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Collagen and glycosaminoglycan (GAG) dermal skin substitutes (membranes) were studied as substrates for cultured human epidermal keratinocytes. Structure of dermal substitutes was optimized for pore size to promote ingrowth of fibrovascular tissue from the wound bed and for culture of human keratinocytes of the membrane's surface. Pore size of the freeze-dried material was regulated by control of the temperature of freezing between -50 degrees C and -20 degrees C and by concentration of starting materials between 0.17% and 1.62% wt/vol. A nonporous surface of collagen-GAG was laminated to the membranes to provide a planar substrate for cultured epidermal keratinocytes. Thickness of dermal substitutes was regulated by control of the volume and concentration of starting materials. Biotin was conjugated to solubilized collagen for binding with avidin of specific quantities of biologically active molecules. The optimized membranes are suitable substrates for the culture of human epidermal keratinocytes, and together with the cells yield a composite material that is histologically similar to skin.

Here we report on investigation of the role of the POU domain genes Skin-lafi (Skn-lafi/Epoc/Oct-ll) and Testes-1 (Tst-1/Oct-6/SCIP) in epidermis where proliferating basal keratinocytes withdraw from the cell cycle, migrate suprabasally, and terminally differentiate to form a muhilayered, stratified epithelium. The expression of the Skn-la/i and Tst-1 genes is linked to keratinocyte differentiation in vivo and in vitro, whereas the ubiquitous POU domain factor Oct-1 is expressed highly in both proliferating and post-mitotic keratinocytes. Analysis of Skn-la/i gene-deleted mice reveals that the Skn-la/i gene modulates the pattern of expression of the terminal differentiation marker loricrin and inhibits expression of genes encoding markers of the epidermal keratinocyte wounding response. Although epidermis from Tst-1 gene-deleted mice develops normally, epidermis from mice deleted for both Skn-la/i and Tst-1 is hyperplastic and fails to suppress expression of K14 and Spr-1 in suprabasal cells when transplanted onto athymic mice. This suggests that Skn-la/i and Tst-1 serve redundant functions in epidermis. Therefore, at least two POU domain genes, Skn-la/i and Tst-1, serve both distinct and overlapping functions to regulate differentiation of epidermal keratinocytes during normal development and wound healing.

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Further evaluation is required to determine the validity of the observed reduction in infection-related deaths in patients treated with interferon gamma.