Continuous‐Gradient Mineralized Hydrogel Synthesized via Gravitational Osmosis for Osteochondral Defect Repair

Abstract The repair of hierarchical osteochondral defects requires complex gradient reconstruction at different levels, with continuous‐gradient mineralization being crucial. Strategies for achieving continuous‐gradient mineralization have rarely been reported. Here, a continuous‐gradient mineralized hydrogel is prepared using simple gravitational osmosis of a ≈2 nm amorphous calcium phosphate nanocluster (ACPC) suspension into composite organic frameworks for osteochondral regeneration. During gravitational infiltration, ACPC underwent gradual mineralization, resulting in the spontaneous formation of hydroxyapatite (HAP). The continuous‐gradient mineralized hydrogel aligned closely with the normal osteochondral structure, thereby effectively promoting repair of the cartilage and subchondral bone. In the cartilage layer, organic compounds improved the oxidative stress environment induced by injury and complemented the extracellular matrix of the cartilage. In the subchondral bone layer, HAP from the continuously mineralized hydrogel induced intracellular calcium accumulation in mesenchymal stem cells (MSCs), activating calcium/calmodulin‐dependent protein kinase 2 (CaMK2) and promoting osteogenic differentiation of MSCs through the calcium signaling pathway. Ultimately, compared with the nongradient hydrogel, this innovative gradient mineralization method exhibited significantly enhanced regeneration capabilities for osteochondral defects, as evidenced by metrics, such as bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N). This holistic strategy provides hope in the field of osteochondral repair.