A simple output-feedback strategy for the control of perfused mammalian cell cultures

This paper presents a framework for the multivariable robust control of perfusion animal cell cultures. It consists of a cascade control structure and an estimation algorithm, which provides the unmeasurable variables needed in the design of the control law, and ensures the regulation of the cell and glucose concentrations at imposed levels by manipulating the bleed and the dilution rates. The cascade control structure uses a feedback linearizing controller in the inner loop and linear (PI) controllers in the outer loops, and requires the measurement of the cell concentration and the glucose concentration in the bioreactor. Two approaches are provided: the first one assumes the availability of an approximate model of the process kinetics and uses an extended Kalman filter (EKF) to estimate the system states; the second approach does not require the prior knowledge of the process kinetics. These are estimated from the available measurements using sliding mode observers (SMO). A receding horizon optimization algorithm is employed to (periodically) tune the gains of the outer loop controllers. The proposed framework is easy to implement and tune, and may be applied to a general class of perfusion cell culture systems. Its effectiveness and robustness are illustrated by means of simulation results.