Macrophage Intracellular “Calcium Oscillations” Triggered Through In Situ Mineralization Regulate Bone Immunity to Facilitate Bone Repair

Abstract Bioceramics are vital for treating bone defects, and bioactive glasses (exemplified by 45S5) and calcium phosphate ceramics (CaPs, exemplified by tricalcium phosphate [β‐TCP]) are extensively explored. β‐TCP exhibits superior biocompatibility, degradability, and osteoconductive properties than 45S5; however, it lacks bioactivity, such as mineralization capability. To harness the synergies of both, four 3D printing bioceramic scaffolds: 45S5, 70% 45S5 + 30% TCP, 30% 45S5 + 70% TCP, and TCP, are manufactured. Furthermore, the investigation elucidates the correlation between their in situ mineralization capabilities and the intracellular calcium oscillations within macrophages and determines how they impact macrophage phenotypic transitions. Notably, during bioceramic degradation, there is an initial rise followed by a decline in calcium ion concentration, which results in intracellular calcium ion oscillations within macrophages. In the 70% 45S5 + 30% TCP group, early release of calcium ions promotes M1 macrophage polarization. Subsequently, rapid in situ mineralization causes a decrease in extracellular calcium ions, thus accelerating the transition of M1 to M2 macrophages and facilitating bone repair. The present study reveals a novel mechanism through which bioceramics modulate macrophage polarization, offers new insights into the initial foreign body response to bioceramics and presents a perspective on expeditious progression toward tissue repair.