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

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 <i>Cd99</i> ⁺ macrophages, establishing an anti-inflammatory microenvironment that promotes osseointegration. Conversely, PEKK implants recruited <i>Icam1</i> ⁺ 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.