Dynamic mechanical cues from hydrogels promote osteogenesis via the YAP signaling pathway

The native bone matrix stiffens dynamically during development, presenting a critical mechanical cue that static biomaterials cannot effectively mimic. To address this, a photo-tunable dynamic stiffening hydrogel was developed using a dual-crosslinking strategy, combining physical crosslinking through freeze-thaw cycles and UV-triggered thiol-ene photo-click crosslinking. This photo-tunable dynamic stiffening hydrogel significantly promoted the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro and enhanced the repair of critical-sized calvarial defects in vivo. Mechanistic studies revealed that the pro-osteogenic effect is mediated through the activation of the Yes-associated protein (YAP) signaling pathway, as evidenced by its nuclear translocation. Our findings underscore the importance of temporal mechanical cues in bone regeneration and offer a novel biomimetic strategy for bone tissue engineering.