Hydrogel microspheres for osteoarthritis treatment: Fabrication strategies, smart responsiveness, and multimodal therapies

Osteoarthritis (OA) is a chronic, progressive degenerative joint disease defined by the degradation of articular cartilage, with pathological involvement of periarticular tissues including the synovium and subchondral bone. Existing conservative interventions for OA are limited to symptomatic relief and cannot reverse established cartilage degeneration, underscoring the critical unmet need to address prevailing clinical treatment bottlenecks. Hydrogel microspheres, as an emerging delivery platform integrating drug delivery capabilities with tissue engineering scaffold functions, hold substantial promise for targeted OA therapy and cartilage repair. Their core beneficial properties include minimally invasive injectability, favorable biocompatibility, sustained drug release capacity, and intelligent responsiveness. This review systematically explores the application of hydrogel microspheres in the treatment of OA and provides a detailed summary of material systems and preparation techniques—covering natural materials, synthetic polymers, and composite/hybrid materials, as well as processes such as emulsion cross-linking, microfluidics, electrospray, photolithography, and 3D printing. This paper places particular emphasis on the modulation of mechanical properties, smart responsive release mechanisms, and strategies to enhance bioactivity. Furthermore, it summarizes various therapeutic strategies supported by hydrogel microspheres, including the precise controlled release of small-molecule drugs, the regulation of endogenous stem cell recruitment and directed differentiation, the targeted delivery of gene therapy drugs, and synergistic treatment modalities. By synthesizing core research advances in this field in recent years and elucidating key technological development directions, this review provides a comprehensive reference for advancing the translation of hydrogel microspheres from basic research to clinical applications in the management of OA.