Role of Macrophages in the Foreign Body Response to Poly(ethylene glycol) Hydrogels

Macrophages are known to be the drivers of the Foreign Body Response (FBR) to implanted biomaterials. While each macrophage population may polarize into distinct phenotypes, the timescales of this process and their functional roles in the FBR are not known. The goal of this study was to investigate temporal changes in macrophage polarization over the course of the FBR to a PEG hydrogel implant. RNA-seq methods were applied to map temporal changes in the transcriptome of implant-associated monocytes, which represent newly arrived blood monocytes prior to their maturation into macrophages, and separately implant-associated macrophages, which represent both recruited and tissue resident macrophages. The transcriptomics analysis of implant-associated monocytes revealed that pro-inflammatory pathways were up-regulated early and continued to increase at day 14, but by day 28 began to subside. On the contrary, macrophages were initially in a pro-inflammatory state, but underwent a shift in their polarization state to an alternatively activated pro-fibrotic state by day 14, correlating with the emergence of the fibrous capsule. They retained this state through day 28, which correlated with the continued growth of the fibrous capsule around the hydrogel implant. Overall design: RNA-seq was used to monitor the transcriptome of Cx3Cr1+Ly6Chi-monocytes and Cx3Cr1+Ly6Clo-macrophages during the FBR at day 2, 14, and 28 post-implantation. Three biological replicates with the exception of the controls (n=2 biological replicates for macrophages) were used.