Click Chemistry for Immobilized Bone Morphogenetic Protein

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DESCRIPTION (provided by applicant): Project Summary/Abstract: There are over 6.3 million fractures each year in the United States of which approximately 700,000 are difficult to heal. The available treatment options for fractures that do not heal or are slow to heal are limited. Bone morphogenetic proteins are growth factors that stimulate new bone production and have received FDA approval for bone fracture repair and spinal fusion. For most clinically approved uses of BMPs, a resorbable collagen sponge is used as the delivery matrix to retain BMP at the site of repair. Low affinity of BMP for the collagen results in the rapid diffusion of BMP and as a result, supraphysiological levels of BMP are required to promote healing. Affinergy develops peptidic macromolecules, interfacial biomaterials (IFBMs) that modulate the critical interface between biological surfaces to initiate and specify interfacial biologic activities. The IFBMs under investigation are composed of different peptide modules that have affinity for BMP and the collagen sponge. A limitation of the technology is the ability to construct many different IFBMs to facilitate rapid screening for subsequent in vivo evaluation. [3+2] cyclo-addition or "click chemistry" will be used to prepare IFBMs since this takes advantage of our modular approach and allows for higher total yields through the coupling of shorter peptides (<25 mers). As a model system we will identify, synthesize, and characterize IFBMs that bind a regenerated collagen sponge and a growth factor for sustained release of Bone Morphogenetic Protein (BMP) to improve bone healing at a fracture site. The specific aims are: Aim 1: Optimize the reaction conditions for coupling peptides of varying molecular weights and sequences using click-chemistry. Aim 2: Screen a library of synthesized IFBMs from peptides identified using phase display and determine binding affinity in vitro to BMP-2. Aim 3: Evaluate the in-vitro ability of BMP-IFBM coated collagen sponges with varying BMP affinities to induce osteoblast differentiation in a C3H10T1/2 mouse mesenchymal cell line. The goal of this SBIR is to demonstrate that IFBMs can be used with a resorbable material to control the delivery of growth factors to bone injuries with the intent of improving healing and clinical outcomes. Project Narrative: There are over 6.3 million fractures each year in the United States of which approximately 700,000 are difficult to heal. Bone morphogenetic proteins (BMPs) are growth factors that stimulate new bone production and have received FDA approval. Currently, a resorbable collagen sponge is used as a delivery matrix for BMP. Low affinity of BMP for the sponge results in poor delivery profiles requiring supraphysiological levels of BMP to promote healing. In this proposal, we describe a novel peptide based approach to enhance the affinity of BMP-2 to the sponge and postulate that this improvement will result in sustained release of BMP resulting in improved bone healing.