title: High resolution imaging of epithelial injury in the sheep cervicovaginal tract: a promising model for testing safety of candidate microbicides.
abstract: BACKGROUND
  Access to readily available large animal models and sensitive noninvasive techniques that can be used for the evaluation of microbicide-induced changes in tissue could significantly facilitate preclinical evaluations of microbicide safety. The sheep cervicovaginal tract, with stratified squamous epithelium similar to humans, holds promise as a large animal model used before nonhuman primates. In addition, optical coherence tomography (OCT) could enable high resolution visualization of tissue morphology and noninvasive assessment of microbicide-induced epithelial injury.
  
  
  METHODS
  We evaluated the dose response of sheep cervicovaginal tract to benzalkonium chloride (BZK). Twenty sheep received treatment with phosphate-buffered saline or BZK solution (2%, 0.2%, or 0.02%). Pre- and posttreatment colposcopy and OCT images were collected and graded based on World Health Organization criteria and a previously reported scoring system, respectively. Biopsies were collected and the degree of epithelial injury and its thickness was assessed based on histology and OCT.
  
  
  RESULTS
  The sheep cervicovagina exhibited anatomic and microscopic features similar to the human. Extensive loss of the epithelium was noted on colposcopy and OCT after application of 2% BZK. Colposcopy detected findings in half of sheep and OCT in all sheep treated with 0.2% BZK. OCT detected differences in the 0.02% BZK-treated group compared with controls, whereas colposcopy failed to detect any changes.
  
  
  CONCLUSIONS
  The sheep cervicovagina is similar to humans, and exhibits dose dependent epithelial changes after BZK treatment. These findings suggest that the sheep model and OCT may become valuable tools for the safety evaluation of candidate microbicides, and warrant continued development.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecology, University of Texas Medical Branch, Galveston, TX 77555, USA. klvincen@utmb.edu
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Vincent
authors.forename: Nigel
authors.initials: N
authors.lastname: Bourne
authors.forename: Brent A
authors.initials: BA
authors.lastname: Bell
authors.forename: Gracie
authors.initials: G
authors.lastname: Vargas
authors.forename: Alai
authors.initials: A
authors.lastname: Tan
authors.forename: Daniel
authors.initials: D
authors.lastname: Cowan
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Stanberry
authors.forename: Susan L
authors.initials: SL
authors.lastname: Rosenthal
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamedi
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D001548:Benzalkonium Compounds / Q000494:pharmacology*; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D006801:Humans; D023421:Models, Animal; D012756:Sheep; D041623:Tomography, Optical Coherence; D014621:Vagina / Q000166:cytology / Q000187:drug effects*
chemical_list: D000891:Anti-Infective Agents, Local; D001548:Benzalkonium Compounds