Three million people in this country have chronic wounds and this number is increasing by 6% per year mainly due to the wounds in the increasing number of type 2 diabetics. The current wound care costs are staggering, reaching $50 billion per year. In our research, innovative and practical methodology to treat wounds is used where individual wounds are treated in sealed transparent chambers. With the use of this model, the wound microenvironment can readily be modified in a specific fashion like a tissue culture in vivo. The wound chamber provides very reproducible experimental conditions and has clinical benefits. A new porcine diabetic wound model using the wound chamber has demonstrated delayed healing compared to healthy pigs. Preliminary data has also demonstrated decreased expression of IGF-1, and a greater response to fibroblast and keratinocyte transplantation in diabetic pigs compared to healthy controls. We hypothesize that transplantation of transgenic keratinocytes and fibroblasts expressing certain growth factors under the control of a tetracycline-regulated gene switch will restore healing in diabetic porcine skin wounds. This research program includes two new methodologies: 1) a streptozotocin-induced diabetic wound model and 2) regulatable delivery of proteins by using autologous keratinocyte and fibroblast cell lines transfected with tetracycline operator/represser controlled genes. Because gene transfer offers targeted and persistent delivery of therapeutic polypeptides, a single genetic intervention might be sufficient to promote wound repair adequately. Furthermore, the use of the tetracycline operator/represser system allows timing of onset and precise titration of the delivered proteins as well as sequential expression of these proteins, which could maximize the biological effect of the growth factors delivered. These methodologies will help us understand and treat diabetic wounds. This constitutes a safe and practical system for in vivo gene delivery to skin wounds, offering therapeutic potential for other skin diseases.
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