Tissue Engineering for the Treatment of Delayed Healing

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DESCRIPTION (provided by applicant): A more effective tissue engineering approach to chronic wounds may require the replacement of phenotypically altered wound cells, possibly through the use of stem ceils. Using green fluorescent protein (GFP) transgenic and wild type mice, we have shown that infusion of GFP + marrow cells can result in the production of blood vessels, keratinocytes, and other structures in wounded skin. A new model of delayed healing we have developed using excisional wounds of routine tails will allow us to extend these observations. In parallel, we have found that non-healing human chronic wounds heal dramatically with the topical application of autologous bone marrow-derived cells. We propose the following specific aims: 1) to characterize the engraftment of unseparated marrow cells in a murine model of delayed healing using GFP - marrow cells and different methods of marrow cell delivery to wounds; 2) to determine the marrow cell subsets that accelerate healing in murine wounds. We will evaluate unseparated marrow, as well as Lin- and positive Lin+ marrow cells, mesenchymal stem cells, and hematopoietic stems cells, including Lin-Sca+ and Lin- Ho/l0Rho/10cells. 3) to assess the topical delivery of marrow-derived cells. In vitro and in vivo studies will determine the feasibility of this approach using specific marrow-derived cells in a Factor XIII cross-linked fibrin gel; 4) Determine whether autologous marrow-derived cells can correct the abnormal cellular phenotype of chronic wounds. We will apply specific subsets of marrow cells to non-healing human wounds and will determine whether healing and normal phenotype are restored in wound fibroblasts. These studies will advance our understanding of how to reconstitute the wound bed and whether it is possible to correct the abnormal cellular phenotype in non-healing wounds.