Designing biomaterials with temporal control of proteins via genetic fusion with coiled coil peptides for enhanced bone repair

Project Summary The use of bone morphogenetic proteins (BMPs) shows promise as therapeutics for improving bone repair; however, high supraphysiological concentrations required for the desired osteoinductive effect, costs, and patient variability have prevented the full advantages of BMP-based therapeutics from being realized. Thus, there is a clinical need to develop new bone tissue engineering approaches that promote osteogenesis at lower BMP doses and prevent adverse side effects. In the native extracellular matrix (ECM), BMP is tightly bound by proteins and glycosaminoglycans with its presentation regulated in time to enhance bioactivity. Furthermore, researchers have shown significant synergies with other signaling molecules, such as cell-matrix or cell-cell adhesion ligands. To mimic these interactions, a number of elegant approaches based on photopatterning and orthogonal chemistries have been developed for presenting biomolecules. However, these approaches rely on highly customized chemical reactions (which may be difficult to implement with full length proteins) and are generally restricted to 1-2 biomolecules. They are also often based on photocleavage reactions for temporal control, which precludes their reversibility over multiple cycles. Given the complexity of the extracellular environment (e.g., the stem cell “niche”) in controlling the fate of cells, a general platform that can control three or more proteins with user-defined, temporal control over protein immobilization would be invaluable for teasing apart the factors that control behavior like cell proliferation, migration, differentiation, and new tissue formation, especially in the context of BMP-induced bone repair. With this in mind, the proposed studies will 1) provide new insight into the temporal role of cell adhesion and growth factor binding during BMP- induced osteogenesis and 2) identify key biomaterial design parameters for promoting bone repair.