Neutrophil‐Mediated Inflammatory Response to Zinc Bone Implants: A Single‐Cell Transcriptomic Landscape

Zinc (Zn)‐based metals have been considered as promising materials for bone regeneration and repair. Neutrophils, as the initial responders in the acute inflammatory phase, play a critical role by generating specialized mediators that facilitate the natural resolution of inflammation. Nevertheless, the mechanisms governing neutrophil‐driven inflammation following the implantation of Zn‐based metals are not fully elucidated. This study investigated neutrophil‐macrophage crosstalk around Zn‐based implants using single‐cell transcriptomic profiling. A high‐resolution cellular atlas of the peri‐implant bone marrow microenvironment was generated in a rat femoral model comparing Zn‐based implants with the titanium (Ti) ones. The results revealed that Zn implants induced a distinct neutrophil (Neu) subset heterogeneity, including Cd177 + Neu, Ifit1bl + Neu, RatNP‐3b + Neu, and Prtn3 + Neu, the latter demonstrating enhanced tissue repair ability through osteoclast differentiation pathways. Zn‐based metallic implants reduced macrophage (Mac) reactivity and promoted Hp + Mac dominance compared to Ti implants, which showed higher Apoe + Mac proportions. Crosstalk analysis identified a significant interaction between the neutrophil subset Ifit1bl + Neu and the macrophage subset Eno3 + Mac under Zn implantation, mediated by the Lgals9‐Ighm ligand‐receptor axis. These findings suggested that degradation products of Zn‐based implants modulated immune cell differentiation and interaction networks, thereby modulating biological response.