046 Characterization of Wound Repair Effects after rAd-p21 Treatment

Excessive scarring is a significant clinical problem, resulting in both adverse tissue form and function and the goal of therapeutic interventions is to reduce and prevent excessive scarring. We have demonstrated that a recombinant adenovirus containing the cyclin-dependent kinase inhibitor p21 (rAd-p21), inhibited scar formation by blocking cell cycle progression and attenuated cell proliferation at the wound site (Perkins et al 2002). Recently, we have shown rAd-p21 specific antiproliferative effects on granulation tissue in vivo(Gu, et al, manuscript submitted). Safety parameters using rAd-p21 for anti-scarring may include effects on wound strength and dehiscence of the wound. We tested effects of rAd-p21 on wound strength in vivo using tensile strength as an endpoint and included comparisons with other clinically relevant antiproliferative agents. Specifically, rAd-p21 at doses from 1 × 107 to 3.8 × 1010 particle (PN) per incision was administered intradermally to linear rat incisions and assayed 14–28 days post treatment. rAd-p21 mildly reduced tensile strength at high doses (≥3 × 1010PN), whereas low to moderate doses (1 × 107 to 1 × 1010PN) had no effect. Interestingly, all rAd-p21 treated wounds regained tensile strength indistinguishable from vehicle control, 4 weeks after treatment, suggesting that rAd-p21 wounds recover with time. An adenovirus control vector, not containing a gene (rAd-Empty), showed subtle reduction of tensile strength that was only statistically significant at day 21. This suggests that delivery of rAd-Empty alone in the wound has little effect on wound strength. Triamcinolone at 5 mg/mL/wound, 5-FU at 10 mg/mL/wound, and low doses of MMC did not significantly reduce tensile strength, although high doses of MMC (0.2 mg/mL/wound) severely reduced tensile strength which failed to recover after 28 days. Morphological analysis of all groups revealed necrosis only in the MMC treatment. This data suggests that rAd-p21 may reduce the hyperproliferative status in excessive scar formation with minimal effects on wound strength.