In-situ pore forming bone adhesives targeting disordered osteoimmune microenvironment and bone metabolic balance to promote osteoporotic fracture healing

• Current study constructed a bone adhesive with in-situ pore forming activity for auxiliary fixation of osteoporotic fracture via Schiff-base bioadhesive chemistry. • Via collaborative introduction of Mg-induced porous structure and alendronate functionalization, the proposed bone adhesive was verified with capability of restoring the dysregulated inflammatory environment and disordered bone metabolism under osteoporotic condition. Treatment of osteoporotic fracture remained challenging due to the disordered inflammatory microenvironment and dysregulated bone metabolism under osteoporosis condition. Restoring the proper osteoimmune microenvironment to guide favorable bone metabolism has emerged as a promising strategy for treating osteoporotic fracture. Herein, an injectable gelatin (G) - oxidized dextran (O) based, alendronate (A) functionalized bone adhesive was further endowed with in-situ pore forming capacity via magnesium (Mg) particle - based Mg-H 2 O gas foaming reaction. Porous structure with porosity of 73.80 ± 5.45 % and pore size of 145.66 ± 13.24 μm was formed in-situ in deployed G-O-A@Mg adhesive. Mechanical stability and adhesive strength were well reserved after pore-forming reaction via Mg 2+ -alendronate coordination to ensure the efficacy of G-O-A@Mg as a bone adhesive. Relying on the Mg-induced porous structure, attunated inflammatory environment characterized by inhibited M1 and enhanced M2 macrophage activities was achieved on the porous G-O-A@Mg adhesive. With further assist of Mg 2+ ions and alendronate released from G-O-A@Mg, the disordered osteogenic/osteoclastic balance was effectively restored as evidenced by superior healing outcome in osteoporotic bone defect model. Overall, current formula provided an alternative strategy in designing bone adhesives customized for osteoporotic fracture.