The ultimate goal of our proposal is to genetically engineer a therapeutic human skin substitute for use in the treatment of skin lesions such as skin wounds (e.g., pathological or traumatic) and ulcers (e.g., venous and diabetic ulcers). Chronic skin ulcers are particularly problematic as they typically become infected resulting in impaired wound healing and increased complications with undesirable consequences such as amputation. Today's marketed therapeutic skin substitute products are cellular or acellular and composed of varying combinations of collagen-based or artificial matrixes supplemented with primary human keratinocytes and/or fibroblasts. These products have been designed to replace or compensate for non-functioning skin. However, none of the marketed products has been optimized to protect the wound bed from infection. Additionally, cellular skin therapies have been shown to be exquisitely sensitive to the toxic effects of commonly used antimicrobial agents. Human-derived, endogenous antimicrobial peptides, such as the defensins, have emerged as an exciting new therapeutic approach to enhance innate host defense mechanisms against invading microorganisms. This presents an opportunity for the development of innovative, genetically enhanced human skin substitute products which express antimicrobial peptides to defend the wound site from bacterial invasion while allowing keratinocyte proliferation and expediting wound closure. In the last year advances in ex vivo genetic engineering of a patented human keratinocyte cell line at Stratatech Corporation has made us uniquely positioned to generate genetically enhanced human skin substitutes for use in the burn and chronic skin wound market.
