Persistent glycolysis defines pathological foreign body–associated inflammation to polymeric implants

The clinical deployment of nondegradable polymeric medical devices is hindered by unresolving inflammation that drives localized fibrosis. This inflammatory niche is distinct; phagocytic macrophages remain persistently activated by biomolecular signals adsorbed to the implant surface, exhibiting profibrotic behavior. Increasingly, alterations to metabolic regulation offers insight into chronically inflamed macrophage function, which remains unexplored in peri-implant inflammation. Here, ex vivo profiling of metabolic dependence and capacity in peri-implant tissues revealed persistent glycolytic reliance by macrophages up to 6 weeks postimplantation. Expression of glucose transporter 1 (GLUT1) increased temporally and with proximity to the implant interface in glycolytically dependent cells, paired with increased capacity for biosynthetic pathways. Glycolytic dependence was notable in multinucleated macrophages, hallmark to the phagocytic behavior of implant pathology. Transcriptomic assessment correlated the up-regulation of pathological wound healing to cells where the capacity for glucose import was highest, highlighting glycolysis as the definitive metabolic system in persistent peri-implant inflammation.