Beyond Encapsulation: Exploring Macrophage-Fibroblast Crosstalk in Implant-Induced Fibrosis.

The foreign body response (FBR) and organ fibrosis are complex biological processes involving the interaction between macrophages and fibroblasts. Understanding the molecular mechanisms underlying macrophage-fibroblast crosstalk is crucial for developing strategies to mitigate implant encapsulation, a major cause of implant failure. This article reviews the current knowledge on the role of macrophages and fibroblasts in the FBR and organ fibrosis, highlighting the similarities between these processes. The FBR is characterized by the formation of a fibrotic tissue capsule around the implant, leading to functional impairment. Various factors, including material properties such as surface chemistry, stiffness and topography influence the degree of encapsulation. Crosstalk between macrophages and fibroblasts plays a critical role in both the FBR and organ fibrosis. However, the precise molecular mechanisms remain poorly understood. Macrophages secrete a wide range of cytokines that modulate fibroblast behavior such as abundant collagen deposition, and myofibroblast differentiation. However, the heterogeneity of macrophages and fibroblasts and their dynamic behavior in different tissue environments add complexity to this crosstalk. Experimental evidence from in vitro studies demonstrates the impact of material properties on macrophage cytokine secretion and fibroblast physiology. However, the correlation between in vitro response and in vivo encapsulation outcomes is not robust. Adverse Outcome Pathways (AOPs) offer a potential framework to understand and predict process complexity. AOPs describe causal relationships between measurable events leading to adverse outcomes, providing mechanistic insights for in vitro testing and predictive modeling. However, the development of an AOP for the FBR does require a comprehensive understanding of the molecular initiating events and key event relationships to identify which events are essential. In this manuscript, we describe the current knowledge on macrophage-fibroblast crosstalk in the FBR and discuss how targeted research can help build an AOP for implant-related fibrosis.