ROS‐Activated Nanohydrogel Scaffolds with Multi‐Factors Controlled Release for Targeted Dual‐Lineage Repair of Osteochondral Defects

Abstract Achieving self‐healing for osteochondral defects caused by trauma, aging, or disease remains a significant challenge in clinical practice. It is an effective therapeutic strategy to construct gradient‐biomimetic biomaterials that replicate the hierarchical structure and complex microenvironment of osteochondral tissues for dual‐lineage regeneration of both cartilage and subchondral bone. Herein, ROS‐activated nanohydrogels composite bilayer scaffolds with multi‐factors controlled release are rationally designed using the combination of 3D printing and gelatin placeholder methods. The resulting nanohydrogel scaffolds exhibit micro‐nano interconnected porous bilayer structure and soft‐hard complex mechanical strength for facilitating 3D culture of BMSCs in vitro. More importantly, multi‐stage continuous responses of anti‐inflammation, chondrogenesis and osteogenesis, are effectively induced via the sequential release of multi‐factors, including diclofenac sodium (DS), kartogenin (KGN) and bone morphogenetic protein 2 (BMP‐2), from ROS‐activated nanohydrogel scaffolds, thereby improved dual‐lineage regeneration of cartilage and subchondral bone tissue in the osteochondral defect model of SD rats. These findings suggest that ROS‐activated nanohydrogel scaffolds with such specific soft‐hard bilayer structure and sequential delivery of functional factors, provides a promising strategy in dual‐lineage regeneration of osteochondral defects.