Abstract
Magnesium (Mg)- and zinc (Zn)-based biodegradable metals are increasingly used as bone-related implants. However, the early immune response, particularly neutrophil–macrophage crosstalk, remains poorly understood. This study aimed to elucidate the communications between neutrophils and macrophages in Mg-based and Zn-based implants, compared with titanium (Ti)-based implants, with a focus on early immune responses and immunoregulatory mechanisms. Using single-cell RNA sequencing, high-resolution transcriptomic maps of the immune cells surrounding Ti, Mg, and Zn implants were constructed in a rat femoral implantation model. Ti-based implants induced a microenvironment stabilization phenotype in neutrophils, characterized by minimal inflammation. In contrast, Mg-based implants triggered acute inflammation, marked by strong crosstalk between neutrophils and Cers6+ macrophages via the LGALS9–CD45 signaling. Zn-based implants, however, promoted immune regulation and bone remodeling through neutrophil–Ccl3+ macrophage interactions mediated by the SEMA4D–PLXNB2 axis. Distinct macrophage subsets (Apoe+ macrophage, Cers6+ macrophage, and Ccl3+ macrophage) were identified, each exhibiting unique functional roles in tissue homeostasis, inflammation, and osteoimmunological activation. This study reveals material-specific immunomodulatory pathways governing neutrophil–macrophage crosstalk, providing significant insights for optimizing the design of biodegradable implants.