An In-Silico Study on the Design of Biological Controllers for Sepsis Regulation

Macrophages are versatile innate immune cells that can dynamically shift between proinflammatory (M₁) and anti-inflammatory (M₂) states to balance immune defense and tissue repair, in response to local microenvironment cues. In sepsis, disrupted macrophage function impairs this balance, reducing pathogen clearance and increasing tissue damage. To address this, we developed a mathematical model integrating ordinary differential equations (ODEs) and a feedback control framework to design targeted interventions that promote healing. Grounded in the current knowledge of immune cell behavior and signaling, our model highlights macrophage-mediated regulation as a critical driver of infection outcomes. With model-based analysis and a biological understanding about the system dynamics, we designed IL-6-responsive feedback controllers to enhance M₁ macrophage-driven pathogen clearance. Simulation results confirmed the efficacy of the controllers in regulating the septic conditions, showing a success of up to 95% in resolving infections when regulating multiple reactions simultaneously. Numerical analysis further demonstrated the robustness of the controllers to biological variabilities and the presence of a secondary infection. We anticipate findings from this work to guide future efforts in designing biological controllers to modulate sepsis-induced inflammation toward a regulated and pro-resolving state.