribution and the corresponding radiation force on the empty spherical cavity were calculated using finite difference modeling and spherical harmonic expansion. It is shown that in histotripsy regimes appropriate conditions appear for the atomization, which may be considered as a possible mechanism of tissue erosion.

We present the results of studying the vibrational velocity distribution over the surface of cylindrical ultrasound transducers by acoustic holography. We describe two approaches for acoustic holography: the spatial spectrum method and the Rayleigh integral method. In the case of cylindrical sources the spectral method has a specific feature in comparison to the case of quasi-plane sources: small-scale spectrum components having the form of evanescent (nonpropagating) waves near the source, turn into propagating waves at a certain distance from the source. The use of such a mixed type of waves makes it possible to increase the holographic resolution. To conduct holography of cylindrical sources by the Rayleigh integral method, a modification consisting in the superimposing of boundaries on the integration region is proposed. We present the results of numerical simulation and physical experiments on holography of small cylindrical piezoelectric transducers. We demonstrate that the proposed methods of holography make it possible to recover the vibration structure of source surfaces up to order of the wavelength scales.

It is proposed to use ultrasonic signals excited by a laser pulse to investigate the elastic properties (impedances, speeds of sound, and densities) of layered media. The results of studying both a model medium with known parameters and a layered composite are reported. The experimental data are in good agreement with the known properties of the samples investigated.

The propagation of nonlinear spherically diverging N-waves in homogeneous air is studied experimentally and theoretically. A spark source is used to generate high amplitude (1.4 kPa) short duration (40 microseconds) N-waves; acoustic measurements are performed using microphones (3 mm diameter, 150 kHz bandwidth). Numerical modeling with the generalized Burgers equation is used to reveal the relative effects of acoustic nonlinearity, thermoviscous absorption, and oxygen and nitrogen relaxation on the wave propagation.

The results of modeling are in a good agreement with the measurements in respect to the wave amplitude and duration. However, the measured rise time of the front shock is ten times longer than the calculated one, which is attributed to the limited bandwidth of the microphone. To better resolve the shock thickness, a focused shadowgraphy technique is used. The recorded optical shadowgrams are compared with shadow patterns predicted by geometrical optics and scalar diffraction model of light propagation. It is shown that the geometrical optics approximation results in overestimation of the shock rise time, while the diffraction model allows to correctly resolve the shock width. A combination of microphone measurements and focused optical shadowgraphy is therefore a reliable way of studying evolution of spark-generated shock waves in air.

A prototype ultrasound-based probe for use in ureteroscopy was used for in vitro measurements of stone fragments in a porcine kidney. Fifteen human stones consisting of three different compositions were placed deep in the collecting system of a porcine kidney. A 2 MHz, 1.2 mm (3.6F) needle hydrophone was used to send and receive ultrasound pulses for stone sizing. Calculated stone thicknesses were compared with caliper measurements. Correlation between ultrasound-determined thickness and caliper measurements was excellent in all three stone types (r(2) = 0.90, p < 0.0001). All 15 ultrasound measurements were accurate to within 1 mm, and 10 measurements were accurate within 0.5 mm. A 3.6F ultrasound probe can be used to accurately size stone fragments to within 1 mm in a porcine kidney.

Standing shear waves in a plane-parallel rubberlike layer fixed without slippage between two rigid plates with finite masses are investigated. The lower plate, which underlies the layer, oscillates in the direction parallel to its surface under an external harmonic force, whereas the upper plate freely overlies the layer. It is shown both theoretically and experimentally that such a system exhibits resonances at frequencies the values of which depend on the mass of the free plate and the shear modulus of the layer. The shapes of the resonance curves are calculated and measured for different values of parameters of the layer and different masses of the upper plate. From the measured resonance curves, it is possible to determine the dynamic shear modulus and the shear viscosity of the rubberlike material.

During high-intensity focused ultrasound (HIFU) treatments in the absence of bubbles, tissue is heated by absorption of the incident ultrasound. However, bubbles present at the focus can enhance the rate of heating. One mechanism for such enhanced heating involves inertial bubble collapses that transduce incident ultrasound to higher frequencies that are more readily absorbed. Previously, it has been reported that bubble-enhanced heating diminishes as treatments progress.

The objective of this effort is to quantify how inertial bubble collapses are affected as the focal temperature rises during treatment. A model of a single, spherical bubble has been developed to couple the thermodynamic state of a strongly driven spherical bubble with the temperature of the surrounding liquid. This model allows for the dynamic transport of heat, vapor, and non-condensable gases to/from the bubble and has been demonstrated to fit experimental data from the collapses and rebounds of millimeter-sized bubbles over a range of temperature conditions. The responses of micron-sized, air-vapor bubbles in water were simulated under exposure to MHz/MPa HIFU excitation at various surrounding liquid temperatures. Each bubble response was characterized by the power spectral density of its radiated pressure in order to emulate a hydrophone measurement. Simulations suggest that bubble collapses are significantly attenuated at temperatures above about 70 deg C. For instance, the acoustically radiated energy at 80 deg C is an order of magnitude less than that at 20 deg C. Simulations that fully include the effect of vapor on bubbles excited during HIFU suggest that the efficacy of bubble-enhanced heating may be limited to temperatures below 70 deg C.

Residual kidney stone fragments often remain months after treatment. These fragments may nucleate new stones and contribute to a 50% recurrence within 5 years. Here, a research focused ultrasound device was used to generate fragment motion with the goal of facilitating passage. Natural and artificial stones 1–8 mm in length were surgically placed in the urine space in pig kidneys. The ultrasound source was a 2.75-MHz, eight-element annular array with a 6-cm radius of curvature. At adjustable focal depths of 5–8 cm, the focal pressure beam width in water was about 2 mm, and peak pressure was about 4 MPa. Targeting was done by ultrasound using B-mode and twinkling artifact that stones produce in Doppler mode. The commercial imaging probe was placed within and oriented down the axis of the therapy probe. Ultrasound and fluoroscopy showed the stones moving in real-time under the influence of the focused ultrasound. Stones moved on the order of 1 cm/s away from the source and several stones moved several centimeters down the ureter. It appeared that stones were affected only when directly in the focal beam, perhaps indicating that radiation pressure not streaming caused the motion.

The holographic approach used here relies on the principle of a time-reversal mirror and the Rayleigh integral. An ultrasonic beam consisting of long tone bursts is directed at a target object and the resulting acoustic field is measured at a large number of points surrounding the object. A computer-controlled positioning system is used to scan a small broadband hydrophone across a grid of measurement points in a single surface near the target. Object reconstruction is then accomplished numerically by back-propagating the acoustic field from measurement locations to a 3D region representing the object. Theoretically, the accuracy and the optimal parameters of the method were studied by modeling forward and backward propagation from a point scatterer. Experimentally set of 3-mm diameter plastic beads was investigated. Ultrasound frequencies from 1 to 1.5 MHz were considered, while hologram measurements were collected with grid spacings between 0.3 and 0.4 mm.

Both theory and measurements show that the spatial resolution of 3D ultrasonic holography is limited by diffraction effects. Discrete scatterers larger than a wavelength are well-resolved. Using this 3D ultrasonic holography method, it is possible to reconstruct the position and shape of objects or collections of objects that do not involve a significant amount of multiple scattering. Because the spatial resolution of the method has a typical diffraction limit on the order of a wavelength, improved spatial resolution can be achieved with higher frequencies.

Histotripsy is a non-invasive ultrasound therapy which utilizes cavitation clouds to mechanically fractionate tissue. The mechanism by which bubble clouds form is important to understand the histotripsy process. We used high speed imaging with frame rates between 0.1-10 million fps to observe the progression of cloud formation. A 1 MHz spherically-focused transducer was used to apply single histotripsy pulses to optically-transparent gelatin tissue phantoms, with peak negative pressure of 19 MPa and 5-50 cycles. Dense bubble clouds were observed to first form at a distal position within the focus, and grow proximally towards the transducer, opposite the ultrasound propagation direction. Growth began from the site of single cavitation bubbles. Based on these observations, it was hypothesized that the shocked waveforms from histotripsy pulses scatter from single bubbles, which invert the shock and induce a large negative pressure in its vicinity. To test this hypothesis, the positive incident shock pressure was reduced without significantly affecting the negative pressure. When the peak positive pressure was lowered, the likelihood and size of bubble clouds initiating at the focus was greatly reduced. These results suggest that the positive pressure of the incident waveform is important for generating bubble clouds in histotripsy.

The application of therapeutic ultrasound for the treatment of atrial fibrillation (AF) is investigated. The results of theoretical and experimental investigation of ultrasound ablation catheter are presented. The major components of the catheter are the high power cylindrical piezoelectric element and parabolic balloon reflector. Thermal elevation in the ostia of pulmonary veins is achieved by focusing the ultrasound beam in shape of a torus that transverses the myocardial tissue. High intensity ultrasound heating in the focal zone results in a lesion surrounding the pulmonary veins that creates an electrical conduction blocks and relief from AF symptoms. The success of the ablation procedure largely depends on the correct choice of reflector geometry and ultrasonic power.

We present a theoretical model of the catheter's acoustic field and bioheat transfer modeling of cardiac lesions. The application of an empirically derived relation between lesion formation and acoustic power is shown to correlate with the experimental data. Developed control methods combine the knowledge of theoretical acoustics and the thermal lesion formation simulations with experiment and thereby establish dosimetry that contributes to a safe and effective ultrasound ablation procedure.

It is demonstrated that, when the classical method of laser vibrometry is used for measurements in a liquid, it gives erroneous results with measurement errors reaching 100% or more. The vibration pattern observed in this case exhibits a false structure with a spatial scale identical to the wavelength of acoustic waves in the liquid. In addition, the laser vibrometer shows displacements in the regions where they are actually absent. In the transient mode of operation, the image displays nonexistent surface waves, which propagate with the velocity of sound in the liquid.

The origin of these distortions lies in the acoustooptic interaction that occurs in the condensed medium on the path of the probing laser beam. An analytic expression is obtained for the Green's function characterizing laser vibrometry in the cases of harmonic and pulsed excitation of the surface under investigation. It is shown that this function explains all the artifacts observed in laser vibrometry in a liquid and can be used to correct the measurement data.

A new method is proposed for measuring temperature in the focal region of a high-intensity ultrasonic emitter on the assumption of axially symmetric temperature field. This method is based on solving the integral equation relating the temperature of the medium to the delay times of the probe ultrasound pulse intersecting the heated region in the transverse direction at different distances from the beam axis. The accuracy of the algorithm for calculating temperature with allowance for the finite experimental data set is analyzed. The calculation results are compared with the experimental data.

Ultrasonic field mapping is an essential component of transducer characterization and of beam forming verification. Such measurements are commonly performed by displacing a hydrophone over a range of points within the field; these procedures can be time consuming. A calibrated hydrophone can provide accurate measurements of the field, subject to limitations of bandwidth and aperture of the device. A rapid qualitative 2D measurement of the spatial acoustic field can be obtained by optical means, in which the change in optical index due to the presence of acoustic pressure is imaged using a Schlieren approach.

This technique illuminates a transparent refracting acoustic medium using a plane collimated source and then focuses the transmitted light using a lens or mirror. In the absence of acoustic field, all of the light focuses to a small spot; acoustically induced refractive index perturbations cause some of the light to focus elsewhere. Obscuring the primary focal spot of unperturbed light with a mask permits imaging only the perturbations in the acoustic medium. We will describe a mirror-based Schlieren system for imaging continuous as well as pulsed fields and with color corresponding qualitatively to the intensity of the field.

Bubble-enhanced heating is a current topic of interest associated with high intensity focused ultrasound (HIFU). For HIFU treatments designed to utilize acoustic radiation from bubbles as a heating mechanism, it has been reported that useful bubble activity diminishes at elevated temperatures. To better understand and quantify this behavior, a model has been implemented that couples the thermodynamic state of a strongly driven spherical bubble with thermal conditions in the surrounding liquid. This model has been validated over a range of temperature conditions against experimental data from the collapses and rebounds of millimeter-sized bubbles.

With this model, the response of a micron-sized bubble was simulated under exposure to MHz/MPa HIFU excitation, while various surrounding liquid temperatures were considered. Characterizing the bubble response through the power spectral density of pressure radiated from the bubble, model calculations suggest that bubble collapses are significantly attenuated at temperatures above about 70°C. For instance, the acoustically radiated energy at 80°C is an order of magnitude less than that at 20°C. These results suggest that the efficacy of bubble-enhanced heating may be limited to temperatures below 70°C. Moreover, temperature will affect hydrophone measurements used to passively assess cavitation activity.

The accurate measurement of pressure waveforms in high intensity focused ultrasound (HIFU) fields is complicated by the fact that many devices operate at output levels where shock waves can form in the focal region. In tissue ablation applications, the accurate measurement of the shock amplitude is important for predicting tissue heating since the absorption at the shock is proportional to the shock amplitude cubed. To accurately measure shocked pressure waveforms, not only must a hydrophone with a broad bandwidth (>100 MHz) be used, but the frequency response of the hydrophone must be known and used to correct the measured waveform.

In this work, shocked pressure waveforms were measured using a fiber optic hydrophone and a frequency response for the hydrophone was determined by comparing measurements with numerical modeling using a KZK-type equation. The impulse response was separately determined by comparing a measured and an idealized shock pulse generated by an electromagnetic lithotripter. The frequency responses determined by the two methods were in good agreement. Calculations of heating using measured HIFU waveforms that had been deconvolved with the determined frequency response agreed well with measurements in tissue phantom.

Localization of kidney stones and targeting for lithotripsy can be challenges especially with ultrasound. However, twinkling artifact has been observed where Doppler ultrasound imagers assign color to the stone. We report a preliminary investigation from our observations in a porcine model and hypothesize why this artifact occurs. Glass beads, cement stones, and human stones were surgically placed into the renal collecting system through the ureter. The stones were imaged using several transducers and ultrasound imagers. In all cases, the twinkling artifact of the stone was observed, and its appearance and radiofrequency signature were unique from those of blood flow. Calcium oxalate monohydrate stones and smooth stones were not more difficult to image, contrary to previous reports. Increasing gain or placing the focal depth distal to the stone enhanced the artifact, but other user controls showed little effect. Twinkling started at the lateral edges of the stone and spread over the stone as gain was increased. The evidence supports the hypothesis that small motions induced by radiation force or elastic waves in the stone cause changes in received backscatter, particularly at imaging angles oblique to the stone surface.

Background: the ability to measure stone fragment size could help prevent attempting to extract too large a stone fragment. We evaluated the ability of a 1.2 mm (3.6 French) ultrasound probe to measure stone fragments in a porcine kidney.

Methods: 15 human stones of three types (five each calcium oxalate, cystine, calcium phosphate) sized 3–7 mm were placed deep in a porcine kidney collecting system. The sound speed of each stone type was determined using a separate reference stone. A 2 MHz, 1.2 mm needle hydrophone was used to send and receive ultrasound pulses. Stone thickness was calculated as d=c*t/2 by determining the signal transit time through the stone and the stone sound speed. Calculated stone thicknesses were compared to digital caliper measurements.

Results: Stone size was determined for all 15 stones. Correlation between ultrasound-determined thickness and caliper measurements was excellent (r²=0.90, p<0.0001) with ultrasound performing well in all three stone types. All stone measurements were accurate within 1 mm, and ten (66%) stone measurements were accurate within 0.5 mm.

Conclusions: Ultrasound-based measurements are accurate and precise using a 3.6 French probe with stone fragments placed deep in a porcine kidney.

Acoustic characterization of high intensity focused ultrasound (HIFU) fields is important both for the accurate prediction of ultrasound induced bioeffects in tissues and for the development of regulatory standards for clinical HIFU devices. In this paper, a method to determine HIFU field parameters at and around the focus is proposed. Nonlinear pressure waveforms were measured and modeled in water and in a tissue-mimicking gel phantom for a 2 MHz transducer with an aperture and focal length of 4.4 cm. Measurements were performed with a fiber optic probe hydrophone at intensity levels up to 24000 W/cm². The inputs to a Khokhlov–Zabolotskaya–Kuznetsov-type numerical model were determined based on experimental low amplitude beam plots. Strongly asymmetric waveforms with peak positive pressures up to 80 MPa and peak negative pressures up to 15 MPa were obtained both numerically and experimentally. Numerical simulations and experimental measurements agreed well; however, when steep shocks were present in the waveform at focal intensity levels higher than 6000 W/cm², lower values of the peak positive pressure were observed in the measured waveforms. This underrepresentation was attributed mainly to the limited hydrophone bandwidth of 100 MHz. It is shown that a combination of measurements and modeling is necessary to enable accurate characterization of HIFU fields.

In extracorporeal electrohydraulic lithotripters, a hemi-ellipsoidal metal reflector is used to focus a spherical wave generated by an electrical discharge. The spark source is positioned at one of the ellipsoid foci (F1); this makes the reflected wave focused at the other focus (F2). Despite the common assumption that the reflector behaves as a rigid mirror, the true reflection phenomenon includes the generation and reverberation of elastic waves in the reflector, which reradiate to the medium. Although these waves are much lower in amplitude than the specularly reflected wave, they may influence cavitation at F2. To explore such effects, waves in water and a brass reflector were modeled in finite differences based on the linearized equations of elasticity. The bubble response was simulated based on a Rayleigh-type equation for the bubble radius. In addition, the role of acoustic nonlinearity was estimated by numerical modeling. It is shown that the elastic waves in the reflector give rise to a long "ringing" tail, which results in nonmonotonic behavior of the bubble radius during its inertial growth after shock wave passage. This numerical result is qualitatively confirmed by experimental observations of bubble behavior using high-speed photography.

Shear modulus is an important property of biological tissue and can be imaged for diagnostic purposes. A related application involves the acquisition of precise shear modulus measurements in excised soft tissue. Because the mechanical properties of tissue are frequency-dependent, it is important to develop methods that characterize the elasticity of soft solids at various frequencies. Here, two methods of measuring shear modulus are presented that employ laser vibrometry. At low frequencies (1–10 Hz), the tissue sample is fixed between plates so that the displacement of one plate induces a shear strain. Vibrometer measurements of the plate displacement define the induced strain so that shear modulus can be deduced if the applied shear force is known. At higher frequencies (0.1–10 kHz), the sample lays flat on a surface and an impulsive force is applied to the exposed surface. Using the vibrometer to measure displacements along the exposed surface enables estimation of the surface wave speed and the implied shear modulus. To demonstrate the capabilities of these techniques, experiments were performed using plastisol tissue phantom samples. These experiments indicated a shear modulus that was 50% greater at high frequencies (300 Hz) than at low frequencies (10 Hz).

Extensive outdoor and laboratory-scale experiments on sonic boom propagation in turbulent atmosphere have shown that shock wave amplitude and rise time are important parameters responsible for sonic boom annoyance. However, accurate measurement of the shock front structure with standard microphone remains a challenge due to the broadband spectrum of the N-wave shock front. In this work the experimental setup utilizing a spark source has been designed and built to investigate nonlinear N-wave propagation in homogeneous medium. Short duration (30µs) and high amplitude (1 kPa) spherically divergent N-waves were generated. In addition to acoustic measurements with 1/8" B&K microphones, the shadowgraphy method using short duration flash lamp (20 ns) and CCD camera was employed to assess the shock front structure at different distances from the spark. It is shown that the shock rise time measured by the shadowgraphy method was in a good agreement with the theoretical predictions and it was 10 times shorter than in microphone measurements. The widening of the shock in acoustic measurements was therefore due to the limited bandwidth of the microphone. The combination of modeling, acoustic and optical measurements provided an accurate calibration of the shock wave measuring system.

The characterization of high intensity focused ultrasound (HIFU) fields is important for both clinical treatment planning as well as for regulation of HIFU medical devices. In previous work, we have used a 100-µm fiber optic probe hydrophone (FOPH) to measure pressure waveforms from a 2-MHz HIFU source with 42-mm aperture and 44-mm focal length. The formation of shock waves with peak positive pressure of up to 80 MPa were measured and modeled in transparent tissue-mimicking gel phantoms and boiling was achieved in milliseconds [Canney MS, et al., J. Acoust. Soc. Am., 120:3110 (2006)].

In this work, the FOPH was also used to measure temperature changes in tissue phantoms from HIFU at peak focal intensities of 5000–20,000 W cm². Temperature measurements were obtained by first low-pass filtering the voltage signal measured from the FOPH to remove the acoustic part of the measurement. Then, calibration of voltage to temperature was performed using results from a separate calibration experiment. Experimental measurements were compared with numerical modeling using a KZK-type model for acoustic propagation coupled with a heat transfer model. In summary, temperatures of 100°C were measured at the HIFU focus in milliseconds, in agreement with modeling.

Correct measurement of acoustic pressure is crucial in many applications, e.g., medical diagnostics and therapy, where the physical effect of ultrasound on tissue depends on specific parameters of the wave, such as positive and negative pressure, shock front thickness, and pulse duration. In our previous paper, we reported building a new low-cost PVDF hydrophone to detect broadband signals from lithotripters and high intensity focused ultrasound (HIFU) sources. The hydrophone was built to complement the fiber optic probe hydrophone (FOPH), which has become the de facto standard broadband hydrophone for high amplitude medical devices. Our PVDF membrane hydrophone is more sensitive than the FOPH, thereby making measurement possible when averaging is not an option. The goal of this research was to develop a reliable method of calibration by comparing the PVDF hydrophone to the FOPH in a repeatable broadband pressure field. The results showed that the PVDF membranes had similar, though not identical responses.

The secular equation for acoustic waves at fluid-solid interfaces yields the common leaky wave and its complement. This complementary wave grows instead of decays with propagation and is time-reversed compared to the leaky wave. Moreover, this growing wave has not yet been observed experimentally, perhaps due to difficulty of its excitation. Experimental observation of this wave was one goal of our work. The second goal was to study mirror reflection of an acoustic beam of special shape when the incident angle is equal to the Rayleigh critical angle. An obliquely incident beam is known to split after reflection into two components: a specular beam and a broad beam generated by the leaky waves. The interference of these two components results in "Schoch displacement" of the reflected beam along the interface and overall beam broadening. Our hypothesis was that by time reversing the reflection at the critical angle, the reflection beam can be made narrower rather than broader.

Identification of stone fragmentation, or comminution, during shock wave lithotripsy (SWL) would aid a urologist in determining the treatment endpoint, but there is currently little feedback available to do so. Here we report the measurement and analysis of SW scattering by kidney stone models in water to study the inverse relationship between stone size and scatter frequency. Stones were exposed to 20 SWs, 120 SWS, or 220 SWs to measure scatter and cause different levels of comminution. Measured scatter signals were processed in frequency to study the effect of stone comminution on the distribution of spectral energy. Comminution was measured by normalizing the mass of stone fragments, separated by size, to the mass of an intact stone. Output from frequency analysis was compared with percent mass comminution, and the shift of spectral energy to higher frequencies was proportional to the percent mass of stone fragments smaller than 2 mm.

Currently there is little feedback available in shock wave lithotripsy (SWL) to determine kidney stone fragmentation. The identification of fragmentation would aid a urologist in deciding to continue or stop treatment, and it could potentially reduce SW dose. Lithotripsy SWs strike stones with a broadband mechanical load. Reverberations excited within the stone are transmitted to surrounding fluid; a process termed resonant acoustic scatter (RAS). The frequency of RAS is inversely proportional to stone size. In experiment, variable SW treatments were applied to two types of stone models in vitro to produce different levels of fragmentation, which were measured by sieving dehydrated fragments and normalizing their mass to intact stone mass. RAS from selected SWs was measured with a broadband receiver and a new frequency analysis method was applied to display the redistribution of spectral energy. Mean percent mass for fragments smaller than 2 mm increased proportionally to the number of SWs applied. Amplitude of the frequency analysis output was directly proportional to fragmentation, and peak frequencies were inversely proportional to stone size. Results show promise that frequency analysis of RAS might provide feedback on fragmentation in SWL.

The goal of this work was to determine the acoustic waveform and beam width at the focus of a therapeutic ultrasound source both in water and in a tissue phantom. The source was a 2 MHz transducer of 45 mm focal length, 42 mm diameter, operating at 50 - 300 W acoustic power. Focal waveforms and beam widths calculated with a KZK-type model were in excellent agreement with values measured with a 100-µm, 100-MHz bandwidth fiber optic probe hydrophone (FOPH). Super focusing of the peak positive pressure and a proximal shift in the peak negative pressure were observed. Shocked distorted waveforms reached 70 MPa and - 15 MPa. Surface waves on the transducer were measured and included in the model but did not significantly affect the results obtained at focus. The change of the FOPH bandwidth to 30- MHz or the diameter of hydrophone to 500-µm resulted in 20% underestimation of the measured peak positive pressure but did not affect the measured negative peak pressure. Initiation of boiling was observed in tissue phantoms in milliseconds as predicted by weak shock theory due to absorption on the shocks. Work was supported by NIH DK43881, NSBRI SMS00402, and RFBR.

Stone breakage is less efficient when lithotripter shock waves (SWs) are delivered at 2 Hz compared to slower 0.5–1-Hz pulse repetition rates (PRFs). This correlates with increased number of transient cavitation bubbles observed along the SW path at fast PRF. The dynamics of this bubble proliferation throughout the bubble lifecycle is investigated in this report. Cavitation bubbles were studied in the free-field of a shock wave lithotripter using fine temporal and microscopic spatial resolution (high-speed camera Imacon-200). A typical cavitation bubble became visible (radius>10 μm) under the tensile phase of the lithotripter pulse, and at its first inertial collapse emitted a secondary SW and formed a micro-jet, which then could break up forming ~25 micro-bubbles. Subsequent rebound and collapse of the parent bubble appeared to produce a further 40–120 daughter bubbles visible following the rebound. Preexisting bubbles hit by the lithotripter SW also formed micro-jets and broke up into micro-bubbles that grew and coalesced, producing irregular-shaped bubbles that, in turn, broke into micro-bubbles upon subsequent inertial collapse. A conventional NTSC-rate camcorder was used to track cavitation bubbles from pulse-to-pulse, showing that a single bubble can give rise to a cavitation cloud verifying high-speed video results.

The identification of comminution during shock wave lithotripsy can be difficult using fluoroscopy or other imaging modalities. However, correct interpretation is necessary to determine if a stone is breaking and to evaluate the endpoint of therapy. Reported here is a passive method to detect acoustic signals generated by shock wave (SW) impact on a model stone and to correlate the spectrum of the detected signals to stone size. Acoustic scatter from model stones in an electrohydraulic lithotripter was measured in water with a passive, focused receiver before and after the application of either 20 SWs or 50 SWs. The five stones used for each case were dehydrated after the experiment, separated with 3 mm, 2 mm, and 1 mm sequential sieves, and weighed to quantify comminution. The detection method was first successfully used to differentiate broken and unbroken stones. Then the system tracked the decreasing size of particles and clearly showed the presence of particles smaller than 2 mm, which was considered passable size. Thus, the detection system gives feedback on whether stones are breaking and when they may be considered fully comminuted.

Objective: The focal zone width appears to be a critical factor in lithotripsy. Narrow focus machines have a higher occurrence of adverse effects, and arguably no greater comminution efficiency. Manufacturers have introduced new machines and upgrades to broaden the focus. Still, little data exists on how focal width plays a role in stone fracture. Thus, our aim was to determine if focal width interacts with established mechanisms known to contribute to stone fracture. Method: A series of experiments were undertaken with changes made to the stone in an effort to determine which is most important, the shock wave (SW) reflected from the back end of the stone (spallation), the SW ringing the stone (squeezing), the shear wave generated at surface of the stone and concentrated in the bulk of it (shear), or SWs generated from bubble collapse (cavitation). Shock waves were generated by a Dornier HM3-style lithotripter, and stones were made from U30 cement. Baffles were used to block specific waves that contribute to spallation, shear, or squeezing, and glycerol was used to suppress cavitation. Numerical simulation and high-speed imaging allowed for visualization of specific waves as they traveled within the stone. Results: For brevity, one result is explained. A reflective baffle was placed around the front edge of a cylindrical stone. The proximal baffle prevented squeezing by preventing the SW from traveling over the stone, but permitted the SW entering the stone through the proximal face and did not affect the other mechanisms. The distal baffle behaved the same as no baffle. The proximal baffle dramatically reduced the stress, and the stone did not break (stone broke after 45±10 SWs without the baffle and did not break after 400 SWs when the experiment stopped). The result implies that since removing squeezing halted comminution, squeezing is dominant. However, there is much more to the story. For example, if the cylindrical stone was pointed, it broke with the point on the distal end but not with the point on the proximal end. In both cases, squeezing was the same, so if squeezing were dominant, both stones should have broken. But the pointed front edge prevents the shear wave. The squeezing wave and its product — the shear wave — are both needed and work synergistically in a way explained by the model. Conclusions: A broad focus enhances the synergism of squeezing and shear waves without altering cavitation's effects, and thus accelerates stone fracture in SWL.

Compression of ultrasonic pulses reflected from layered structures is studied. A short pulse is emitted into water towards a structure consisting of solid plates backed with an air layer. Due to multiple reflections in the structure, the signal is elongated. The reflected signal is received by the same transducer and digitized. After that, the wave is reversed in time and emitted towards the layered structure for the second time; then, the reflected signal is received. Due to the invariance of the processes under the time reversal, the pulse is compressed by the structure: the reflected signal becomes shorter and acquires the waveform of the initial pulse. The possibility of an efficient compression of signals is demonstrated experimentally. Numerical simulations show that the use of more complex structures can considerably increase the compression ratio and produce short signals of a much higher amplitude than that emitted by the transducer. An efficient compression algorithm is proposed.

In vitro experiments and an elastic wave model were used to analyze how stress is induced in kidney stones by lithotripsy and to test the roles of individual mechanisms—spallation, squeezing, and cavitation. Cylindrical U30 cement stones were treated in an HM-3-style lithotripter. Baffles were used to block specific waves responsible for spallation or squeezing. Stones with and without surface cracks added to simulate cavitation damage were tested in glycerol (a cavitation suppressive medium). Each case was simulated using the elasticity equations for an isotropic medium. The calculated location of maximum stress compared well with the experimental observations of where stones fractured in two pieces. Higher calculated maximum tensile stress correlated with fewer shock waves required for fracture. The highest calculated tensile stresses resulted from shear waves initiated at the proximal corners and strengthened along the side surfaces of the stone by the liquid-borne lithotripter shock wave. Peak tensile stress was in the distal end of the stone where fracture occurred. Reflection of the longitudinal wave from the distal face of the stone—spallation—produced lower stresses. Surface cracks accelerated fragmentation when created near the location where the maximum stress was predicted.

There is currently little feedback as to whether kidney stones have fractured during shock wave lithotripsy. Resonant scattering of the lithotripter shock wave was used here to differentiate intact and fractured stone models in water. Scattering, including reflection and radiation due to reverberation from within the stone, was calculated numerically with linear elasticity theory and agreed well with measurements made with a focused receiver. Identification of fracture was possible through frequency analysis, where scatter from fractured stones was characterized by higher energy in distinct bands. High-speed photography concurrent with measurement indicated the effect was not due to cavitation.

A new parabolic equation is derived to describe the propagation of nonlinear sound waves in inhomogeneous moving media. The equation accounts for diffraction, nonlinearity, absorption, scalar inhomogeneities (density and sound speed), and vectorial inhomogeneities (flow). A numerical algorithm employed earlier to solve the KZK equation is adapted to this more general case. A two-dimensional version of the algorithm is used to investigate the propagation of nonlinear periodic waves in media with random inhomogeneities. For the case of scalar inhomogeneities, including the case of a flow parallel to the wave propagation direction, a complex acoustic field structure with multiple caustics is obtained. Inclusion of the transverse component of vectorial random inhomogeneities has little effect on the acoustic field. However, when a uniform transverse flow is present, the field structure is shifted without changing its morphology. The impact of nonlinearity is twofold: it produces strong shock waves in focal regions, while, outside the caustics, it produces higher harmonics without any shocks. When the intensity is averaged across the beam propagating through a random medium, it evolves similarly to the intensity of a plane nonlinear wave, indicating that the transverse redistribution of acoustic energy gives no considerable contribution to nonlinear absorption.

Few hydrophones are capable of measuring high-intensity fields such as shock waves accurately. One of the more reliable is the fiberoptic probe hydrophone. However, this system is expensive and insensitive. We created a new PVDF hydrophone and compared it with a fiberoptic system. The hydrophone consisted of a 25 µm thick PVDF membrane with a 0.5 mm active element and a preamplifier, which were each held in separate attached polycarbonate housings. The amplifier had adjustable gain and could account for membrane resonance to flatten the frequency response. A model of the frequency response for the system was developed, which agreed well with the measured response. Shock waves were measured in two Dornier HM-3 clones and an electromagnetic lithotripter. Measurements were also recorded using a 2 MHz focused piezoceramic source and a broadband PVDF source. Shock-wave measurements closely matched those recorded by the fiberoptic hydrophone and calculations made with a KZK-type model. Very little damage to the membrane was found after applying several thousand shock waves. This new membrane hydrophone is robust and sufficiently accurate to measure high-intensity fields, while greatly reducing cost, increasing sensitivity, and simplifying measurements of shock waves.

The responses of bubbles subjected to a lithotripsy shock wave have been investigated numerically and experimentally to elucidate the role of heat and mass transfer in the underlying dynamics of strongly excited bubbles. Single spherical bubbles were modeled as gas–vapor bubbles by accounting for liquid compressibility, heat transfer, vapor transport, vapor trapping by noncondensable gases, diffusion of noncondensable gases, and heating of the liquid at the bubble wall. For shock-wave excitations, the model predicts bubble growth and collapse, followed by rebounds whose durations are significantly affected by vapor trapping. To experimentally test these predictions, bubble rebound durations were measured using passive cavitation detectors, while high-speed photographs were captured to evaluate the local cavitation field and to estimate radius–time curves for individual bubbles. Data were acquired for bubbles in water with varying temperature and dissolved gas content. Measurements verify that vapor trapping is an important mechanism that is sensitive to both temperature and dissolved gas content. While this work focuses primarily on individual bubbles, some bubble cloud effects were observed. Analysis with a simple multibubble model provides noteworthy insights.

Shock wave lithotripsy (SWL) is currently conducted with little feedback on whether kidney stones are breaking. To determine if fragmentation could be assessed, acoustic scatter from intact and fractured stone models was calculated numerically and measured in vitro. Acoustic scatter from the stones, which were modeled with glass spheres, was calculated numerically using a linear elastic model, initialized with known elastic constants, and propagated from the stone model surface using the Helmholtz–Kirchhoff integral. Experimentally, shock waves were generated with a research lithotripter and scatter was measured with a broadband, spherically focused receiver. Calculated and measured results agreed well in the time domain. In frequency, power spectra were integrated to find energy and showed that scatter from the fractured stone model had higher energy in specific frequency bands that were related to the reverberation period. High-speed photography indicated that cavitation did not adversely affect the analysis of scatter. In this work it was possible to distinguish between the intact and fractured stone models. This method could be applied to stones that fragment gradually under the application of shock waves and potentially be used to estimate fragment size, and therefore the endpoint of therapy.

Recent experiments and calculations show that a focusing shear wave generated by the shock wave traveling along the length of a cylindrical stone creates the dominant stress and causes fracture of cylindrical model stones. A small disk placed on the proximal face of the stone suppressed the longitudinal wave responsible for spallation in calculations yet had little effect on the number of shock waves required to fracture the stone in experiment. However, a disk placed around the stone blocked the shock wave traveling along the stone in calculations and suppressed fracture in measurements. The conclusion was that so-called dynamic squeezing was a dominant mechanism to spallation. Here, photo-elastic, high-speed imaging was used to observe the suppression of various waves in cylindrical stones made of acrylic. Glycerol was used to avoid artifact from the curvature of the stone. Comparison was made to calculations using the elasticity equations for an isotropic medium. Agreement between measurement and calculation was excellent and supports dynamic squeezing. The results help validate the model, and the technique and modeling may help us understand where and how stress is created in other shock wave therapies.

Detection of kidney stones and estimation of their sizes is an important part of the lithotripsy treatment. Fluoroscopy is often used to target stones, but not every stone is radio-opaque and, in addition, fluoroscopy produces ionizing radiation. Acoustic waves offer an alternative way to visualize stones. The acoustic impedance of kidney stones typically differs significantly from that of surrounding tissue. A useful consequence of the impedance mismatch is the possibility to target stones with diagnostic mode ultrasound. Another consequence is that radiation force pushes the stone. Stone displacement may be responsible for the twinkling artifact that has been observed by several authors in color Doppler mode of ultrasound imaging. This effect can be used to detect not only renal and ureteral stones, but also calcifications in other organs (e.g., breast). In this paper we model the radiation force associated with the Doppler diagnostic pulse. The problem is divided into three parts: (1) acoustic scattering; it is solved in finite differences; (2) radiation force calculation; (3) stone velocity estimation supposing the stone sits in soft tissue.

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

Calibration of medical shock wave sources is critical and challenging. Aside from the fiber optic probe hydrophone, there are few if any commercially available hydrophones designed for measuring medical shock waves. We have developed a new PVDF membrane hydrophone and compared it to measurements with a fiber optic probe hydrophone (FOPH) in several lithotripters. One part of the hydrophone held the 5 cm times 5 cm times 25 µm PVDF film with geometrical element size 0.5 mm. The other part housed the preamplifier. By substitution comparison to FOPH and an NTR hydrophone, the sensitivity was found to be 0.035 MPa/mV at 2 MHz. Initial spot frequency comparisons showed the response to be fairly flat from 1-20 MHz but showed an elevated sensitivity at 15-20 MHz, and lithotripsy waveforms indicated some high-pass filtering. The impulse response of a 25 µm membrane was calculated and used to de-convolve the signal after which agreement with waveforms from the other hydrophones was excellent. The hydrophone is sufficiently robust to measure 1000 s of lithotripter shock waves. It is inexpensive, sensitive, and has a lower signal to noise ratio than the FOPH.

The accurate characterization of high intensity focused ultrasound (HIFU) fields is important for the prediction of thermal and mechanical bio-effects in tissue, as well as for the development of standards for therapeutic systems. At HIFU intensity levels, the combined effects of nonlinearity and diffraction result in the formation of asymmetric shocked waveforms and a corresponding distortion of the spatial distributions of various acoustic parameters that are responsible for different bio-effects. Acoustic probes that are capable of withstanding high pressures and that can measure waveforms with a high spatial and temporal resolution are required to capture the shock fronts and highly localized field structures that can arise at therapeutically relevant treatment regimes. An experimentally validated numerical model can also be an effective tool when direct measurements are not possible. In this work, acoustic measurements using force balance, acoustic holography, broadband fiber optic and PVDF hydrophones, were combined with simulations based on a KZK-type model to demonstrate an effective approach for the calibration of HIFU transducers in water and for derating these results to tissue.

It is currently difficult to assess whether a kidney stone has fractured during shock wave lithotripsy. Here we report the calculation and measurement of shock wave scattering by stone models in water. Calculations were based on linear elastic theory to find pressure in the fluid and stress in the stone models, and on scattering theory to find radiation from the stone models. Measurements were made with a spherical, broadband receiver. Calculation and measurement agree well in the time domain and through frequency analysis of detected acoustic scattering it was possible to distinguish between fractured and intact model stones. Cavitation was visualized with high speed photography and was not a dominant effect in the measurements.

A multi-frame high-speed photography was used to investigate the dynamics of cavitation bubbles induced by a passage of a lithotripter shock wave in a water tank. Solitary bubbles in the free field each radiated a shock wave upon collapse, and typically emitted a micro-jet on the rebound following initial collapse. For bubbles in clouds, emitted jets were directed toward neighboring bubbles and could break the spherical symmetry of the neighboring bubbles before they in turn collapsed. Bubbles at the periphery of a cluster underwent collapse before the bubbles at the center. Observations with high-speed imaging confirm previous predictions that bubbles in a cavitation cloud do not cycle independently of one another but instead interact as a dynamic bubble cluster.

Mechanisms of stone fragmentation by lithotripter shock waves were studied. Numerically, an isotropic-medium, elastic-wave model was employed to isolate and assess the importance of individual mechanisms in stone comminution. Experimentally, cylindrical U-30 cement stones were treated in an HM-3-style research lithotripter. Baffles were used to block specific waves responsible for spallation, squeezing, or shear. Surface cracks were added to stones to simulate the effect of cavitation, and then tested in water and glycerol (a cavitation suppressive medium). The calculated location of maximum stress compared well with the experimental observations of where cracks naturally formed. Shear waves from the shock wave in the fluid traveling along the stone surface (a kind of dynamic squeezing) led to the largest stresses in the cylindrical stones and the fewest shock waves to fracture. Reflection of the longitudinal wave from the back of the stone — spallation — and bubble-jet impact on the proximal and distal faces of the stone produced lower stresses and required more shock waves to fracture stones, but cavitation stresses become comparable in small stone pieces. Surface cracks accelerated fragmentation when created near the location where the maximum stress was predicted.

A transient acoustic holography method based on the Rayleigh integral and the time-reversal mirror principle is described. The method reconstructs the particle velocity of the surface of an acoustic source from the waveform of the signal measured over a surface lying in front of the source. The possibility of applying the transient holography to studying pulsed sources used in ultrasonic diagnostics is investigated. A rectangular source that produces a short acoustic pulse and has a nonradiating defect on its surface is considered. A numerical simulation is used to demonstrate the possibility of a holographic reconstruction of the source vibrations. The effects of the spatial sampling step and the size of the measurement region on the reconstruction quality are demonstrated.

Although extracorporeal shock wave lithotripsy (a procedure of kidney stone comminution using focused shock waves) has been used clinically for many years, a proper monitoring of the stone fragmentation is still undeveloped. A method considered here is based on recording shock wave scattering signals with a focused receiver placed far from the stone, outside the patient body. When a fracture occurs in the stone or the stone becomes smaller, the elastic waves in the stone will propagate differently (e.g. shear waves will not cross a fracture) which, in turn, will change the scattered acoustic wave in the surrounding medium. Theoretical studies of the scattering phenomenon are based on a linear elastic model to predict shock wave scattering by a stone, with and without crack present in it. The elastic waves in the stone and the nearby liquid were modeled using a finite difference time domain approach. The subsequent acoustic propagation of the scattered waves into the far-field was calculated using the Helmholtz–Kirchhoff integral.

Experimental studies were conducted using a research electrohydraulic lithotripter that produced the same acoustic output as an unmodified Dornier HM3 clinical lithotripter. Artificial stones, made from Ultracal-30 gypsum and acrylic, were used as targets. The stones had cylindrical shape and were positioned co-axially with the lithotripter axis. The scattered wave was measured by focused broadband PVDF hydrophone. It was shown that the size of the stone noticeably changed the signature of the reflected wave.

Shock waves are now used to treat a variety of musculoskeletal indications and the worldwide demand for shock wave therapy (SWT) is growing rapidly. It is a concern that very little is known about the mechanisms of action of shock waves in SWT. The technology for SWT devices is little changed from that of shock wave lithotripters developed for the treatment of urinary stones. SWT devices are engineered on the same acoustics principles as lithotripters, but the targets of therapy for SWT and shock wave lithotripsy (SWL) are altogether different. For SWT to achieve its potential as a beneficial treatment modality it will be necessary to determine precisely how SWT shock waves interact with biological targets. In addition, for SWT to evolve, the future design of these devices should be approached with caution, and lithotripsy may serve as a useful model. Indeed, there is a great deal to be learned from the basic research that has guided the development of SWL.

The main objective of this study was to evaluate the feasibility of the optoacoustic (OA) technique for the monitoring of HIFU therapy. Optoacoustic phenomenon is the generation of wideband ultrasonic transients through absorption of laser radiation and subsequent expansion of the heated volume. The excited OA transient can be detected by a wideband piezo-electric transducer and contains information on the distribution of optical properties (absorption and scattering) within the medium. If thermal lesions have different optical properties than the untreated tissue, the lesions will be detectable on the OA waveform. We used boiled and raw porcine liver as phantoms mimicking treated and untreated tissue correspondingly. Optical attenuation, absorption and scattering coefficients of raw and boiled porcine liver were measured by the optoacoustic technique, previously developed by our group. Measured optical absorption in raw liver was at least two times lower than in boiled liver at the laser wavelength of 1064 nm. Then OA technique was employed to detect a lesion produced by a 1.1 MHz focused ultrasound in a liver sample. The lesion was about 2 mm thick located about 1 cm below tissue surface. The feasibility and high promise of the OA approach to lesion detection was demonstrated.

The tensile stress imposed by the negative-pressure phase of lithotripter shock pulses can cause cavitation. Bubbles continue to grow after the passage of the acoustic pulse; thus, some of the pulse energy is transformed to the kinetic and potential energy of the liquid surrounding the cavitation bubbles and, therefore, no longer belongs to the acoustic field. One might predict that this energy loss should be more pronounced for strong pulses that produce more cavitation. To investigate this, acoustic pulses were measured at the geometric focus of a Dornier HM-3 electrohydraulic lithotripter (water 39°C, dissolved gas ~8% saturation) using a fiber--optic probe hydrophone FOPH-500. Measurements showed that, while the amplitude and duration of the leading positive-pressure phase increased dramatically as charging potential was increased from 12 to 24 kV, the trailing negative-pressure phase of the pulse remained unchanged. This stabilization of the negative-pressure phase could be due to cavitation restricting the amplitude of the negative pressure that can be transmitted through the liquid, such that further increase of the amplitude at the source would not increase the negative amplitude at the target but would only result in stronger cavitation along the acoustic path.

Direct measurement of HIFU fields in situ is important for the accurate prediction of thermal and mechanical bioeffects, as well as for the development of standards for medical systems. An experimentally validated numerical model can be an effective tool in both laboratory and clinical settings when direct measurements are not possible. Calculations with a KZK-type model and measurements with a fiberoptic probe hydrophone were employed together to characterize HIFU fields in water and in a tissue-mimicking gel. To determine the boundary conditions for simulations, the normal velocity distribution on the transducer surface was reconstructed using acoustic holography and combined with acoustic power measurements. At the focus, highly nonlinear waveforms ( 700 and –150 bars peak pressures) were obtained both experimentally and numerically, which differed significantly from waveforms linearly extrapolated from low-amplitude results. Strongly distorted shock waveforms were localized in an axial region much smaller than the half-maximum beamwidth of the transducer excited at low level. At the highest excitation levels, the simulations predicted frequency content higher than was measurable in our configuration. Simulations also show that if these frequencies are not included, predicted heating rates are significantly lower.

Ed Carstensen has made many contributions to biomedical ultrasound but among those that are becoming more and more relevant to current clinical practice are those that determine the conditions under which cavitation is induced in vivo. For many years, it was assumed that the medical ultrasound devices were unable to induce cavitation in living tissue because either the acoustic conditions were not sufficient or the nucleation sites that are required were too small. With the advent of lithotripters and high-intensity focused ultrasound (HIFU) devices, cavitation generation in vivo is commonplace. Our current research at the University of Washington has focused on the role that cavitation plays in stone comminution and tissue damage during lithotripsy, as well as the enhancement or reduction of desirable coagulative necrosis during HIFU application. During HIFU application, we find enhanced heating that results from nonlinear acoustic wave propagation (a key Carstensen contribution) leads to vapor bubble formation. This presentation will review our recent studies in this area.

An optically transparent phantom was developed for use in high-intensity focused ultrasound (US), or HIFU, dosimetry studies. The phantom is composed of polyacrylamide hydrogel, embedded with bovine serum albumin (BSA) that becomes optically opaque when denatured. Acoustic and optical properties of the phantom were characterized as a function of BSA concentration and temperature. The speed of sound (1544 m/s) and acoustic impedance (1.6 MRayls) were similar to the values in soft tissue. The attenuation coefficient was approximately 8 times lower than that of soft tissues (0.02 Np/cm/MHz for 9% BSA). The nonlinear (B/A) coefficient was similar to the value in water. HIFU lesions were readily seen during formation in the phantom. In US B-mode images, the HIFU lesions were observed as hyperechoic regions only if the cavitation activity was present. The phantom can be used for fast characterization and calibration of US-image guided HIFU devices before animal or clinical studies.

In vitro experiments and an elastic wave model were employed to isolate and assess the importance of individual mechanisms in stone comminution in lithotripsy. Cylindrical U-30 cement stones were treated in an HM-3-style research lithotripter. Baffles were used to block specific waves responsible for spallation, squeezing, or shear. Surface cracks were added to stones to simulate the effect of cavitation, then tested in water and glycerol (a cavitation suppressive medium). Each case was simulated using the elasticity equations for an isotropic medium. The calculated location of maximum stress compared well with the experimental observations of where cracks naturally formed. Shear waves from the shock wave in the fluid traveling along the stone surface (a kind of dynamic squeezing) led to the largest stresses in the cylindrical stones and the fewest SWs to fracture. Reflection of the longitudinal wave from the back of the stone — spallation — and bubble-jet impact on the proximal and distal faces of the stone produced lower stresses and required more SWs to break stones. Surface cracks accelerated fragmentation when created near the location where the maximum stress was predicted.

A system was built to detect cavitation in pig kidney during shock wave lithotripsy (SWL) with a Dornier HM3 lithotripter. Active detection, using echo on B-mode ultrasound, and passive cavitation detection (PCD), using coincident signals on confocal, orthogonal receivers, were equally sensitive and were used to interrogate the renal collecting system (urine) and the kidney parenchyma (tissue). Cavitation was detected in urine immediately upon SW administration in urine or urine plus X-ray contrast agent, but in tissue, cavitation required hundreds of SWs to initiate. Localization of cavitation was confirmed by fluoroscopy, sonography, and by thermally marking the kidney using the PCD receivers as high intensity focused ultrasound sources. Cavitation collapse times in tissue and native urine were about the same but less than in urine after injection of X-ray contrast agent. Cavitation, especially in the urine space, was observed to evolve from a sparse field to a dense field with strong acoustic collapse emissions to a very dense field that no longer produced detectable collapse. The finding that cavitation occurs in kidney tissue is a critical step toward determining the mechanisms of tissue injury in SWL.

Comminution of axisymmetric stones by a lithotripter shock wave was studied experimentally and theoretically. In experiments, shock waves were generated by a research electrohydraulic lithotripter modeled after the Dornier HM-3, and stones were made from U-30 cement. Cylindrical stones of various length to diameter ratios, stones of conical shape, and stones with artificial cracks were studied. In other cases, baffles to block specific waves that contribute to spallation or squeezing were used, and glycerol was used to suppress cavitation. The theory was based on the elasticity equations for an isotropic medium. The equations were written in finite differences and integrated numerically. Maximum compression, tensile and shear stresses were predicted depending on the stone shape and side-surface condition in order to investigate the importance of the stone geometry. It is shown that the theoretical model used explains the observed position of a crack in a stone. The theory also predicts the efficiency of stone fragmentation depending on its shape and size, as well as on the presence of cracks on the stone surface and baffles near the stone.

A classical effect of nonlinear acoustics is that a plane sinusoidal acoustic wave propagating in a nonlinear medium transforms to a sawtooth wave with one shock per cycle. However, the waveform evolution can be quite different in the near field of a plane source due to diffraction. Previous numerical simulations of nonlinear acoustic waves in the near field of a circular piston source predict the development of two shocks per wave cycle [Khokhlova et al., J. Acoust. Soc. Am. 110, 95-108 (2001)]. Moreover, at some locations the peak pressure may be up to 4 times the source amplitude. The motivation of this work was to experimentally verify and further explain the phenomena of the nonlinear waveform distortion. Measurements were conducted in water with a 47-mm-diameter unfocused transducer, working at 1-MHz frequency. For pressure amplitudes higher than 0.5 MPa, two shocks per cycle were observed in the waveform beyond the last minimum of the fundamental harmonic amplitude. With the increase of the observation distance, these two shocks collided and formed one shock (per cycle), i.e., the waveform developed into the classical sawtooth wave. The experimental results were in a very good agreement with the modeling based on the Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation.

Shock wave lithotripsy (SWL) is the use of shock waves to fragment kidney stones. We have undertaken a study of the physical mechanisms responsible for stone comminution and tissue injury in SWL. SWL was originally developed on the premise that stone fragmentation could be induced by a short duration, high amplitude positive pressure pulse. Even though the SWL waveform carries a prominent tensile component, it has long been thought that SW damage to stones could be explained entirely on the basis of mechanisms such as spallation, pressure gradients, and compressive fracture. We contend that not only is cavitation also involved in SWL, bubble activity plays a critical role in stone breakage and is a key mechanism in tissue damage.

Our evidence is based upon a series of experiments in which we have suppressed or minimized cavitation, and discovered that both stone comminution and tissue injury is similarly suppressed or minimized. Some examples of these experiments are: (1) application of overpressure, (2) time reversal of acoustic waveform, (3) acoustically-transparent, cavitation-absorbing films, and (4) dual pulses. In addition, using passive and active ultrasound, we have observed the existence of cavitation, in vivo, and at the site of tissue injury.

Numerical and experimental results showed mitigation of bubble collapse intensity by time-reversing the lithotripsy pulse and in vivo treatment showed a corresponding drop from 6.1% ± 1.7% to 0.0% in the hemorrhagic lesion. The time-reversed wave did not break stones. Stone comminution and hemolysis were reduced to levels very near sham levels with the application of hydrostatic pressure greater than the near 10-MPa amplitude of the negative pressure of the lithotripter shock wave. A Mylar sheet 3-mm from the stone surface did not inhibit erosion and internal cracking, but a sheet in contact with the stone did. In water, mass lost from stones in a dual pulse lithotripter is 8 times greater than with a single lithotripter, but in glycerol, which reduces the pressures generated in bubble implosion, the enhancement is lost.

This cavitation-inclusive mechanistic understanding of SWL is gaining acceptance and has had clinical impact. Treatment at slower SW rate give- s cavitation bubble clusters time to dissolve between pulses and increases comminution. Some SWL centers now treat patients at slower SW rate to take advantage of this effect. An elegant cavitation-aware strategy to reduce renal trauma in SWL is being tested in experimental animals. Starting treatment at low amplitude causes vessels to constrict and this interferes with cavitation-mediated vascular injury. Acceptance of the role of cavitation in SWL is beginning to be embraced by the lithotripter industry, as new dual-pulse lithotripters—based on the concept of cavitation control—have now been introduced.

High-speed photography was used to analyze cavitation bubble activity at the surface of artificial and natural kidney stones during exposure to lithotripter shock waves in vitro. Numerous individual bubbles formed at the surface of stones, but these bubbles did not remain independent and combined with one another to form bubble clusters. Bubble clusters formed at the proximal end, the distal end, and at the sides of stones. Each cluster collapsed to a narrow point of impact. Collapse of the proximal cluster caused erosion at the leading face of the stone and the collapse of clusters at the sides of stones appeared to contribute to the growth of cracks. Collapse of the distal cluster caused minimal damage. We conclude that cavitation-mediated damage to stones was due not to the action of solitary bubbles, but to the growth and collapse of bubble clusters.

Therapeutic ultrasound is an emerging field with many medical applications. High intensity focused ultrasound (HIFU) provides the ability to localize the deposition of acoustic energy within the body, which can cause tissue necrosis and hemostasis. Similarly, shock waves from a lithotripter penetrate the body to comminute kidney stones, and transcutaneous ultrasound enhances the transport of chemotherapy agents. New medical applications have required advances in transducer design and advances in numerical and experimental studies of the interaction of sound with biological tissues and fluids. The primary physical mechanism in HIFU is the conversion of acoustic energy into heat, which is often enhanced by nonlinear acoustic propagation and nonlinear scattering from bubbles. Other mechanical effects from ultrasound appear to stimulate an immune response, and bubble dynamics play an important role in lithotripsy and ultrasound-enhanced drug delivery. A dramatic shift to understand and exploit these nonlinear and mechanical mechanisms has occurred over the last few years. Specific challenges remain, such as treatment protocol planning and real-time treatment monitoring. An improved understanding of the physical mechanisms is essential to meet these challenges and to further advance therapeutic ultrasound.

High-speed photography was used to investigate cavitation at the surface of artificial and natural kidney stones during exposure to lithotripter shock pulses in vitro. It was observed that numerous individual bubbles formed over virtually the entire surface of the stone, but these bubbles did not remain independent and combined with one another to form larger bubbles and bubble clusters. The movement of bubble boundaries across the surface left portions of the stone bubble free. The biggest cluster grew to envelop the proximal end of the stone (6.5 mm diameter artificial stone) then collapsed to a small spot that over multiple shots formed a crater in that face of the stone. The bubble clusters that developed at the sides of stones tended to align along fractures and to collapse into these cracks. High-speed camera images demonstrated that cavitation mediated damage to stones was due not to the action of solitary, individual bubbles, but to the forceful collapse of dynamic clusters of bubbles.

Cavitation appears to contribute to tissue injury in lithotripsy. Reports have shown that increasing pulse repetition frequency [(PRF) 0.5–100 Hz] increases tissue damage and increasing static pressure (1–3 bar) reduces cell damage without decreasing stone comminution. Our hypothesis is that overpressure or slow PRF causes unstabilized bubbles produced by one shock pulse to dissolve before they nucleate cavitation by subsequent shock pulses. The effects of PRF and overpressure on bubble dynamics and lifetimes were studied experimentally with passive cavitation detection, high-speed photography, and B-mode ultrasound and theoretically. Overpressure significantly reduced calculated (100–2 s) and measured (55–0.5 s) bubble lifetimes. At 1.5 bar static pressure, a dense bubble cluster was measured with clinically high PRF (2–3 Hz) and a sparse cluster with clinically low PRF (0.5–1 Hz), indicating bubble lifetimes of 0.5–1 s, consistent with calculations. In contrast to cavitation in water, high-speed photography showed that overpressure did not suppress cavitation of bubbles stabilized on a cracked surface. These results suggest that a judicious use of overpressure and PRF in lithotripsy could reduce cavitation damage of tissue while maintaining cavitation comminution of stones.

A dosimetry study of the high-temperature and pressure regimes involved in high-intensity focused ultrasound (HIFU) requires experiments on biological tissues because no synthetic tissue-mimicking phantom is available. Unfortunately, the development of coagulative lesions cannot be observed in real-time in opaque tissues. Furthermore, the natural heterogeneous structure of tissue complicates direct comparison with numerical models. In this study, a new optically transparent phantom is evaluated. It is principally composed of a polyacrylamide gel, and includes a thermally sensitive indicator protein that becomes optically diffusive when denatured. Various tests were undertaken to characterize the acoustical, thermal, and optical properties of this material for a range of protein concentrations. The attenuation coefficient can be usefully modified by adjusting the quantity of embedded proteins to permit some selection of acoustic regime. It is also possible to emphasize cavitation activity at lower BSA concentrations, or thermal effects at higher concentrations. This new phantom adequately matches tissue for most of the measured parameters and facilitates the study of the HIFU bioeffects.

It is supposed that inertial cavitation plays a significant role in tissue damage during extracorporeal shock wave lithotripsy (ESWL). In this work we attempted to detect cavitation in tissue. In vivo experiments with pigs were conducted in a Dornier HM3 electrohydraulic lithotripter. Kidney alignment was made using fluoroscopy and B-mode ultrasound. Cavitation was detected by a dual passive cavitation detection (DPCD) system consisting of two confocal spherical bowl PZT transducers (1.15 MHz, focal length 10 cm, radius 10 cm). An ultrasound scanhead was placed between the transducers, an hyperechoic spots in the image indicated pockets of bubbles during ESWL. A coincidence-detection algorithm and the confocal transducers made it possible to localize cavitation to within a 4 mm diameter region. The signals from both the collecting system and kidney tissue were recorded. The targeting of the DPCD focus was confirmed by using the DPCD transducers as high intensity focused ultrasound (HIFU) sources at HIFU durations below the lesion formation threshold. In this HIFU regime, a bright spot appears in the B-mode image indicating the position of the DPCD focus. In this way we could confirm that refraction and scattering in tissue did not cause a misalignment. The tissue region interrogated was also marked with a lesion produced by HIFU. Clear cavitation signals were detected from the collecting system and from pools of blood that formed near the kidney capsule and weak signals were recorded from tissue during the ESWL treatment.

Two theoretical models and the corresponding numerical codes for the description of nonlinear acoustic beams radiated from intense cw sources in water are presented. In the first model, diffraction effects are included using the Rayleigh integral, whereas nonlinearity and thermoviscous absorption are accounted for in a quasi-plane approximation. The simulations are performed in the time domain using the code previously developed for single-pulse propagation in medium having arbitrary frequency-dependent absorption. The second model is based on the Khokhlov–Zabolotskaya–Kuznetsov equation, which, contrary to the first model, accounts for diffraction in the parabolic approximation. The simulations are performed in the frequency domain using a novel algorithm that has been developed. A variable number of harmonics, which follows the nonlinear broadening of the wave spectrum are employed in the algorithm to speed up calculations. In order to prove the validity and the accuracy of the two codes developed, the simulation of diffraction and nonlinear effects in the near field of an intense ultrasound circular piston source in water is performed. The results of modeling obtained by both codes are compared with each other and with known experimental data, and are found to be in a good agreement. Frequency-domain code is then used for detailed study of the strongly nonlinear regime of propagation, when shocks are developed in the waveform close to the source. It is demonstrated that diffraction plays a major role in shock formation. Development of two shocks in each cycle and their further collision is predicted. It is also shown that nonlinear propagation and shock formation result at some distance in the two times excess of peak positive pressure in comparison with the maximum value obtained in the case of linear propagation. The beam total power decay due to formation of shocks as a function of the propagation distance is compared with the intensity in a plane wave propagation without diffraction. It is shown that nonlinear energy decay starts earlier for the beam, but decreases slower over longer distances.

Overpressure–elevated hydrostatic pressure–was used to assess the role of gas or vapor bubbles in distorting the shape and position of a high-intensity focused ultrasound (HIFU) lesion in tissue. The shift from a cigar-shaped lesion to a tadpole-shaped lesion can mean that the wrong area is treated. Overpressure minimizes bubbles and bubble activity by dissolving gas bubbles, restricting bubble oscillation and raising the boiling temperature. Therefore, comparison with and without overpressure is a tool to assess the role of bubbles. Dissolution rates, bubble dynamics and boiling temperatures were determined as functions of pressure. Experiments were made first in a low-overpressure chamber (0.7 MPa maximum) that permitted imaging by B-mode ultrasound (US). Pieces of excised beef liver (8 cm thick) were treated in the chamber with 3.5 MHz for 1 to 7 s (50% duty cycle). In situ intensities (ISP) were 600 to 3000 W/cm². B-mode US imaging detected a hyperechoic region at the HIFU treatment site. The dissipation of this hyperechoic region following HIFU cessation corresponded well with calculated bubble dissolution rates; thus, suggesting that bubbles were present. Lesion shape was then tested in a high-pressure chamber. Intensities were 1300 and 1750 W/cm² ( ± 20%) at 1 MHz for 30 s. Hydrostatic pressures were 0.1 or 5.6 MPa. At 1300 W/cm², lesions were cigar-shaped, and no difference was observed between lesions formed with or without overpressure. At 1750 W/cm², lesions formed with no overpressure were tadpole-shaped, but lesions formed with high overpressure (5.6 MPa) remained cigar-shaped. Data support the hypothesis that bubbles contribute to the lesion distortion.

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

The clustering of cavitation bubbles may lead to enhanced stone comminution and influence the extent of tissue damage during shock wave lithotripsy (SWL) treatment. Recent research has focused on changing the SWL pulse, or timing between pulses, to intensify or mitigate collapse or localize these clusters. Such research has targeted radial, not translational motion. We investigate whether bubble translation due to radiation force is sufficiently large to influence cluster formation. The translational dynamics of a single spherical bubble were modeled according to the formulation proposed by Watanabe and Kukita [Phys. Fluids 5(11) (1993)]. After radius-time data were obtained using the Gilmore equation, translational motion was calculated by numerical integration of the Watanabe equation. Calculations were performed for a range of bubble sizes (R₀=2–20 μm) and pressure rise times (10^-9 – 10^-7 s). The results show that, during bubble growth and collapse induced by a single pulse or two pulses with microsecond delays, bubble translations are ~0.1 mm. Although bubble translation from a single pulse may not have a noticeable effect on bubble distribution, the effect may be cumulative for the +1000 shots fired during clinical SWL treatment.

Fast shock wave (SW) rates in lithotripsy (SWL) generate enhanced cavitation that could promote stone fragmentation. We tested the idea that SWL at the high end of clinical SW rate (2 Hz) acts to improve stone comminution. Model stones (Ultracal-30 cement) were exposed to SWs (20 kV, 400 SWs) at 0.2, 0.5, 1, and 2 Hz in a research electrohydraulic lithotripter. Fragmentation was assessed by measuring number, size, and projected surface area of the fragments. Stones treated at 0.2 Hz exhibited significantly greater fragmentation (p<0.01) than stones at 1 or 2 Hz, while fragmentation between 0.2 and 0.5 Hz was similar. Mean ± SEM for fragment area increase was 370±53% at 0.2 Hz (n=10 stones), 280±34 at 0.5 Hz (8), 130±31 at 1 Hz (5), and 101±16 at 2 Hz (20). This pronounced enhancement of fragmentation at very slow SW rate was unexpected. High-speed camera images of cavitation at solid objects show an increased bubble cloud at faster SW rates. The bubble cloud may interfere with transmission of acoustic energy to the stone surface. These in vitro data suggest the possibility that patient treatment at fast SW delivery rates may decrease the efficiency of stone comminution.

A passive cavitation detector (PCD) identifies cavitation events by sensing acoustic emissions generated by the collapse of bubbles. In this work, a dual passive cavitation detector (dual PCD), consisting of a pair of orthogonal confocal receivers, is described for use in shock wave lithotripsy. Cavitation events are detected by both receivers and can be localized to within 5 mm by the nature of the small intersecting volume of the focal areas of the two receivers in association with a coincidence detection algorithm. A calibration technique, based on the impulse response of the transducer, was employed to estimate radiated pressures at collapse near the bubble. Results are presented for the in vitro cavitation fields of both a clinical and a research electrohydraulic lithotripter. The measured lifetime of the primary growth-and-collapse of the cavitation bubbles increased from 180 to 420 μs as the power setting was increased from 12 to 24 kV. The measured lifetime compared well with calculations based on the Gilmore–Akulichev formulation for bubble dynamics. The radiated acoustic pressure 10 mm from the collapsing cavitation bubble was measured to vary from 4 to 16 MPa with increasing power setting; although the trends agreed with calculations, the predicted values were four times larger than measured values. The axial length of the cavitation field correlated well with the 6-dB region of the acoustic field. However, the width of the cavitation field (10 mm) was significantly narrower than the acoustic field (25 mm) as bubbles appeared to be drawn to the acoustic axis during the collapse. The dual PCD also detected signals from "rebounds," secondary and tertiary growth-and-collapse cycles. The measured rebound time did not agree with calculations from the single-bubble model. The rebounds could be fitted to a Rayleigh collapse model by considering the entire bubble cloud as an effective single bubble. The results from the dual PCD agreed well with images from high-speed photography. The results indicate that single-bubble theory is sufficient to model lithotripsy cavitation dynamics up to time of the main collapse, but that upon collapse bubble cloud dynamics becomes important.