Mechanism Driven Adaptation of Smart Hydrogels to the Osteoarthritis Pathological Microenvironment

Abstract

Osteoarthritis (OA) arises from interconnected pathological processes, including persistent inflammation, mitochondrial dysfunction, cartilage matrix degeneration, and abnormal neurovascular remodeling. Current clinical care remains largely symptomatic and targets only a narrow set of mechanisms, which limits modification of the disease course. Smart hydrogels, owing to their injectability, biocompatibility, and responsiveness to intrinsic and extrinsic cues, offer notable advantages for OA therapy. By sensing changes in the joint microenvironment, they enable precise control of drug release in space and time and shift treatment from symptomatic control toward targeted repair. This review first synthesizes the roles and interactions of the principal mechanisms that shape the OA microenvironment. It then surveys recent advances in smart hydrogels for OA, with emphasis on applications that suppress inflammation, regulate mitochondrial function, promote cartilage repair, and modulate abnormal neurovascular remodeling. Design strategies for responsive crosslinking networks and their integration with delivery vehicles such as bioactive molecules, nanomaterials, and exosomes are also outlined. Remaining challenges are discussed, including harmonized efficacy endpoints, durability and safety in vivo, scalable manufacturing, and translation to clinical practice, together with opportunities for future research. By coupling mechanistic insight with materials design, this review highlights the potential of smart hydrogels to deliver microenvironment adaptive, multitarget interventions and aims to support rational optimization of new materials and progress toward clinical.