Disintegration of Tissue Using High Intensity Focused Ultrasound: Two Approaches That Utilize Shock Waves

DISINTEGRATION OF TISSUE USING HIGH INTENSITY FOCUSED ULTRASOUND: TWO APPROACHES THAT UTILIZE SHOCK WAVES Adam Maxwell Zhen Xu Center for Industrial and Medical Ultrasound, Applied Physics Department of Biomedical Engineering Laboratory University of Michigan University of Washington Ann Arbor, Michigan 48109 Seattle, Washington 98105 and Brian Fowlkes Department of Urology Department of Biomedical Engineering University of Washington University of Michigan Seattle, Washington 98105 Ann Arbor, Michigan 48109 Oleg Sapozhnikov and Center for Industrial and Medical Ultrasound, Applied Physics Department of Radiology Laboratory University of Michigan University of Washington Ann Arbor, Michigan 48109 Seattle, Washington 98105 and Charles Cain Department of Acoustics, Physics Faculty Department of Biomedical Engineering Moscow State University University of Michigan Moscow 119991, Russia Ann Arbor, Michigan 48109 Michael Bailey Center for Industrial and Medical Ultrasound, Applied Physics Vera Khokhlova Laboratory Center for Industrial and Medical Ultrasound, Applied Physics University of Washington Laboratory Seattle, Washington 98105 University of Washington Lawrence Crum Seattle, Washington 98105 Center for Industrial and Medical Ultrasound, Applied Physics and Laboratory Department of Acoustics, Physics Faculty University of Washington Moscow State University Seattle, Washington 98105 Moscow 119991, Russia Introduction “Ultrasound-induced tissue For many years, HIFU surgery was urgery is moving more and more centered on utilizing a thermal effect— toward minimally-invasive proce- disintegration opens a new tissue heating and denaturation caused Sdures – using laparoscopic approach- by absorption of ultrasound.6 As the es with instruments inserted through direction in development of heating rate is dependent on local tiny incisions or catheters placed in acoustic intensity, the temperature rises blood vessels through puncture sites. HIFU medical technology” significantly enough to ablate tissue These techniques minimize the risks to only in the focal region. While thermal the patient such as bleeding complications or infection dur- ablation is the dominant interaction at lower HIFU focal ing surgery. Taken a step further, high-intensity focused intensities, higher intensities can introduce other bioeffects ultrasound (HIFU) can provide a tool to accomplish many (Fig. 2). If the temperature rises to 100oC during sonication, of the same procedures without any incision at all.1-5 With boiling bubbles appear in the tissue, inducing additional HIFU, an ultrasound transducer can be positioned outside mechanical as well as thermal damage. At higher focal inten- the body and focused through the skin and overlying tissue sities, mechanical effects of the ultrasound wave itself to deliver high-amplitude ultrasound to a target structure become significant.7,8 The large tension phase of the wave can such as a tumor (Fig. 1). Absorption of acoustic energy cause sporadic inertial cavitation or even a cloud of cavita- within the focal volume is high enough to rapidly heat the tion bubbles in the focal region in tissue—a process where tissue, effectively ‘cooking’ it within seconds or even a frac- the small gas bubbles grow and violently collapse, creating tion of a second. This procedure also removes the need for destructive effects on the tissue. Nonlinear propagation a sterile operating room: without the risk of infection, effects result in formation of high-amplitude shock waves HIFU noninvasive therapy could be done in the doctor’s around the focus which themselves create mechanical stress office or outpatient clinic. in the tissue. In addition, significantly enhanced heat deposi- 24 Acoustics Today, October 2012 Fig. 1. Diagram of HIFU surgery. The transducer emits a focused ultrasound beam through the overlying tissue layers to create a high intensity region within the organ. The focus can be translated to ablate the entire volume of interest. (Adapted from part of a figure in reference 6) tion at the shocks can induce boiling in tissue in millisec- This ultrasound-induced tissue disintegration opens a onds, much faster than typical HIFU exposures. new direction in development of HIFU medical technology. Extracorporeal shockwave lithotripsy uses such focused The technique has been dubbed ‘histotripsy’ (the prefix histo- shock waves and cavitation to break up kidney stones.9 translated from Greek to mean tissue), as an analog to Recent HIFU studies have shown that the presence of shocks lithotripsy. Two separate techniques to perform histotripsy and cavities, induced by HIFU either as a cavitation cloud or with ultrasound shock waves have been demonstrated thus millisecond boiling, can be also used to break up or mechan- far: one using a cloud of cavitation bubbles and another that ically fractionate soft tissues to tiny debris—an outcome sim- uses boiling bubbles. The cavitation-based approach has ilar to disintegration in a “remote” blender. been developed over the last 11 years at the University of Fig. 2. Bioeffects of focused ultrasound at different focal intensity levels. At lower intensities, heating through acoustic absorption is the dominant mechanism, denaturing proteins within the tissue, leaving a blanched appearance. Boiling cavities form in the lesion when the temperature reaches 100oC. At higher intensities, heating combined with microbubble cavitation can cause mechanical trauma to the tissue structure. At very high intensities, shockwaves form at the focus and the wave itself can impart significant mechanical damage such as comminution of kidney stones (lithotripsy) or fractionation of soft tissues (histotripsy). Disintegration of Tissue Using HIFU 25 Michigan,10-12 while the boiling-based method was discovered ers with multiple distinct elements. The phase of the output a few years ago at the University of Washington.13-15 The between different elements is controlled to create construc- mechanisms of generating bubbles through each mode are tive interference at a desired focal point. The advantage of quite different, but surprisingly, both techniques produce this last technique is that the focus can be electronically similar lesions through tissue disintegration. steered to different locations without physically changing the Histotripsy could be employed as a noninvasive treat- position of the device. Ultrasound imaging probes that typi- ment for many diseases, such as malignant tumors, benign cally comprise lensing and array focusing are often combined prostatic hyperplasia (BPH), deep vein thrombosis, and with HIFU transducers to create high-resolution images of congenital heart defects. The unique ability of histotripsy to the treatment site and provide treatment feedback to the actually liquefy the tissue (rather than just thermally operator. destroying it) means that the lesion content can be passed Sources used for histotripsy studies are highly focused out of natural body orifices or easily reabsorbed by sur- having similar apertures and radii of curvature ranging rounding tissue. For instance, excess prostate tissue for BPH from about 5 to 15 cm. The sources operate at high power can be passed through the urinary system, offering imme- outputs to provide intensity levels at the focus from 10 to diate decompression and relief of symptoms. Thus far, both >30 kW/cm2. Although initially sinusoidal waves are irradi- cavitation and boiling techniques have been demonstrated ated from the transducer, they become distorted while in animal studies.16-18 This article discusses the acoustics of propagating to the focus due to combined nonlinear and both types of histotripsy – including the processes of gener- diffraction effects. ation and focusing of intense ultrasound, the formation of The sound speed of high amplitude acoustic waves cavitation clouds and rapid boiling in tissue, and the inter- depends on the local pressure causing nonlinear propagation actions of ultrasound shock waves with bubbles leading to effects. The speed of sound is increased under compressive tissue disintegration. pressure and decreased for rarefactive pressure in compari- son with the ambient sound speed, c0, which leads to distor- Background tions of acoustic waveform. These nonlinear distortions The majority of HIFU sources (including those for his- accumulate over the propagation distance as a gradual steep- totripsy) are piezoelectric, made from ceramics such as leading of the wave front and finally result in formation of shocks. zirconate-titanate (PZT) or composites of PZT with passive For an initially harmonic wave, the shock formation distance 3 materials. High-voltage periodic signals are applied to the xsh is xsh = c 0r0/(2pp0f0b), where r0 is the density, p0 is piezoelectric element by a radiofrequency amplifier to gener- acoustic pressure amplitude, f0 is the ultrasound frequency, ate ultrasound vibration of the transducer surface. Focusing and b is the nonlinear parameter of the propagation medium. is accomplished by several techniques. One method is to sim- For example, the shock formation distance in water for an ply form the piezoelectric material to the shape of a spherical ultrasound wave of 2 MHz frequency and 15 MPa pressure bowl with a natural focal point at its radius of curvature (Fig. amplitude (8 kW/cm2) is 5 mm. High amplitude focal regions 3). An alternative to this approach is to couple an acoustic of HIFU transducers are typically longer than this distance lens to a flat source, which creates similar focusing

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