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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.

Previously, noninvasive methods of estimating local tissue thermal and acoustic properties using backscattered ultrasound have been proposed in the literature. In this article, a noninvasive method of estimating local thermal diffusivity in situ during focused ultrasound heating using beamformed acoustic backscatter data and applying novel signal processing techniques is developed. A high intensity focused ultrasound (HIFU) transducer operating at subablative intensities is employed to create a brief local temperature rise of no more than 10 degrees C. Beamformed radio-frequency (RF) data are collected during heating and cooling using a clinical ultrasound scanner. Measurements of the time-varying "acoustic strain", that is, spatiotemporal variations in the RF echo shifts induced by the temperature related sound speed changes, are related to a solution of the heat transfer equation to estimate the thermal diffusivity in the heated zone. Numerical simulations and experiments performed in vitro in tissue mimicking phantoms and excised turkey breast muscle tissue demonstrate agreement between the ultrasound derived thermal diffusivity estimates and independent estimates made by a traditional hot-wire technique. The new noninvasive ultrasonic method has potential applications in thermal therapy planning and monitoring, physiological monitoring and as a means of noninvasive tissue characterization.

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.

Backscattered radio frequency (RF) data collected in a series of in vitro experiments, in which HIFU lesions were created in bovine liver tissue, were analyzed using two signal processing approaches to visualize temporal evolution of lesion formation. Change in round-trip travel time provides information related to temperature change during and after therapy. Changes in the RF spectrum related to changes in scattering properties of the heated region were observed before visible changes appeared on B-mode images. Effect of increased attenuation in the necrosed tissue region was also observed. Results demonstrate potential for these two techniques in image-guided HIFU therapy.

This paper describes a series of high intensity focused ultrasound (HIFU) phased array transducers with a single Archimedean spiral close packed element arrangement on a spherical surface extending from the central axis outward. Simulation and measurement reveal using the spiral element arrangement on a spherical bowl reduces grating side lobes while maximizing power density at the focus.

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)/spl times/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.

A twinkling artifact (TA) associated with urinary calculi has been described as rapidly changing colors on Doppler ultrasound. The purpose of this study was to investigate the mechanism of the TA. Doppler processing was performed on raw per channel radio-frequency data collected when imaging human kidney stones in degassed water. Suppression of twinkling by an ensemble of computer generated replicas of a single received signal demonstrated that the TA arises from variability among the acoustic signals and not from electronic signal processing. This variability was found to be random in nature, and its suppression by elevated static pressure, and its return when the pressure was released, suggests that the presence of surface bubbles on the stone is the mechanism of the TA. Submicron size bubbles are often trapped in crevices on solid objects, but the presence of these bubbles in vivo is unexpected. To further check this mechanism under conditions identical to in vivo, stone-producing porcine kidneys were harvested en bloc with a ligated ureter and then placed into a pressure chamber and imaged at elevated atmospheric pressure. The result was similar to in vitro. Work supported by NIH DK43881, DK092197, RFBR 11-02-01189, 12-02-00114, and NSBRI through NASA NCC 9-58.

The properties of nonlinear acoustic wave propagation are known to be able to improve the resolution of ultrasound imaging, and could be used to dynamically estimate the physical properties of tissue. However, transducers capable of launching a wave that becomes nonlinear through propagation do not typically have the necessary bandwidth to detect the higher harmonics. Here we present the design and characterization of a novel multilayer transducer for high intensity transmit and broadband receive. The transmit layer was made from a narrow‐band, high‐power piezoceramic (PZT), with nominal frequency of 2.0 MHz, that was diced into an array of 32 elements. Each element was 0.300 mm wide and 6.3 mm in elevation, and with a pitch of 0.400 mm the overall aperture width was 12.7 mm. A quarter‐wave matching layer was attached to the PZT substrate to improve transmit efficiency and bandwidth. The overlaid receive layer was made from polyvinylidene fluoride (PVDF) that had gold metalization on one side. A custom two‐sided flex circuit routed electrical connections to the PZT elements and patterned the PVDF elements; the PZT and PVDF elements had identical apertures. A low viscosity and electrically nonconductive epoxy was used for all adhesion layers. Characterization of electrical parameters and acoustic output were performed per standard methods, where transmit and receive events were driven by a software‐controlled ultrasound engine. Echo data, collected from ex vivo tissue and digitized at 45 MS/s, exhibited frequency content up to the 4th harmonic of the 2 MHz transmit frequency.

For high-intensity focused ultrasound (HIFU) to be widely applicable in the clinic, robust methods of treatment planning, guidance and delivery need to be developed. These technologies would greatly benefit if patient specific tissue parameters could be provided as inputs so that the treatment planning and monitoring schemes are customized and tailored on a case by case basis. A noninvasive method of estimating the local in situ acoustic heating rate using the heat transfer equation (HTE) and applying novel signal processing techniques is presented in this article. The heating rate is obtained by experimentally measuring the time required to raise the temperature of the therapeutic focus from a baseline temperature to boiling (here assumed to be 100 degrees C for aqueous media) and then solving the heat transfer equation iteratively to find the heating rate that results in the onset of boiling. The onset of boiling is noninvasively detected by measuring the time instant of onset of acoustic emissions in the audible frequency range due to violent collapse of bubbles. In vitro experiments performed in a tissue mimicking alginate phantom and excised turkey breast muscle tissue demonstrate that the noninvasive estimates of heating rate are in good agreement with those obtained independently using established methods. The results show potential for the applicability of these techniques in therapy planning and monitoring for therapeutic dose optimization using real-time acoustic feedback.

Nonlinear mechanisms of lesion formation by high intensity focused ultrasound (HIFU) were investigated experimentally and numerically in a transparent polyacrylamide gel phantom. Numerical predictions were made with a finite‐amplitude acoustic propagation model. A 2‐MHz transducer of 42‐mm diameter and 44.5‐mm radius of curvature was operated above the cavitation threshold of the gel phantom at various peak acoustic powers and duty cycles. Acoustic waveforms were recorded in the gel by a fiber optic hydrophone. Bubble activity was detected actively by B‐mode diagnostic imaging, passively by a remote focused hydrophone, and optically by CCD and high‐speed cameras. Elevated static pressure was applied to suppress bubble activity and increase the boiling temperature, thus isolating the pure effect of acoustic nonlinearity. In overpressure experiment performed at 32 W acoustic power, both cavitation and nonlinear ultrasound propagation accelerated lesion inception and growth, but acoustic nonlinearity, which led to shock formation, played the dominant role. Rapid localized heating, particularly by increased absorption in the shocked wave, led to boiling and then to proximal growth and migration of the lesion even at low overpressure. At 90W acoustic power, boiling was observed and predicted in less than 50 ms.

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.

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.

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.

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.

While many tissue-mimicking phantoms have been developed for ultrasound imaging applications, none is suitable for exploration of the high temperature and pressure regimes involved in High Intensity Focused Ultrasound (HIFU). HIFU dosimetry studies are usually performed on biological tissues, but this approach has two drawbacks: 1) tissues are opaque and development of coagulative lesions cannot be visually observed in real-time, and 2) the natural heterogeneous structure of tissue may complicate direct comparison with numerical models. To address these issues, a new optically transparent tissue phantom was developed. It is a polyacrylamide hydrogel with a thermally sensitive indicator protein (Bovine Serum Albumin, 3 - 9%) that becomes optically diffusive when denatured. We describe various measurements undertaken to characterize this material and to demonstrate how well it matches tissue in terms of bulk acoustic and thermal properties. In summary, this new phantom material simulates many of the lesion-forming characteristics of soft tissue under HIFU exposures.

The relative performance of two different ultrasonic units commonly used clinically for post removal was evaluated using tips designed specifically for post vibration. Twenty-four extracted maxillary and mandibular cuspids with crowns removed at the labial cementoenamel junction were treated endodontically. Post spaces were made 10 mm into the roots before cementing a 16 mm #5 (0.050-inch) Para-Post with zinc phosphate cement. The teeth were divided into three similar groups of eight. Post retention was assessed in group 1. Ultrasonic vibration was applied to groups 2 and 3 until post removal. The average force required to dislodge the posts from the teeth in group 1 (control group, no ultrasound) was 40.5 kg (SD = 12.3 kg). The average time for post removal in group 2 (Spartan) was 4:52 min (SD = 2:26). The average time for post removal in group 3 (Enac) was 1:31 min (SD = 0:34). The difference between groups 2 and 3 was statistically significant (p < 0.005). Use of ultrasonic tips designed for post vibration and maximization of audible sound level during ultrasonic treatment of posts seem to play an important role in the effectiveness and efficiency of post removal. The results obtained indicate that both the Enac ultrasonic unit with the ST-09 vibration tip and the Spartan ultrasonic unit with the Analytic VT-S tip were effective. Nevertheless, the Enac ultrasonic unit with the ST-09 vibration tip was clearly more efficient under these study conditions, resulting in typical post removal times of

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. [Work supported by NI...

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 ultra...

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. [Work supported by NIH (DK070618, EB007643, and DK007742) and NSBRI through NASA NCC 9‐58.]

Accurate monitoring of high‐intensity focused ultrasound (HIFU) therapy is critical for ensuring proper treatment. Changes in time of flight for diagnostic ultrasound (DU) backscatter have been recognized as a means to identify temperature changes between two DU frames, captured before and after HIFU therapy. Estimates of heating from precisely controlled HIFU experiments strongly indicate that DU measurements are formed by an interaction between the heated material and a diffuse DU beam, as opposed to the commonly assumed ray model for the DU beam. The existence of a diffuse beam can be explained using the Rytov method, where temperature induced changes in material properties affect the phase and amplitude of the probing signal, with cumulative effects produced over characteristic volumes, and not simply depths. In particular, the temperature effect for on‐axis backscatter is shown to be a generalization of the models proposed by Simon (1998) and Moreno (1996), with the phase determined by a complex weig...

Characterizing the performance of diagnostic ultrasound (DU) for monitoring high intensity focused ultrasound (HIFU) therapy is essential for identifying effective treatment protocols. Such protocols ensure accurate therapy monitoring in media with known thermal and perfusive properties. The protocols are specified by treatment duration, transducer motion, and the DU acquisition characteristics. The HIFU transducer is constrained to move in the plane perpendicular to its axis, with the DU positioned to capture the focal plane of the HIFU transducer. Differences in RF backscattering observed between two frames, one captured before and one after treatment, are known to result from a temperature distribution generated by the heat deposited during therapy. A functional expansion for the heating is used which provides minimum variance coefficient estimates for stationary backscattering by averaging the Fisher information matrix. We show through approximation, simulation, and experiment that these functions att...

Residual kidney stone fragments often remain months after treatment. These fragments may nucleate new stones and contribute to a 50% recurrence within 5 years. Here, a research focused ultrasound device was used to generate fragment motion with the goal of facilitating passage. Natural and artificial stones 1–8 mm in length were surgically placed in the urine space in pig kidneys. The ultrasound source was a 2.75‐MHz, eight‐element annular array with a 6‐cm radius of curvature. At adjustable focal depths of 5–8 cm, the focal pressure beam width in water was about 2 mm, and peak pressure was about 4 MPa. Targeting was done by ultrasound using B‐mode and twinkling artifact that stones produce in Doppler mode. The commercial imaging probe was placed within and oriented down the axis of the therapy probe. Ultrasound and fluoroscopy showed the stones moving in real‐time under the influence of the focused ultrasound. Stones moved on the order of 1 cm/s away from the source and several stones moved several centi...

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 wil...

The present invention employs hydrogels as acoustic couplings for clinical applications of ultrasound imaging and therapy, but is particularly applicable to high intensity focused ultrasound (HIFU) based therapy. While other materials can be used, it has been determined that polyacrylamide is sufficiently robust and transmissive to withstand the high temperatures encountered in HIFU therapy. One embodiment of a hydrogel coupling (16) is configured in shape and size (length) to ensure that a focal region (14) of an ultrasound transducer (10a) is disposed proximate the target area when the distal tip (18) of the transducer (10a) is in contact with tissue. These couplings (16) can be shaped to correspond to the beam focus characteristics of specific transducers (10a). Water can be applied to hydrate the tip of the hydrogel coupling during use, and medication absorbed into the hydrogel material can be applied to the tissue in contact with the distal surface of the hydrogel.

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. [Work supported by the NSBRI‐SMS00402, RFBR, NIH FIRCA and DK43881.]

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. [Work supported by Army MRMC, NIH DK43881, NSBRI SMS00402, and RFBR.]

The spatial distribution and temporal history of tissue temperature is an essential indicator of thermal therapy progress, and treatment safety and efficacy. Magnetic resonance methods provide the gold standard noninvasive measurement of temperature but are costly and cumbersome compared to the therapy itself. We have been developing the use of ultrasound backscattering for real‐time temperature estimation; ultrasonic methods have been limited to relatively low temperature rise, primarily due to lack of sensitivity at protein denaturation temperatures (50−70 °C). Through validation experiments on gel phantoms and ex vivo tissue we show that temperature rise can be accurately mapped throughout the therapeutic temperature range using a new BioHeat Transfer Equation (BHTE) model‐constrained inverse approach. Speckle‐free temperature and thermal dose maps are generated using the ultrasound calibrated model over the imaged region throughout therapy delivery and post‐treatment cooling periods. Results of turkey breast tissue experiments are presented for static HIFU exposures, in which the ultrasound calibrated BHTE temperature maps are shown to be very accurate (within a degree) using independent thermocouple measurements. This new temperature monitoring method may speed clinical adoption of ultrasound‐guided HIFU therapy. [Work supported by Army MRMC.]

Bioheat transfer equation (BHTE) estimates of applied dose during HIFU therapy typically use prior knowledge or assume standard values for tissue properties that determine thermal diffusivity (K) and heat source (Q). We have developed a novel signal‐processing based technique to noninvasively estimate these parameters in situ based on analysis of raw backscattered RF data from two localized HIFU exposures, one at sub‐ablative intensities to determine K, and another at therapeutic intensities to obtain Q. Both exposures are performed prior to therapy. To estimate K, a short HIFU exposure is applied resulting in a temperature rise of less than 15° C. The Gaussian radius of the temperature induced apparent strain profile during cool down is estimated and fit to an approximate analytical heat diffusion expression to obtain K. Independent estimates of K derived using the transient hotwire technique validated the ultrasonic measurements. To estimate Q, an audio range hydrophone was acoustically coupled to the s...

The spatial distribution of tissue temperature is an essential indicator of thermal therapy progress, treatment safety and efficacy. Here, it is shown through in vitro experiments that temperature rise can be accurately measured during therapy delivery and post‐treatment cool down phases using RF backscatter data collected with a modified ultrasound scanner. RF data is acquired prior to, during, and after HIFU exposures, in tissue mimicking phantoms and excised animal tissue. Through two calibration experiments, initial estimates for key BHTE parameters (local thermal diffusivity, and magnitude of the HIFU heat source) and the temperature dependence of ultrasonic travel time are obtained prior to therapy. Tissue heterogeneity over a larger targeted region of interest is modeled as a change in the magnitude of the focal heat source. During therapy this magnitude is updated using an iterative optimization technique that minimizes the difference between predicted and measured travel time values. Temperature ...

A new noninvasive temperature estimation technique using the bioheat transfer equation (BHTE) to constrain inversion of ultrasonic travel time data has been developed for HIFU therapy monitoring. Initial estimates for BHTE parameters and ultrasonic travel time temperature dependence δτ(T) are noninvasively obtained in situ using ultrasound backscatter signals acquired during two probe heating exposures performed prior to therapy: one to obtain medium thermal parameters, the other to estimate the magnitude of the local HIFU heat source. These estimates are used in BHTE simulations and compared to local travel time changes measured periodically during therapy using a medical ultrasound imager. Quantitative 2‐D temperature maps are obtained by constrained data fitting. Preliminary results obtained from in vitro experiments in tissue mimicking phantoms will be presented. Temperature maps are computed throughout therapy delivery and posttreatment cooling periods, and validated against independent temperature m...

The use of moving high intensity focused ultrasound (HIFU) treatment protocols is of interest in achieving efficient formation of large‐volume lesions in tissue. However, potentially unwanted thermal effects, such as prefocal heating, should be considered. A KZK acoustic model coupled with the BioHeat Transfer Equation has been extended to simulate multiple, moving scans in tissue. Simulation results are compared with experimental data collected over a range of exposure regimes for linear and concentric circular scans with a 3.5‐MHz single‐element transducer in ex vivo bovine liver. Of particular interest are investigating prefocal thermal buildup and ablating the central core of a circular pattern through conductive heating, that is without direct HIFU exposure. Qualitative agreement is observed between experimental and simulated data; limits of the predictive capability of the model in cavitation regimes will be discussed. [Support provided by the U.S. Army Medical Research Acquisition Activity through ...

The relative importance of the effects of acoustic nonlinearity and cavitation in HIFU lesion production is studied experimentally and theoretically in a polyacrylamide gel. A 2‐MHz transducer of 40‐mm diameter and 45‐mm focal length was operated at different regimes of power, and in cw or duty‐cycle regimes with equal mean intensity. Elevated static pressure was applied to suppress bubbles, increase boiling temperature, and thus to isolate the effect of acoustic nonlinearity in the enhancement of lesion production. Experimental data were compared with the results of simulations performed using a KZK acoustic model combined with the bioheat equation and thermal dose formulation. Boiling and the typical tadpole‐shaped lesion shifting towards the transducer were observed under standard atmospheric pressure. No boiling was detected and a symmetric thermal lesion formed in the case of overpressure. A delay in lesion inception time was registered with overpressure, which was hypothesized to be due to suppressed microbubble dynamics. The effect of acoustic nonlinearity was revealed as a substantial decrease in the lesion inception time and an increase in the lesion size for high‐amplitude waves under both standard and overpressure conditions. [Work supported by ONRIFO, NASA/NSBRI, NIH Fogarty, and CRDF grants.]

In our research group, we desire measurements of the large pressure amplitudes generated by the shock waves used in shock wave lithotripsy (SWL) and the large acoustic intensities used in High Intensity Focused Ultrasound (HIFU). Conventional piezoelectric or PVDF hydrophones can not be used for such measurements as they are damaged either by cavitation, in SWL applications, or heat, in HIFU applications. In order to circumvent these difficulties, we have utilized optical fiber hydrophones in SWL that do not cavitate, and small glass probes and a scattering technique for measurements of large HIFU intensities. Descriptions of these techniques will be given as well as some typical data.

HIFU can be used to destroy tumors. The conversion of acoustic energy into heat causes protein coagulation (Lesion) in tissue. Attenuation measurements have been proposed to monitor the progression of thermal therapy. The goal of this work is to study and separate the effects of cavitation and thermal coagulation in attenuation measurements. A HIFU transducer was used to treat Bovine liver. A receiving transducer mounted across from the transmitting HIFU transducer measured attenuation during the treatment. A pressure chamber provided static pressure greater than the pressure amplitude of the HIFU wave, which suppressed cavitation. rf data from a commercial ultrasound scanner was also obtained. A large increase in attenuation was observed with cavitation present, while a subtle increase in attenuation was observed with cavitation suppressed. Attenuation estimated from the RF data showed an increase in attenuation downstream of the location of the lesion with cavitation present, while a subtle increase in ...

Instrumentation and protocols for creating scanned HIFU lesions in freshly excised bovine liver were developed in order to study the in vitro HIFU dose response and validate models. Computer‐control of the HIFU transducer and 3‐axis positioning system provided precise spatial placement of the thermal lesions. Scan speeds were selected in the range of 1 to 8 mm/s, and the applied electrical power was varied from 20 to 60 W. These parameters were chosen to hold the thermal dose constant. A total of six valid scans of 15 mm length were created in each sample; a 3.5 MHz single‐element, spherically focused transducer was used. Treated samples were frozen, then sliced in 1.27 mm increments. Digital photographs of slices were downloaded to computer for image processing and analysis. Lesion characteristics, including the depth within the tissue, axial length, and radial width, were computed. Results were compared with those generated from modified KZK and BHTE models, and include a comparison of the statistical variation in the across‐scan lesion radial width. [Work supported by USAMRMC.]

Backscattered radio frequency (rf) data from a modified commercial ultrasound scanner were collected in a series of in vitro experiments in which high intensity focused ultrasound (HIFU) was used to create lesions in freshly excised bovine liver tissue. Two signal processing approaches were used to visualize the temporal evolution of lesion formation. First, apparent tissue motion due to temperature rise was detected using cross‐correlation techniques. Results indicate that differential processing of travel time can provide temperature change information throughout the therapy delivery phase and after HIFU has been turned off, over a relatively large spatial region. Second, changes in the frequency spectrum of rf echoes due to changes in the scattering properties of the heated region were observed well before the appearance of hyper‐echogenic spots in the focal zone. Furthermore, the increase in attenuation in the lesion zone changes the measured backscatter spectrum from regions distal to it along the im...

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. [Work supported by ONR Grant No. N00014‐96‐1‐0630 and NIH Grant No. HL64208‐02.]

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. [Work supported by NSF, NSBRI, DARPA/ONR, and NIH SBIR.]

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 ...

A promising therapeutic application of high‐intensity focused ultrasound (HIFU) is hemostasis. In one possible hemostatic application, ultrasound induced heating will be used to stop bleeding during open surgery. To achieve substantial heat deposition on the surface of the bleeding organ, intense acoustic fields will be used, and therefore nonlinear effects on wave propagation in the coupling liquid between the transducer and the treated region must be taken into account. Moreover, nonlinearity can be used to increase the efficiency of heat deposition in shallow tissues by transforming wave energy to higher harmonics. Theoretical characterization of acoustic field is performed using a one‐dimensional spherical wave model and the KZK equation. On‐axis and off‐axis waveforms, spatial distributions of harmonics, acoustic intensity, and heat deposition are calculated numerically in water and in tissue using a frequency‐domain scheme. The influence of operating frequency, initial intensity, transducer aperture, amplitude shading, focal depth, and position of the water–tissue interface on acoustic propagation regimes and associated tissue heating is studied. For given absorption properties of the tissue and desirable spatial shape of the thermal lesion, an optimal set of transducer parameters and corresponding nonlinear effects are presented and discussed. [Work supported by DARPA, ONR, CRDF and RFBR.]

Noninvasive monitoring of high‐intensity focused ultrasound (HIFU) treatment by diagnostic ultrasound is currently limited by a poor understanding of the bioacoustic effects of tissue heating. Sound‐speed measurement has been proposed as a means of noninvasive thermal mapping. The sound speed in most tissues changes monotonically but nonlinearly with temperature to around 60 °C. Above that temperature, at which the tissue proteins begin to denature, irreversible changes occur in the tissue and its corresponding acoustic properties. Sound‐speed data around and above the range in which the tissue ‘‘cooks’’ is a challenge to obtain because of changes in tissue shape, compressibility, and overall dimensions associated with the cooking process. In this research, an apparatus to measure sound speed during a controlled temperature change was used to study the effects of temperature, thermal dose, and thermal dose rate on the speed of sound in various mammalian tissues. The apparatus, potential sources of error, and results will be presented, and implications for forward and inverse HIFU propagation modeling and acoustic remote sensing of HIFU‐induced temperature changes will be discussed. [Work supported by DARPA.]

A surgical application of high‐intensity focused ultrasound (HIFU) is hemostatis. In this application, both tissue and blood will be subjected to HIFU. What will happen to blood? The intent of this study is to explore via experiment some of the bioeffects of HIFU on whole human blood. A 1.1‐MHz piezoceramic source with a 60‐mm radius of curvature and 100‐mm aperture was used. Special acoustically transparent containers were made of handmade, low‐density polyethylene tubing. Phenomena studied included hemolysis, morphologic changes in erythrocytes, white blood cell differential, and platelet activation, all as a function of acoustic intensity and dosage. Intensities up to 6000 W/cm2 were used in cw pulses of one second. The bioeffects noted above were correlated with temperature and a passive acoustic measure of bubble activity within the blood created by the ultrasound. Under the acoustic conditions considered for this work, nonthermal acoustic effects were most strongly associated with bioeffects. [Work sponsored by DARPA.]

The paper presents a noninvasive method of estimating the bioheat transfer equation (BHTE) parameters (namely, thermal diffusivity, K, and the normalized local heat source, Q) in situ during HIFU therapy. The method analyses the raw acoustic backscatter data using novel signal processing techniques. First, a heat exposure at sub-ablative intensities is performed to determine K, followed by another at therapeutic intensities to obtain Q. In vitro experiments, performed in a tissue-mimicking alginate phantom, demonstrate that the noninvasive estimates of K and Q are in good agreement with those obtained independently using established methods. The results show potential for the applicability of these techniques in therapy planning and monitoring for therapeutic dose optimization using real-time temperature feedback.

We show that a 2 MHz HIFU field can be measured in water and with high spatial resolution by placing a small scatterer in the field and sensing the scattered wave. We use a bistatic configuration placing a hydrophone at a safe distance. Glass and steel tips are fabricated using simple techniques and evaluated. Tapered tip geometry proves to be mechanically robust and not prone to internal resonance or scattering from other sites than the tip. Glass proves to be superior to polished carbide steel in its ability to delay the initiation of cavitation, and relatively easy to manufacture using common pipette drawing technology. In our tests, a highly nonlinear 2 MHz HIFU field is mapped in degassed water with a 0.1 mm glass tip. The fundamental, 2/sup nd/, 3/sup rd/, and 4/sup th/ harmonics are mapped with at least 25 dB dynamic range and are comparable with numerical results. Numerical simulations for nonlinear fields in water are obtained using a well established KZK equation based calculation.