Tissue engineered models of skin regeneration for the design and evaluation of drug release systems

The dissertation work presented here outlines the development of biomaterials for the application of drug-delivery matrices in models of skin regeneration in vitro and in vivo. The effects of fibrin hydrogels in two- and three-dimensional models of reepithelialization was studied using wounded cell monolayers, tissue engineered skin equivalents, and grafted tissues in vivo. Data obtained from this work resulted in a proposed role of fibrin in wound healing that was previously undiscovered. Furthermore, these findings helped formulate an idea for using fibrin gels as a drug release system that could greatly benefit the healing of acute and chronic wounds. As a result, a drug-delivery device for controlling the release of recombinant human keratinocyte growth factor (rHuKGF) in skin wounds was engineered to accelerate healing of wounded grafts in vivo. The mode of delivery using this device was very unique where the release of the rHuKGF was controlled by the migrating epithelial cells as they degraded the fibrin gel material. Migration and growth of the grafted skin equivalent tissues was greatly accelerated and could be attenuated with the addition an inhibitor that prevented gel degradation. Thus, local delivery was achieved in a controlled manner to those cells that are directly involved with healing of the tissues and not systemically as in bolus delivery.; This research has important implications for the treatment of chronic wound conditions and is currently being tested in a wound model using genetically diabetic mice. In addition, the conjugation scheme was cleverly designed so that it could be applied to other growth factors and therapeutics that are known to have a strong effect on wound healing. It also demonstrates that efficient design and implementation of novel models of wound healing can greatly help the invention of devices for drug-delivery and tissue engineering applications.