Regulation of Inflammatory and Metabolic Microenvironment With a D‐Mannose Functionalized Hydrogel for Improved Osteochondral Regeneration

ABSTRACT Endogenous regenerative strategy for osteochondral defect (OCD) repair remains challenging, largely due to the need to regulate the local inflammatory and metabolic microenvironment while preserving the stemness of bone marrow mesenchymal stem cells (BMSCs). Here, D‐mannose we identify as a potent immunometabolic modulator that enhances BMSC‐mediated osteochondral repair. Through in vitro experiments, we determined the optimal concentration of D‐mannose and evaluated its ability to preserve the osteogenic and chondrogenic differentiation potential of BMSCs under inflammatory microenvironment. Transcriptomic analysis demonstrated that D‐mannose contributed to the amelioration of inflammation by downregulating the NLRP3 inflammasome pathway. The metabolomic analysis further revealed that D‐mannose treatment alleviated inflammation‐induced dysregulation of the tricarboxylic acid cycle and facilitated the maintenance of glycolytic metabolic state in BMSCs. Furthermore, we fabricated a multifunctional GelMA‐based hydrogel incorporating D‐mannose (DM@GelMA). Macroscopic observation, micro‐CT analysis and histological evaluation confirmed that DM@GelMA hydrogel effectively promoted osteochondral tissue remodeling and integration in the OCD model of rats. These findings suggested that the multifunctional D‐mannose‐loaded composite hydrogel is a promising biomaterial for enhanced osteochondral regeneration.