Injectable Porous Nanocomposite Microgel Assemblies Engineered via a Triple-Dynamic Crosslinking Strategy for Vascularized Bone Regeneration

The repair of critical-sized bone defects remains a significant clinical challenge. Microgel assemblies, a kind of emerging bone regenerative material, combine injectability with an interconnected macroporous structure, which facilitates efficient cell infiltration. Nevertheless, current assembly strategies suffer from inherent flaws: photo-crosslinking requires open wounds for ultraviolet light irradiation, Schiff base crosslinking proceeds slowly, and host-guest interaction exhibits insufficient mechanical strength. Additionally, organic-inorganic composites, which mimic natural bone composition, face the challenges of non-uniform inorganic particle distribution and poor precision in size control. To address these limitations, we developed an injectable, self-healing, porous bisphosphonate-magnesium/hyaluronic acid-Poly(L-glutamate) (BP-Mg/HA-PLG) nanocomposite microgel assembly for vascularized bone regeneration, fabricated via a triple-dynamic crosslinking strategy (BP-Mg chelation, host-guest interaction, Schiff base linkage). This design enables rapid reassembly, robust mechanics, excellent self-healing, and in-situ formation of uniformly distributed BP-Mg nanoparticles, which enhance mechanical strength and achieve sustained release of BP and Mg 2+ . In vitro , the system exerts synergistic pro-angiogenic, anti-osteoclastogenic, and pro-osteogenic effects. In a rat femoral condyle defect model, it significantly promotes bone regeneration within 8 weeks, offering a novel, translatable multifunctional solution to overcome key limitations in bone repair materials.