Bioelectrically Reprogramming Hydrogels Rejuvenate Vascularized Bone Regeneration in Senescence.

Senescent bone tissue displays a pathological imbalance characterized by decreased angiogenesis, disrupted bioelectric signaling, ion dysregulation, and reduced stem cell differentiation. Once bone defects occur, this pathological imbalance makes them difficult to repair. An innovative synergistic therapeutic strategy is utilized to reverse these pathological imbalances via a conductive hydrogel doped with magnesium ion (Mg)-modified black phosphorus (BP). The hydrogel reprograms electrical signals, restores Mg homeostasis, reconstructs physiological signals, and promotes blood vessel regeneration in senile bone defects. The conductive hydrogel synergistically restores both the chemical and bioelectric signals within the bone microenvironment. This hydrogel increases the expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR2), activates the PI3K-AKT-eNOS pathway, and significantly increases the angiogenic ability of vascular endothelial cells in the aged state. In addition, the conductive hydrogel normalizes calcium ion (Ca) influx, increases the accumulation of osteogenic transcription factors in the nucleus, and promotes the osteogenic differentiation of senescent stem cells. This innovative treatment strategy restores bone-vascular coupling in areas of senile bone defects, achieves effective vascularized bone regeneration, and has good potential for the treatment of senile bone defects.