Enhanced Survival and Accelerated Perfusion of Skin Flap to Recipient Site Following Administration of Human α1-Antitrypsin in Murine Models

Abstract

Objective:

Skin flaps are routinely used in reconstructive surgery yet remain susceptible to ischemia and necrosis. Distant flaps require lengthy time to detach causing patient discomfort. Human α1-antitrypsin (hAAT) is a clinically available serum glycoprotein. hAAT was shown to support mature vessel formation and enhance tissue survival following ischemia–reperfusion injuries. The purpose of the presented study was to examine the effect of hAAT on skin flap survival and distant “tube” flap perfusion through its recipient site.

Approach:

Random-pattern skin flaps were performed on mice treated with clinical-grade hAAT using three unique routes of administration (transgenic, i.p. and s.c. infiltration); necrotic area and tissue perfusion were assessed. Blockade of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) were used to explore aspects of mechanism of action. A distant tube flap model was performed to examine time to perfusion.

Results:

hAAT-treated mice displayed approximately two-fold smaller necrotic flap areas versus controls across all hAAT administration routes. Flaps displayed greater perfusion as early as 3 days postsurgery (64.6% ± 4.0% vs. 43.7% ± 1.7% in controls; p = 0.007). hAAT-mediated flap survival was prominently NOS dependent, but only partially VEGF dependent. Finally, distant flaps treated with hAAT displayed significantly earlier perfusion versus controls (mean 9.6 ± 1.6 vs. 13.1 ± 1.0 days; p = 0.0005).

Innovation:

The established safety record of hAAT renders it an attractive candidate toward improving skin flap surgery outcomes, particularly during VEGF blockade.

Conclusions:

hAAT treatment enhances survival and accelerates perfusion of skin flaps in animal models in a NOS-dependent manner, partially circumventing VEGF blockade. Further mechanistic studies are required.