Agent-based modeling of macrophage-fibroblast interactions in the immune response to biomaterials

Foreign body reaction (FBR) denotes the reaction to the implantation of a biomaterial into the body. It triggers cascades of responses in the tissue and involves different cell types including, among others, macrophages, fibroblasts and endothelial cells. Macrophages regulate the inflammatory and healing processes. They exhibit a variety of functional phenotypes (or states) induced by the stimulus they receive and the microenvironment. This polarization process is governed by chemical mediators, known as cytokines, that are secreted by the macrophage itself and induce cellular activation and recruitment. Cytokines determine the macrophage phenotype within a heterogeneous range that spans between two extremes: pro-inflammatory or M1 and anti-inflammatory (or pro-healing) or M2. Fibroblasts are recruited in response to cytokine secretion and play a crucial role in tissue remodeling. These cells generate key components of the extracellular matrix (ECM), such as elastin, fibrin, and collagen, and have the ability to isolate the implanted biomaterial from surrounding tissue by encapsulating it within a fibrotic layer. The formation of this fibrotic capsule is a major factor contributing to the failure of many biomaterials. Macrophage and fibroblasts interact in tissues both in physiological and pathological conditions. One of the major signaling factor is the colony-stimulating factor 1 (CSF1) and its specific receptor (CSF1R). In the past, simulation works have focused only on the description of the phenotype transition from M1 to M2 for macrophages, possibly connected to physiological and pathological conditions (e.g. hypoxia), but neglecting the relevant macrophage/fibroblast interaction. Our long term aim is to exploit an agent-based (AB) modeling approach to develop a predictive digital twin for simulating the response over time of the cell populations involved in a FBR. Our first step in this direction is the explicit introduction of the interaction between macrophages and fibroblasts. To achieve this goal, we consider here at first the existing ordinary differential equation (ODE) and AB models, that simulate intra- and inter-cellular dynamics for macrophages, respectively. We validate them against in vitro data taken from experiments that recapitulate the reaction to a pathogen and in vivo data taken from the literature. This approach highlights a better agreement of the AB model over the ODE models taken into account in our study. Therefore, we propose a more advanced and comprehensive simulation platform based on AB modeling, which also includes fibroblasts and their mutual interaction with macrophages, as well as fibrosis resulting from the implantation of a biomaterial, allowing us to simulate in vivo scenarios. We validate this tool on experimental results from the literature finding a remarkable agreement. The application of this extended AB model allows us to replicate the kinetics of the cell populations involved, including, among others, the effect of different types of stimulus, chemotaxis, recruitment, and formation of the fibrotic capsule typical of the chronic FBR.