Agent-based model of inflammation and wound healing: Insights into diabetic foot ulcer pathology and the role of transforming growth factor-β1

Inflammation and wound healing are inextricably linked and complex processes, and are deranged in the setting of chronic, nonhealing diabetic foot ulcers (DFU). An ideal therapy for DFU should both suppress excessive inflammation while enhancing healing. We reasoned that biological simulation would clarify mechanisms and help refine therapeutic approaches to DFU. We developed an agent-based model (ABM) capable of reproducing qualitatively much of the literature data on skin wound healing, including changes in relevant cell populations (macrophages, neutrophils, fibroblasts) and their key effector cytokines (tumor necrosis factor-α [TNF], interleukin [IL]-1β, IL-10, and transforming growth factor [TGF]-β1). In this simulation, a normal healing response results in tissue damage that first increases (due to wound-induced inflammation) and then decreases as the collagen levels increase. Studies by others suggest that diabetes and DFU are characterized by elevated TNF and reduced TGF-β1, although which of these changes is a cause and which one is an effect is unclear. Accordingly, we simulated the genesis of DFU in two ways, either by (1) increasing the rate of TNF production fourfold or (2) by decreasing the rate of TGF-β1 production 67% based on prior literature. Both manipulations resulted in increased inflammation (elevated neutrophils, TNF, and tissue damage) and delayed healing (reduced TGF-β1 and collagen). Our ABM reproduced the therapeutic effect of platelet-derived growth factor/platelet releasate treatment as well as DFU debridement. We next simulated the expected effect of administering (1) a neutralizing anti-TNF antibody, (2) an agent that would increase the activation of endogenous latent TGF-β1, or (3) latent TGF-β1 (which has a longer half-life than active TGF-β1), and found that these therapies would have similar effects regardless of the initial assumption of the derangement that underlies DFU (elevated TNF vs. reduced TGF-β1). In silico methods may elucidate mechanisms of and suggest therapies for aberrant skin healing.