Sampled-data Robust Control of Electrically Stimulated Engineered Cell Factories

TL;DR

This paper presents a robust closed-loop control framework for electrically stimulated engineered cell factories, enabling stable regulation of thyroid hormone production despite biological uncertainties and delays.

Contribution

It introduces a novel sampled-data adaptive PID controller with robustness features tailored for bioelectronic regulation of engineered cells.

Findings

The control scheme maintains stable T4 production despite uncertainties.

In silico experiments confirm effective regulation across various targets.

The framework accounts for delays, noise, and parameter mismatches.

Abstract

Closed-loop bioelectronic regulation of engineered secretory cell systems is challenging because electric-field (EF) stimulation acts indirectly through transcription-factor activation, in the presence of delayed, nonlinear, and noisy intracellular dynamics, sparse measurements, and constrained burst-based actuation. We develop a framework for robust closed-loop endocrine regulation in electrically stimulated engineered cell factories, illustrated through extracellular thyroid hormone \(T_4\) production in engineered thyroid-like cells. The plant is modeled by a control-oriented ODE formulation combining a reduced mechanistic \(T_4\) pathway, an EF-responsive Hill module, and a linear-chain Erlang cascade representing distributed intracellular delay. On this basis, we design a sampled-data adaptive proportional-integral-derivative (PID) controller with derivative filtering, anti-windup, saturation and rate limits, and hysteretic band-locking, together with a robust adaptive extension that accounts for parameter mismatch, sensor noise and bias, actuator mismatch, delay/jitter, and exogenous rhythmic disturbance through a scenario-based risk-aware update. We provide local sampled-data input-to-state stability interpretations for both APID and RAPID, showing that, under standard local Lyapunov and bounded-disturbance conditions, the sampled tracking error is ultimately bounded by a disturbance-dependent constant. In silico experiments demonstrate sustained regulation of extracellular \(T_4\) across prescribed targets despite significant uncertainty.