Mapping Macrophage Polarization and Origin during the Progression of the Foreign Body Response to a Poly(ethylene glycol) Hydrogel Implant

Abstract

Poly(ethylene glycol) (PEG) hydrogels hold promise for in vivo applications but induce a foreign body response (FBR). While macrophages are key in the FBR, many questions remain. This study investigates temporal changes in the transcriptome of implant‐associated monocytes and macrophages. Proinflammatory pathways are upregulated in monocytes compared to control monocytes but subside by day 28. Macrophages are initially proinflammatory but shift to a profibrotic state by day 14, coinciding with fibrous capsule emergence. Next, this study assesses the origin of macrophages responsible for fibrous encapsulation using wildtype, C‐C Motif Chemokine Receptor 2 (CCR2)–/– mice that lack recruited macrophages, and Macrophage Fas‐Induced Apoptosis (MaFIA) mice that enable macrophage ablation. Subpopulations of recruited and tissue‐resident macrophages are identified. Fibrous encapsulation proceeds in CCR2–/– mice similar to wildtype mice. However, studies in MaFIA mice indicate that macrophages are necessary for fibrous capsule formation. These findings suggest that macrophage origin impacts the FBR progression and provides evidence that tissue‐resident macrophages and not the recruited macrophages may drive fibrosis in the FBR to PEG hydrogels. This study demonstrates that implant‐associated monocytes and macrophages have temporally distinct transcriptomes in the FBR and that profibrotic pathways associated with macrophages may be enriched in tissue‐resident macrophages.

Immunomodulatory biomaterials on chemokine signaling in wound healing

“…Since tissue resident macrophages are still active in CCR2−/− mice, the authors conclude that tissue resident macrophages may play a greater role in capsule formation. They also conclude that the chemokine CCL2, which was not affected by the stiff PEGhydrogel, is not the main chemokine responsible for fibrotic encapsulation (Saleh et al, 2022).…”

“…The effects of a "stiff" PEG-hydrogel and its ability to elicit a foreign body response is examined in a study by Saleh et al (2022). Typically, "stiffer" PEG-hydrogels have been reported to produce more significant inflammatory and foreign body responses.…”

“…The authors postulate that this increased inflammation seen using MAA based materials is contributing to the advances in wound healing seen in prior studies, but no chemokines associated with anti-inflammatory or angiogenic signaling are identified in this study. The role of CCL7 as we understand it is mainly limited to binding of CCR2 expressed on macrophages to induce inflammatory cell recruitment (Saleh et al, 2022).…”

“…Following hemostasis, recruited mast cells release histamine, leading to vasodilation and increased blood flow to the injury site, which carries along additional immune cells. Mast cells secrete CXCL8 but secrete larger quantities of CCL2 and CCL4, along with smaller quantities produced by neutrophils, to recruit peripheral monocytes from the blood, bone marrow and spleen (Nakkala et al, 2021;Saleh et al, 2022). CCL2 is also produced by basal keratinocytes at the wound edge (Satish, 2015).…”

“…CCL2 is also produced by basal keratinocytes at the wound edge (Satish, 2015). Peripheral monocytes express the chemokine receptor CCR2, which binds CCL2, 7, 8, and 12, and differentiates them from tissue-resident monocytes which are recruited locally by chemokines CCL17, 18, and 22 (Saleh et al, 2022). Both types of monocytes differentiate into macrophages and clear dead cells and necrotic tissue from the injury site.…”