Sampled-data Robust Control of Electrically Stimulated Engineered Cell Factories

Researchers from the team of Papri Dey, Ksenia Zoblina, Nicholas A. Rondoni, and Marcella M. Gomez have introduced a new control framework for closed-loop bioelectronic regulation of engineered secretory cell systems. Their work, published on arXiv under title "Sampled-data Robust Control of Electrically Stimulated Engineered Cell Factories," addresses the inherent challenges of electric-field (EF) stimulation—indirect activation through transcription factors, delayed and nonlinear intracellular dynamics, sparse measurements, and constrained burst-based actuation. The plant model is built using a control-oriented ordinary differential equation (ODE) that integrates a reduced mechanistic pathway for extracellular thyroid hormone T4 production, an EF-responsive Hill module, and a linear-chain Erlang cascade to represent distributed intracellular delays. On this basis, the team designed a sampled-data adaptive proportional-integral-derivative (APID) controller enhanced with derivative filtering, anti-windup, saturation and rate limits, and hysteretic band-locking.

To achieve robustness, the authors extended the controller to a robust adaptive PID (RAPID) that explicitly accounts for parameter mismatch, sensor noise and bias, actuator mismatch, delay/jitter, and exogenous rhythmic disturbances via a scenario-based risk-aware update. They provide local sampled-data input-to-state stability interpretations for both APID and RAPID, proving that under standard Lyapunov and bounded-disturbance conditions, the sampled tracking error remains ultimately bounded by a disturbance-dependent constant. In silico experiments focus on sustained regulation of extracellular T4 in engineered thyroid-like cells, demonstrating the controller's ability to maintain prescribed targets despite significant uncertainty. This work represents a significant step toward reliable closed-loop bioelectronic control of engineered cell factories, with potential applications in therapeutic hormone production and cellular manufacturing.