Temporal-responsive hydrogels reprogramming energy metabolic pathway in the bone-angiogenic cascade for diabetic bone regeneration.

Diabetes-associated metabolic dysregulation disrupts the angiogenic-osteogenic cascade required for bone healing by impairing oxygen delivery and suppressing mitochondrial oxidative phosphorylation. Here, transcriptome sequencing data reveal significant temporal differences in energy metabolism between early and late diabetic bone defects. Guided by this temporal energy demand, we developed an injectable temporal-responsive hydrogel (TRH) integrating continuously released strontium-doped hydroxyapatite (Sr-HA) with berberine (Ber)-loaded chitosan microspheres for delayed mitochondrial regulation. The temporal release profile closely matches the metabolic transition during bone regeneration. Continuous Sr2+ release rescued endothelial migration and network formation under hyperglycemia, whereas sustained Ber release was associated with activation of the AMPK/PGC-1α-related mitochondrial pathway, restoration of mitochondrial membrane potential and ultrastructure, and improved ATP production to support osteogenic differentiation and mineralization. In a critical-sized calvarial defect in diabetic mice, TRH markedly increased bone volume and improved trabecular microarchitecture, accompanied by enhanced CD31-positive vascularization, OCN/OPN-mediated osteogenesis, and elevated PGC-1α signaling. This work therefore provides a temporally programmed metabolic intervention that restores angiogenesis and osteogenesis for diabetic bone regeneration.