High-Rate Histotripsy Methods for the Rapid Removal of Soft and Fibrous Tissue

Histotripsy is a non-invasive, focused ultrasound ablation modality that uses the precise control of acoustic cavitation to disintegrate tissue. Acoustic cavitation is the transient expansion of pre-existing nuclei to dimensions orders of magnitude beyond their original size due to large increases in the tensile (peak-negative) pressure of the medium. The peak-negative pressure required to generate a cavitation bubble is defined as the cavitation threshold. Once the cavitation threshold has been reached by an applied acoustic pressure, the remaining internal pressure of the bubble results in violent expansion. Histotripsy utilizes focused ultrasound to tightly control the region in which the acoustic pressure exceeds the cavitation threshold forming cavitation bubbles within a precise focal volume. The rapid expansion and collapse of the cavitation bubbles cause large deformations to the surrounding medium at high strain rates capable of mechanically disrupting cellular structures. During histotripsy therapy, numerous cavitation events are generated from a single pulse within the tightly bound focus of the transducer, defined as the bubble cloud. The disintegration of the targeted tissue volume occurs from the rapid expansion and collapse of bubble clouds over the course of many pulses. By maneuvering the transducer array through the use of robotics or by electronically steering the focus of the array, volumetric ablation of tissue can be performed non-invasively. Histotripsy was recently granted de novo clearance from the FDA for the ablation of liver cancer establishing its clinical relevancy in the field of medicine. This work is inspired by the amazing impact of this therapy and fulfilled with the desire to expand the knowledge of the underlying mechanics of histotripsy to allow for the treatment of malignancies that have not been previously investigated. This dissertation proposal outlines the development of high-rate, non-invasive ablation of soft and fibrous tissue using single-cycle histotripsy. My Ph.D. thesis is motivated to develop histotripsy for the ablation of larger volumes than previously considered feasible and tissues that are more resistant to histotripsy-induced damage by utilizing high pulse repetition frequencies (PRF). In this work, (1) I propose histotripsy for the ablation of uterine fibroids, which are large, fibrous tumors that would require unsuitably long treatment times using traditional histotripsy methods. To deliver higher doses and treat larger volumes within a clinically relevant treatment time, (2) I investigate the effects of PRF on reiterative bubble cloud dynamics in single-cycle histotripsy, and (3) demonstrate how bubble clouds form under high PRF conditions. In the last chapters of this work, (4-5) I developed a high PRF pulsing strategy that can efficiently ablate large volumes of soft tissue and uterine fibroids. The findings and implications found in this document aim to increase the robustness of histotripsy as a non-invasive ablation therapy for many new applications by developing faster ablations and furthering the understanding of the underlying mechanics of histotripsy at clinically relevant pulsing rates.