Mapping Immune-Inflammatory Niches on Zirconia Bone Implants: Single-Cell Transcriptomic Profiling

Zirconia (ZrO₂) has become a promising alternative to titanium (Ti) for bone implants due to its excellent biocompatibility. Despite this, the osseointegration of ZrO₂ remains lower than that of Ti implants. However, the underlying biological mechanisms, particularly the osteoimmune response, remain not fully elucidated. Herein, we employed single-cell RNA sequencing to profile the immune-inflammatory niches of ZrO₂ and Ti-based implants, to elucidate mechanisms that could guide the osteogenic functionalization of ZrO₂ implants. The analysis provides a high-resolution atlas of immune-stromal cell dynamics at the bone-implant interface, identifying distinct cellular subsets and ligand-receptor axes activated by each material. Ti implants preferentially enriched stem-cell niches and up-regulated collagen organization through fibroblast-specific collagen type I alpha 1 chain/syndecan 1 signaling, promoting regenerative extracellular matrix remodeling and early osteogenic microenvironment. In contrast, ZrO₂ implants triggered lymphoid-dominated responses, characterized by collagen type VI alpha 2 chain/cluster of differentiation 44-mediated macrophage activation, and pro-inflammatory pathway activation. In vivo validation via bulk RNA sequencing confirmed these material-specific immunomodulatory programs, with Ti favoring osteogenic microenvironments and ZrO₂ inducing fibro-inflammatory niches. These findings provide mechanistic targets for designing immunomodulatory biointerfaces to enhance the osseointegration of ZrO₂ implants.