Stimuli-responsive hydrogels: orchestrating microenvironment remodeling in musculoskeletal therapeutics

The pronounced heterogeneity of the pathological microenvironment in musculoskeletal disorders poses significant challenges to the spatiotemporal regulation capabilities of conventional therapeutic strategies. Stimuli-responsive hydrogels have exhibited immense potential for the treatment of musculoskeletal disorders owing to their excellent intelligent response characteristics and versatile design. This review systematically summarizes the major response mechanisms of stimuli-responsive hydrogels and analyzes the characteristics of their structural and functional design. It further focuses on recent advances of their applications in typical musculoskeletal disorders, including degenerative diseases such as osteoarthritis (OA); autoimmune diseases such as rheumatoid arthritis (RA); traumatic injuries such as fractures and cartilage injury; infectious diseases such as infected bone defects; metabolism-related bone disorders such as diabetic bone injury and hyperlipidemia bone injury; as well as soft tissue complications such as tendon adhesion and rotator cuff injury. Finally, this review proposes a design concept for multimodal stimuli-responsive hydrogels and discusses the key challenges in their clinical translation. We hope this review will serve as a reference for promoting the treatment of musculoskeletal disorders from passive repair to active regulation.