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.

Public Health Relevance

Histotripsy is potentially a transformational technology that could evolutionize the way many surgical diseases are treated. For BPH treatment, noninvasive debulking of the transition zone of the prostate is possible with fractionated tissue simply voided with urination. Research is proposed to quantify tissue damage threshold for periprostatic structures, define the precision of histotripsy ablation, and investigate issues with translation of this technology to a human model. Histotripsy could significantly reduce surgical risk and comorbid complications among patients in need of definitive prostate debulking for BPH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087871-05
Application #
8699758
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2010-08-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$316,937
Indirect Cost
$111,512
Name
University of Michigan Ann Arbor
Department
Urology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Schade, George R; Styn, Nicholas R; Ives, Kimberly A et al. (2014) Prostate histotripsy: evaluation of prostatic urethral treatment parameters in a canine model. BJU Int 113:498-503
Roberts, William W (2014) Development and translation of histotripsy: current status and future directions. Curr Opin Urol 24:104-10
Allam, Christopher L; Wilkinson, J Erby; Cheng, Xu et al. (2013) Histotripsy effects on the bladder trigone: functional and histologic consequences in the canine model. J Endourol 27:1267-71
Schade, George R; Styn, Nicholas R; Hall, Timothy L et al. (2012) Endoscopic assessment and prediction of prostate urethral disintegration after histotripsy treatment in a canine model. J Endourol 26:183-9
Wang, Tzu-Yin; Xu, Zhen; Hall, Timothy et al. (2011) Active focal zone sharpening for high-precision treatment using histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 58:305-15
Styn, Nicholas; Hall, Timothy L; Fowlkes, J Brian et al. (2011) Histotripsy homogenization of the prostate: thresholds for cavitation damage of periprostatic structures. J Endourol 25:1531-5