Macrophages Primed with Hyaluronic Acid Promote Bone Regeneration in Mouse Peri-Implantitis Model

Peri-implantitis is characterized by bacterial infection and progressive destruction of surrounding tissues, with limited long-term therapeutic strategies. Although macrophages could have therapeutic effects on peri-implantitis, macrophage-based cell therapies have yet to be widely applied in clinical settings. In this study, we developed a macrophage-based approach using hyaluronic acid (HA)-mediated priming and evaluated its in vitro functions and therapeutic efficacy in a mouse model of peri-implantitis. Mouse spleen-derived macrophages were cultured with HA (1.5, 1.8, or 2.0 MDa), and phenotypes were analyzed by Reverse transcription quantitative polymerase chain reaction (RT-qPCR) (inducible nitric oxide synthase [iNOS], tumor necrosis factor-α [TNFα], vascular endothelial growth factor [VEGF], Dectin-1) and flow cytometry (F4/80, VEGF, Dectin-1). Phagocytic and migratory capacities were evaluated, and endothelial cell (HUEhT-2) migration was examined. In vivo, HA-treated macrophages were locally injected into a ligature-induced peri-implantitis model and assessed histologically. HA treatment of macrophages suppressed M1-related (iNOS, TNF-α) and M2a, b, c-related (Dectin-1) gene expression while enhancing the M2d-related gene (VEGF). Flow cytometry revealed an increased proportion of M2d-like cells (Dectin-1^-/VEGF⁺). HA priming enhanced macrophage phagocytic and migratory capacities and promoted HUEhT-2 migration. In vivo, the HA-treated macrophage group exhibited reduced fibrotic tissue formation and enhanced alveolar bone regeneration, particularly in the MΦ18 group. HA-mediated priming modulates macrophage phenotype and function, supporting its therapeutic potential.Impact StatementThe treatment for peri-implantitis includes infection control and tissue regeneration. Although macrophages exerting anti-infectious and regenerative activities could mitigate peri-implantitis, macrophage-based cell therapies have not yet been widely applied in clinical settings. In this study, we demonstrated the therapeutic efficacy of hyaluronic acid-primed macrophages in a mouse model of peri-implantitis. Our findings not only provide insights into the establishment of new therapies for peri-implantitis but also potentially enhance clinical applications of macrophage-based cell therapies for a wide range of diseases.