In Situ Programmable Modulation of Hydrogel Stiffness for Stage‐Adaptive Bone Regeneration

Bone defect healing is a dynamic process involving changes in the mechanical properties of the extracellular matrix (ECM), which significantly influence cellular behavior and tissue regeneration. In this study, we developed a dynamic stiffness hydrogel system designed to mimic the stiffness variation of the ECM during bone repair. The hydrogel, based on a 3D interpenetrating polymer network, enables in situ modulation of matrix stiffness by adjusting calcium ion concentrations through photothermal effects induced under near-infrared (NIR) irradiation. The dynamic stiffness of the hydrogel was shown to support stem cell maintenance and promote osteogenic differentiation, aligning with the ECM characteristics observed in natural bone repair processes. Both in vitro and in vivo studies demonstrated that the mechanical cues provided by the hydrogel system significantly impact stem cell stemness and osteogenic potential. Furthermore, the hydrogel exhibited the ability to repair critical-sized bone defects, underscoring its therapeutic potential. This work introduces a novel platform for bone tissue engineering, combining biomimicry and functional adaptability to optimize bone regeneration and laying the foundation for future clinical applications.