Oleg A. Sapozhnikov

Physical mechanisms of the therapeutic effect of ultrasound (a review)

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.

Nonlinear Wave Processes in Acoustics

Preface 1. Nonlinearity, dissipation and dispersion in acoustics 2. Simple waves and shocks in acoustics 3. Nonlinear geometrical acoustics 4. Nonlinear sound beams 5. Sound-sound interaction (nondispersive medium) 6. Nonlinear acoustic waves in dispersive media 7. Self-action and stimulated scattering of sound Conclusion Subject index.

Acoustic characterization of high intensity focused ultrasound fields : A combined measurement and modeling approach

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 24,000 W/cm(2). 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/cm(2), 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.

Cavitation clouds created by shock scattering from bubbles during histotripsy

Histotripsy is a therapy that focuses short-duration, high-amplitude pulses of ultrasound to incite a localized cavitation cloud that mechanically breaks down tissue. To investigate the mechanism of cloud formation, high-speed photography was used to observe clouds generated during single histotripsy pulses. Pulses of 5-20 cycles duration were applied to a transparent tissue phantom by a 1-MHz spherically focused transducer. Clouds initiated from single cavitation bubbles that formed during the initial cycles of the pulse, and grew along the acoustic axis opposite the propagation direction. Based on these observations, we hypothesized that clouds form as a result of large negative pressure generated by the backscattering of shockwaves from a single bubble. The positive-pressure phase of the wave inverts upon scattering and superimposes on the incident negative-pressure phase to create this negative pressure and cavitation. The process repeats with each cycle of the incident wave, and the bubble cloud elongates toward the transducer. Finite-amplitude propagation distorts the incident wave such that the peak-positive pressure is much greater than the peak-negative pressure, which exaggerates the effect. The hypothesis was tested with two modified incident waves that maintained negative pressure but reduced the positive pressure amplitude. These waves suppressed cloud formation which supported the hypothesis.

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.

Cavitation bubble cluster activity in the breakage of kidney stones by lithotripter shockwaves.

BACKGROUND AND PURPOSE There is strong evidence that cavitation bubble activity contributes to stone breakage and that shockwave-bubble interactions are involved in the tissue trauma associated with shockwave lithotripsy. Cavitation control may thus be a way to improve lithotripsy. MATERIALS AND METHODS High-speed photography was used to analyze cavitation bubble activity at the surface of artificial and natural kidney stones during exposure to lithotripter shockwaves in vitro. RESULTS Numerous individual bubbles formed on the surfaces of stones, but these bubbles did not remain independent but rather combined to form clusters. Bubble clusters formed at the proximal and distal ends and at the sides of stones. Each cluster collapsed to a narrow point of impact. Collapse of the proximal cluster eroded 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. CONCLUSION Cavitation-mediated damage to stones is attributable, not to the action of solitary bubbles, but to the growth and collapse of bubble clusters.

Effect of overpressure and pulse repetition frequency on cavitation in shock wave lithotripsy

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

A mechanistic analysis of stone fracture in lithotripsy

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

Modeling of pulsed finite-amplitude focused sound beams in time domain

A time-domain numerical model is presented for simulating the finite-amplitude focused acoustic pulse propagation in a dissipative and nonlinear medium with a symmetrical source geometry. In this method, the main effects responsible in finite-amplitude wave propagation, i.e., diffraction, nonlinearity, and absorption, are taken into account. These effects are treated independently using the method of fractional steps with a second-order operator-splitting algorithm. In this method, the acoustic beam propagates, plane-by-plane, from the surface of a highly focused radiator up to its focus. The results of calculations in an ideal (linear and nondissipative) medium show the validity of the model for simulating the effect of diffraction in highly focused pulse propagation. For real media, very good agreement was obtained in the shape of the theoretical and experimental pressure-time waveforms. A discrepancy in the amplitudes was observed with a maximum of around 20%, which can be explained by existing sources of error in our measurements and on the assumptions inherent in our theoretical model. The model has certain advantages over other time-domain methods previously reported in that it: (1) allows for arbitrary absorption and dispersion, and (2) makes use of full diffraction formulation. The latter point is particularly important for studying intense sources with high focusing gains.

Modeling elastic wave propagation in kidney stones with application to shock wave lithotripsy.

A time-domain finite-difference solution to the equations of linear elasticity was used to model the propagation of lithotripsy waves in kidney stones. The model was used to determine the loading on the stone (principal stresses and strains and maximum shear stresses and strains) due to the impact of lithotripsy shock waves. The simulations show that the peak loading induced in kidney stones is generated by constructive interference from shear waves launched from the outer edge of the stone with other waves in the stone. Notably the shear wave induced loads were significantly larger than the loads generated by the classic Hopkinson or spall effect. For simulations where the diameter of the focal spot of the lithotripter was smaller than that of the stone the loading decreased by more than 50%. The constructive interference was also sensitive to shock rise time and it was found that the peak tensile stress reduced by 30% as rise time increased from 25 to 150 ns. These results demonstrate that shear waves likely play a critical role in stone comminution and that lithotripters with large focal widths and short rise times should be effective at generating high stresses inside kidney stones.