title: Histotripsy of the Prostate in a Canine Model: Characterization of Post-Therapy Inflammation and Fibrosis.
abstract: BACKGROUND
  Histotripsy is a nonthermal, noninvasive, pulsed ultrasound technology that homogenizes tissue within the targeted volume. From previous experiments, it appeared that the resultant fibrotic response from histotripsy was limited compared with the typical tissue response seen after thermoablation. The objective of this study was to characterize the inflammatory response and quantify patterns of collagen deposition 6 weeks after in vivo canine prostate histotripsy.
  
  
  METHODS
  Histotripsy was applied to the left half of eight canine prostates to produce an intraparenchymal zone of tissue homogenization. Six weeks after treatment, prostates were harvested, sectioned, and stained with hematoxylin and eosin for histologic evaluation, CD3, CD20, and Mac387 immunohistochemistry to characterize the inflammatory components, and picrosirius red staining to identify collagen.
  
  
  RESULTS
  Seven of eight treated prostates exhibited only minimal residual inflammation. Visual microscopic analysis of picrosirius red slides revealed a band of dense collagen (0.5 mm wide) immediately adjacent to the cavity produced by histotripsy. This was surrounded by a second band (1 mm wide) of less dense collagen interspersed among glandular architecture. A lobar distribution of epithelial atrophy and basal cell hyperplasia reminiscent of periurethral glands and ducts was apparent surrounding the margin of the treatment cavities. Tissue loss (-31%) was apparent on the treated side of all prostates while four demonstrated a net decrease in collagen content.
  
  
  CONCLUSIONS
  In vivo histotripsy of canine prostate produced a decrease in prostate volume coupled with a limited inflammatory and fibrotic response. A narrow (1.5 mm) band of fibrosis around the empty, reepithelialized treatment cavity was observed 6 weeks after treatment. In four cases, an overall reduction in collagen content was measured. Further studies are planned to correlate these histologic findings with alteration in mechanical tissue properties and to explore histotripsy strategies for treatment of benign prostatic hyperplasia that optimize tissue volume removal with minimization of fibrosis.
authors.affiliation: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Darnell
authors.affiliation: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Hall
authors.affiliation: 2 Department of Pathology, University of Michigan , Ann Arbor, Michigan.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: 3 Department of Urology, University of Michigan , Ann Arbor, Michigan.
authors.forename: Xu
authors.initials: X
authors.lastname: Cheng
authors.affiliation: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Ives
authors.affiliation: 3 Department of Urology, University of Michigan , Ann Arbor, Michigan.
authors.forename: William W
authors.initials: WW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005355:Fibrosis; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008297:Male; D011467:Prostate / Q000473:pathology*; D011470:Prostatic Hyperplasia / Q000209:etiology / Q000473:pathology; D014464:Ultrasonic Therapy / Q000009:adverse effects* / Q000379:methods; D036761:Ultrasound, High-Intensity Focused, Transrectal / Q000009:adverse effects*
chemical_list: D003094:Collagen