title: Histotripsy homogenization of the prostate: thresholds for cavitation damage of periprostatic structures.
abstract: OBJECTIVE
  Histotripsy is a noninvasive, pulsed ultrasound technology that produces mechanically homogenized tissue within targeted volumes. Previous work has demonstrated prostatic tissue debulking in a canine model. The aim was to establish safety thresholds by evaluating histologic changes of urinary sphincter, neurovascular bundle (NVB), and rectum after targeted histotripsy treatment of these critical structures.
  
  
  METHODS
  Rectum, urinary sphincter, and NVB in five anesthetized canines were targeted for histotripsy treatment (50 total points). Locations received 1k, 10k, or 100k acoustic pulses (4 microsecond, 1 MHz) at a repetition frequency of 500 Hz. Canine subjects were euthanized immediately (2), survived 3 days (1), or 2 weeks (3) after treatment. Prostates, periprostatic tissue, and rectum were harvested and processed for histology.
  
  
  RESULTS
  The sphincter was structurally intact with minimal muscle fiber disruption even after 100k pulses (n=10). Undamaged nerves, arteries, and veins of the NVB were seen despite mechanical homogenization of surrounding loose connective tissue (n=19). The rectum, however, exhibited dose-dependent damage (n=20). 1k pulses yielded mild submucosal hemorrhage. 10k pulses resulted in moderate collagen disruption and focal mucosal homogenization. 100k pulses produced damage to the mucosa and muscularis propria with extensive hemorrhage and collagen disruption. One canine treated with 100k pulses needed early euthanasia (day 3) because of complications from a urine leak.
  
  
  CONCLUSIONS
  Histotripsy histologic tissue effect varied based on targeted structure with substantial structural preservation of NVB and sphincter. Rectal subclinical damage was apparent after 1k pulses and increased in extent and severity with escalating doses. Future work will include assessment of functional outcomes and refinement of these initial safety thresholds.
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Styn
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Hall
authors.forename: J Brian
authors.initials: JB
authors.lastname: Fowlkes
authors.forename: Charles A
authors.initials: CA
authors.lastname: Cain
authors.forename: William W
authors.initials: WW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D004285:Dogs; D006416:Hematoxylin / Q000378:metabolism; D008297:Male; D059351:Organ Sparing Treatments / Q000379:methods*; D011467:Prostate / Q000098:blood supply / Q000294:innervation / Q000473:pathology*; D012007:Rectum / Q000473:pathology; D013194:Staining and Labeling; D014464:Ultrasonic Therapy / Q000009:adverse effects* / Q000379:methods*
chemical_list: D006416:Hematoxylin