Tunable-Stiffness Hydrogel Enhances Bone Regeneration

Bone tissue regeneration is a highly orchestrated biological process involving the time-dependent evolution of the mechanical properties of the extracellular matrix (ECM), where the dynamic mechanical microenvironment regulates cellular fate decisions through mechanotransduction mechanisms. This study aims to develop a dynamically stiffening hydrogel system that mimics the ECM, enabling temporal regulation of cellular behavior to enhance bone defect repair. A hydrogel system with in situ tunable stiffness was designed using thermosensitive polymer molecular chains as the primary framework. The system incorporates near-infrared modulation to dynamically adjust the crosslinking density of the hydrogel network, thereby achieving controllable stiffness enhancement in situ. In vitro cytological experiments demonstrated that matrix stiffness dynamically influenced the maintenance of stem cell stemness and promoted osteogenic differentiation over time. A critical-sized rat calvarial defect model was established to evaluate the bone regeneration efficacy of the hydrogel in vivo. The hydrogel system exhibited excellent physicochemical properties, allowing for in situ enhancement of crosslinking density to elevate matrix stiffness, replicating the mechanical characteristics of the ECM. It maintained stem cell stemness at lower stiffness and facilitated osteogenic lineage differentiation under higher stiffness conditions. The hydrogel demonstrated significant efficacy in promoting the repair of critical-sized bone defects. The hydrogel system's tunable stiffness supports stem cell maintenance and osteogenic differentiation, mimicking ECM mechanical dynamics during bone repair. This biomimetic platform integrates dynamic adaptability and versatility, offering a promising strategy for bone tissue engineering and clinical translation.