Systemic T-cell and local macrophage interactions mediate granule size-dependent biological hydroxyapatite foreign body reaction

Biological hydroxyapatite (BHA) has been widely used in alveolar bone augmentation, while unfavorable outcomes can still be encountered. Among several reasons, we noticed a chaotic granule size application issue. The principle behind the choice of proper granule size mainly lies in the fitness of defect shape and size. However, granule size has been shown to elicit significant biological effects, with the underlying mechanisms still unknown. BHA granules of five different sizes were first prepared and characterized to investigate their biological effects. We found that the biomimetic porous structure of BHA gradually disappeared with decreasing size, affecting the structure of the blood clot fibrin network, leading to different local immune microenvironments and foreign body reactions (FBRs). Among them, <0.2 mm BHA granules completely lost their biomimetic porous structure and their fibrin network was loosened with strong immune response and strongest FBR. We found Gata3 (+)/Nfat3 (+) Th2 cells were recruited from activated systemic immune organs, inducing CD206 (+)/CD163 (low) M2 macrophages through direct contact with Ptprc-Mrc1, thereby promoting their fusion to form foreign body giant cells leading to strong FBR. This study expanded the understanding of the size effect of BHA granules from a biological perspective and unveiled the mechanisms of systemic immune towards BHA mediated FBR, providing regulatory targets to improve bone regeneration outcomes.