# Macrophage-related immune responses to polyetherketoneketone bone implants: Single-cell transcriptome analysis

## TL;DR

This study uses single-cell RNA sequencing to compare how titanium and PEKK bone implants affect macrophage responses and inflammation in the early stages of implantation.

## Contribution

The study reveals material-specific macrophage polarization patterns and their impact on osseointegration and hematopoietic homeostasis using single-cell transcriptomics.

## Key findings

- Titanium implants recruit Cd99+ macrophages, promoting anti-inflammatory environments and osseointegration.
- PEKK implants recruit Icam1+ macrophages, causing inflammation and hematopoietic stem cell stress.
- Single-cell RNA sequencing identifies distinct immune responses to biomaterials affecting clinical outcomes.

## Abstract

Polyetherketoneketone (PEKK) has emerged as a potential alternative to titanium (Ti) for bone implants. Nevertheless, its osseointegration performance is inferior to that of Ti, primarily due to the limited understanding of its early immune reactions. To address this limitation, this study utilized single-cell RNA sequencing to investigate the distinct early macrophage responses triggered by Ti-based and PEKK-based implants. This approach enabled the characterization of macrophage-polarization dynamics and intercellular interactions within the bone-marrow microenvironment post-implantation. The findings revealed a material-dependent dichotomy in macrophage phenotype: Ti implants preferentially recruited Cd99+ macrophages, establishing an anti-inflammatory microenvironment that promotes osseointegration. Conversely, PEKK implants recruited Icam1+ macrophages, leading to persistent inflammation and hematopoietic stem cells (HSCs) stress. Additionally, Ti surfaces facilitated CD99-dependent crosstalk between macrophages and T cells, enhancing Th2 responses, which are indicative of an anti-inflammatory effect. In contrast, PEKK-associated macrophages triggered ICAM1-driven necroptosis in HSCs, disrupting hematopoietic homeostasis. These results indicate the early macrophage-related responses as key determinants of the clinical-outcome differences between Ti and PEKK implants.

Image 1

•Titanium and polyetherketoneketone (PEKK) evoke distinct macrophage responses.•Titanium promotes regeneration via the anti-inflammatory Cd99+ macrophages.•PEKK-caused inflammation via Icam1+ macrophages perturbs hematopoietic stem cells.•Single-cell RNA sequencing advances biomaterial immunogenicity evaluation.

Titanium and polyetherketoneketone (PEKK) evoke distinct macrophage responses.

Titanium promotes regeneration via the anti-inflammatory Cd99+ macrophages.

PEKK-caused inflammation via Icam1+ macrophages perturbs hematopoietic stem cells.

Single-cell RNA sequencing advances biomaterial immunogenicity evaluation.