Osteoporosis is a disease characterized by a decrease in bone mineral density, thereby increasing the risk of sustaining a fragility fracture. Most medical therapies are systemic and do not restore bone in areas of need, leading to undesirable side effects. Injectable hydrogels can locally deliver therapeutics with spatial precision, and this study reports the development of an injectable hydrogel containing a peptide mimic of bone morphogenetic protein-2 (BMP-2). To create injectable hydrogels, hyaluronic acid was modified with norbornene (HANor) or tetrazine (HATet) which upon mixing click into covalently crosslinked Nor-Tet hydrogels. By modifying HANor macromers with methacrylates (Me), thiolated BMP-2 mimetic peptides were immobilized to HANor via a Michael addition reaction, and coupling was confirmed with 1H NMR spectroscopy. BMP-2 peptides presented in soluble and immobilized form increased alkaline phosphatase (ALP) expression in MSCs cultured on 2D and encapsulated in 3D Nor-Tet hydrogels. Injection of bioactive Nor-Tet hydrogels into hollow intramedullary canals of Lewis rat femurs showed a local increase in trabecular bone density as determined by micro-CT imaging. The presented work shows that injectable hydrogels with immobilized BMP-2 peptides are a promising biomaterial for the local regeneration of bone tissue and for the potential local treatment of osteoporosis.

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