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

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.