Premium
Evolution of ischemia and neovascularization in a murine model of full thickness human wound healing
Author(s) -
Karim Aos S.,
Liu Aiping,
Lin Christie,
Uselmann Adam J.,
Eliceiri Kevin W.,
Brown Matthew E.,
Gibson Angela L. F.
Publication year - 2020
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/wrr.12847
Subject(s) - neovascularization , wound healing , cd31 , skin grafting , medicine , pathology , angiogenesis , in vivo , epidermis (zoology) , transplantation , ex vivo , ischemia , regeneration (biology) , immunohistochemistry , surgery , anatomy , biology , microbiology and biotechnology , cancer research
Abstract Translation of wound healing research is limited by the lack of an appropriate animal model, due to the anatomic and wound healing differences in animals and humans. Here, we characterize healing of grafted, full‐thickness human skin in an in vivo model of wound healing. Full‐thickness human skin, obtained from reconstructive operations, was grafted onto the dorsal flank of NOD.Cg‐ Kit W41J Tyr + Prkdc scid Il2rg tm1Wjl /ThomJ mice. The xenografts were harvested 1 to 12 weeks after grafting, and histologic analyses were completed for viability, neovascularization, and hypoxia. Visual inspection of the xenograft shows drying and sloughing of the epidermis starting at week four. By week 12, the xenograft appears healed but has lost 63.05 ± 0.24% of the initial graft size. There is histologic evidence of epidermolysis as early as 2 weeks, which progresses until week 4, when new epidermis appears from the wound edges. Epidermal regeneration is complete by week 12, although the epidermis appears hypertrophied. An initial increase of infiltrating immune mouse cells into the xenograft normalizes to baseline 6 months after grafting. Neovascularization, as evidenced by positive staining for the proteins human CD31 and alpha smooth muscle actin, is present as early as 2 weeks after grafting at the interface between the xenograft and the mouse tissue. CD31 and alpha smooth muscle actin staining increased throughout the xenograft over the 12 weeks, leading to greater viability of the tissue. Likewise, there is increased Hypoxia Inducible Factor 1‐alpha expression at the interface of viable and nonviable tissue, which suggest a hypoxia‐driven process causing early graft loss. These findings illustrate human skin wound healing in an ischemic environment, providing a timeline for use of full thickness human skin after grafting in a murine model to study mechanisms underlying human skin wound healing.