Cubic multi-ions-doped Na₂TiO₃ nanorod-like coatings: Structure-stable, highly efficient platform for ions-exchanged release to immunomodulatory promotion on vascularized bone apposition

The dissolution-derived release of bioactive ions from ceramic coatings on metallic implants, despite improving osseointegration, renders a concern on the interfacial breakdown of the metal/coating/bone system during long-term service. Consequently, persistent efforts to seek alternative strategies instead of dissolution-derived activation are pressingly carrying out. Inspired by bone mineral containing ions as Ca²⁺, Mg²⁺, Sr²⁺ and Zn²⁺, here we hydrothermally grew the quadruple ions co-doped Na₂TiO₃ nanorod-like coatings. The co-doped ions partially substitute Na⁺ in Na₂TiO₃, and can be efficiently released from cubic lattice via exchange with Na⁺ in fluid rather than dissolution, endowing the coatings superior long-term stability of structure and bond strength. Regulated by the coatings-conditioned extracellular ions, TLR4-NFκB signalling is enhanced to act primarily in macrophages (MΦs) at 6 h while CaSR-PI3K-Akt1 signalling is potentiated to act predominately since 24 h, triggering MΦs in a M1 response early and then in a M2 response to sequentially secrete diverse cytokines. Acting on endothelial and mesenchymal stem cells with the released ions and cytokines, the immunomodulatory coatings greatly promote Type-H (CD31^hiEmcn^hi) angiogenesis and osteogenesis in vitro and in vivo, providing new insights into orchestrating insoluble ceramics-coated implants for early vascularized osseointegration in combination with long-term fixation to bone.