Phase II clinical trials have reported that acute treatment of surgical skin
wounds with the therapeutic
peptide alpha
Connexin Carboxy-Terminus 1 (αCT1) improves cutaneous
scar appearance by 47% 9-month postsurgery. While
Cx43 and ZO-1 have been identified as molecular targets of αCT1, the mode-of-action of the
peptide in
scar mitigation at cellular and tissue levels remains to be further characterized.
Scar histoarchitecture in αCT1 and vehicle-control treated skin
wounds within the same patient were compared using biopsies from a Phase I clinical trial at 29-day postwounding. The sole effect on
scar structure of a range of epidermal and dermal variables examined was that αCT1-treated
scars had less alignment of
collagen fibers relative to control
wounds-a characteristic that resembles unwounded skin. The with-in subject effect of αCT1 on
scar collagen order observed in Phase I testing in humans was recapitulated in Sprague-Dawley rats and the IAF hairless guinea pig. Transient increase in histologic
collagen density in response to αCT1 was also observed in both animal models. Mouse NIH 3T3 fibroblasts and primary human dermal fibroblasts treated with αCT1 in vitro showed more rapid closure in scratch
wound assays, with individual cells showing decreased directionality in movement. An agent-based computational model parameterized with fibroblast motility data predicted
collagen alignments in simulated
scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D
collagen matrix postwounding that is similar to unwounded skin-changes that correlate with long-term improvement in
scar appearance.