Hemostasis, or the prevention of blood loss, and tissue sealing are of critical importance in response to vascular injury, whether those injuries are a result of traumatic accidents or planned injuries as in the case of surgery. While several biomaterials are currently on the market to address this need, the body's own coagulation system based on the polymerization of fibrinogen, still represents the best approach. Since the early 20th century surgeon's have used formulations of plasma fibrinogen to prevent hemorrhage;however, it was not until advances in protein purification were made that fibrinogen-based polymer systems became commercially available, in the early 1990s. Today, fibrinogen-based products are the overwhelming choice of surgeons for hemostasis and tissue sealing, yet these systems are not without their flaws. In particular, commercially available fibrinogen formulations form polymers that are not instructive in nature, nor are they permissive to rapid wound repair. These poor behaviors are primarily attributed to the polymer's lack of integrin-specific ligands and proper porosity. A fibrin polymer is capable of engaging many integrins on mostly inflammatory cells;however the lack of specificity with which cells engage fibrin-based polymers leads to hyperproliferation, rather than organized tissue remodeling. Furthermore, while the polymer supports the mechanical loads necessary for early tissue sealing, it lacks the porosity necessary for efficient vascularization. In this application we propose the development of a novel technology that could potentially enable physicians to design their fibrin polymers for specific clinical outcomes (e.g. angiogenesis). Our central hypothesis is that enhanced angiogenic responses will be elicited from fibrin polymers modified both biochemically and physically with fibrin binding peptides associated with integrin-specific ligands and polyethylene glycol (PEG), respectively. We will address this hypothesis through four specific aims.
Aim 1 entails developing peptide motifs that specifically bind fibrinogen and fibrin.
In specific aim 2 we will develop a 'plug-and-play'expression system that allows for the rapid production of proteins displaying the fibrin-binding peptides. We will explore the effect of these proteins on fibrin polymerization, biochemical characteristics and angiogenic potential using an in vitro angiogenesis assay. We will then, in Aim 3, modify various forms of PEG to display fibrin binding peptides in order to alter polymer structure and determine the effects of these conjugates on fibrin polymer structure and angiogenic potential. Finally, in Aim 4 we will test our modified fibrin system in vivo. The results of our study will have a significant impact on fibrin-based biomaterials design and enhance the clinical uses of fibrin polymers for wound healing, tissue repair, and regenerative medicine.
This proposed project addresses the fundamental control of fibrin-based biomaterials for enhance angiogenesis, or new blood vessel formation. This project will have direct relevance to wound healing and regenerative medicine by establishing new methods to manipulate fibrin for specific clinical outcomes.
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