Histotripsy is the application of pulsed focused ultrasound to targeted tissue to induce cavitational processes that lead to non-thermal, mechanical tissue fractionation (ultimately converting the targeted tissue into an acellular liquid). Each ultrasound pulse creates a localized, highly dynamic cluster of microbubbles (a bubble cloud) that oscillates and violently collapses. Over the course of successive pulses architectural structure is mechanically fractionated and the cells destroyed within the targeted volume. Histotripsy is applicable to a broad spectrum of diseases within a variety of organs. For the purposes of this proposal, we focus on further studying this technology within the prostate, specifically assessing the suitability of histotripsy for treatment of benign prostatic hyperplasia (BPH). BPH is a common disease where overgrowth of prostate tissue results in difficulty urinating and debilitating lower urinary tract symptoms. Unfortunately, current therapy designed to debulk or remove excess BPH tissue is lacking in that surgical transurethral resection of the prostate (TURP), albeit an effective therapy, is an invasive operative procedure with associated surgical risks. Pharmacologic management and minimally invasive treatments, although widely employed for BPH, produce uniformly inferior results compared to TURP. Histotripsy may therefore be an ideal technology for treatment of BPH, combining the morbidity profile of minimally invasive ablative technologies with the effectiveness (tissue debulking) achieved with TURP. We have previously demonstrated the feasibility of using histotripsy to transcutaneously ablate prostate tissue in a canine model. The proposed research will quantify the dose dependent threshold for collateral damage of critical periprostatic structures such as the urinary sphincter, neurovascular bundles, rectum, and bladder trigone. Furthermore, the accuracy and precision of ultrasound guided histotripsy will be assessed in an in-vivo chronic canine model that incorporates inflammatory effects and wound healing processes. Histotripsy prostate treatment in cadaver models is also planned to explore how anatomic differences of prostate tissue composition and anatomic location between the canine and human will impact histotripsy effectiveness. A thorough understanding of these histotripsy-tissue interactions will provide a rational basis for further development and optimization of histotripsy BPH treatment.