TP508 is a synthetic
peptide corresponding to
amino acids 508 through 530 of human
prothrombin. We previously demonstrated that a single topical application of
TP508 stimulates revascularization and healing of acute incisional and excisional
wounds in normal, healthy rat skin. To determine if
TP508 would enhance wound healing in ischemic skin, we used bipedicle flaps, cranially based flaps, and free grafts to surgically create ischemic regions on the backs of rats. Full-thickness, circular excisions were made within the flaps or grafts and immediately treated with a single application of saline +/-
TP508 (0.1 microg/
wound). Compared to
wound closure in normal skin, ischemic skin
wounds exhibited delayed closure, and the length of delay correlated with the degree of surgically induced
ischemia.
TP508 significantly accelerated closure in both normal and ischemic skin, resulting in closure rates that were increased within the first 7 days of wounding by 30% in normal tissue and bipedicle flaps, 50% in cranially based flaps, and 225% in free grafts. Moreover, in both flap models,
TP508 restored the rate of closure to a rate approximating the control rate observed in normal skin. Histological comparisons of
wound tissue from normal skin and cranially based flaps showed that
ischemia reduced early recruitment of inflammatory cells at day 1 but increased inflammatory cell numbers in
wound beds at day 14.
TP508 treatment of ischemic flap
wounds significantly increased early inflammatory cell recruitment and restored the normal rapid resolution of the inflammatory phase. In addition, at day 7, TP508-treated
wounds appeared to have an increased number of large functional blood vessels compared to saline controls. These studies support the potential efficacy of
TP508 in treating ischemic
wounds in humans.