Titanium-guided neutrophil dynamics for inflammation resolution and tissue integration.

Abstract

Most synthetic implants trigger a foreign-body reaction that envelops the device in a dense fibrotic capsule, blocking close tissue integration. By contrast, titanium establishes direct bone-implant contact and long-term clinical function. Exactly how the initial immune cues at the titanium interface redirect inflammation toward rapid resolution and pro-regenerative pathways, thereby maximizing implant tissue integration and functional performance, remains to be fully elucidated. Here, we profile the early immune microenvironment around titanium implants and find neutrophils to dominate the cellular dynamics using single cell RNA sequencing in a large animal model. Neutrophils are recruited sooner and cleared faster than in standard tissue healing process, and their depletion in mice markedly impairs integration. Titanium implants activate neutrophil NF-κB signaling, provoking chemokine release that attracts mesenchymal stem cells (MSCs) while simultaneously inducing neutrophil apoptosis; extracellular vesicles (EVs) from these apoptotic cells further enhance MSC osteogenesis. These findings offer valuable insights into biomaterial-tissue interactions and provide a foundation for optimizing implant design and clinical outcomes.