An appropriate biomatrix is a key structural element for tissue regeneration since a provisional extracellular matrix is required to support the highly organized repair processes involved. Fibrin is the natural provisional matrix for wound healing and tissue repair. The fibrin clot provides a structural scaffold for the adhesion, proliferation, and migration of cells important in wound healing. Also, fibrin and the associated proteins making up a physiologic clot have intrinsic biological activities that support and control the cellular differentiation important in wound healing. Finally, fibrin clots are readily remodeled and resorbed through normal fibrinolytic processes as cells deposit the tissue-specific extracellular matrix components during the regeneration of functional tissues.
The first function of fibrin(ogen) is to rapidly control bleeding at the site of injury. Once hemostasis is achieved, the fibrin clot serves as the foundation of a complex provisional matrix to both initiate and support subsequent tissue repair. The fibrin(ogen) protein has several specific domains that actively control cell behavior during wound healing. The fibrinopeptides, FpA and FpB, released by thrombin during clot formation, and fibrin degradation products released later during fibrinolysis, are chemoattractants and activators of leukocytic cells. The clot provides a physical scaffold for the migration of neutrophils and monocytes into the wound as part of the initial inflammatory response to protect the injured tissue. The release of FpB from the ß-chain of fibrinogen exposes a new N-terminal peptide domain on fibrin that serves as a unique binding site for the vascular endothelial cell surface receptor VE-cadherin. Fibrin-specific signaling through this receptor causes the vascular endothelial cells in injured blood vessels to migrate, proliferate, differentiate, and form new blood capillaries. The fibrin clot then serves as the physical scaffold for this angiogenesis at within the wound site. The resulting neovascularization is critical for successful tissue regeneration.
The biological activities inherent in the final clot are not limited to fibrin, but include a complex mixture of other proteins that specifically bind to the fibrin matrix. This forms the basis for using fibrin-based biomatrix preparations to deliver factors that can enhance tissue regeneration. Certain growth factors, i.e., basic fibroblast growth (bFGF), the insulin-like growth factor-1/insulin-like growth factor binding protein-3 complex (IGF-1/IGFBP-3), and the vascular endothelial growth factor isoform VEGF165, bind non-covalently to fibrin(ogen). These bioactive proteins can be delivered using fibrin-based biomaterials without further modifications. Other therapeutic proteins or drug molecules that do not specifically bind can be added to the biomaterial preparations and delivered by freely diffusing from the biopolymer matrix. However, this latter approach does not allow for careful control over the timing or extent of delivery. Methods are being developed to modify either the fibrin-based matrix or the bioactive substance such that therapeutic proteins or drugs can be delivered in a controlled manner.
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