Sr/Zn-doped TiO₂ coating enhances implant osseointegration by directing macrophage M2 polarization mediated...

Bioinert titanium implants lack immunomodulatory capacity to direct favorable osteoimmune responses during osseointegration. While Sr/Zn-doped TiO₂ micro-arc oxidation coatings have been shown to enhance bone regeneration through multicellular crosstalk, the direct immunoregulatory mechanism remain unclear. Here we demonstrate that Sr/Zn coating actively induces macrophage M2 polarization through modulation of key inflammatory pathways, establishing a pro-regenerative osteoimmune microenvironment. In vitro, the coating facilitated RAW264.7 macrophage transition from M1 to M2 phenotype, confirmed by immunofluorescence staining, RT-qPCR and Flow Cytometry. Transcriptomic profiling with KEGG enrichment revealed significant modulation of IL-17, NF-κB, TNF, Toll-like receptor, chemokine, and Wnt signaling pathways. Macrophage-conditioned medium from Sr/Zn-coated surfaces significantly enhanced osteoblast differentiation and angiogenic factor expression. In vivo, Sr/Zn-coated implants reduced M1 marker iNOS while elevating M2 marker Arg-1, accompanied by enhanced BMP2, Runx2, CD31 and VEGF expression. Micro-CT and histological analyses confirmed superior osseointegration with increased bone volume fraction and bone-implant contact. This study provides the first direct evidence that Sr/Zn-doped TiO₂ coatings enhance osseointegration through macrophage M2 polarization-directed osteoimmunomodulation, advancing our understanding of bioactive coating design for orthopedic and dental applications.