Therapeutic potential of natural polymer-based microgels for cartilage regeneration with implications for osteoarthritis.

Articular cartilage has a limited intrinsic capacity for self-repair because of its avascular, aneural, and alymphatic nature, making cartilage repair a major clinical challenge. This limitation is particularly important in osteoarthritis (OA), where cartilage loss occurs within a complex whole-joint pathological environment involving inflammation, extracellular matrix (ECM) degradation, oxidative stress, chondrocyte senescence, and altered mechanical loading. Cartilage tissue engineering (CTE) has emerged as a promising strategy to restore cartilage structure and function by integrating cells, biomaterials, and bioactive signals. While traditional bulk hydrogels have been widely explored, injectable microgels assemble into microporous constructs whose interparticle voids support the convective and diffusive mass transport that bulk gels restrict, together with precise control over cell-matrix interactions and release kinetics for optimal therapeutic delivery and tissue regeneration. Natural polymers, including chitosan, alginate, hyaluronic acid, gelatin, collagen, and silk fibroin, are attractive for microgel preparation due to their biocompatibility, biodegradability, structural similarity to native ECM, natural abundance, and tunable chemical groups. Beyond static delivery platforms, stimuli-responsive microgels that respond to disease-relevant cues such as pH, temperature, enzymatic activity, and magnetic or electrical fields add spatiotemporal control over therapeutic release. Compared to conventional intra-articular injections of free drugs or cells, natural polymer microgels prolong local retention and sustain release. Rather than acting only as passive carriers, they can modulate the OA microenvironment by delivering anti-inflammatory agents and supporting matrix regeneration. This review critically discusses recent advances in natural polymer-based microgels for CTE, emphasizing OA-oriented therapeutic ap NLM plications. We review material selection, design criteria, preparation and crosslinking strategies. Furthermore, we provide specific examples of cell, small-molecule, growth-factor, and gene delivery, including nucleic-acid and exosome-based strategies, and finally discuss current challenges and outline future directions toward clinically relevant microgel-based therapies for OA.