In this article, the negative pressure values at which inertial cavitation consistently occurs in response to a single, 2-cycle, focused ultrasound pulse were measured in several media relevant to cavitation-based ultrasound therapy. The pulse was focused into a chamber containing one of the media, which included liquids, tissue-mimicking materials, and ex-vivo canine tissue. Focal waveforms were measured by two separate techniques using a fiber-optic hydrophone. Inertial cavitation was identified by high-speed photography in optically transparent media and an acoustic passive cavitation detector. The probability of cavitation (Pcav) for a single pulse as a function of peak negative pressure (p−) followed a sigmoid curve, with the probability approaching 1 when the pressure amplitude was sufficient. The statistical threshold (defined as Pcav = 0.5) was between p− = 26.0–30.0 MPa in all samples with a high water content, but varied between p− = 13.7 to > 36 MPa for other media. A model for radial cavitation bubble dynamics was employed to evaluate the behavior of cavitation nuclei at these pressure levels. A single bubble nucleus with an inertial cavitation threshold of p− = 28.2 MPa was estimated to have a 2.5 nm radius in distilled water. These data may be valuable for cavitation-based ultrasound therapy to predict the likelihood of cavitation at different pressure levels and dimensions of cavitation-induced lesions in tissue.

This pulsed cavitational ultrasound system is capable of transcutaneous nonthermal destruction of renal tissue. Refinement of this technology for noninvasive ablation of small renal masses is currently under way.

The ability of ultrasound to produce highly controlled tissue erosion was investigated. This study is motivated by the need to develop a noninvasive procedure to perforate the neonatal atrial septum as the first step in treatment of hypoplastic left heart syndrome. A total of 232 holes were generated in 40 pieces of excised porcine atrial wall by a 788 kHz single-element transducer. The effects of various parameters [e.g., pulse repetition frequency (PRF), pulse duration (PD), and gas content of liquid] on the erosion rate and energy efficiency were explored. An Isppa of 9000 W/cm2, PDs of 3, 6, 12, and 24 cycles; PRFs between 1.34 kHz and 66.7 kHz; and gas saturation of 40-55% and 79-85% were used. The results show that very short pulses delivered at certain PRFs could maximize the erosion rate and energy efficiency. We show that well-defined perforations can be precisely located in the atrial wall through the controlled ultrasound tissue erosion (CUTE) process. A preliminary in vivo experiment was conducted on a canine subject, and the atrial septum was perforated using CUTE.

Purpose In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently, there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Material and Methods Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapor cavity causes tissue disintegration. Results Recent pre-clinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumors, kidney stone fragmentation, enhancing antitumor immune response, and tissue decellularization for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Conclusions Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilize different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of noninvasive surgery.

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Cavitation memory effects occur when remnants of cavitation bubbles (nuclei) persist in the host medium and act as seeds for subsequent events. In pulsed cavitational ultrasound therapy, or histotripsy, this effect may cause cavitation to repeatedly occur at these seeded locations within a target volume, producing inhomogeneous tissue fractionation or requiring an excess number of pulses to completely homogenize the target volume. We hypothesized that by removing the cavitation memory, i.e., the persistent nuclei, the cavitation bubbles could be induced at random locations in response to each pulse; therefore, complete disruption of a tissue volume may be achieved with fewer pulses. To test the hypothesis, the cavitation memory was passively removed by increasing the intervals between successive pulses, Δt, from 2, 10, 20, 50 and 100, to 200 ms. Histotripsy treatments were performed in red blood cell tissue phantoms and ex vivo livers using 1-MHz ultrasound pulses of 10 cycles at P−/P+ pressure of 21/59 MPa. The phantom study allowed for direct visualization of the cavitation patterns and the lesion development process in real time using high-speed photography; the ex vivo tissue study provided validation of the memory effect in real tissues. Results of the phantom study showed an exponential decrease in the correlation coefficient between cavitation patterns in successive pulses from 0.5 ± 0.1 to 0.1 ± 0.1 as Δt increased from 2–200 ms; correspondingly, the lesion was completely fractionated with significantly fewer pulses for longer Δts. In the tissue study, given the same number of therapy pulses, complete and homogeneous tissue fractionation with well-defined lesion boundaries was achieved only for Δt ≥ 100 ms. These results indicated that the removal of the cavitation memory resulted in more efficient treatments and homogeneous lesions.

Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. Conventional histotripsy treatments have used longer pulses from 3 to 10 cycles wherein the lesion-producing bubble cloud generation depends on the pressure-release scattering of very high peak positive shock fronts from previously initiated, sparsely distributed bubbles (the “shock-scattering” mechanism). In our recent work, the peak negative pressure (P−) for generation of dense bubble clouds directly by a single negative half cycle, the “intrinsic threshold,” was measured. In this paper, the dense bubble clouds and resulting lesions (in RBC phantoms and canine tissues) generated by these supra-intrinsic threshold pulses were studied. A 32-element, PZT-8, 500 kHz therapy transducer was used to generate very short (< 2 cycles) histotripsy pulses at a pulse repetition frequency (PRF) of 1 Hz and P− from 24.5 to 80.7 MPa. The results showed that the spatial extent of the histotripsy-induced lesions increased as the applied P− increased, and the sizes of these lesions corresponded well to the estimates of the focal regions above the intrinsic cavitation threshold, at least in the lower pressure regime (P− = 26–35 MPa). The average sizes for the smallest reproducible lesions were approximately 0.9 × 1.7 mm (lateral × axial), significantly smaller than the −6dB beamwidth of the transducer (1.8 × 4.0 mm). These results suggest that, using the intrinsic threshold mechanism, well-confined and microscopic lesions can be precisely generated and their spatial extent can be estimated based on the fraction of the focal region exceeding the intrinsic cavitation threshold. Since the supra-threshold portion of the negative half cycle can be precisely controlled, lesions considerably less than a wavelength are easily produced, hence the term “microtripsy.”

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technology guided by realtime imaging. Using focused ultrasound delivered from outside the body, histotripsy mechanically destroys tissue through cavitation, rendering the target into acellular debris. The material in the histotripsy ablation zone is absorbed by the body within 1-2 months, leaving a minimal remnant scar. Histotripsy has also been shown to stimulate an immune response and induce abscopal effects in animal models, which may have positive implications for future cancer treatment. Histotripsy has been investigated for a wide range of applications in preclinical studies, including the treatment of cancer, neurological diseases, and cardiovascular diseases. Three human clinical trials have been undertaken using histotripsy for the treatment of benign prostatic hyperplasia, liver cancer, and calcified valve stenosis. This review provides a comprehensive overview of histotripsy covering the origin, mechanism, bioeffects, parameters, instruments, and the latest results on preclinical and human studies.