Mechanobiology-instructed biomaterials for osteoarthritis: Bridging mechanotransduction and disease modification

Osteoarthritis (OA) is a whole-joint disease characterized by progressive cartilage degeneration, synovial inflammation, and subchondral bone remodeling. Disrupted mechanical homeostasis contributes to these interconnected changes by altering load distribution, tissue deformation, and cellular responses to mechanical stimuli. Inflammation, aging, and matrix remodeling further modify cellular mechanosensitivity, allowing similar mechanical inputs to produce distinct biological outcomes. Conventional biomaterials have largely emphasized defect filling, structural support, and matching the mechanical properties of native cartilage. However, reproducing tissue stiffness does not necessarily restore the dynamic mechanical microenvironment experienced by cells, underscoring the need to regulate pathological mechanical information rather than static material properties alone. This review examines the multiscale mechanical pathology of OA and the mechanosensing and mechanotransduction processes that connect local physical cues with disease progression. It synthesizes biomaterial design strategies involving spatially regulated mechanics, viscoelastic adaptation, mechanical energy conversion, external physical actuation, and mechanically coupled therapeutic delivery. These approaches are discussed in relation to chondrocyte homeostasis, stem cell fate, synovial immune responses, osteochondral remodeling, and aging-associated dysfunction. A phenotype-guided framework is proposed to align material functions with priority mechanical abnormalities across different disease stages and patient-specific pathological contexts, while recognizing that multiple pathological features often coexist and evolve within individual joints. We further identifies requirements for disease-modifying evaluation, including causal mechanistic evidence, physiologically relevant dynamic testing, whole-joint functional outcomes, and durability after material degradation or treatment withdrawal. Together, these perspectives connect mechanobiological principles with rational material design and outline a path toward sustained OA intervention.