Biomaterial Strategies in Osteoarthritis: New Insights Bridging Aging Phenotypes and Hypoxic Microenvironment Pathology

Abstract Osteoarthritis (OA) is a chronic degenerative disease characterized by joint degradation and severe pain, with no effective clinical treatments currently available. Biomaterials, due to their functional and structural diversity, hold significant clinical translation potential to meet various needs in OA management. However, the development of biomaterial scaffold strategies must align closely with advancements in the understanding of OA pathophysiology. This review revisits the interplay between aging, hypoxic microenvironments, and OA progression from a novel perspective. It details the aging‐related phenotypes characterized by impaired autophagy and inflammation in various OA‐affected tissues and introduces NDRG‐mediated hypoxia regulation mechanisms that function independently of the hypoxia‐inducible factor (HIF) family. Additionally, it systematically summarizes biomaterial scaffold strategies for OA treatment, including hydrogels, nanoparticles, microneedles, and exosomes. These strategies, inspired by new insights, aim to enhance drug bioavailability, reduce systemic effects, prolong therapeutic duration, and ameliorate the adverse microenvironment of OA through multiple modes of action. This approach holds promise for providing novel ideas for microenvironment‐targeted interventions in other degenerative diseases.