An Injectable and Self-Reinforced Piezoelectric Hydrogel for Irregular Bone Defects Regeneration: Dynamic Epigenetic Regulation Approach.

Irregular bone defects demand biomaterials that can be delivered into complex shapes while offering gradually developing mechanical strength and bioactive electrical stimulation-two critical properties rarely obtained simultaneously. Here, we develop an injectable, polymer-induced self-reinforcing and piezoelectric hydrogel engineered from regenerated silk fibroin, tyramine-modified CMC, and MXene-cellulose nanofiber nanosheets through enzymatically dynamic Cross-linking. This material is designed to overcome two major limitations of current injectable hydrogels: inadequate mechanical maturation and unstable bioelectrical output. The dynamic dual-network structure undergoes gradual β-sheet alignment and nanointerfacial ordering, which increases the compressive modulus from ∼0.08 to ∼0.8 MPa and elevates piezoelectric output from 3 to 60 mV over 5 days, establishing a mechanically stable and electrically active microenvironment within the defect. The hydrogel-derived electrical signals induce Ca2+ influx and activate the CaMKII/CREB/P300 axis, enhancing H3K9 acetylation and reinitiating osteogenic transcription, with PTH1R emerging as a key downstream effector. This hydrogel promotes osteogenic differentiation, mineralization, and angiogenesis in vitro and accelerates new bone formation while restoring trabecular architecture in critical-sized defects in vivo. Overall, this mechanoadaptive hydrogel provides sustained piezoelectric stimulation while functioning as an epigenetic activator to reprogram the osteogenic microenvironment, offering a promising strategy for irregular bone defect repair.