Sepsis remains a critical healthcare challenge due to disordered immune responses that lead to excessive inflammation and subsequent immune dysfunction. To design new classes of therapeutics that regulate the critical divergence of the immune response during septicemia, here we integrate an ordinary differential equation (ODE)-based model, control theory concepts and synthetic biology technique, to design a biological regulator to facilitate the stalled healing process. Based on understandings of the immune response to pathogen invasion, we first develop a first principle-based ODE model to describe the key dynamics of the dysregulated immune response, and then perform model-based analysis to identify the regulation and sensing points of the system, to design a synthetic gene circuit that functions as a biological feedback controller. Simulation analysis demonstrates that the controller can effectively regulate macrophage dysregulation observed in sepsis, significantly improving the healing process. Our work presents a systems biology approach to predicting and exploring critical parameters as potential therapeutic targets that promise to transition sepsis-induced inflammation toward an improved healing state. While acknowledging the inherent limitations of the simplified dynamics in the ODE model used in this study, we anticipate findings from this work to benefit the experimental design of the sepsis biological regulators, and that future experimental efforts to further benefit the validation and improvement of the proposed approach in return.
