Sequential Regulation of Neurovascular Bone Regeneration in Large Bone Defects Using Black Phosphorus-Europium...

Titanium alloy scaffolds (Ti-6Al-4 V) are widely used to repair bone defects. However, conventional titanium-based implants lack customized functional surface interfaces that promote coordinated local nerve and blood vessel regeneration, thereby limiting bone regeneration and long-term stability. To address this limitation, we utilize a topologically optimized triple-periodic minimal surface (TPMS) porous titanium (Ti) scaffold. Polydopamine (PDA) surface engineering is used to stably immobilize europium ions (Eu³⁺)-coordinated black phosphorus (BP) nanosheets onto the surface, forming a Ti-PDA@(BP+Eu) (TPBE) scaffold with photothermal-ionic synergistic release to coordinate early neurovascular reconstruction and subsequent bone regeneration. In vitro studies demonstrate that under periodic near-infrared irradiation, the TPBE scaffold enables on-demand release of Eu^{3 +}/phosphate ions (PO₄ ^3-), thereby promoting adhesion, migration, differentiation, and gene expression of neural, vascular, and osteogenic cells. Further, activating the PI3K/Akt pathways enhances neurite outgrowth and axonal regeneration of rat adrenal pheochromocytoma cells. In vivo large-segment bone defect models demonstrate that TPBE scaffolds combined with mild photothermal therapy increases neurovascular network density and upregulate osteogenic-neuro-vascular coupling factors, thereby accelerating bone regeneration. This study presents an innovative method for the fabrication of Ti-based implant materials capable of cascade regeneration of nerve, vascular, and bone tissues, establishing the basis for the exploration of multitissue regenerative biomaterials.