A DERATING METHOD FOR THERAPEUTIC APPLICATIONS OF HIGH INTENSITY FOCUSED ULTRASOUND.

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.

FOCUSING OF HIGH POWER ULTRASOUND BEAMS AND LIMITING VALUES OF SHOCK WAVE PARAMETERS.

In this work, the influence of nonlinear and diffraction effects on amplification factors of focused ultrasound systems is investigated. The limiting values of acoustic field parameters obtained by focusing of high power ultrasound are studied. The Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation was used for the numerical modeling. Solutions for the nonlinear acoustic field were obtained at output levels corresponding to both pre- and post- shock formation conditions in the focal area of the beam in a weakly dissipative medium. Numerical solutions were compared with experimental data as well as with known analytic predictions.

Activation, aggregation and adhesion of platelets exposed to high-intensity focused ultrasound.

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/cm(2). 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 (r(2) = 0.11) between aggregation and ultrasound intensity, but a substantial correlation (r(2) = 0.76) between aggregation and cavitation occurrence.

Color Doppler detection of acoustic streaming in a hematoma model.

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/cm(2) 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.

Use of a dual-pulse lithotripter to generate a localized and intensified cavitation field.

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 2 x 10 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-microm-thick aluminum foil. Our dual-pulse lithotripter (DPL) uses two shock wave sources, facing each other, confocal, and triggered simultaneously to create a 4 x 5 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.

Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery.

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.

Near-infrared emissions in single-bubble and multibubble sonoluminescence.

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.

Use of overpressure to assess the role of bubbles in focused ultrasound lesion shape in vitro.

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 (I(SP)) were 600 to 3000 W/cm(2). 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/cm(2) ( +/- 20%) at 1 MHz for 30 s. Hydrostatic pressures were 0.1 or 5.6 MPa. At 1300 W/cm(2), lesions were cigar-shaped, and no difference was observed between lesions formed with or without overpressure. At 1750 W/cm(2), 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.

Ultrasound accelerates functional recovery after peripheral nerve damage.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Thresholds for inertial cavitation in albunex suspensions under pulsed ultrasound conditions.

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 (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 II (Coulter Diagnostics, Miami, FL) and whole blood solutions, showed that P1 increased with increasing Albunex concentration and decreased with increasing PRF, whereas P2 decreased with increasing Albunex 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 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.

Real-time visualization of high-intensity focused ultrasound treatment using ultrasound imaging.

High-intensity focused ultrasound (HIFU) and conventional B-mode ultrasound (US) imaging were synchronized to develop a system for real-time visualization of HIFU treatment. The system was tested in vivo in pig liver. The HIFU application resulted in the appearance of a hyperechoic spot at the focus that faded gradually after cessation of HIFU exposure. The duration of HIFU exposure needed for a hyperechoic spot to appear, was inversely related to the HIFU intensity. The threshold intensity required to produce a hyperechoic spot in liver in < 1 s was 970 W/cm(2), in situ. At this HIFU dose, no immediate cellular damage was observed, providing a potential for pretreatment targeting. The real-time visualization method was used in hemostasis of actively bleeding internal pelvic vessels, allowing targeting and monitoring of successful treatment. Real-time US imaging may provide a useful tool for image-guided HIFU therapy.

Correlation between sonoluminescence, sonochemistry and cavitation noise spectra.

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.

Treatment of uterine fibroid tumors in a nude mouse model using high-intensity focused ultrasound.

OBJECTIVE: The purpose of this study was to investigate the potential efficacy of high-intensity focused ultrasound for the treatment of uterine fibroid tumors in a nude mouse model. STUDY DESIGN: A total of 60 female athymic nude mice were inoculated subcutaneously with 3 to 5 x 10(6) ELT-3 cells, a uterine fibroid tumor cell line. Tumor size was monitored with transcutaneous caliper measurements. The high-intensity focused ultrasound probe was a concave, single-element, high-power transducer that operated at a frequency of 3.5 MHz. The tumors were treated for 30 to 60 seconds using a high-intensity focused ultrasonic intensity of 2000 W/cm(2), depending on the tumor size. RESULTS: A single high-intensity focused ultrasonic treatment resulted in an average reduction in tumor volume of 91% within 1 month of the treatment. Histologic analysis of tumors treated with high-intensity focused ultrasound showed coagulation necrosis and nuclear fragmentation of tumor cells. CONCLUSION: High-intensity focused ultrasound effectively reduced uterine fibroid tumor size in a nude mouse model. Further studies are needed to assess the in situ response of uterine fibroids to high-intensity focused ultrasonic treatment.

A dual passive cavitation detector for localized detection of lithotripsy-induced cavitation in vitro.

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 microseconds 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.

Surface modification of polymers with self-assembled molecular structures: multitechnique surface characterization.

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 degrees C. Unpolarized Fourier transform infrared-attenuated total reflection showed that, after 30 min, the stretching frequencies, vCH2,asym and vCH2,sym, decreased and approached 2920 and 2850 cm-1, indicative of a crystalline phase. The distance between two hydroxyl groups is roughly 4 A. A tilt angle of 33.5 degrees +/- 2.4 degrees was estimated by dichoric 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.

Numerical simulations of heating patterns and tissue temperature response due to high-intensity focused ultrasound.

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.

Sonographic detection of acute parenchymal injury in an experimental porcine model of renal hemorrhage: gray-scale imaging using a sonographic contrast agent.

OBJECTIVE: The purpose of this study was to determine the usefulness of contrast-enhanced sonography in the detection of acute parenchymal injury. SUBJECTS AND METHODS: In a model of acute renal injury in pigs, four separate renal parenchymal bleeds were created by puncturing an interlobar artery of the upper and lower poles of the kidneys. B-mode gray-scale scans of the kidneys before and after injury, and after the administration of i.v. and intraarterial (i.a.) contrast agents were recorded on videotape for 5 min for each condition (baseline, after injury, after i.v. contrast administration, and after i.a. contrast administration). For each condition and injury, selected frames were analyzed with regions of interest of the normal renal parenchyma, the area of injury, and the perinephric space. Randomized videotape clips from each of the experimental conditions were rated by three sonologists as to the presence or absence of increased intrarenal parenchymal echogenicity, perinephric echogenicity, and confidence as to whether renal injury was present. RESULTS: Areas of renal injury were isoechoic with normal parenchyma on unenhanced scans. After both i.v. and i.a. contrast material injection, areas of injury were visible as areas of increased echogenicity. Contrast increased from 0.2 on unenhanced images to 4.0 and 4.5, respectively, after i.v. and i.a. administration of the new contrast agent. The three observers' ability to diagnose renal injury increased from 0.61, 0.64, and 0.54 to 0.71, 0.70, and 0.74 after i.v. injection and to 0.93, 0.92, and 0.97 after i.a. injection as indicated by the area under the curve in the receiver operating characteristic analysis. CONCLUSION: Transabdominal contrast-enhanced gray-scale sonography can reveal the area of acute renal hemorrhage. This procedure may be applicable in patients when sonographic contrast agents, imaging procedures, and modes of contrast administration are optimized for clinical use in trauma.

A review and examination of ultrasound for lipoplasty.

Ultrasonic lipoplasty occurs through a complex and describable but currently unquantified series of processes. Ample opportunity exists for the creation of deleterious effects, such as burning tissue and destroying blood vessels and nerves; however, as reported by others, the skilled user seems able to avoid these problems. The possibility of free radical-induced cancer being caused by ultrasonic lipoplasty seems extremely unlikely to the authors. Still, the authors cannot categorically rule out the possibility of significant long-term, harmful, biologic effects caused by free-radical production. All the authors have been able to do is produce an extremely generous upper bound on hydrogen peroxide production and note the uphill climb that any free radical would have to surmount to do lasting damage. Also, users should ensure that no preexisting cancers are present in the fatty tissue or adjoining tissue. Finally, these and other issues, concerns, and hypotheses would all benefit from significant tests on appropriate animal models.

Detection of high-intensity focused ultrasound liver lesions using dynamic elastometry.

A novel ultrasound technique was developed for detecting the distribution of stiffness in biological tissue. The method, which we call 'dynamic elastometry,' involves applying a low-frequency vibration (< or = 5 Hz) to the tissue and measuring the resulting velocity pattern within the sample using Doppler spectral analysis. Based upon the velocity differences, an elastically stiff region can be differentiated from surrounding soft tissue. Dynamic elastometry was used to both detect and quantify lesions produced by high-intensity focused ultrasound (HIFU) in porcine livers. Measurements of the lesion position and length agreed well with independent geometric measurements. The mean and standard deviation of the differences between the two types of measurement were -0.01 cm and 0.10 cm for lesion position, and -0.05 cm and 0.12 cm for lesion length, respectively. The relative stiffness between lesions and normal liver tissue was estimated by the velocity gradient ratio. Results were compared with the Young's modulus ratios between lesion and normal liver tissue obtained from mechanical measurement. The dynamic elastometric estimates had a strong linear correlation with the mechanical measurements (r = 0.93) but were smaller than the latter by 26%.