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

## TL;DR

This study uses single-cell RNA sequencing to compare immune responses to zirconia and titanium bone implants, revealing differences in how each material affects bone integration.

## Contribution

The study provides a high-resolution immune cell atlas and identifies material-specific signaling pathways affecting osseointegration.

## Key findings

- Titanium implants promote regenerative extracellular matrix remodeling via fibroblast signaling.
- Zirconia implants trigger lymphoid-dominated, pro-inflammatory responses and macrophage activation.
- In vivo validation confirms distinct immunomodulatory programs for each material.

## Abstract

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.