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

Ultrasound (US) has gained widespread use in diagnostic cardiovascular applications. At amplitudes and frequencies typical of diagnostic use, its biomechanical effects on tissue are largely negligible. However, these parameters can be altered to harness US's thermal and non-thermal effects for therapeutic indications. High-intensity focused ultrasound (HIFU) and extracorporeal shock wave therapy (ECWT) are two therapeutic US modalities which have been investigated for treating cardiac arrhythmias and ischemic heart disease, respectively. Here, we review the biomechanical effects of HIFU and ECWT, their potential therapeutic mechanisms, and pre-clinical and clinical studies demonstrating their efficacy and safety limitations. Furthermore, we discuss other potential clinical applications of therapeutic US and areas in which future research is needed.

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.

Water is becoming an increasingly valuable commodity, with population growth demanding more and more amounts of this limited resource. Increased efforts are directed toward recycling and remediation, as well as desalination of the large quantities of seawater available. Dr. Bertwin Langenecker was a pioneer in utilizing hydrodynamic cavitation in a variety of applications that would remove dissolved solids from water and other liquids. His combination of intense cavitation using a rotor-stator combination, as well as simultaneously adding an adsorbent, demonstrated impressive results in desalination and waste water remediation. In this presentation, a description will be given of Dr. Langenecker's technology as well as a sampling of some of his most impressive results. Speculations as to why this approach works as well as it does will be presented.

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 temperature dependence of an agar/gelatin phantom was evaluated. The purpose was to predict the material property response to high-intensity focused ultrasound (HIFU) for developing ultrasound guided dosing and targeting feedback. Changes in attenuation, sound speed, shear modulus and thermal properties with temperature were examined from 20°C to 70°C for 3 weeks post-manufacture. The attenuation decreased with temperature by a power factor of 0.15. Thermal conductivity, diffusivity and specific heat all increased linearly with temperature for a total change of approximately 16%, 10% and 6%, respectively. Sound speed had a parabolic dependence on temperature similar to that of water. Initially, the shear modulus irreversibly declined with even a slight increase in temperature. Over time, the gel maintained its room temperature shear modulus with moderate heating. A stable phantom was achieved within 2 weeks post-manufacture that possessed quasi-reversible material properties up to nearly 55°C.

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.

BACKGROUND AND PURPOSE:
Partial nephrectomy (PN) can be technically challenging, especially if performed in a minimally invasive manner. Although ultrasound technology has been shown to have therapeutic capabilities, including tissue ablation and hemostasis, it has not gained clinical use in the PN setting. The purpose of this study is to evaluate the ability of a high-intensity ultrasound clamp to create an ablation plane in the kidney providing hemostasis that could potentially aid in laparoscopic PN.
METHODS:
A new instrument was created using a laparoscopic Padron endoscopic exposing retractor. Ultrasound elements were engineered on both sides of the retractor to administer high-intensity ultrasound energy between the two sides of the clamp. This high-intensity focused ultrasound (HIFU) clamp was placed 2 to 2.5 cm from the upper and lower poles of 10 porcine kidneys to evaluate its effectiveness at different levels and duration of energy delivery. PN transection was performed through the distal portion of the clamped margin. Kidneys postintervention and after PN were evaluated and blood loss estimated by weighing gauze placed at the defect. Histologic analysis was performed with hematoxylin and eosin and nicotinamide adenine dinucleotide staining to evaluate for tissue viability and thermal spread.
RESULTS:
Gross parenchymal changes were seen with obvious demarcation between treated and untreated tissue. Increased ultrasound exposure time (10 vs 5 and 2 min), even at lower power settings, was more effective in causing destruction and necrosis of tissue. Transmural ablation was achieved in three of four renal units after 10 minutes of exposure with significantly less blood loss (<2 g vs 30-100 g). Nonviable tissue was confirmed histologically. There was minimal thermal spread outside the clamped margin (1.2-3.2 mm).
CONCLUSION:
In this preliminary porcine evaluation, a novel HIFU clamp induced hemostasis and created an ablation plane in the kidney. This technology could serve as a useful adjunct to laparoscopic PN in the future and potentially obviate the need for renal hilar clamping.

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)-induced hyperthermia is a promising tool for cancer therapy. Three-dimensional nonlinear acoustic-bioheat transfer-blood flow-coupling model simulations and in vivo thermocouple measurements were performed to study hyperthermia effects in rabbit auricular vein exposed to pulsed HIFU (pHIFU) at varied duty cycles (DCs). pHIFU-induced temperature elevations are shown to increase with increasing DC. A critical DC of 6.9% is estimated for temperature at distal vessel wall exceeding 44°C, although different tissue depths and inclusions could affect the DC threshold. The results demonstrate clinic potentials of achieving controllable hyperthermia by adjusting pHIFU DCs, while minimizing perivascular thermal injury.

Wesley Nyborg's contributions to a theoretical description of acoustic streaming were pioneering, rigorous, and so thorough that little additional work has been published. Acoustic streaming has had many applications in acoustics, especially medical acoustics, in which it is difficult to avoid. In many cases, it can be used to enhance or accelerate a particular therapeutic effect. This presentation will provide a few examples of the role of acoustic streaming in therapeutic ultrasound as well as share a few warm memories of this kind and generous man.

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.

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.

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

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.

"Twinkling" is a widely reported ultrasound artifact whereby kidney stones and other similar calcified, strongly reflective objects appear as turbulent, flowing blood in color and power Doppler. The twinkling artifact has been shown to improve kidney stone detection over B-mode imaging alone, but its use has several limitations. Principally, twinkling can be confused with blood flow, potentially leading to an incorrect diagnosis. Here a new method is reported for explicitly suppressing the display of color from blood flow to enhance and/or isolate the twinkle signal. The method applies an autoregressive model to standard Doppler pulses in order to differentiate tissue, blood flow, and twinkling. The algorithm was implemented on a software-based, open architecture ultrasound system and tested by a sonographer on phantoms and on stones implanted in a live porcine kidney. Stones of 3-10 mm were detected reproducibly while suppressing blood flow in the image. In conclusion, a new algorithm designed to specifically detect stones has been tested and has potential clinical utility especially as efforts are made to reduce radiation exposure on diagnosis and monitoring.

Details of the collapse of single bubbles and bubble clusters leading to the emission of a shock wave under high overpressures will be presented. Ultrahigh speed photography captures the events at various stages of bubble (or cluster) growth and collapse. Shock waves are observed millimeters from the collapse center, suggesting very violent conditions at the source. For example, shock waves emitted by single-bubble sonoluminescence can reach 3 mm/microsecond about 5 micrometers from the bubble center. With a cluster, we observe shock waves at this speed over 500 micrometers from the center. The strength of the collapse is estimated by measuring the emitted shock wave velocity from images taken with the ultrahigh speed imaging system. Cluster collapses can be much stronger than from single bubbles. Cluster collapse appears to be initiated by the collapse of outer bubbles.

Low intensity pulsed ultrasound (LIPUS) has been used to accelerate tissue regeneration; however, the biological mechanisms of LIPUS induced regeneration is not completely understood. The aim for this study is to elucidate the mechanical effect generated by US for the stimulation of mesenchymal stem cells (MSCs). MSCs were cultured on flexible cell culture membranes and stimulated by US for 10 min daily with acoustic intensities of 0, 6, 13.5, and 22.5 W/cm². Cell proliferation and viability were evaluated by direct cell count and Alamar Blue assay. Morphological evaluation was performed and cell-matrix interactions were evaluated. Cell-matrix interaction was analyzed by immunochemical staining of focal adhesion proteins. LIPUS enhanced cell proliferation at higher intensities and there was an increase in cell viability after 4 consecutive days of US treatment. No morphological changes were observed in all treatments. Expression of focal adhesion protein, vinculin, was enhanced after 3 consecutive days of ultrasound treatment. Studies of media agitation did not show any enhancement effect in cell proliferation or focal adhesion protein expression. The results validates that US is able to influence the cell matrix interaction. Application of higher acoustic pressure on cell growth environment can stimulate MSC proliferation and focal adhesion.

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

As recently shown, shock wave heating and millisecond boiling can be used to obtain mechanical emulsification of tissue with or without evident thermal damage, which can be controlled by varying the parameters of the high intensity focused ultrasound exposure. The goal of this work was to examine these bioeffects using histological and biochemical analysis. Lesions were created in ex vivo bovine heart and liver using a 2-MHz transducer and pulsing scheme with 71 MPa in situ shock amplitude, 0.01 duty factor, and 5-500 ms pulse duration. Mechanical tissue damage and viability of cells in the lesions were evaluated histologically using conventional staining techniques (H&E and NADH-diaphorase). Thermal effects were quantified by measuring denaturation of salt soluble proteins in the treated area and confirmed by histology. By visual observation, the liquefied lesions obtained with shorter pulses (< 15 ms) did not show any thermal damage that correlated well with the results of both histology and protein analysis. Increasing the pulse duration resulted in an increase in thermal damage; both protein analysis and NADH-diaphorase staining showed denaturation that was visually observed as whitening of the lesion content.

Shock-wave heating and millisecond boiling in high intensity focused ultrasound fields have been shown to result in mechanical emulsification of ex-vivo tissue. In this work, the same in situ exposures were applied in vivo in pig liver and in mice bearing 5-7 mm subcutaneous tumors (B16 melanoma) on the hind limb. Lesions were produced using a 2-MHz annular array in the case of pig liver (shock amplitudes up to 98 MPa) and a 3.4-MHz single-element transducer in the case of mouse tumors (shock amplitude of 67 MPa). The parameters of the pulsing protocol (1-500 ms pulse durations and 0.01-0.1 duty factor) were varied depending on the extent of desired thermal effect. All exposures were monitored using B-mode ultrasound. Mechanical and thermal tissue damage in the lesions was evaluated histologically using H&E and NADH-diphorase staining. The size and shape of emulsified lesions obtained in-vivo agreed well with those obtained in ex-vivo tissue samples using the same exposure parameters. The lesions were successfully produced both in bulk liver tissue at depths of 1-2 cm and in superficial tumors at depths less than 1 mm without damaging the skin.

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.

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

Prof. Rongjue Wei was very interested in ensuring that students at the Institute of Acoustics in Nanjing had an opportunity to do graduate work in the United States. He had many contacts with researchers at institutions around the world that performed acoustics research. Over a period of 25 years, Prof. Wei communicated with one of the authors (L.A.C.) about various research efforts undertaken in his laboratory and at various times, suggesting that students at Nanjing could move directly into these programs. On several occasions, these students were admitted to the author's institution and worked under him or his colleagues. This relationship with Nanjing was very productive, producing some outstanding graduates, and still continues.

Violent cavitation activity has been observed in water under hundreds of bars static pressure using Impulse Devices spherical resonators. To better understand the extreme conditions inside and in the immediate vicinity of the collapsing bubbles, we simultaneously recorded multi-frame shadowgraph images, acoustic pressure, and sonoluminescence (SL) flashes from the bubbles. Images of bubbles and shock waves were captured using a V710 Phantom high-speed camera (400 000 frames/s). The tip of a fiber-optic probe hydrophone was positioned in the field of view of the camera to correlate acoustic pressure with shadowgraph images of shock waves and bubble dynamics. SL flashes were collected with two photomultiplier tubes (PMTs, Hamamatsu, 1-ns rise time). The PMTs had identical ultraviolet filters but different sensitivities to extend the dynamic range from a single to thousands of photons. Typically a single bubble was spontaneously nucleated at the center of the sphere. After the first collapse, the bubble reemerged as a cluster of bubbles. The relationships among the static pressure, driving acoustic amplitude, the maximum bubble size, SL flashes, and shock wave amplitude will be discussed and compared with numerical results obtained using the hydrocode HYADES.

Communicating with journalists poses a major dilemma: We have an obligation to explain science to the public because there are so many voices that denigrate scientists and their work; yet, in order for the journalists to effectively communicate, they often dumb it down so much that they get it wrong, and then we are embarrassed in front of our scientific colleagues. This dilemma can be mitigated somewhat by speaking only to those journalists who understand the science and to whom will allow you to edit their work. Of course, it is often difficult to determine, in the middle of an interview, the scientific capability of an interviewer, and often journalists do not like to have their work edited. In the end, a greater understanding of science by the general public is in our best interests and interviews with journalists should (nearly) always be granted. Some reflections on my experiences with such interviews will be given.

Cavitation collapse can generate intense concentrations of energy, sufficient to erode even the hardest metals and to generate light emissions visible to the naked eye [sonoluminescence (SL)]. The phenomenon of 'single bubble sonoluminescence' (SBSL) in which a single stable cavitation bubble radiates light flashes each acoustic cycle typically occurs near 0.1 MPa static pressures. Impulse Devices, Inc. has developed a new tool for the study of SL and cavitation: a high quality factor, spherical resonator capable of achieving acoustic cavitation at ambient pressures in excess of 30 MPa. This system generates bursts of violent inertial cavitation events lasting only a few milliseconds (hundreds of acoustic cycles). Cavitation observed in this system is characterized by flashes of light with intensities up to 1000 times brighter than SBSL flashes as well as spherical shock waves with amplitudes exceeding 100 MPa (1000 bars) at 1 cm from the cavitation center. Computer simulations indicate shock wave amplitudes near the collapsing bubble around 1-10 TPa (10-100 mbars) and liquid temperatures on the order of 5000 K, possibly causing the liquid to become opaque. The implications of these extreme conditions on SL emission will be discussed.

Phantoms used for high intensity focused ultrasound (HIFU) applications require rigorous evaluation of material properties since, locally, the material experiences extreme changes in temperature and stresses with the HIFU treatment. Here we present the testing of an agar-gelatin phantom intended for both acoustic radiation force imaging (ARFI) and HIFU applications. The phantom shear modulus, speed of sound, attenuation, and thermal properties were all evaluated over the range of room temperature to 80C. With the exception of the thermal properties, all measurements were taken during both heating and cool down. Cavitation threshold and melting point were also tested. The change in material sound speed and thermal properties with temperature were quasireversible and similar to that of water. Material attenuation showed a slight decrease with temperature, but appeared to also be reversible. Shear modulus decreased significantly with temperature, going to near zero. The response was not reversible, returning to only approximately one-third of the starting value. These results demonstrate the complex material response that can occur with HIFU treatment. The results also raise the question of how well the test procedures, and thus results, properly reflect the true HIFU conditions.

The success of surgical management of lower pole stones is principally dependent on stone fragmentation and residual stone clearance. Choice of surgical method depends on stone size, yet all methods are subjected to post-surgical complications resulting from residual stone fragments. Here we present a novel method and device to reposition kidney stones using ultrasound radiation force delivered by focused ultrasound and guided by ultrasound imaging. The device couples a commercial imaging array with a focused annular array transducer.

Feasibility of repositioning stones was investigated by implanting artificial and human stones into a kidney-mimicking phantom that simulated a lower pole and collecting system. During experiment, stones were located by ultrasound imaging and repositioned by delivering short bursts of focused ultrasound. Stone motion was concurrently monitored by fluoroscopy, ultrasound imaging, and video photography, from which displacement and velocity were estimated. Stones were seen to move immediately after delivering focused ultrasound and successfully repositioned from the lower pole to the collecting system. Estimated velocities were on the order of 1 cm/s. This in vitro study demonstrates a promising modality to facilitate spontaneous clearance of kidney stones and increased clearance of residual stone fragments after surgical management.

Violent impacts, such as vehicle accidents, frequently yield injuries of the liver due to its size and its location in the abdominal cavity. Frequently these injuries are fractures which may lead to life-threatening hemorrhage. Currently, a fast means of non-invasively visualizing areas of injuries in the liver due to blunt force trauma does not exist; hence there is a need to develop better imaging modalities of hepatic injuries to assist in clinical assessments. In this study, we investigate the feasibility of visualizing liver fractures using shear wave elastography.

We hypothesize that there is a shear modulus discontinuity between the two edges of a fracture, and we expect that these discontinuities can be observed from the imaging at the boundary of the split. In testing the hypothesis, we first use optical methods to track and study the displacements and motion trajectories of different regions of a hepatic injury phantom in response to shear wave excitations. Then, following Fink et al. [Proc. IEEE Ultrason. Symp. 1767 (2002)], we implement similar methods with a Verasonics ultrasound system and examine the propagation of shear waves induced by the acoustic radiation force in tissue-mimicking phantoms and ex vivo liver.

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

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

It is well known that cavitation collapse can generate intense concentrations of mechanical energy, sufficient to erode even the hardest metals and to generate light emissions visible to the naked eye [sonoluminescence (SL)]. Considerable attention has been devoted to the phenomenon of "single bubble sonoluminescence" (SBSL) in which a single stable cavitation bubble radiates light flashes each and every acoustic cycle. Most of these studies involve acoustic resonators in which the ambient pressure is near 0.1 MPa (1 bar), and with acoustic driving pressures on the order of 0.1 MPa.

This study describes a high-quality factor, spherical resonator capable of achieving acoustic cavitation at ambient pressures in excess of 30 MPa (300 bars). This system generates bursts of violent inertial cavitation events lasting only a few milliseconds (hundreds of acoustic cycles), in contrast with the repetitive cavitation events (lasting several minutes) observed in SBSL; accordingly, these events are described as "inertial transient cavitation." Cavitation observed in this high pressure resonator is characterized by flashes of light with intensities up to 1000 times brighter than SBSL flashes, as well as spherical shock waves with amplitudes exceeding 30 MPa at the resonator wall. Both SL and shock amplitudes increase with static pressure.

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

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

Nonlinear propagation effects result in the formation of weak shocks in high intensity focused ultrasound (HIFU) fields. When shocks are present, the wave spectrum consists of hundreds of harmonics. In practice, shock waves are modeled using a finite number of harmonics and measured with hydrophones that have limited bandwidths.

The goal of this work was to determine how many harmonics are necessary to model or measure peak pressures, intensity, and heat deposition rates of the HIFU fields. Numerical solutions of the Khokhlov-Zabolotskaya-Kuznetzov-type (KZK) nonlinear parabolic equation were obtained using two independent algorithms, compared, and analyzed for nonlinear propagation in water, in gel phantom, and in tissue. Measurements were performed in the focus of the HIFU field in the same media using fiber optic probe hydrophones of various bandwidths. Experimental data were compared to the simulation results.

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.

A wide variety of treatment protocols have been employed in high intensity focused ultrasound (HIFU) treatments, and the resulting bioeffects observed include both mechanical as well as thermal effects. In recent studies, there has been significant interest in generating purely mechanical damage using protocols with short, microsecond pulses. Tissue erosion effects have been attained by operating HIFU sources using short pulses of 10–20 cycles, low duty cycles (<1%), and pulse average intensities of greater than 20 kW/cm².

The goal of this work was to use a modified pulsing protocol, consisting of longer, millisecond-long pulses of ultrasound and to demonstrate that heating and rapid millisecond boiling from shock wave formation can be harnessed to induce controlled mechanical destruction of soft tissue. Experiments were performed in excised bovine liver and heart tissue using a 2-MHz transducer. Boiling activity was monitored during exposures using a high voltage probe in parallel with the HIFU source. In situ acoustic fields and heating rates were determined for exposures using a novel derating approach for nonlinear HIFU fields. Several different exposure protocols were used and included varying the duty cycle, pulse length, and power to the source. After exposures, the tissue was sectioned, and the gross lesion morphology was observed. Different types of lesions were induced in experiments that ranged from purely thermal to purely mechanical depending on the pulsing protocol used. Therefore, shock wave heating and millisecond boiling may be an effective method for reliably generating significant tissue erosion effects.

High-intensity focused ultrasound (HIFU) transducers can be operated at high-pressure amplitudes of greater than 60 MPa and low-duty cycles of 1% or less to induce controlled bubble activity that fractionates tissue. The goal of this work was to investigate fractionation not from mechanically induced cavitation but from thermally induced boiling created by HIFU shock waves. Experiments were performed using a 2-MHz HIFU source. The focus was placed in ex vivo bovine heart and liver samples. Cavitation and boiling were monitored during exposures using a high-voltage probe in parallel with the HIFU source and with an ultrasound imaging system. Various exposure protocols were performed in which the time-averaged intensity and total energy delivered were maintained constant. The types of lesions induced in tissue ranged from purely thermal to purely mechanical depending on the pulsing protocol used. A pulsing protocol in which the pulse length was on the order of the time to boil (of only several milliseconds) and duty cycle was low (<1%) was found to be a highly repeatable method for inducing mechanical effects with little evidence of thermal damage, as confirmed by histology.

Nonlinear propagation causes high-intensity ultrasound waves to distort and generate higher harmonics, which are more readily absorbed and converted to heat than the fundamental frequency. Although such nonlinear effects have been investigated previously and found to not significantly alter high-intensity focused ultrasound (HIFU) treatments, two results reported here change this paradigm. One is that at clinically relevant intensity levels, HIFU waves not only become distorted but form shock waves in tissue. The other is that the generated shock waves heat the tissue to boiling in much less time than predicted for undistorted or weakly distorted waves.

In this study, a 2-MHz HIFU source operating at peak intensities up to 25,000 W/cm² was used to heat transparent tissue-mimicking phantoms and ex vivo bovine liver samples. Initiation of boiling was detected using high-speed photography, a 20-MHz passive cavitation detector and fluctuation of the drive voltage at the HIFU source. The time to boil obtained experimentally was used to quantify heating rates and was compared with calculations using weak shock theory and the shock amplitudes obtained from nonlinear modeling and measurements with a fiber optic hydrophone. As observed experimentally and predicted by calculations, shocked focal waveforms produced boiling in as little as 3 ms and the time to initiate boiling was sensitive to small changes in HIFU output. Nonlinear heating as a result of shock waves is therefore important to HIFU, and clinicians should be aware of the potential for very rapid boiling because it alters treatments.

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

Current methods of determining high intensity focused ultrasound (HIFU) fields in tissue rely on extrapolation of measurements in water assuming linear wave propagation both in water and in tissue. Neglecting nonlinear propagation effects in the derating process can result in significant errors. In this work, a new method based on scaling the source amplitude is introduced to estimate focal parameters of nonlinear HIFU fields in tissue. Focal values of acoustic field parameters in absorptive tissue are obtained from a numerical solution to a KZK-type equation and are compared to those simulated for propagation in water. Focal waveforms, peak pressures, and intensities are calculated over a wide range of source outputs and linear focusing gains. Our modeling indicates, that for the high gain sources which are typically used in therapeutic medical applications, the focal field parameters derated with our method agree well with numerical simulation in tissue. The feasibility of the derating method is demonstrated experimentally in excised bovine liver tissue.

Before ultrasound-imaging systems became widely available, ultrasound therapy devices showed great promise for general use in medicine. However, it is only in the last decade that ultrasound therapy has begun to obtain clinical acceptance. Recently, a variety of novel applications of therapeutic ultrasound have been developed that include sonothrombolysis, site-specific and ultrasound-mediated drug delivery, shock wave therapy, lithotripsy, tumor ablation, acoustic hemostasis and several others. This paper reviews a few selected applications of therapeutic ultrasound. It will address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. As a plenary presentation, its audience is intended for the ultrasound scientist or engineer, and thus is not presented at the level of the experienced medical ultrasound professional.

High intensity focused ultrasound (HIFU) therapy is an emerging medical technology in which acoustic pressure amplitudes of up to 100 MPa are used to induce tissue ablation, often in combination with real-time imaging. The ultrasound energy is typically focused into a millimeter-size volume and used to thermally coagulate the tissue of interest while ideally sparing surrounding tissue. Nonlinear effects are important in HIFU as in situ intensities for clinical applications of up to 30 000 W/cm² have been reported. Since controlled experiments are often difficult to perform, especially in vivo, modeling can aid in understanding the physical phenomena involved in HIFU-induced tissue ablation. The Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation is applicable to HIFU because it includes all of the basic physical phenomena that are relevant to HIFU including acoustic beams, diffraction, focusing, nonlinear propagation, shock formation, and dissipation. In this paper, an overview of several recent advances in KZK modeling for HIFU applications are described. It is shown that shock-induced heating in tissue can cause localized boiling in milliseconds; furthermore, the bubbles associated with boiling can significantly alter HIFU treatments.

In this work, a new derating method to extrapolate nonlinear ultrasound fields in water to biological tissue is proposed and tested for therapeutic medical systems. Focal values of acoustic field parameters in absorptive tissue are obtained from a numerical solution to a KZK-type equation and are compared to those derated, using the proposed method, from the results of simulations in water. It is validated in modeling that for high gain sources, which are typically used for therapeutic medical applications, the focal field parameters in tissue can be obtained from the results obtained in water. The feasibility of the derating method is also demonstrated experimentally in water and excised bovine liver tissue using a 2 MHz HIFU source of 44 mm aperture and focal length.

High-intensity focused ultrasound (HIFU) is being promoted as a noninvasive method to treat certain primary solid tumors, metastatic disease, and enhance drug delivery. The field of medicine is evolving towards increasing use of noninvasive and minimally invasive therapies such as HIFU. This article provides an overview of current clinical applications of HIFU and future requirements to expand the clinical applications of this technique.

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

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

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.

Both mechanically induced acoustic cavitation and thermally induced boiling can occur during high intensity focused ultrasound (HIFU) medical therapy. The goal was to monitor the temperature as boiling was approached using magnetic resonance imaging (MRI). Tissue phantoms were heated for 20 s in a 4.7-T magnet using a 2-MHz HIFU source with an aperture and radius of curvature of 44 mm. The peak focal pressure was 27.5 MPa with corresponding beam width of 0.5 mm.

The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73 degrees C after 7 s of continuous HIFU exposure when boiling started. Boiling was detected by visual observation, by appearance on the MR images, and by a marked change in the HIFU source power. Nonlinear modeling of the acoustic field combined with a heat transfer equation predicted 100 degrees C after 7 s of exposure. Averaging of the calculated temperature field over the volume of the MRI voxel (0.3 x 0.5 x 2 mm(3)) yielded a maximum of 73 degrees C that agreed with the MR thermometry measurement. These results have implications for the use of MRI-determined temperature values to guide treatments with clinical HIFU systems.

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.

A current topic of interest for high intensity focused ultrasound (HIFU) treatments involves the relative roles of bubbles and nonlinear acoustic propagation as heating mechanisms. At high amplitudes, nonlinear propagation leads to the generation of boiling bubbles within milliseconds; at lower amplitudes, cavitation bubbles can enhance heating through viscous dissipation, acoustic radiation, and heat conduction. In this context, understanding the physics attendant to HIFU bubbles requires consideration of gas–vapor bubble dynamics, including thermal effects in the nearby liquid. To this end, recent experimental observations with high-speed photography suggest that bubbles undergo a brief period of growth after application of HIFU has stopped. To explain this observation, a model is implemented that couples the thermodynamic state of a strongly driven bubble with thermal conditions in the surrounding liquid. From model simulations, liquid heating in the vicinity of a HIFU bubble is estimated. Calculations suggest that thermal conduction and viscous dissipation can lead to the evolution of a nontrivial thermal boundary layer. Development of a boundary layer that reaches superheated temperatures would explain the aforementioned experimental observation. As such, cavitation bubbles and boiling bubbles share important characteristics during HIFU.

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

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.

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

Cessation of hemorrhage using extrinsic, interventional methods is possible with delivery of energy to bleeding tissues, i.e., cauterization. High intensity focused ultrasound (HIFU) is one such method, with significant advantages of delivering high levels of energy to well-defined regions of deep-seated tissues, even during profuse bleeding. The physical mechanisms involved in this process include thermal and mechanical effects of HIFU, leading to various biological effects. Our results using HIFU devices of 1–5 MHz, and focal, derated intensities of 1,000–10,000 W/cm², in solid organs such as liver, spleen, and kidneys and major and minor blood vessels, show that temperature of targeted tissues reaches 70–100°C within seconds, with formation of microbubbles, approximately 5–200 µ in size, and concentration of 100 bubbles/mm³. It appears that boiling of interstitial fluids and blood and acoustic cavitation are both involved. The biological effects include coagulative necrosis, mechanical disruption of tissue structure potentially leading to release of tissue factors enhancing the coagulation, coagulum and thrombus formation at a wound site, tissue fusion via collagen and elastin remodeling, and fibrin plug formation, with minimal damage of the surrounding tissues. These mechanisms appear to provide an effective and safe method of hemorrhage control.

Microbubble activity is significantly involved in both diagnostic and therapeutic aspects of ultrasound image-guided HIFU therapy. Ultrasound interrogation techniques (A-, B-, M-mode, Doppler, harmonic and contrast imaging, and passive and active cavitation detection) were integrated with HIFU. Our results using HIFU devices of 1–5 MHz, and focal, derated intensities of 1,000–10,000 W/cm², show the formation of microbubbles (about 100 bubbles/mm³, 5–100 microns in size) at the HIFU focus. Boiling, stable, and inertial acoustic cavitation activities were detected during therapy. The presence of bubbles allows the observation of the treatment spot as bright hyperechoic regions in ultrasound images, providing an effective method for guidance and monitoring of therapy. The stable cavitation of microbubbles may provide a mechanism for enhanced HIFU energy delivery, as well as induction of biological responses for stimulation and regulation of specific physiological events such as coagulum and thrombus formation for hemostasis applications, apoptotic activity in treating tumor margins, and stimulation of immune response. Stable cavitation of extrinsic bubbles (contrast agents) is used in detection and localization of internal occult bleeding, using harmonic imaging. There appears to be benefits in utilizing stable cavitation in both diagnostic and therapeutic objectives of ultrasound image-guided HIFU.

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.

This study evaluated the cavitation activity induced by shock wave (SW) pulses, both in vitro and in vivo, based on the area measurements of echogenic regions observed in B-mode ultrasound images. Residual cavitation bubble clouds induced by SW pulses were detected as echogenic regions in B-mode images. The temporal evolution of residual bubble clouds, generated by SWs with varying lithotripter charging voltage and pulse repetition frequency (PRF), was analyzed by measuring the time-varying behaviors of the echogenic region areas recorded in B-mode images. The results showed that (1) the area of SW-induced echogenic regions enlarged with increased SW pulse number; (2) echogenic regions in the B-mode images dissipated gradually after ceasing the SWs, which indicated the dissolution of the cavitation bubbles; and (3) larger echogenic regions were generated with higher charging voltage or PRF.

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.

Nonlinear propagation effects during high-intensity focused ultrasound (HIFU) treatments can induce shocks in the acoustic waveform, dramatically accelerate heating rates, and result in rapid boiling of tissue at the focus. Localized boiling can be used for targeting and calibration of clinical HIFU treatments. In our previous work, millimeter size boiling bubbles were observed in several milliseconds in a weakly absorptive transparent tissue phantom, and temperature rise to 100<th>°C was calculated using weak shock theory from experimentally measured and numerically simulated focal waveforms. In this work, experiments are extended to an opaque phantom that has higher attenuation (0.5 dB/cm/MHz in the new phantom versus 0.15 dB/cm/MHz in the previous one) more similar to real tissue. Focal acoustic waveforms are measured using a fiber optic probe hydrophone and time to boil is monitored using a 20-MHz acoustic detector. Modeling of experimental conditions is performed with a KZK-type numerical model. Results demonstrate that although higher source amplitude is needed to attain the same focal amplitudes in the new, more attenuative phantom, similar amplitude shocks can be formed, resulting in equally fast heating rates.

Bubbles generated by acoustic cavitation or boiling are often observed during high intensity focused ultrasound (HIFU) medical treatments. In this work, high-speed video imaging, a 20-MHz focused acoustic transducer, and the driving voltage to our 2-MHz HIFU source are used to distinguish between cavitation and boiling in a tissue-mimicking gel phantom at peak focal intensities up to 30,000 W/cm². Bubble dynamics are modeled using a reduced order model that accounts for evaporation and condensation, heat and gas transfer across the interface, and temperature changes in the surrounding liquid. The model includes vapor trapping, whereby the noncondensable gas slows diffusion of vapor to the interface, thereby limiting condensation. At the transducer focus, evidence of cavitation is observed in the first millisecond before disappearing. Boiling is observed several milliseconds later, after sufficient heating of the focal volume to 100&$176;C. The disappearance of cavitation can be explained in part by the observed motion of bubbles away from the focal region due to radiation-pressure forces and in part by the softening of bubble collapses by vapor trapping. Thus, at clinical HIFU amplitudes, bubble dynamics and their impact on image-feedback and/or therapy change dramatically in only milliseconds.

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.

High-intensity focused ultrasound (HIFU) has the potential to become a modality of treatment for a wide range of clinical conditions. HIFU enables non-invasive, selective ablation of tissues including tumors and punctured vessels. Another promising area of research within the field of therapeutic ultrasound is the application of HIFU to treat neurological disorders by selectively targeting the brain, spinal cord, or nerves. This paper provides an overview of the current applications of focused ultrasound in medicine with an emphasis on its use in the fields of neurology and neurosurgery.

A noncontact transport experiment in water using ultrasonic traveling waves was investigated. Acrylic, aluminum, and brass discs were used as test objects. Traveling waves were generated using two ultrasonic transducers attached at the ends of a vibrating plate. One side was used as the wave-source side and the other side was used as the wave-receiving side. Acrylic plates cemented to the sides of the vibrating plate formed a tank to hold water. Object transportation was accomplished by adding a small amount of water to the vibrating structure. The transport velocity of floating objects in water is faster than for floating transport in air because of buoyancy. The transport velocity of an object depends on water height. The minimum value of the velocity occurs when the disc thickness is equal to the water height. The transport velocity increases as the height of water increases. For very shallow depths, the largest velocity is obtained when cavitation-induced streaming occurs.

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.

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.

Slow clinical shock wave rates more effectively comminute stones. Higher rates create more cavitation bubbles along the focusing axis. Bubble clouds potentially reflect or attenuate the shock wave and also may collapse less energetically. Here, high-speed photo-elastography was used to visualize the dynamic stress distribution inside a transparent model stone. Photo-elastography records constant-stress lines, making quantification possible. PVDF sensors (4 mm diameter) measured force on the proximal face of the stones. The impulsive force of the shock wave and the cloud collapse at various clinical rates (single shocks, 1 Hz, 2 Hz, 3 Hz) in degassed and non-degassed water were calculated from the measurements. Impulse forces from the shock wave and cavitation collapse were comparable in the range 4–7 x 10^-4 Ns. At clinical rates in gas-saturated water, the stress fringes of the tensile component of the shock wave were reduced; the observable maximum stress was decreased; and impulsive force from the shock and the cavitation were decreased over single shocks. The results are evidence of reduced stress in the stone at higher rates due to attenuation by bubbles and less so to softened cavitation collapse.

Nonlinear propagation effects leading to shock formation at the focus of hig-intensity focused ultrasound (HIFU) treatments can accelerate heating and cause rapid boiling in tissue. Boiling can be utilized for targeting the treatment with B-mode ultrasound and should be taken into account when planning the treatment, because bubbles reflect ultrasound and thereby displace and distort the lesion shape. In these experiments, an HIFU transducer of 2 MHz frequency, 4 cm aperture, and 4.5 cm focal length was used to investigate heating effects from shock formation in tissue-mimicking phantoms. The time required to attain 100<th>°C at the focus was calculated with weak shock theory from the peak amplitudes calculated with a KZK-type model, and time to boiling was measured by high-speed video and a 20-MHz passive cavitation detector (PCD) for different values of phantom absorption (both lower than tissue absorption) and HIFU power (100–200 W). Boiling was observed in 3 ms at the highest power level used by the observation of visible bubbles and by a significant change in the PCD time signal and spectrum.

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.

Different peak and average acoustic parameters determine the efficiency of different physical mechanisms of high-intensity focused ultrasound (HIFU) interaction with biological tissue. Spatial distributions of these parameters are therefore important for transducer calibration and extrapolation of measurements in water to application in tissue. In the case of linear focusing, all parameters of the acoustic field can be obtained from the spatial distribution of the wave amplitude. However, in nonlinear focused beams, each parameter has its own characteristic spatial structure, which changes with the increase of the HIFU power level. This work compares the focal size and location calculated for the peak positive and peak negative pressure, mean intensity, and effective acoustic energy absorption in water and in tissue. Numerical solutions, obtained with the KZK-type model, are analyzed for various regimes of linear, quasilinear, and strongly nonlinear propagation which includes formation of shocks. The results of simulations are validated by comparison with measurements performed with a fiberoptic probe hydrophone in water and in a tissue mimicking phantom. The peak positive pressure and effective absorption are finely focused, whereas the negative pressure, responsible for cavitation, is broad and displaced towards the transducer.

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.

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.

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

A numerical model for simulating nonlinear pulsed beams radiated by rectangular focused transducers, which are typical of diagnostic ultrasound systems, is presented. The model is based on a KZK-type nonlinear evolution equation generalized to an arbitrary frequency-dependent absorption. The method of fractional steps with an operator-splitting procedure is employed in the combined frequency-time domain algorithm. The diffraction is described using the implicit backward finite-difference scheme and the alternate direction implicit method. An analytic solution in the time domain is employed for the nonlinearity operator. The absorption and dispersion of the sound speed are also described using an analytic solution but in the frequency domain. Numerical solutions are obtained for the nonlinear acoustic field in a homogeneous tissue-like medium obeying a linear frequency law of absorption and in a thermoviscous fluid with a quadratic frequency law of absorption. The model is applied to study the spatial distributions of the fundamental and second harmonics for a typical diagnostic ultrasound source. The nonlinear distortion of pulses and their spectra due to the propagation in tissues are presented. A better understanding of nonlinear propagation in tissue may lead to improvements in nonlinear imaging and in specific tissue harmonic imaging.

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.

The importance of nonlinear acoustic wave propagation and ultrasound-induced cavitation in the acceleration of thermal lesion production by high intensity focused ultrasound was investigated experimentally and theoretically in a transparent protein-containing gel. A numerical model that accounted for nonlinear acoustic propagation was used to simulate experimental conditions. Various exposure regimes with equal total ultrasound energy but variable peak acoustic pressure were studied for single lesions and lesion stripes obtained by moving the transducer. Static overpressure was applied to suppress cavitation. Strong enhancement of lesion production was observed for high amplitude waves and was supported by modeling. Through overpressure experiments it was shown that both nonlinear propagation and cavitation mechanisms participate in accelerating lesion inception and growth. Using B-mode ultrasound, cavitation was observed at normal ambient pressure as weakly enhanced echogenicity in the focal region, but was not detected with overpressure. Formation of tadpole-shaped lesions, shifted toward the transducer, was always observed to be due to boiling. Boiling bubbles were visible in the gel and were evident as strongly echogenic regions in B-mode images. These experiments indicate that nonlinear propagation and cavitation accelerate heating, but no lesion displacement or distortion was observed in the absence of boiling.

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.

A cavitation bubble cloud typically acts as a strong acoustic scatterer; however, at certain frequencies and amplitudes waves transmitted by a cloud are amplified. A long-term goal is to break up kidney stones by using a two-frequency ultrasound forcing method with one frequency that generates the cloud followed by a lower second frequency that excites its violent collapse. The goal of this study is to determine the frequency and pressure amplitudes which produce the largest pressures as measured by a PVDF membrane on the stone surface. Reflection was also measured by a concave PVDF sensor placed 40 mm from the surface, and cloud sizes were determined by high-speed camera images. Transmission is quantified by the force. Reflection and transmission showed a reciprocal relation: peak in transmission corresponded to a minimum in reflection. The largest cloud observed created the largest reflection, whereas the smallest clouds created the largest transmitted signals. Forces generated by the small clouds were five times larger than the amplitude without a cloud. Thus, in using a two-frequency excitation combination, the pressures generated by the cloud cavitation might be optimized for lithotripsy applications.

The investigation of high-intensity focused ultrasound (HIFU) as a tool for noninvasive thermally ablative therapy has required deeper understanding of the relative roles of nonlinear mechanisms involved in heat deposition. Attempts at quantifying the dose response to particular exposure conditions in vitro are complicated by the interplay of several mechanisms. These include microbubble cavitation, nonlinear acoustic propagation and attenuation, dependence of tissue parameters on temperature and temperature history, and formation and evolution of vapor bubbles due to boiling. One immediately evident consequence of such effects is distortion of coagulative lesion shape and size, colloquially evolving from cigars to tadpoles. Developing a quantitative understanding of the relative roles of relevant nonlinear mechanisms is not straightforward, yet is desirable for design of algorithms for therapy planning and real-time monitoring using ultrasound. A historical perspective of research toward this end will be presented along with a recommendation for suitable terminology for the various physical acoustic regimes encountered in HIFU therapy.

Two major nonlinear mechanisms are known to influence HIFU heating: acoustic nonlinearity and cavitation. Heating may also result in formation of boiling vapor bubbles that grow much larger than the cavitation bubbles. The relevant role of these phenomena was investigated experimentally and numerically in a gel phantom. HIFU pressure thresholds for shock formation, cavitation, and boiling were measured using a fiber-optic probe hydrophone, passive cavitation detection, ultrasound and optical imaging, and thermocouples. The KZK and Bio-heat equations were employed to simulate experimental conditions. Elevated static pressure was applied to suppress bubbles and increase the boiling temperature, thus isolating the pure effect of acoustic nonlinearity in comparison of heating between short, high-amplitude and long, low-amplitude pulses of equal average intensity. The experimental results indicated that both nonlinear mechanisms accelerated lesion production with acoustic nonlinearity responsible for the greater effect. It was observed that lesion distortion and migration was due to boiling detected in as little as 40 ms within the center of the lesion, in agreement with nonlinear acoustic simulations. These data indicate that acoustic nonlinearity and the boiling play a significant role earlier in HIFU treatments than previously anticipated.

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.

For treatments that use high-intensity focused ultrasound (HIFU), it is important to understand the behavior of bubbles in the context of both large acoustic pressures and elevated temperatures in the surrounding medium. Based upon clinical and experimental observations, any preexisting cavitation nuclei in tissue or blood are likely to be less than 1 micron. For HIFU conditions characterized by megahertz frequencies and pressures on the order of megaPascals, gas bubbles less than a micron in radius can grow explosively. Calculations for a single, spherical bubble imply that the resulting bubble motions are significantly influenced by evaporation and condensation processes. Consequently, at both high and low ambient temperatures, HIFU-driven bubbles may best be described as gas-vapor bubbles that can exhibit rectified transfer of both heat and noncondensable gases. Moreover, increased vapor pressures associated with ambient temperatures at or above "boiling" may not lead to unbounded bubble growth as expected for a quasistatic bubble in a superheated medium. Instead, calculations suggest that growth of boiling bubbles can be confined.

Ultrasound imaging is useful for monitoring high-intensity, focused ultrasound (HIFU) therapy; however, interference on the ultrasound image, caused by HIFU excitation, must be avoided. A method to synchronize HIFU excitation with ultrasound imaging is described here. Synchronization was tested with two unmodified, commercial imagers and two tissue phantoms.

The importance of nonlinear acoustic wave propagation and ultrasound-induced cavitation in the acceleration of thermal lesion production by high intensity focused ultrasound was investigated experimentally and theoretically in a transparent protein-containing gel. A numerical model that accounted for nonlinear acoustic propagation was used to simulate experimental conditions. Various exposure regimes with equal total ultrasound energy but variable peak acoustic pressure were studied for single lesions and lesion stripes obtained by moving the transducer. Static overpressure was applied to suppress cavitation. Strong enhancement of lesion production was observed for high amplitude waves and was supported by modeling. Through overpressure experiments it was shown that both nonlinear propagation and cavitation mechanisms participate in accelerating lesion inception and growth. Using B-mode ultrasound, cavitation was observed at normal ambient pressure as weakly enhanced echogenicity in the focal region, but was not detected with overpressure. Formation of tadpole-shaped lesions, shifted toward the transducer, was always observed to be due to boiling. Boiling bubbles were visible in the gel and were evident as strongly echogenic regions in B-mode images. These experiments indicate that nonlinear propagation and cavitation accelerate heating, but no lesion displacement or distortion was observed in the absence of boiling.

The importance of nonlinear acoustic wave propagation and ultrasound-induced cavitation in the acceleration of thermal lesion production by high intensity focused ultrasound was investigated experimentally and theoretically in a transparent protein-containing gel. A numerical model that accounted for nonlinear acoustic propagation was used to simulate experimental conditions. Various exposure regimes with equal total ultrasound energy but variable peak acoustic pressure were studied for single lesions and lesion stripes obtained by moving the transducer. Static overpressure was applied to suppress cavitation. Strong enhancement of lesion production was observed for high amplitude waves and was supported by modeling. Through overpressure experiments it was shown that both nonlinear propagation and cavitation mechanisms participate in accelerating lesion inception and growth. Using B-mode ultrasound, cavitation was observed at normal ambient pressure as weakly enhanced echogenicity in the focal region, but was not detected with overpressure. Formation of tadpole-shaped lesions, shifted toward the transducer, was always observed to be due to boiling. Boiling bubbles were visible in the gel and were evident as strongly echogenic regions in B-mode images. These experiments indicate that nonlinear propagation and cavitation accelerate heating, but no lesion displacement or distortion was observed in the absence of boiling.

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

High-intensity focused ultrasound (HIFU) has been shown to provide an effective method for hemorrhage control of blood vessels in acute animal studies. The objective of the current study was to investigate the long-term effects of HIFU-induced hemostasis in punctured arteries. The femoral arteries ( approximately 2mm in diameter) of 25 adult anesthetized rabbits were surgically exposed, and either punctured and treated with HIFU (n=15), served as control (no puncture and no HIFU application: n=7), or were punctured and left untreated (n=3). Treated animals were allowed to recover, and examined and/or sacrificed on days 0, 1, 3, 7, 14, 28, and 60 after treatment to obtain ultrasound images and samples of blood and tissue. Hemostasis (arrest of bleeding) was achieved in all 15 of the HIFU-treated arteries. Eleven of the arteries were patent after HIFU treatment, and four arteries were occluded, as determined by Doppler ultrasound. The median HIFU application time to achieve hemostasis was 20s (range 7-55 s) for the patent arteries and 110 s (range 50-134 s) for the occluded arteries. In untreated animals, bleeding had not stopped after 120 s. One of the occluded arteries had reopened by day 14. No immediate or delayed re-bleeding was observed after HIFU treatment. Maximal blood flow velocities were similar in HIFU-treated patent vessels and control vessels. No significant difference in hematocrits was found between HIFU-treated and control groups at different time points after the procedure. Light microscopy observations of the HIFU-treated arteries showed disorganization of adventitia, and coagulation and thinning of the tunica media. The general organization of the adventitia and tunica media recovered to normal appearance within 28 days, with some thinning of the tunica media observed up to day 60. Neointimal hyperplasia was observed on days 14 and 28. The results show that HIFU can produce effective and long-term (up to 60 days) hemostasis of punctured femoral arteries while preserving normal blood flow and vessel wall structure in the majority of vessels.

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.

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 using coincident signals on confocal orthogonal receivers, were used to interrogate the renal collecting system (urine) and the kidney parenchyma (tissue). Cavitation was detected in urine immediately upon shock-wave (SW) administration in urine or urine plus X-ray contrast agent but, in native tissue, cavitation required hundreds of SWs to initiate. Localization of cavitation was confirmed by fluoroscopy, sonography and by thermally marking the kidney using the passive cavitation detection 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. The finding that cavitation occurs in kidney tissue is a critical step toward determining the mechanisms of tissue injury in SWL.

Ultrasound guidance of HIFU therapy is attractive because of its portability, low cost, real-time image processing, simple integration with HIFU instruments, and the extensive availability of diagnostic ultrasound; however, the use of ultrasound visualization for the guidance and monitoring of HIFU therapy often relies on the appearance of a hyperechoic region in the ultrasound image. It is often assumed that the formation of a hyperechoic region at the HIFU treatment site results from bubble activity generated during HIFU exposure. However, it has been determined that this region can be generated with relatively short bursts of HIFU (on the order of 30 ms), bursts so short that negligible temperature elevations are expected to occur. In examining the histology associated with these hyperechoes, there is little evidence of traditional cavitation damage; rather, it appears as if there are many bubbles generated within the individuals cells, suggesting a thermal mechanism. Thermocouple measurements of the temperature elevation were inaccurate due to the short insonation period, but showed only a few-degree temperature rise. These anomalous results will be presented, along with additional data on HIFU hyperechogenicity, and a hypothesis given for the phenomenological origins of this effect.

We have investigated the use of ultrasound-based imaging to develop a non-invasive, safe and real-time method of guidance and monitoring for HIFU therapy. HIFU application was synchronized with the imaging frame rate to allow interference-free visualization of the region of interest. The regions treated with HIFU at intensities above the cavitation threshold appear immediately (within 30–60 ms) as hyperechoic structures in ultrasound images, confirmed to be due to microbubble activity at the focus. This HIFU dose is shown to produce minimal tissue damage, in the form of capillary rupture in an area of approximately 0.5 mm around the focus. The appearance of hyperechoic regions is potentially useful for pre-treatment targeting to ensure that the focus is located at the correct spot. The hyperechoic structures persist for 1–2 min, while the microbubbles still remain at the focus, before being absorbed. Microbubbles at the focus also provide a shield for HIFU, to prevent thermal damage of the healthy tissues located post-focally. Challenges of ultrasound-image-guided HIFU are in monitoring the tissue thermal behavior in and around the focus, and follow-up monitoring of tissues treated with HIFU. Ultrasound imaging is developing into a promising method for guidance of HIFU therapy.

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

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

There have been several recent reports that active sonar systems can lead to serious bioeffects in marine mammals, particularly beaked whales, resulting in strandings, and in some cases, to their deaths. We have devised a series of experiments to determine the potential role of low-frequency acoustic sources as a means to induce bubble nucleation and growth in supersaturated ex vivo bovine liver and kidney tissues, and blood. Bubble detection was achieved with a diagnostic ultrasound scanner. Under the conditions of this experiment, supersaturated tissues and blood led to extensive bubble production when exposed to short pulses of low frequency sound.

In therapeutic applications of biomedical ultrasound, it is important to understand the behavior of cavitation bubbles. Herein, the dynamics of a single, spherical bubble in water are modeled using the Gilmore equation closed by an energy balance on bubble contents for calculation of pressures inside the bubble. Moreover, heat and mass transfer at the bubble wall are incorporated using the Eller–Flynn zeroth-order approximation for gas diffusion, an estimation of non-equilibrium phase change based on the kinetic theory of gases, and assumed shapes for the spatial temperature distribution in the surrounding liquid. Bubble oscillations predicted by this model are investigated in response to a lithotripter shock wave. Model results indicate that vapor trapped inside the bubble during collapse plays a significant role in the afterbounce behavior and is sensitively dependent upon the ambient liquid temperature. Initial experiments have been conducted to quantify the afterbounce behavior of a single bubble as a function of ambient temperature; however, the results imply that many bubbles are present and collectively determine the collapse characteristics.

The goal of this work was to compare measured and numerically predicted HIFU pressure waveforms in water and a tissue-mimicking phantom. Waveforms were measured at the focus of a 2-MHz HIFU transducer with a fiber optic hydrophone. The transducer was operated with acoustic powers ranging from 2W to 300W. A KZK-type equation was used for modeling the experimental conditions. Strongly asymmetric nonlinear waves with peak positive pressure up to 80 MPa and peak negative pressure up to 20 MPa were measured in water, while waves up to 50 MPa peak positive pressure and 15 MPa peak negative pressure were measured in tissue phantoms. The values of peak negative pressure corresponded well with numerical simulations and were significantly smaller than predicted by linear extrapolation from low-level measurements. The values of peak positive pressures differed only at high levels of excitation where bandwidth limitations of the hydrophone failed to fully capture the predicted sharp shock fronts.

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

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.

In therapeutic applications of biomedical ultrasound, it is important to understand the behavior of cavitation bubbles. For applications that use high-intensity focused ultrasound (HIFU), both large negative acoustic pressures and heating can independently lead to bubble formation. Although neglected previously, heating during HIFU is expected to affect the growth and dissolution of bubbles by both raising the vapor pressure and promoting outgassing from gas-saturated tissues. Herein, the dynamics of a single, spherical bubble in water have been modeled using the Gilmore equation closed with an energy balance on bubble contents for calculation of pressures inside the bubble. Moreover, heat and mass transfer at the bubble wall are incorporated using the Eller–Flynn zeroth-order approximation for gas diffusion, an estimation of non-equilibrium phase change based on the kinetic theory of gases, and assumed shapes for the spatial temperature distribution in the surrounding liquid [Yasui, J. Phys. Soc. Jpn. 65, 2830-2840 (1996)]. This model allows explicit coupling of the ambient heating during HIFU to the thermodynamic state of an oscillating bubble and is currently being used to explore the growth rates of initially small, undetectable bubbles exposed to various HIFU treatment protocols.

The effects of nonlinear enhancement of focusing gain and saturation are studied and compared for high-intensity focused ultrasound sources with an initial Gaussian shading and uniform amplitude distribution. Simulations are performed using the Khokhlov Zabolotskaya (KZ) nonlinear parabolic equation for weakly dissipative medium in a wide range of source linear focusing gains and source pressure amplitudes, including the strongly nonlinear regime with shocks. An artificial absorption proportional to the fourth power of frequency or an asymptotic frequency-domain approach is employed in the algorithm in order to reduce the number of harmonics for accurate modeling of strongly distorted waveforms with shocks. The effect of focusing gain and amplitude shading of the source on nonlinear enhancement of acoustic energy concentration and saturation levels at the focus is discussed. It is shown that nonlinear enhancement of focusing gain is different for different values of linear gain, different spatial distributions of the source amplitude, and different parameters of acoustic field. The levels of nonlinear saturation at the focus are obtained for very high source amplitudes. The results of simulations give lower enhancement and higher saturation levels compared to the known approximate analytic predictions.

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

Classical acoustic streaming results when an acoustic field is absorbed in a liquid, and the resulting momentum transfer causes the liquid to be translated. Acoustic microstreaming results when a bubble or other compressible entity is caused to oscillate by an acoustic field and hydrodynamic flow is induced in the vicinity of the oscillating surface. Much of the pioneering work on this general topic was performed by Wesley Nyborg and his students at the University of Vermont. There are a number of conditions for which acoustic streaming can be useful in medical ultrasound; e.g., one can enhance diffusion rates of drugs by inducing streaming at a specific site in tissue; together with Doppler imaging, one can determine the consistency of a particular sample of fluid, such as a blood clot. These and other examples of the use of streaming in medical ultrasound will be presented.

A noncontact transport experiment in water using a traveling-wave-type linear motor was investigated. Acrylic disks were used as the floating objects. A vibrating plate was enclosed in acrylic plates, and a water tank was made that would allow the vibrating plate to be placed on the bottom. In order to propagate the traveling wave, two ultrasonic transducers were attached at both ends to the bottom of the vibrating plate. One side was used as the wave-sending side and the other side was used as the wave-receiving side. Comparing the transport experiments conducted in water with those conducted in air, the transport velocity becomes faster for floating transport in water than for floating transport in air. The occurrence of cavitation bubbles acts as a resistive force on the movement of the object being transported, and causes the transport velocity to be reduced. Transport velocity depends on the height of the water. If the height of the water surface is too shallow, the water surface freely deforms and the water surface forms bumpy standing waves, making it difficult for the object to be transported.

Acoustic properties of a vibro-acoustography system designed to detect kidney stones were measured. Our system was formed with two spherical transducers (10 cm diameter, 20 cm curvature) in degassed water that were confocal and separated by an angle of 30 degrees. They were driven at 1.1 MHz and 1.125 MHz to generate a difference frequency of 25 kHz. The acoustic field was characterized by scattering from a known target, the curved surface of a steel cylinder with 6.4 mm diameter. Waveforms of both the low and high frequency scattered signals were measured for different target locations, different hydrophone locations encircling the target, and different acoustic pressures. Focal dimensions of the –6 db pressure profile measured at 25 kHz and the fundamental were both 3 x 10 mm, in an elliptical shape, which is highly localized. Scatter amplitude was rather insensitive to hydrophone position when the target was in the focus, quite sensitive to hydrophone position when the target was out of the focus, and increased linearly with the sum of the sources. It is hoped that this characterization will help improve the understanding of the mechanisms of the targeting technique.

To determine efficacy of high intensity focused ultrasound (HIFU) in occlusion of pelvic vessels a 3.2 MHz HIFU transducer was synchronized with color-Doppler ultrasound imaging for real-time visualization of flow within blood vessels during HIFU therapy. HIFU was applied to pig and rabbit pelvic vessels in vivo, both transcutaneously and with skin removed. The in situ focal intensity was 4000 W/cm² on average. Vessel occlusion was confirmed by color or audio Doppler, and gross and histological observations. In rabbits, five out of 10 femoral arteries (diameter of 2 mm) were occluded after 30–60 s of HIFU application. The average blood flow reduction of 40% was observed in the remaining arteries. In pigs, out of 7 treated superficial femoral arteries (2 mm in diameter), 4 were occluded, one had 80% blood flow reduction, and 2 were patent. In addition, 3 out of 4 superficial femoral arteries, punctured with 18 gauge needle, were occluded after 60–90 s of HIFU application. Larger vessels (diameter of 4 mm) were patent after HIFU treatment. Doppler-guided HIFU has potential application in occlusion of injured pelvic vessels similar to angiographic embolization.

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.

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

Numerical simulations of focused acoustic beams are performed in water over a wide range of linear gains and source amplitudes, in order to demonstrate the combined effect of acoustic nonlinearity, diffraction, and focusing on extrapolation (derating) of the main parameters of high intensity acoustic fields at the focus from the linear theory. It is shown that nonlinear corrections to the focusing gain are different for different parameters of the acoustic field and for different values of the linear gain. Nonlinear enhancement of the focusing gain is found to be more pronounced for the peak positive pressure and for higher linear gains. The levels of nonlinear saturation for various parameters of the field at the focus are obtained for very high source amplitudes. The results of simulations give higher saturation levels compared to the approximate analytic predictions.

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.

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

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

The objective was to investigate the long-term efficacy of hemostasis and healing of arteries after HIFU application. The femoral arteries of 22 adult rabbits were surgically exposed. Fifteen arteries were punctured with a needle and treated with HIFU, and 7 arteries were sham-treated (no puncture or HIFU was applied). The tip of the HIFU applicator was positioned on the bleeding site, and HIFU energy was applied until hemostasis was achieved. The focal intensity was approximately 3,000 W/cm², at the resonant frequency of 9.6 MHz. Serial ultrasound images, blood and tissue samples were collected immediately and on days 1, 3, 7, 14, 28, and 60 after the treatment. Eleven of the arteries were patent after the treatment, and four arteries were occluded, as confirmed using Doppler imaging. One of the occluded arteries reopened at day 14. HIFU exposure time to achieve hemostasis was 27 ±17 seconds for patent arteries and 101 ± 38 seconds for the occluded arteries. The blood flow velocities were not statistically different between HIFU-treated patent vessels and sham-treated vessels. The tunica adventitia and media, disrupted and coagulated immediately after the treatment, recovered to normal appearance within 28 days, with localized thinning of the tunica media observed up to day 60. Neo-intimal hyperplasia was observed in the arteries at days 14 and 28. HIFU produced an effective and long-term (up to 60 days) hemostasis of injured femoral arteries while preserving a normal blood flow and vessel wall structure in the majority of vessels.

The persistence of acoustic cavitation in a pulsed wave ultrasound regime depends upon the ability of cavitation nuclei, i.e., bubbles, to survive the off time between pulses. Due to the dependence of bubble dissolution on surface tension, surface-active agents may affect the stability of bubbles against dissolution. In this study, measurements of bubble dissolution rates in solutions of the surface-active polymer poly(propyl acrylic acid) (PPAA) were conducted to test this premise. The surface activity of PPAA varies with solution pH and concentration of dissolved polymer molecules. The surface tension of PPAA solutions (55–72 dynes/cm) that associated with the polymer surface activity was measured using the Wilhelmy plate technique. Samples of these polymer solutions then were exposed to 1.1 MHz high intensity focused ultrasound, and the dissolution of bubbles created by inertial cavitation was monitored using an active cavitation detection scheme. Analysis of the pulse echo data demonstrated that bubble dissolution time was inversely proportional to the surface tension of the solution. Finally, comparison of the experimental results with dissolution times computed from the Epstein–Plesset equation suggests that the radii of residual bubbles from inertial cavitation increase as the surface tension decreases.

Our previous study showed that high-intensity focused ultrasound (HIFU) is capable of producing "primary acoustic hemostasis" in the form of ultrasound (US)-induced platelet activation, aggregation and adhesion to a collagen-coated surface. In the current study, 1.1 MHz continuous-wave HIFU was used to investigate the role of cavitation as a mechanism for platelet aggregation in samples of platelet-rich plasma. A 5 MHz passive cavitation detector was used to monitor cavitation activity and laser aggregometry was used to measure platelet aggregation. Using spatial average intensities from 0 to 3350 W/cm2, the effects of HIFU-induced cavitation on platelet aggregation were investigated by enhancing cavitation activity through use of US contrast agents and by limiting cavitation activity through use of an overpressure system. Our results show that increased cavitation activity lowers the intensity threshold to produce platelet aggregation and decreased cavitation activity in the overpressure system raises the intensity threshold for platelet aggregation.

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

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 intensity focused ultrasound (HIFU) can destroy tumors or stop internal bleeding. The primary physical mechanism in HIFU is the conversion of acoustic energy to heat, which as HIFU amplitude increases is enhanced by nonlinear acoustic propagation and nonlinear scattering from bubbles. The goal of this work is to study and separate the effects of nonlinear propagation and cavitation during HIFU heating of tissue. Transparent polyacrylamide gel was used as a tissue-mimicking phantom to visualize HIFU lesion growth. Lesion size was also measured in excised turkey breast. Lesions were produced by the same time-averaged intensity, but with different peak acoustic pressure amplitudes compensated by different duty cycles. In order to separate cavitation and nonlinear wave effects, experiments were performed under static pressure (10.34MPa) greater than the peak negative pressure amplitude of the sound waves (8.96MPa). Suppression of cavitation by overpressure was measured by reduced acoustic scattering and transmission loss in the treatment region. We found that, with the same time-averaged intensity, a shorter, higher amplitude wave created a larger lesion than a longer, lower amplitude wave with or without overpressure.

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

High-intensity, focused ultrasound (HIFU) applicators have been developed for arresting bleeding with the ultimate intent of use in surgery. The design uses a tapered titanium component for transmission coupling of the ultrasound energy from a spherically curved transducer to biological tissues. The nominal operating frequency is 5.5 MHz, in a highly resonant mode (quality factor of 327 with water load). Liquid cooling is used to remove energy loss important at net applied power greater than 18 W/cm² at the surface of the piezoelectric element. A downward resonance frequency shift (>20 kHz) occurs, even with cooling, as the applicator warms with normal operation. A feedback technique is used for maintaining the excitation near optimum resonance. Standing wave ratios of the applied power of 1.6 or less are thus sustained. The system and applicators have been found to be highly robust, effective in achieving hemostasis in the hemorrhaging liver, spleen, lung, or blood vessels in rabbit and pig experiments. One unit has been operated for over 1.7 hours in treating organ hemorrhage in blunt trauma experiments with nine swine with electrical net power of up to 158 W (31 W/cm² across the transducer) and intensity of 2560 W/cm² at focus.

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.

A hydrogel acoustic coupling medium was investigated as a practical alternative to water for clinical applications of focused ultrasound (US) therapy. Material characterization and functional testing of polyacrylamide gel couplers were performed. Acoustic, bulk and thermal properties were measured. Conical couplers were designed and fabricated to fit a 3.5-MHz, spherically concave transducer for functional tests, including Schlieren imaging, power efficiency measurements and in vivo hemostasis experiments. Polyacrylamide was shown to have favorable acoustic properties that varied linearly with acrylamide concentration from 10% to 20% weight in volume. Attenuation coefficient, sound speed and impedance ranged from 0.08 to 0.14 dB/cm at 1 MHz, 1546 to 1595 m/s and 1.58 to 1.68 Mrayl, respectively. An intraoperative in vivo hemostasis experiment in a sheep model demonstrated that the gel-coupled transducer was capable of inducing hemostasis in actively bleeding splenic and hepatic incisions. The results of this study show that polyacrylamide may be a promising coupling material for focused US therapy.

Lithotripsy is a common effective treatment for kidney stones. However, focal volumes are often larger than stones, and surrounding tissue is often injured. Our goal was to test in vitro a new lithotripter consisting of two opposing, confocal and simultaneously triggered electrohydraulic sources. The pulses superimpose at the common focus, resulting in pressure doubling and enhanced cavitation growth in a localized, ~ 1-cm wide volume. Model gypsum stones and human erythrocytes were exposed to dual pulses or single pulses. At the focus, model stones treated with 100 dual pulses at a charging voltage of 15 kV broke into 8 times the number of fragments as stones treated with 200 single pulses at 18 kV. At axial positions 2 and 4 cm away from the focus, lysis of erythrocytes was reduced or equivalent for dual pulses vs. single pulses. Hence, in half the time, dual pulses increased comminution at the focus without increasing injury in surrounding regions.

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

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

The ability to accurately track and monitor the progress of lesion formation during HIFU (High Intensity Focused Ultrasound) therapy is important for the success of HIFU-based treatment protocols. To aid in the development of algorithms for accurately targeting and monitoring formation of HIFU induced lesions, we have developed a software system to perform RF data acquisition during HIFU therapy using a commercially available clinical ultrasound scanner (ATL HDI 1000, Philips Medical Systems, Bothell, WA). The HDI 1000 scanner functions on a software dominant architecture, permitting straightforward external control of its operation and relatively easy access to quadrature demodulated RF data. A PC running a custom developed program sends control signals to the HIFU module via GPIB and to the HDI 1000 via Telnet, alternately interleaving HIFU exposures and RF frame acquisitions. The system was tested during experiments in which HIFU lesions were created in excised animal tissue. No crosstalk between the HIFU beam and the ultrasound imager was detected, thus demonstrating synchronization. Newly developed acquisition modes allow greater user control in setting the image geometry and scanline density, and enables high frame rate acquisition. This system facilitates rapid development of signal-processing based HIFU therapy monitoring algorithms and their implementation in image-guided thermal therapy systems. In addition, the HDI 1000 system can be easily customized for use with other emerging imaging modalities that require access to the RF data such as elastographic methods and new Doppler-based imaging and tissue characterization techniques.

The lesions generated by high intensity ultrasound were studied in transparent tissue phantoms premixed with and without ultrasound contrast agents (UCA) at 1.1- and 3.5-MHz acoustic waves. Generation of small bubbles was observed at the very beginning of exposure, whereas cigar-shaped thermal lesions began to form at the focus after a delay. After further heating, boiling occurred and changed the lesion to tadpole-shape, with advancement toward the transducer. Broadband noise was detected in phantoms with UCA initially. UCA also lowered the pressure threshold and enlarged the lesion. Although thermal and cavitation effects are believed to be both important in lesion formation, tadpole-shaped transformation results from boiling activity.

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.

The field of therapeutic ultrasound is emerging with strong potential and broad medical applications. Characterized by its ability to penetrate at depth inside the body without harming intervening tissue, ultrasound has posed the basis for a new array of noninvasive therapies. Al low intensities, important interactions occur in the tissue; wound healing is accelerated, functional recovery is enhanced, and bone growth is more rapid. At moderate intensities, cellular membranes show transient permeability, blood clots dissolution is increased, and gene-transfection is accomplished. At higher intensities, ultrasound produces lesions and stops bleeding by heating the tissue beyond its protein denaturalization threshold and thus provides a noninvasive, bloodless alternative to conventional surgery. This article presents a review of moderate and high intensity applications, including their mechanisms of action and the imaging modalities used for guidance and monitoring.

Recent interest in using High Intensity Focused Ultrasound (HIFU) for surgical applications such as hemostasis and tissue necrosis has stimulated the development of image-guided systems for non-invasive HIFU therapy. Seeking an all-ultrasound therapeutic modality, we have developed a clinical HIFU system comprising an integrated applicator that permits precisely registered HIFU therapy delivery and high quality ultrasound imaging using two separate arrays, a multi-channel signal generator and RF amplifier system, and a software program that provides the clinician with a graphical overlay of the ultrasound image and therapeutic protocol controls. Electronic phasing of a 32 element 2 MHz HIFU annular array allows adjusting the focus within the range of about 4 to 12 cm from the face. A central opening in the HIFU transducer permits mounting a commercial medical imaging scanhead (ATL P7-4) that is held in place within a special housing. This mechanical fixture ensures precise coaxial registration between the HIFU transducer and the image plane of the imaging probe. Recent enhancements include development of an acoustic lens using numerical simulations for use with a 5-element array. Our image-guided therapy system is very flexible and enables exploration of a variety of new HIFU therapy delivery and monitoring approaches in the search for safe, effective, and efficient treatment protocols.

Poly(propylacrylic acid) is a pH%u2010sensitive membrane disruptive polymer designed to release therapeutic molecules from endosomes to the cell cytoplasm before degradation. In mildly acidic environments, the polymer becomes more hydrophobic and less soluble in aqueous medium. Previous research has demonstrated the capacity of polyelectrolytes and therapeutic ultrasound to synergistically disrupt red blood cell membranes, resulting in hemolysis [Mourad (2000)]. In this investigation, the ability of therapeutic ultrasound and PPAA to disrupt cell membranes and deliver fluorescently labeled polymer to the cell cytoplasm was demonstrated. The ultrasound/polymer synergy was dependent upon the solubility of PPAA and acoustic cavitation activity. The solubility of PPAA in phosphate buffered saline was quantified by measuring variations in liquid/gas interfacial tension with polymer concentration and acidity. Reductions of surface tension up to 28% were measured using the Wilhemy plate technique. Acoustic cavitation activity was measured using a passive cavitation detection scheme, quantified, and correlated with the number of fluorescent cells. This study demonstrates the potential of combining therapeutic ultrasound and membrane%u2010disruptive polymers for drug delivery.

Natural kidney stones are heterogeneous in structure, composition, material properties and fragility, and as such are problematic for use in determining the mechanisms of SW-action in SWL. A variety of model stones have been developed. We have adopted Ultracal-30 gypsum [Dahake and Gracewski, J. Acoust. Soc. Am. 102, 2138 (1997)] for in vitro and in vivo studies. U-30 stones (7.5x6.5 mm) cast in polystyrene molds were liberated with chloroform and stored in water. Drop-impact testing of dry stones showed a linear relationship between increase in surface area of fragments and energy applied. Breakage of hydrated stones in a research-electrohydraulic lithotripter, likewise showed a linear increase in fragment area with increased SW number and SW voltage. The density (1800 kg/m³) and transverse (1520 m/s) and longitudinal (3100 m/s) wave speeds of U-30 stones place them in the range determined for natural stones. U-30 stones implanted in pig kidneys exhibited cavitation erosion and spall fracture similar to stones in vitro, and U-30 stones in vitro and in vivo showed equivalent response to SW rate (200% higher fragmentation at 0.5 Hz compared to 2 Hz). U-30 stones softened with prolonged exposure to water and degraded during long-term implantation in vivo. With these caveats U-30 stones provide a useful model for SWL research.

An initial prototype design for a cavitation probe that uses the property of a collapsing cavitation bubble to produce visible photons (sonoluminescence) has been designed and constructed. These light emissions can be easily detected within a small, finite volume and thus this probe provides a direct means of measuring the cavitation density (activity/per unit volume) within a cavitating fluid and the delivery of ultrasonic energy at an engineered surface. As a result, ultrasonic methods treating a surface can be directly monitored and controlled in real-time, leading to the ability to improve and predict the performance of the resulting structure. This probe provides the potential for constructing a real-time monitor of ultrasonic/megasonic cleaner efficiency and effectiveness. In addition, because the entire three-dimensional cavitation field can be measured with this probe, it can also serve as a useful tool in ultrasonic/megasonic cleaner design. A real-time cavitation-density measuring device would have great utility in the semiconductor cleaning industry and thus this probe provides considerable promise for commercial development. A description of the probe will be presented as well as some preliminary data on cavitation density within a commercial megasonic cleaner.

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

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.

Peak acoustic pressures and cavitation generated in shock wave lithotripsy (SWL) appear to contribute to both desired stone comminution and undesired injury to surrounding renal tissue. Our dual pulse system, comprised of two opposing, confocal lithotripters and generating simultaneous, converging shock pulses, localizes and intensifies the peak pressures and cavitation. Comparison of cavitation damage to aluminum foil shows an 8-cm stripe of pits produced by a single pulse lithotripter and a 1-cm stripe of deep pits produced by the dual pulse lithotripter. 100 dual pulses generated at 15 kV comminuted gypsum stones placed at the geometric focus F2 into 8 times as many fragments and significantly reduced hemolysis in dilute blood 2 and 4 cm off F2 when compared to 200 single pulses generated at 18 kV. Thus the dual pulse lithotripter enhanced comminution and reduced injury while cutting treatment time in half. Additionally, when cavitation was suppressed by placing the stones in glycerol, the improvement in comminution was reduced to only a twofold increase. This result indicates that the localized and intensified cavitation is the dominant mechanism in the accelerated comminution produced by the dual pulse lithotripter.

A numerical solution of the KZK-type parabolic nonlinear evolution equation is presented for finite-amplitude sound beams radiated by rectangular sources. The initial acoustic waveform is a short tone burst, similar to those used in diagnostic ultrasound. The generation of higher harmonic components and their spatial structure are investigated for media similar to tissue with various frequency dependent absorption properties. Nonlinear propagation in a thermoviscous fluid with a quadratic frequency law of absorption is compared to that in tissue with a nearly linear frequency law of absorption. The algorithm is based on that originally developed by Lee and Hamilton [J. Acoust. Soc. Am. 97, 906-917 (1995)] to model circular sources. The algorithm is generalized for two-dimensional sources without axial symmetry. The diffraction integral is adapted in the time-domain for two dimensions with the implicit backward finite difference (IBFD) scheme in the nearfield and with the alternate direction implicit (ADI) method at longer distances. Arbitrary frequency dependence of absorption is included in this model and solved in the frequency-domain using the FFT technique. The results of simulation may be used to better understand the nonlinear beam structure for tissue harmonic imaging in modern medical diagnostic scanners.

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.

In thoracic surgery, bleeding and air leaks from the lungs can be difficult to control. We have investigated the use of high intensity focused ultrasound (HIFU) for control of lung bleeding and air leaks in operative situations. An intraoperative HIFU device, equipped with a Titanium coupler, was used. The HIFU transducer was a PZT-8 concave element, with a focal length of 5 cm, and a diameter of 2.5 cm. The transducer was operated at 5.7 MHz and intensity of 5000 W/cm². The coupler length was 4 cm, placing the focal volume, defined by full-width half-maximum at approximately 1 cm from the tip of the coupler. A pig animal model was used. Incisions in the lung were made, having lengths of 2–5 cm, and depths of 3–10 mm which created both parenchymal hemorrhage and air leakage from the lung. HIFU was applied within 10 seconds of inducing the injury. The average hemostasis time was approximately 60 seconds. All incisions were completely sealed, and no blood or air leaked from the incisions. Intraoperative HIFU may provide an effective method in various pulmonary surgery indications, and hemostasis and control of air leaks from lacerations due to trauma.

Several strategies were used to assess the importance of cavitation in the breakage of stones by an electrohydraulic lithotripter in vitro. (1) Stones exposed to SWs at atmospheric pressure broke readily. However, stones treated at high overpressure (OP~125%u2009atm) sufficient to eliminate cavitation did not break into fragments even with twice the number of SWs. Stones at OP did, however, develop transverse fractures typical of spall. This suggests that cavitation contributes to stone fragmentation, but is clearly not the only mechanism involved in stone breakage. (2) Cylindrical model stones positioned vertically in the acoustic field of a research%u2010EHL showed proximal erosion and spall. However, placement of a mylar disk against the flat leading face of the stone eliminated cavitation%u2010erosion, and spall did not occur. This suggests that cavitation may contribute to stone fracture by spall. (3) Time reversal of the lithotripter wave form using a pressure release reflector (Prel) also prevented stone fragmentation. With the Prel insert the tensile phase of the SW preceding the compressive wave bubble growth is interrupted by P and, thus, cavitation is suppressed. Together, these results suggest that cavitation plays an important role in the breakage of stones by lithotripter shock waves.

High intensity focused ultrasound (HIFU) can necrose tumors or cauterize tissue bleeds at intensities on the order of 1000 w/cm². A synchronized HIFU and B-mode ultrasound system reveals a hyperechoic region at the treatment site, which grows with treatment duration and intensity. Our goal was to segment the hyperechoic region representing the lesion via image analysis and measure the ratio of its major and minor axes. Our algorithm uses the RF data as input, processes it, and outputs a binary image that represents the lesions cross-sectional profile. With depth settings from the clinical ultrasound imager, it is possible to calculate lesion dimensions from the binary image. The algorithm was tested with lesions made in a transparent polyacrylamide tissue phantom that became opaque in response to focal heating during HIFU exposure. Lesion size was recorded simultaneously with ultrasound and a CCD camera, and both measurements agreed well. Additionally, computer segmentation agreed well with segmentation by HIFU users blinded to the experimental conditions. The average difference of the determined ratio was 13% for lesions less than 0.5 cm in length. Thus, it is possible to localize precisely the treated tissue region.

Cavitation is an effective physical mechanism for concentrating mechanical energy. Accordingly, it has wide applications in such diverse fields as sonochemistry, in which chemical reactions are initiated or accelerated, or in the electronic component cleaning industry in which particles (and other materials) are removed from surfaces. However, devices designed to act as cavitation monitors have had little success, partly because their intrusiveness often affects the cavitation field itself. Presented here is a brief description of a unique cavitation monitor that utilizes the phenomenon of sonoluminescence as an indirect quantifier of cavitation. It appears to work efficiently over a broad range of acoustic field intensities and its application to megasonic cleaning has provided interesting and valuable insights into this technology.

Sonoluminescence and sonochemistry from a cavitation field generated by an electrohydraulic shock-wave lithotripter were investigated as functions of spark discharge voltage (13 to 21 kV) and pulse-repetition frequency (PRF) (0.5 to 2.0 Hz). Sonochemical activity, measured with an iodide dosimeter, increased with both voltage and PRF. Sonoluminescence was measured in an acoustically matched light-tight box. The envelope of the light intensity was measured in a temporally gated region extending from the initial arrival of the shock wave (resulting in bubble compression) to the final inertial collapse of the bubble cloud, which follows hundreds of micros after passage of the shock wave. The initial compression resulted in greater sonoluminescence emissions, suggesting that the initial bubble compression due to the leading positive pressure spike from the lithotripter generated higher temperatures than the inertial collapse of the bubble. These unexpected results are consistent with some recent calculations in which the vapor pressure of the liquid limits compressional heating.

Quantitative studies of the correlation between sonochemical activity and acoustical noise spectra have been performed. The width of the second harmonic (fwhm2) of the acoustical signal in the frequency domain shows a sensitive dependence to the presence of small amounts (mM range) of an anionic surfactant in water. This sensitive dependence is also observed for other characteristics of the cavitation noise spectrum and in the sonochemical production of peroxides and correlates well with the sonoluminescence intensity observed by other researchers. Analysis of the experimental data shows that SDS probably modifies the coalescence phenomena.

The destruction process of biSphere and Optison ultrasound (US) contrast microbubbles were studied at 1.1 MHz. High-amplitude tone bursts caused shell disruption and/or fragmentation of the microbubbles, leading to dissolution of the freed gas. The bubble destruction and subsequent dissolution process was imaged with a high pulse-repetition frequency (PRF) 10-cycle, 5-MHz bistatic transducer configuration. Three types of dissolution profiles were measured: In one case, biSphere microbubbles showed evidence of dissolution through resonance, during which a temporary increase in the scattering amplitude was observed. In another case, both biSphere and Optison microbubbles showed evidence of fragmentation, during which the scattering amplitude decreased rapidly. Finally, in some cases, we observed the impulsive growth and subsequent rapid decay of signals that appear to be due to cavitation nucleation. Simulations of bubble dissolution curves show good agreement with experiments.

High-intensity focused ultrasound (HIFU) has been shown to generate lesions that destroy brain tissue while disrupting the blood-brain barrier (BBB) in the periphery of the lesion. BBB opening, however, has not been shown without damage, and the mechanisms by which HIFU induces BBB disruption remain unknown. We show that HIFU is capable of reversible, nondestructive, BBB disruption in a targeted region-of-interest (ROI) (29 of 55 applications; 26 of 55 applications showed no effect); this opening reverses after 72 h. Light microscopy demonstrates that HIFU either entirely preserves brain architecture while opening the BBB (18 of 29 applications), or generates tissue damage in a small volume within the region of BBB opening (11 of 29 applications). Electron microscopy supports these observations and suggests that HIFU disrupts the BBB by opening capillary endothelial cell tight junctions, an isolated ultrastructural effect that is different from the mechanisms through which other (untargeted) modalities, such as hyperosmotic solutions, hyperthermia and percussive injury disrupt the BBB.

Acoustic streaming may have practical utility in diagnostic medical ultrasound in distinguishing between stagnant blood and tissue as well as clotted and unclotted blood. This distinction can be difficult with conventional ultrasound but have high value in managing trauma patients with internal hemorrhage. Ultrasound energy applies a force to blood by momentum transfer, resulting in bulk streaming that is a function of the acoustic attenuation, sound speed, acoustic intensity, blood viscosity, and the boundary conditions posed by the geometry around the hematoma. A simple tubular model was studied analytically, by finite element simulation, and experimentally by in vitro measurement. The simulation agreed closely with measurements while the analytic solutions were found to be valid only for beam diameters approximating the diameter of the tubular channel. Experimentally, the acoustic streaming in blood decreased as the blood began to clot and the streaming flow was not detected in clotted blood. In contrast, the echogenicity of the same blood samples did not change appreciably from the unclotted to the clotted state for the stagnant blood studied. Streaming detection appears to offer a potential tool for improving hemorrhage diagnosis.

Recent success in using high-intensity focused ultrasound (HIFU) for surgical applications has stimulated the development of image-guided systems for noninvasive therapy. With the goal of developing an all ultrasound modality, we have developed a clinical HIFU system comprising an integrated transducer probe that permits precisely registered HIFU therapy delivery and high-quality ultrasound imaging, a multi-channel signal generator and rf amplifier system, and a software program that provides the clinician with a graphical overlay of the ultrasound image and therapeutic protocol controls. Electronic phasing of the 2-MHz HIFU annular array allows adjusting the focus within the range of about 4–12 cm from the face. A central opening in the transducer permits mounting of a commercial medical imaging scanhead (ATL P7-4) that is held in place within a special housing. This mechanical fixture ensures precise registration between the HIFU transducer axis and the image plane of the imaging probe. We will present a description of the various system components along with experimental in vitro results of therapy targeting and lesion visualization.

Using platelet-rich plasma, we investigated the effect of 1.1-MHz continuous wave high-intensity focused ultrasound (HIFU) on platelet activation, aggregation and adhesion to a collagen-coated surface. Platelets were exposed for durations of 10-500 s at spatial average intensities of up to 4860 W/cm². To avoid heating effects, the average temperature in the HIFU tank was maintained at 33.8 ± 4.0 degrees C during platelet experiments. Flow cytometry, laser aggregometry, environmental scanning electron microscopy and passive cavitation detection were used to observe and to quantify platelet activation, aggregation, adhesion to a collagen-coated surface and associated cavitation. It was determined that HIFU can activate platelets, stimulate them to aggregate and promote their adherence to a collagen-coated surface. In principle, HIFU can stimulate primary, or platelet-related, hemostasis. Cavitation was monitored by a passive cavitation detector during aggregation trials and was quantified to provide a relative measure of the amount of cavitation that occurred in each aggregation trial. Regression analysis shows a weak correlation (r² = 0.11) between aggregation and ultrasound intensity, but a substantial correlation (r² = 0.76) between aggregation and cavitation occurrence.

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.

Dual pulses, generated by opposing, confocal, and simultaneously triggered electrohydraulic shock wave sources, can be used to localize and intensify cavitation for application to lithotripsy. It has been reported that the dual-pulse lithotripter (DPL) may be a safer and more effective lithotripter [Sokolov et al., J. Acoust. Soc. Am. 100 (2001)]. Fragmentation of cement stones and hemolysis in dilute suspensions of human red blood cells were assessed at several positions along the focal axis of the DPL. Pulse repetition frequency was varied from 0.5 to 2 Hz and charging voltage was varied from 12 to 20 kV. At 1 Hz and 15 kV, the number of stone fragments > 1.5 mm, at the focus, remained the same while hemolysis, 2 cm away, decreased by one-half, when compared to the conventional lithotripter at the same PRF and a higher voltage of 18 kV. By varying PRF and voltage, an optimal in vitro protocol for shock wave delivery that maximizes stone fragmentation at the focus and minimizes hemolysis away from the focus might be determined. Results support the hypothesis that cavitation plays a more significant role than shock waves in both stone fragmentation and cell damage in the dual-pulse lithotripter.

Clinical diagnostic ultrasound (US) can be used to target and to monitor in real-time high-intensity focused ultrasound (HIFU) therapy. In our system, the HIFU transducer (3.5 MHz, 35 mm aperture, 55 mm radius of curvature) and US scan head (several were tested, center frequencies 3–8 MHz) are fixed with the HIFU focus in the imaging plane. HIFU and US are either synchronized real time to relegate interference to the image fringe or HIFU and US are interlaced for nearly real-time imaging. HIFU produces a localized hyperechoic region visible on B-mode US. Coagulatively necrosed lesions produced have similar size, shape, and location to measurements made from the corresponding US images. Thresholds are also comparable. However, in vivo, if HIFU is turned off as soon as hyperecho appears, no lesion is seen (the tissue was fixed within four hours of treatment). Thus, a short HIFU burst can be used to target treatment. Bubbles appear to be largely but perhaps not entirely responsible for the increase in echogenicity. Times for dissipation of the hyperecho and dissolution of a bubble as a function of hydrostatic pressure compare well. Significant overpressure (50 bar) can suppress hyperecho produced by HIFU.

Noninvasive ultrasound has been shown to increase the release rate on demand from drug delivery systems; however, such systems generally suffer from background drug leaching. To address this issue, a drug-containing polymeric monolith coated with a novel ultrasound-responsive coating was developed. A self-assembled molecular structure coating based on relatively impermeable, ordered methylene chains forms an ultrasound-activated on-off switch in controlling drug release on demand, while keeping the drug inside the polymer carrier in the absence of ultrasound. The orderly structure and molecular orientation of these C12 n-alkyl methylene chains on polymeric surfaces resemble self-assembled monolayers on gold. Their preparation and characterization have been published recently (Kwok et al. [Biomacromolecules 2000;1(1):139-148]). Ultrasound release studies showed that a copolymer of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (MW 400) coated with such an ultrasound-responsive membrane maintained sufficient insulin for multiple insulin delivery, compared with a substantial burst release during the first 2 h from uncoated samples. With appropriate surface coating coverage, the background leach rate can be precisely controlled. The biological activity of the insulin releasate was tested by assessing its ability to regulate [C14]-deoxyglucose uptake in 3T3-L1 adipocyte cells in a controlled cell culture environment. Uptake triggered by released insulin was comparable to that of the positive insulin control. The data demonstrate that the released insulin remains active even after the insulin had been exposed to matrix synthesis and the methylene chain coating process.

A technique that utilizes light-scattering from a low-powered laser to probe ultrasound contrast agents is described. A He-Ne laser illuminates the focal zone of a high-intensity focused ultrasound (HIFU) source operating at 1.1 MHz. A focusing lens is used to collect the scattered light from bubbles in the focal region, focusing the scattered light onto a photodetector. During application of the HIFU source, the bubbles oscillate, and the resulting fluctuation in the light-scattering signal is detected by the photodetector. Measurements of the light fluctuation can be correlated with bubble activity, especially inertial cavitation. A description of the technique, and preliminary results of measurements with ultrasound contrast agents are shown.

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.

The acoustic signal from the sonochemical production of H₂O₂ in water, as measured by the intensity and the width of the second harmonic, show a sensitive and correlated dependence to the presence of small amounts (millimolar range) of an anionic surfactant (SDS) in water. The graphic shows the link from the ultrasonic reaction to the measurable quantities. New possibilities to reliably control such processes is therefore opened.

Accurate differentiation between stagnant blood and soft tissue or clotted and unclotted blood has potential value in managing trauma patients with internal hemorrhage. Determination by regular ultrasound (US) imaging is sometimes difficult because the sonographic appearance of blood, clots and soft tissue may be similar. A hematoma model was developed to investigate the use of acoustic streaming for hematoma diagnosis in an in vivo environment. The results showed that a derated spatial peak temporal average (SPTA) intensity of 30 W/cm² was needed to generate color-Doppler-detectable streaming in stirred blood. The streaming velocity increased in proportion to the derated intensity. Streaming was also detected in stagnant blood, but at higher intensities. In clots, streaming was not detected even at high intensities. The streaming detection may be a valuable tool for improving the distinction between liquid blood and clots or soft tissue in hematoma diagnosis.

Localizing cavitation to the kidney stone in extracorporeal shock wave lithotripsy may be desirable since cavitation appears to play a major role in both stone comminution and renal tissue damage. A method has been developed to localize and intensify cavitation damage in vitro. Cavitation fields in water were filmed with a high-speed digital video camera. In a conventional lithotripter (CL), the shock wave produced by a single source creates a 2x10 cm cylindrical cloud of bubbles in water. Bubbles in the CL field collapse simultaneously along the focal axis to produce a nearly uniform 1-mm x 8-cm line of pits in 25-µm-thick aluminum foil. Our dual-pulse lithotripter (DPL) uses two shock wave sources, facing each other, confocal, and triggered simultaneously to create a 4x5 cm cylindrical cloud of bubbles that collapse over a range of times and strengths such that the greatest pit damage on foils is contained within a few square millimeters of the focus. The time for bubbles to grow and collapse was measured with a focused hydrophone and compared with calculations based on the Gilmore equation. Pressure doubling due to synchronous arrival of the two pulses at the focus created increased bubble growth and increased foil pit depth. Asynchronous timing between the two pulses elsewhere in the DPL field resulted in disruption of radial dynamics and negligible pitting to foils. Translation of bubbles was also investigated, both numerically and experimentally. While net translation was calculated to be <0.3 mm in all cases, the rapid acceleration of bubbles in a small region may contribute to their premature destruction in that region. Overall, radial dynamics were found to be largely responsible for the observed pattern of cavitation in the dual-pulse lithotripsy field.

The potential role of therapeutic ultrasound in medicine is promising. Currently, medical devices are being developed that utilize high-intensity focused ultrasound as a noninvasive method to treat tumors and to stop bleeding (hemostasis). The primary advantage of ultrasound that lends the technique so readily to use in noninvasive therapy is its ability to penetrate deep into the body and deliver to a specific site thermal or mechanical energy with submillimeter accuracy. Realizing the full potential of acoustic therapy, however, requires precise targeting and monitoring. Fortunately, several imaging modalities can be utilized for this purpose, thus leading to the concept of image-guided acoustic therapy. This article presents a review of high-intensity focused ultrasound therapy, including its mechanisms of action, the imaging modalities used for guidance and monitoring, some current applications, and the requirements and technology associated with this exciting and promising field.

Comparisons of light emissions from multibubble and single-bubble sonoluminescence in the near-infrared band extending from 800 to 1050 nm have been investigated. In argon-water mixtures, single-bubble and multibubble spectra are similar in appearance. In sodium chloride-water mixtures, the multibubble spectrum shows evidence of the 3d-3p sodium emission line, whereas the single-bubble spectrum shows no such emission. For single bubbles, the near-infrared emissions change linearly with driving pressure. No evidence of near-infrared emissions are observed below the visible luminescence threshold.

Acoustic hemostasis is a new field of ultrasound research in which high intensity focused ultrasound (HIFU) is used to induce hemostasis in actively bleeding, injured solid organs and blood vessels. In animal studies, moderate to profuse bleeding from parenchymal and vascular injuries has been arrested within approximately 1 minute of HIFU application, even when a large dose of heparin was administered. Moreover, acoustic hemostasis has shown promise in cauterizing large regions of liver, providing a method for bloodless resectioning of abnormal tissue. Two distinct physical mechanisms of HIFU appear to contribute to hemostasis: (1) a thermal mechanism in which absorption of sound leads to temperature elevations, and (2) mechanical mechanisms (acoustic cavitation) in which gas and vapor-filled voids oscillate with large displacement amplitudes. While the thermal mechanism results in a temperature increase in excess of 70 degrees C in about 1 second, the mechanical mechanism appears to result in structural disruption of tissue and possible release of coagulation-inducing tissue factors. Of utmost importance in further development of HIFU as a clinical tool is targeting and monitoring of the HIFU treatment. We have obtained initial success in integrating HIFU with ultrasound imaging so as to develop an image-guided therapy system. Image-guided acoustic hemostasis may provide a valuable method of hemostasis in surgical and prehospital settings with applications in trauma and elective surgery.

High-intensity focused ultrasound (HIFU) is becoming a widely accepted and "clean" modality to induce noninvasive coagulative necrosis of biological tissue for both cancer treatment and hemostasis. Theoretical predictions via the medusa (medical ultrasound algorithm) computer model of ultrasonic fields, temperature responses, and lesion dynamics are simulated for turkey breast. The model accounts for nonlinear sound propagation in inhomogeneous media, arbitrary frequency power law for acoustic attenuation, and temperature and lesion time histories. Generation of gas bubbles within the tissue may also be considered. Results are presented in terms of a comparison study with in vitro experiments on common turkey breast. Attention is mainly focused on temperature and lesion evolutions; in particular, induced lesion boundaries and collateral damage to surrounding areas.

Our previous studies showed that high-intensity focused ultrasound (HIFU) is capable of producing "primary acoustic hemostasis" in the form of platelet activation, aggregation, and adhesion to a collagen-coated surface. In current studies, 1.1 MHz CW HIFU was used to investigate the role of cavitation as a mechanism for platelet aggregation in samples of platelet rich plasma. A 5 MHz passive cavitation detector was used to monitor cavitation activity, and laser aggregometry was used to measure platelet aggregation. Using spatial average intensities from 0 to 4000 W/cm², the effects of HIFU induced cavitation on platelet aggregation were investigated by enhancing cavitation activity through use of ultrasound contrast agents, and by limiting cavitation activity through use of an overpressure system. Our results show that increased cavitation activity lowers the intensity threshold to produce platelet aggregation, and decreased cavitation activity in the overpressure system raises the intensity threshold for platelet aggregation.

Axonal injury in the peripheral nervous system is common, and often it is associated with severe long-term personal and societal costs. The objective of this study is to use an animal model to demonstrate that transcutaneous ultrasound can accelerate recovery from an axonotmetic injury.

The sciatic nerve of adult male Lewis rats was crushed in the right midthigh to cause complete distal degeneration of axons yet maintain continuity of the nerve. Beginning 3 days after surgery, various transcutaneous ultrasound treatments or sham treatments were applied 3 days per week for 30 days to the crush site of rats that were randomly assigned to two groups. In the preliminary experiments, there were three animals in each ultrasound group and two control animals. In the final experiment, there were 22 animals in the ultrasound group and 20 animals in the control group. Recovery was assessed by use of a toe spread assay to quantify a return to normal foot function in the injured leg. Equipment included a hand-held transducer that emitted continuous-wave ultrasound. The most successful ultrasound protocol had a spatial peak, time-averaged intensity of 0.25 W/cm² operated at 2.25 MHz for 1 minute per application.

Rats subjected to the most successful ultrasound protocol showed a statistically significant acceleration of foot function recovery starting 14 days after injury versus 18 days for the control group. Full recovery by the ultrasound group occurred before full recovery by the control group.

Transcutaneous ultrasound applied to an animal model of axonotmetic injury accelerated recovery. Future studies should focus on identification of the mechanism(s) by which ultrasound creates this effect, as a prelude to optimization of the protocol, demonstration of its safety, and its eventual application to humans.

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.

Improved high-intensity focused ultrasound (HIFU) surgical applicators are required for use in a surgical environment. We report on the performance and characteristics of a new solid-cone HIFU applicator. Previous HIFU devices used a water-filled stand-off to couple the ultrasonic energy from the transducer to the treatment area. The new applicator uses a spherically-focused element and a solid aluminum cone to guide and couple the ultrasound to the tissue. Compared with the water-filled applicators, this new applicator is simpler to set up and manipulate, cannot leak, prevents the possibility of cavitation within the coupling device, and is much easier to sterilize and maintain during surgery. The design minimizes losses caused by shear wave conversion found in tapered solid acoustic velocity transformers operated at high frequencies. Computer simulations predicted good transfer of longitudinal waves. Impedance measurements, beam plots, Schlieren images, and force balance measurements verified strong focusing and suitable transfer of acoustic energy into water. At the focus, the -3 dB beam dimensions are 1.2 mm (axial) x 0.3 mm (transverse). Radiation force balance measurements indicate a power transfer efficiency of 40%. In vitro and in vivo tissue experiments confirmed the applicator's ability to produce hemostasis.

Stabilized microbubbles used as echo-contrast agents can be destroyed by ultrasonic irradiation. We have identified two pressure thresholds at which these microbubbles undergo inertial cavitation (here, defined as the collapse of gas bubbles followed by emission of an acoustic broadband noise). The first threshold (P1) corresponds to the pressure at which all the microbubbles in a cavitation field lose their property as an effective scatterer because of fragmentation or deflation. The second threshold (P2) is associated with the acoustic reactivation of the remnants of the contrast agents and is related to the onset of more violent inertial cavitation. P1 and P2 were measured as a function of the concentration of Albunex(R) (Molecular Biosystems Inc., San Diego, CA) contrast agent, the number of transmitting acoustic cycles, and the pulse repetition frequency (PRF). The ultrasound frequency used was 1.1 MHz, and the peak negative acoustic pressures ranged from 0 to 8 MPa. Our results, measured in Isoton(R) II (Coulter Diagnostics, Miami, FL) and whole blood solutions, showed that P1 increased with increasing Albunex(R) concentration and decreased with increasing PRF, whereas P2 decreased with increasing Albunex(R) concentration and was independent of the PRF. Both P1 and P2 decreased with increasing number of acoustic cycles N for N<10 and were independent of the number of cycles for N>10. Ultrasound images of Albunex(R) acquired by a commercial scanner showed echo enhancement not only at pressure levels below P1 but also at levels above P2. The threshold P2 was achieved at ultrasound energies above the diagnostic level. Inertial cavitation produced at P2 was associated with a higher level of hemolysis compared with P1. The results of this investigation have potential significance for both diagnostic and therapeutic ultrasound applications.

An electrohydraulic lithotripter uses an ellipsoidal reflector to focus shock waves on to a kidney stone. The shock wave generates a cylindrical cavitation field, ~1-cm wide x 10-cm long, that has been implicated in both stone fragmentation and damage to healthy tissue during lithotripsy treatment. A dual-reflector lithotripter, consisting of two identical spark-gap lithotripters facing each other and firing simultaneously, creates a more localized cavitation field, ~3 cm wide x 5 cm long (Sokolov, Berlin 1999). Such a field may increase the rate of stone fragmentation while mitigating damage to surrounding tissue. Breakage of model stones at the focus and hemolysis of red blood cells 3 cm from the focus were assessed for both conventional lithotripsy (CL) and dual-reflector lithotripsy (DRL). To equalize total energy input, the number of shots was halved from CL to DRL. Stones subjected to DRL were broken into several major fragments while stones subjected to CL remained intact except for some dust. Human blood was diluted to 3% hematocrit in degassed PBS and placed in acoustically transparent sample tubes. There was no statistical difference in percent hemolysis between CL (5.12±1.01%) and DRL (5.39±0.57%).

In previous studies, we have shown that membrane-disrupting polymers may also act as cavitation promoters. These polymers are designed to efficiently disrupt red blood cells in a pH-dependent fashion (Murthy et al.). When combined with high-intensity focused ultrasound (HIFU), there is a noted increase in relative cavitation activity and a corresponding increase in red blood cell lysis. Varying the chemical composition of the polymer (length of hydrocarbon chains, molecular weight, etc.) modifies the hemolytic and cavitation-promoting activity of the polymer. For example, the hemolytic and cavitation promoting activity of poly(ethyl acrylic acid) (PEAAc) rises as the pH of the solvent decreases from 7.4 to 6.1. However, the polymer poly(propyl acrylic acid) (PPAAc), which has a more hydrophobic pendant alkyl group, promotes cavitation and, therefore, hemolysis at a pH of 5.0, 6.1, and 7.4. Variations in the polymer molecular weight change the number of hydrophobic regions which also alters the hemolytic and cavitation activity. From these results, polymers may be designed which, when combined with ultrasound, optimize drug transport across cell membranes in a pH-dependent or -independent manner.

Using platelet-rich plasma, we investigated the capability of 1.1-MHz cw high-intensity focused ultrasound (HIFU) to produce "acoustic primary hemostasis," including platelet activation, aggregation, and adhesion to a collagen-coated surface. Platelet activity was evaluated for exposure durations of 100–500 s at intensities of 0–2250 W/cm². In order to avoid heating effects, temperatures in platelet trials were maintained below 42°C through use of a tank cooling system and control of exposure parameters. Flow cytometry, laser aggregometry, conventional microscopy, environmental scanning electron microscopy, and passive cavitation detection were used to quantify platelet activation, aggregation, adhesion, and associated cavitation. HIFU can activate platelets and cause them to adhere to a collagen-coated surface. Cavitation was monitored during aggregation trials and was quantified to provide a relative measure of the amount of cavitation that occurred in each aggregation trial. Regression analysis shows weak correlation between aggregation and intensity, and a strong correlation between aggregation and cavitation occurrence.

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.

Biomedical ultrasound has seen remarkable advances in recent years. By utilizing the properties of nonlinear acoustics, diagnostic ultrasound has shown increased applicability to a wide number of clinical conditions and pathologies. Techniques such as harmonic imaging and the use of ultrasound contrast agents (stabilized microbubbles) have enabled such long-sought goals as noninvasive determination of myocardial perfusion to be clearly within our grasp. Advancements in semiconductor miniaturization have led to the construction of ultrasonic scanners that are now hand-held, and together with telemedicine techniques, it is now reasonable to expect that diagnostic ultrasound will soon be the doctor's stethoscope. An even more promising future is seen for therapeutic ultrasound. Although the mechanism is not yet clearly understood, ultrasound can transiently permeabilize cell membranes, thus permitting the delivery of therapy to specific sites within the body; indeed, together with drug-carrying ultrasound contrast agents, "site-specific drug delivery" is now in clinical trials. Finally, the application of High Intensity Focused Ultrasound can induce coagulative necrosis at well-controlled sites within tissue. When imaging and therapy are combined, "image-guided, transcutaneous, bloodless surgery" devices are now under development. With acoustics, "Star Trek medicine"is just around the corner.

Ultrasound has been used for decades as a means for noninvasive treatment of diseases. Low-intensity ultrasound is routinely applied in physical therapy for muscular and neurological related illnesses. In contrast, high-intensity focused ultrasound (HIFU) is used to induce coagulative necrosis of tissue for cancer treatment or hemostasis. Our efforts concern the latter. Predictions of ultrasound fields, temperature response, and lesion dynamics are obtained by a model which accounts for nonlinear sound propagation in inhomogeneous media, an arbitrary frequency power law for acoustic attenuation, and temperature time history [J. Acoust. Soc. Am. 107, No. 5, Pt. 2 (2000)]. The model is expanded from its previous version to include attenuation and sound speed dependence on temperature levels and also to consider generation of gas bubbles within the tissue. Results are presented in terms of treatment strategies that provide maximum energy transfer for coagulating the targeted tissue while minimizing damage to the surrounding area.

High intensity focused ultrasound (HIFU) is being considered as a noninvasive method to halt internal bleeding, thus we investigated the capability of HIFU to produce "acoustic primary hemostasis", including platelet activation, aggregation and adhesion to a collagen-coated surface. Various HIFU doses were applied to platelet rich plasma (PRP) with and without ultrasound contrast agents. Flow cytometry, laser aggregometry, environmental scanning electron microscopy and passive cavitation detection were used to quantify platelet activation, aggregation, adhesion and associated cavitation. HIFU can activate platelets and cause them to adhere to a collagen-coated surface. Cavitation was monitored during aggregation trials and was quantified to provide a relative measure of the amount of cavitation that occurred in each aggregation trial. Regression analysis shows weak correlation between aggregation and intensity, and a strong correlation between aggregation and cavitation occurrence.

Low concentrations of short chain aliphatic alcohols and organic acids and bases suppress single-bubble sonoluminescence (SBSL) in water. The degree of SL quenching increases with the length of the aliphatic end of the alcohol, and is related to the concentration of the alcohol at the bubble/water interface. The light is preferentially quenched in the shorter wavelength region of the spectrum. Radius–time measurements of the bubble are not dramatically affected by the low levels of alcohol used. Butyric acid and propylamine behave in the same manner, but only in their neutral forms, indicating that the SBSL suppression is due to processes occurring within the bubble.

Sonoluminescence from a single bubble was studied under microgravity and hypergravity environments to determine how buoyancy affects the light emission. The long-term objective of these experiments is to determine if buoyancy-related instabilities play a role in limiting the parameter space of single-bubble sonoluminescence. Understanding the parameter space limitations may ultimately lead to novel approaches for enhancing the extreme conditions within the bubble. Our results reveal several buoyancy-related effects, which should be further investigated in an extended microgravity environment.

The results of this paper show—for an existing high intensity, focused ultrasound (HIFU) transducer—the importance of nonlinear effects on the space/time properties of wave propagation and heat generation in perfused liver models when a blood vessel also might be present. These simulations are based on the nonlinear parabolic equation for sound propagation and the bio-heat equation for temperature generation. The use of high initial pressure in HIFU transducers in combination with the physical characteristics of biological tissue induces shock formation during the propagation of a therapeutic ultrasound wave. The induced shock directly affects the rate at which heat is absorbed by tissue at the focus without significant influence on the magnitude and spatial distribution of the energy being delivered. When shocks form close to the focus, nonlinear enhancement of heating is confined in a small region around the focus and generates a higher localized thermal impact on the tissue than that predicted by linear theory. The presence of a blood vessel changes the spatial distribution of both the heating rate and temperature.

In order to simulate ultrasound propagation and subsequent thermal effects in biological media in which blood vessels and other structures may be present, a three-dimensional model has been developed that eliminates the need for symmetry constraints. The model is based on the coupled solution of the full wave nonlinear equation of sound in a lossy medium and the bioheat equation obtained by a pseudospectral finite-difference method in the time domain. It includes nonlinear sound propagation, an arbitrary frequency power law for attenuation, and is capable of treating material inhomogeneities. Unlike other models based on parabolic approximations, it is not restricted to near-axis solutions and can account for reflections and backscattered fields. The program was used to simulate the application of high-intensity focused ultrasound (HIFU) in liver with a blood vessel placed perpendicular to the axis of the transducer and near the focus. This approach follows recent work by the authors [Curra et al., IEEE Trans. Ultrason. Ferroelectr., Freq. Control (in press)]. Simulations are presented for different levels of driving pressure, sound nonlinearities, exposure times, and the relative position between the transducer focus and the blood vessel.

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.

Certain therapeutic applications of ultrasound may be enhanced by the use of ultrasound contrast agents, whose controlled destruction may produce a desired bioeffect. It is therefore important to understand the mechanisms of microbubble destruction, and to quantify the relationship between bioeffects and the acoustical signature of these agents. In previous studies, we found two distinct thresholds for the ultrasonic destruction of shelled microbubbles: a fragmentation threshold (P1) at which the microbubble shell is disrupted, creating smaller bubbles, and an inertial cavitation [IC] threshold (P2) for sustained, vigorous IC activity. The inertial cavitation dose (ICD) was used to monitor continuous changes in IC activity. The samples, containing mixtures of Optison with either a buffer solution or whole blood, were insonified with a 1.1-MHz focused transducer (up to 4.4 MPa peak-to-0peak). Below P2, the ICD increased slowly with increasing pressure amplitude; hemolysis accumulated more rapidly. Above P2, the ICD decreased. Increased hemolysis was observed between P1 and P2, and was associated with short bursts of IC activity. At fixed PRF, or fixed total "on" time (by adjustment of pulse length and PRF), a pulse length threshold existed for the ICD and hemolysis measurements.

High-intensity focused ultrasound (HIFU) has been examined as a noninvasive means for achieving acoustic hemostasis [Delon–Martin et al., UMB 21, 113-119 (1995); Hynynen et al., UMB 22, 193-201 (1996); Vaezy et al., UMB 24, 903-910 (1998)]. Our own efforts in acoustic hemostasis are directed toward using diagnostic ultrasound to locate a hemorrhage and HIFU to halt the bleeding. To enhance the imaging of blood, the use of ultrasound contrast agents (UCAs; gas-filled microbubbles that increase the echogenicity of fluids) has been proposed as a means to locate internal bleeding; however, the combination of UCAs and ultrasound has been found to cause bioeffects in whole blood [Miller et al., UMB 23, 625-633 (1997); Poliachik et al., UMB 25, 991-998 (1999)]. Our results have shown that HIFU can cause platelets in a platelet rich plasma (PRP) sample to activate, aggregate, and adhere to a collagen-coated surface. Furthermore, UCAs can increase the amount of cavitation induced by HIFU, and thus lead to an increase in platelet activity. Although HIFU exposure alone can induce platelet activity, the addition of UCAs increases the amount and the rate of cavitation (cavitation dose); therefore, cavitation is the likely mechanism of HIFU-induced platelet activity.

The effect of numerous stimuli upon the release of drugs and other molecules from polymeric substrates has been of great interest in the drug delivery community. Ultrasound has proven to be an effective stimulus for the controlled release of drugs from polymer films. However, the mechanism by which this controlled response occurs has yet to be fully understood. In this study, the ability of shear forces generated by microstreaming around a single ultrasonically stimulated bubble to reversibly increase the release of the drugs from a coated polymer film is demonstrated. The polymer film is loaded with the drug ciprofloxacin and then coated with methylene chains consisting of 12 hydrocarbon chains. The leaching rate of the drug thus depends upon the extent of surface coverage by the methylene chains. A single oscillating bubble in a fluid medium has the capacity to drive streaming at the surface of the polymer film and disrupt the methylene chain coating. An increase of drug concentration in suspension as high as ten times the baseline and controls was achieved, which implies an increase in the leaching rate. After treatment, the leaching rate returns to baseline levels, suggesting the methylene chains reorganize upon the polymer surface.

Ultrasound contrast agents have proven to be an effective agent for producing cavitation-associated bioeffects. A comparative analysis of the strength and duration of cavitation activity and the lifetime of nucleation sites during red blood cell (RBC) lysis and sonoporation was performed. The RBCs were treated with 1.1-MHz tone-burst ultrasound in the presence of contrast agents and analyzed for hemoglobin release and the uptake of FITC-0dextran (MW= 4 kD). Pulse durations ranged from 100 to 10,000 ms and the total number of bursts for each pulse duration was selected to ensure a constant exposure. The extent and duration of cavitation activity during treatment was monitored using a passive cavitation detection system. The collected cavitation-activity data was analyzed quantitatively and correlated with the percent of hemolysis and the ratio of fluorescent cells to total cells treated.

A typical pulse in electrohydraulic shock wave lithotripsy (SWL) consists of an intense positive pressure pulse, followed by a longer negative-pressure tail. Computer models of the bubble dynamics associated with such a pulse suggest that the positive pressure pulse compresses the bubble (R_{0}=3–10 μm) to a submicron size. The negative-pressure tail then causes the bubble to undergo a dramatic expansion, followed by an inertially dominated (presumably spherical) collapse hundreds of microseconds later. Acoustic and light emissions are generated at both collapses. We have examined the simultaneous acoustic and optical emission from a cavitation field generated by SWL in order to determine whether the sonoluminescence is principally due to the initial compression of the bubble, or the final inertial collapse. Using two confocal 1-MHz, piezoceramic hydrophones and a PMT mounted on a light-tight water-filled container, we have observed acoustic and light emission corresponding to both the compression and inertial collapse of the bubble field. Our initial results suggest that the light emission occurs most frequently during the initial bubble compression. These results may have implications for understanding the sphericity of the bubble dynamics produced in SWL.

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.

There has been some research in the late 1980s on the development and use of biologically compatable, drug-carrying polymers for the purpose of subcutaneous release of the drug. In those papers, ultrasound was used to release the drug. This intriguing method for temporally targeted drug release has been hampered by a large, non-ultrasonic drug release rate. In other words, even without the application of ultrasonic stimulation, an excessive amount of the drug leaches out of the drug-carrying implant. We have developed a bio-compatable, drug-carrying polymer that can release a drug of interest upon ultrasonic stimulation, but whose background leaching rate is negligible. The advance in the present study over previous work is the coating of the drug-carrying polymer with a self-assembling membrane (SAM). Before and after the application of ultrasound, the SAM acts as an effective barrier. During and shortly after the application of ultrasound, the SAM transiently disassembles — thereby releasing the drug — then reassembles, which cuts off the drug flux. We present in vitro results demonstrating this effect, with insulin and ciprofloxin as candidate drugs.

A simple, one-step procedure for generating ordered, crystalline methylene chains on polymeric surfaces via urethane linkages was developed. The reaction of dodecyl isocyanate with surface hydroxyl functional groups, catalyzed by dibutyltin dilaurate, formed a predominantly all-trans, crystalline structure on a cross-linked poly(2-hydroxyethyl methacrylate) (pHEMA) substrate. Allophanate side-branching reactions were not observed. Both X-ray photoelectron spectrocopy and time-of-flight secondary ion mass spectrometry show that the surface reaction reached saturation after 30 min at 60°C. Unpolarized Fourier transform infrared-attenuated total reflection showed that, after 30 min, the stretching frequencies, vCH_2,asym and vCH_2,sym, decreased and approached 2920 and 2850 cm^-1, indicative of a crystalline phase. The distance between two hydroxyl groups is roughly 4 Å. A tilt angle of 33.5° ± 2.4° was estimated by dichroic ratios measured in polarized ATR according to the two-phase and Harrick thin film approximations. The findings reported here are significant in that the possibilities for using structures similar to self-assembled monolayers (SAMs) are expanded beyond the rigid gold and silicon surfaces used through most of the literature. Thus, SAMs, biomimetics for ordered lipid cell wall structures, can be applied to real-world biomedical polymers to modify biological interactions. The terminal groups of the SAM-like structure can be further functionalized with biomolecules or antibodies to develop surface-based diagnostics, biosensors, or biomaterials.

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.