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High Resolution Imaging of Epithelial Injury in the Sheep Cervicovaginal Tract: A Promising Model for Testing Safety of Candidate Microbicides

Vincent, Kathleen L. MD*†‡; Bourne, Nigel PHD§; Bell, Brent A. BS; Vargas, Gracie PHD‡∥; Tan, Alai PHD; Cowan, Daniel MD#; Stanberry, Lawrence R. MD, PHD††; Rosenthal, Susan L. PHD; Motamedi, Massoud PHD‡**

Sexually Transmitted Diseases: May 2009 - Volume 36 - Issue 5 - p 312-318
doi: 10.1097/OLQ.0b013e31819496e4

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.

Optical coherence tomography, a high resolution imaging method, used with colposcopy in the sheep cervicovaginal tract detected a dose-dependent response to benzalkonium chloride, demonstrating potential for microbicide safety evaluations.

From the *Department of Obstetrics and Gynecology, Division of Gynecology; †Department of Pediatrics, Division of Adolescent and Behavioral Health; ‡Center for Biomedical Engineering; §Department of Pediatrics, Division of Pediatric Vaccinology, Sealy Center for Vaccine Development; ∥Department of Neuroscience and Cell Biology; ¶Department of Preventive Medicine and Community Health, Office of Biostatistics and Epidemiology; #Department of Pathology, Division of Anatomic Pathology; and **Department of Ophthalmology, University of Texas Medical Branch, Galveston, Texas; and ††Department of Pediatrics, New York City, New York

The authors thank Katie Johnston, Jingna Wei, and Rachael Stegall for technical assistance, and Dan Freeman for statistical consultation.

Supported by National Institutes of Health (U19 AI060598) and Starpharma (Melbourne, Australia).

Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Correspondence: Kathleen L. Vincent, MD, 301 University Boulevard, Galveston, Texas 77555-0319. E-mail:

Received for publication July 31, 2008, and accepted Nov 8, 2008.

© Copyright 2009 American Sexually Transmitted Diseases Association