1. Comparison of Prostaglandin Analog Exposure on Wound Healing Response in the Porcine Model Mark McDermott, Fu-Shin X. Yu, Jia Yin, Ashok Kumar, Ke-Ping Xu Kresge Eye Institute Wayne State University, Detroit, MI This study was funded by an unrestricted grant from Allergan, Inc. The authors have no financial relationships to disclose.

2. Abstract  Purpose: To determine the effect of prostaglandin analog exposure on corneal wound healing.  Methods: Standardized 5 mm epithelial wounds were made with ex vivo whole globe porcine eyes (n = 3). Globes were incubated for 24 hours in MEM before topical administration of 30 µL of test agents (saline control, toxic control [Triton], Travatan Z ®, Travatan ®, Lumigan ®, and Xalatan ® ). Wounds were exposed for 10 minutes to test agent, rinsed twice with 3 mL PBS, and subsequently 2 mL fresh MEM were added. Forty-eight hours postincision, wound healing response and epithelial defects were evaluated by staining (Richardson’s staining solution).  Results: Forty-eight hours after 5-mm incision, corneoepithelial wounds had a mean healed percentage of: baseline saline control = 96.89%, toxic control = 6.06%, Lumigan ® = 97.32%, Travatan ® = 84.76%, Travatan Z ® = 99.80%, and Xalatan ® = 80.51%. The wound size differences of Lumigan ®, Travatan ® and Travatan Z ® were not statistically significant from the saline control (P =.260, P =.141, P =.278 respectively). Xalatan ® statistically significantly delayed wound closure compared to saline control, Lumigan ®, and Travatan Z ® (P <.001 and P <.001, respectively).  Conclusion: The ex vivo porcine model permits the quantitative assessment of the impact of pharmaceutical agents on corneoepithelial wound healing. Lumigan ® and Travatan Z ® did not delay wound healing response rates. The effect of antihypertensive treatment on wound healing should be considered for patients following glaucoma filtration and/or cataract surgery.

3. Introduction  Exposure of corneal epithelial cells to irritants can trigger a cellular stress response, altering expression of factors involved in initiation of wound healing.  Ocular irritancy of ophthalmic medications in humans can be predicted using ex vivo models. 1 –In a bovine cornea model, benzalkonium chloride (BAK) and sodium dodecyl sulfate (SDS)  Induced tight junction disruption, increased permeability of corneal epithelium, and caused breakdown of epithelial barrier  Altered dose- and time-dependent binding activity of transcription factors (eg, AP-1 and NF  B)  A porcine cornea model is introduced to evaluate ophthalmic medication tolerability and toxicity on epithelial wound healing. 1. Xu et al. Toxicol Sci. 2000; 58:306-314.

4. Purpose  To determine the effect of prostaglandin analog exposure on corneal wound healing.

5. Methods  Standardized 5-mm epithelial wounds were made with ex vivo whole globe porcine eyes (n = 3).  Globes were incubated for 24 hours in minimum essential medium (MEM) before topical administration of 30 µL of test agents: –Saline control –Toxic control (Triton) –Travatan Z ® (travoprost 0.004%; sofZia TM ; Alcon Laboratories, Inc.; Fort Worth, TX) –Travatan ® (travoprost 0.004%; 0.015% BAK; Alcon Laboratories, Inc.; Fort Worth, TX) –Lumigan ® (bimatoprost 0.03%; 0.005% BAK; Allergan, Inc.; Irvine, CA) –Xalatan ® (latanoprost 0.005%; 0.02% BAK; Pfizer, Inc.; New York, NY)  Wounds were exposed for 10 minutes to test agent, rinsed twice with 3 mL PBS and subsequently 2 mL fresh MEM were added.  Wound healing response and epithelial defects were evaluated by staining (Richardson’s staining solution) 48 hours postincision.

6. Corneoepithelial Wound Healing Original wound 48 hours post-wounding ControlTriton X-100Lumigan ® Travatan ® Travatan Z ® Xalatan ®

7. Corneoepithelial Wound Healing  Wound healing with Lumigan ®, Travatan ®, and Travatan Z ® did not differ significantly from control. * *Significantly (P <.001) delayed healing compared with control, Lumigan ®, and Travatan Z ®. ControlTritonLumigan ® Travatan ® Travatan Z ® Xalatan ®

8. Discussion  Wound healing response in porcine eyes differs among the PGAs evaluated. –This may be dependent on a combination of the active ingredient and the preservative.

9. Conclusion  The ex vivo porcine model permits the quantitative assessment of the impact of pharmaceutical agents on corneoepithelial wound healing.  Lumigan ®, Travatan ®, and Travatan Z ® did not delay wound healing response rates, while wound healing was delayed with Xalatan ®.  The effect of IOP-lowering agents on wound healing may be a consideration for patients following glaucoma filtration or cataract surgery.