Chondrogenic niche hydrogel microspheres facilitate cartilage regeneration in osteoarthritis.

Abstract

Tissue regeneration is a central frontier in biomedicine, yet articular cartilage defect repair in osteoarthritis (OA) remains a formidable challenge. Although mesenchymal stem cell (MSC)-based therapies show great potential for cartilage regeneration, their clinical translation is hindered by sequential barriers: low cell retention, oxidative stress-induced apoptosis, and inefficient MSC homing to defect sites and subsequent integration. Herein, we fabricate chondrogenic niche hydrogel microspheres (Chonichspheres) via microfluidics. These HMs are composed of gelatin methacryloyl (GelMA)/aldehyde-hyaluronic acid methacrylate (AHAMA) composite matrices loaded with amino fullerenes (AF) and transforming growth factor-β3 (TGF-β3). Chonichspheres exert four synergistic functions: GelMA acts as a structural scaffold to promote MSC adhesion; AF exert sustained antioxidant effects to regulate redox homeostasis in MSCs and OA chondrocytes; AHAMA enables precise targeted homing and tissue integration; and TGF-β3 induces MSC chondrogenic differentiation. Validated by an HM-adapted custom microphysiological system (MPS) and <i>in vivo</i> experiments, Chonichspheres activate the integrin-PI3K-AKT-mTOR axis, protecting MSCs and facilitating chondrogenic differentiation under OA-mimicking dynamic culture conditions. By synergizing active covalent tissue integration with durable, non-sacrificial antioxidant defense, this programmatic platform provides a robust precision regenerative strategy for OA cartilage repair.