Sex differences in susceptibility to ischemia/reperfusion injury have been documented in humans. Premenopausal women have a lower risk of ischemic heart disease than age-matched men, whereas after menopause, the risk is similar or even higher in women. However, little is known about the effects of sex on myocutaneous ischemia/ reperfusion. To explore sex differences in wound revascularization, we utilized a murine myocutaneous flap model of graded ischemia. A cranial-based, peninsularshaped, myocutaneous flap was surgically created on the dorsum of male and female mice. Physiological, pathological, immunohistochemical, and molecular parameters were analyzed. Flaps created on female mice were re-attached to the recipient site resulting in nearly complete viability at post-operative day 10. In contrast, distal fullthickness myocutaneous necrosis was evident at 10 days post-surgery in male mice. Over the 10 day study interval, laser speckle imaging documented functional revascularization in all flap regions in female mice, but minimal distal flap reperfusion in male mice. Day 10 immunostained histologic sections confirmed significant increases in distal flap vessel count and vascular surface area in female compared to male mice. RT-PCR demonstrated significant differences in growth factor and metabolic gene expression between female and male mice at day 10. In conclusion, in a gradedischemia wound healing model, flap revascularization was more effective in female mice. The recognition and identification of sex-specific wound healing differences may lead to a better understanding of the underlying mechanisms of myocutaneous revascularization and drive novel discovery to improve soft tissue wound healing following tissue transfer for traumatic injury and cancer resection.

Background: Despite increasing survival following damage control laparotomy and open abdomen technique, little is known about the biology of visceral skin graft revascularization and separation from peritoneal contents. Methods: Following laparotomy for trauma, patients with visceral edema preventing fascial closure underwent Vicryl mesh closure followed by visceral split-thickness skin grafting and readmission graft excision and abdominal wall reconstruction. Utilizing laser speckle contrast imaging, immunochemical staining of histologic sections, and RT-PCR array technology, we examined the revascularization, microvascular anatomy, morphology, and change in gene expression of visceral skin grafts. Results: Ten patients ranging in age from 25 to 46 years underwent visceral grafting for cutaneous coverage of an open abdomen. Skin graft perfusion peaked at a mean of 350 PU by post-operative day 14 synchronous with closure of meshed interstices, and remained constant until excision. Time to graft excision ranged from 6 to 18 months. CD-31 immunostaining documented a significant (p = 0.04) increase in vascular surface area in excised grafts compared to control skin. Trichrome staining revealed an 8-fold increase in excised graft thickness. Mesothelial cells were identified within the dermal matrix of excised grafts. RT-PCR demonstrated significant up-regulation of genes involved in matrix structure and remodeling, cytoskeleton regulation, and WNT signaling; and down-regulation of genes involved in inflammation and matrix proteolysis in excised grafts compared to control skin. Conclusion: Our data document early visceral skin graft perfusion and a plateau in revascularization. Histology reveals a robust dermal matrix populated by fibroblasts and mesothelial cells within a complex supporting vascular network. Genetic analysis of excised grafts reveals growth factor, collagen, and matrix remodeling gene expression.