Novel "hot spring"-mimetic scaffolds for sequential neurovascular network reconstruction and osteoporosis reversion

Neurovascular network damage and excessive hydrogen peroxide (H₂O₂) accumulation are the main obstacles for osteoporotic bone defect repair. It is extremely essential to endow the implants with sequential neuroangiogenesis promotion and osteoporosis pathological microenvironment improvement. Hot springs exhibits excellent facilitation on angiogenesis and bone regeneration due to abundant minerals, trace elements and modest thermal stimulation. Inspired by the hot spring effect, we propose a novel porous photothermal calcium magnesium phosphate bone cement (MCPC) compounded with manganese-substituted Fe₃O₄ (Mn_xFe_3-xO₄), which is perfused by temperature-responsive PLGA hydrogel loaded with vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). At the initial stage of implantation, Mn_xFe_3-xO₄ scavenges excessive H₂O₂ under the heat stimulation triggered by near-infrared (NIR) light, and the factors are released from the hydrogel that stimulate the impaired neurovascular network reconstruction; at the later stage, the continuous hot spring effect maintains mild thermal stimulation and sustained release of bioactive ions (Ca²⁺, Mn²⁺, Mg²⁺ and PO₄^3-), which inhibits osteoclast function and activity, and promotes osteogenic differentiation and mineralization. The osteoporotic bone defect model in ovariectomized (OVX) rats further verifies that a synergy effect of photothermal therapy and bioactive factors/ions significantly promotes neurovascular bone regeneration. It demonstrates that the hot spring mimetic effect possesses huge potential for the sequential treatment of osteoporosis bone defect.