DERIVATIZED HYALURONAN FOR WOUND HEALING

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DESCRIPTION (Adapted from the applicant's abstract) The fibrin clot provides the initial provisional matrix for parenchymal cell repopulation of a wound in which the tissue architecture has been destroyed. Purified fibrin, however, does not support this function. Fibronectin, in fact, is required for fibroblast transmigration from a collagenous milieu, as found in the periwound stroma, into a fibrin clot. As fibroblasts repopulate the wound space they replace the fibronectin-rich fibrin clot with a second provisional matrix composed of hyaluronan and fibronectin. We have found that fibronectin is also required for fibroblast migration through tissue concentrations (2 percent) of hyaluronan. Clearly fibronectin plays a fundamental role in mesenchymal cell recruitment into wounds. Recently we have identified three distinct fibronectin domains required for fibroblast migration. The global aim of this proposal is to engineer a hyaluronan construct which is derivatized with fibronectin sequences necessary and sufficient to promote maximal cell migration to a site of injury. Such a product would be useful in clinical settings where hemostasis is achieved and rapid formation of new tissue are needed, for example freshly debrided chronic cutaneous ulcers and fresh surgical and traumatic cutaneous wounds that cannot be closed. To this end a recently designed in vitro assay for cell migration across three-dimensional extracellular matrix boundaries will be used for screening potential candidate constructs. Finally it will be determined whether hyaluronan constructs that are optimal in vitro for cell migration are also optimal in vivo for cutaneous wound healing.