Testosterone promotes nerve tethering and acellular biomaterial perineural fibrosis in a rat wound repair model.

Abstract

Nerve scarring after traumatic or iatrogenic exposure can lead to impaired function and pain. Nerve-adjacent biomaterials promoting a regenerative tissue response may help reduce perineural fibrosis. Our prior work suggests testosterone may promote fibrotic skin scarring, but it is unknown how testosterone alters nerve fibrosis or shifts the response to biomaterials. Sterilized Lewis rats received either testosterone cypionate (+T) or placebo (-T) biweekly. Fifteen days later, wounds were created over the sciatic nerve and covered with acellular extracellular matrix (AM) or closed primarily (PC). At day 42, force gauge testing measured the force required to mobilize the nerve and wound tissue was analyzed. Nerve mobilization force was greater in +T vs -T wounds (p<0.01). Nerves tore before gliding in 60% of +T vs 6% of -T rats. Epidermal gap (p<0.01), scar width (p<0.01), and cross-sectional scar tissue area (p=0.02) were greater in +T vs -T rats. -T vs +T rats expressed more Col-3 (p=0.02) and CD68 (p=0.02). Nerve mobilization force trended non-significantly higher for PC versus AM wounds and for +T versus -T wounds within the AM cohort. Testosterone increases nerve tethering in the wound healing milieu, altering repair and immune cell balances. Testosterone significantly increases the force required to mobilize nerves in wound beds and elevates histologic markers of scarring, suggesting that testosterone-induced inflammation may increase perineural adhesion. Testosterone may reduce the potential anti-tethering protective effect of AM. Androgen receptor antagonism may represent a therapeutic target to reduce scar-related nerve morbidity.