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

Abstract

ABSTRACT 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.