Model-guided Design of Biological Controller for Septic Wound Healing Regulation

Immune response is critical in septic wound healing. The aberrant and imbalanced signaling dynamics primarily cause a dysfunctional innate immune response, exacerbating pathogen invasion of injured tissue and further stalling the healing process. To design biological controllers that regulate the critical divergence of the immune response during septicemia, we need to understand the intricate differences in immune cell dynamics and coordinated molecular signals of healthy and sepsis injury. Here, we deployed an ordinary differential equation (ODE)-based model to capture the hyper and hypo-inflammatory phases of sepsis wound healing. Our results indicate that impaired macrophage polarization leads to a high abundance of monocytes, M1, and M2 macrophage phenotypes, resulting in immune paralysis. Using a model-based analysis framework, we designed a biological controller which successfully regulates macrophage dysregulation observed in septic wounds. Our model describes a systems biology approach to predict and explore critical parameters as potential therapeutic targets capable of transitioning septic wound inflammation toward a healthy, wound-healing state.