Modeling Suspension Cultures of Microbial and Mammalian Cells with an Adaptable Six‐Compartment Model

Abstract

Process models can be used for model‐based control strategies, but model development is a time‐consuming and laborious task. To reduce the modeling effort, a new structured compartment model was developed, which may easily be adapted to different cultivation processes. The proposed six‐compartment model was used to describe the time courses of cultivations of bacteria, yeast, fungi, and mammalian cell lines, namely, Escherichia coli, Lactobacillus delbrueckii, Saccharomyces cerevisiae, Cyathus striatus, and a hybridoma mammalian cell line. The model can describe the time courses of important state variables and can be adapted to the cultivation processes by parameterization. This reduces the modeling effort for a new process significantly.

Model-assisted DoE software: optimization of growth and biocatalysis in Saccharomyces cerevisiae bioprocesses

“…A novel structured compartment model, capable of being adapted to different biotechnological expression systems (e.g., bacteria, yeast, fungi, mammalian cell lines), was used to describe yeast growth, metabolism, and biocatalysis [ 27 , 40 ]. The model was previously introduced by Brüning et al [ 27 ] and is briefly explained in the following. The main part of the model is the segregation of the biomass into six distinct compartments, which are linked and individually described by mathematical equations representing different essential metabolic tasks.…”

“…Biomass synthesis is based on a carbon (SC) and a nitrogen substrate (SN) and biocatalysis is modeled based on an educt (SBC). Furthermore, physicochemical state variables, such as DO, pH, and temperature, have a direct influence on cell metabolism, biomass growth and/or biocatalytic activity [ 27 ]. The uptake rates (rS) of the substrates (S) are rate-limiting steps, which are modeled by Monod kinetics typically used in bioprocess modeling [ 14 , 26 , 28 , 40 ]: is the half-saturation constant.…”

“…The uptake rates (rS) of the substrates (S) are rate-limiting steps, which are modeled by Monod kinetics typically used in bioprocess modeling [ 14 , 26 , 28 , 40 ]: is the half-saturation constant. The Monod-like term for the uptake rates is multiplied with the product of multiple double sigmoidal functions ( ) of the state variables ( ), which describe changes of the cell metabolism [ 27 , 41 ]: The value of a state variable is described by x . is the value of at low x , and is the value at high x .…”

“… is the value between and , which are location parameters of the low/high side of the function. determines the gradient of the slope [ 27 ]. The sigmoidal functions are also used to describe the influence of operating parameters on the activation and inactivation rates as well as yield coefficients.…”

“…The mDoE-toolbox is designed to be applied in the initial phase of process development for which very little data are available. Therefore, structurally simple [ 14 , 26 ] or generalized models [ 27 ] are applied, for which model parameters can be adapted based on few data points typically generated in medium tests or first cultivations. After defining a mathematical model, the model-parametric uncertainties are derived with Monte Carlo sampling based on the experimental uncertainty (i.e., measurement error, Fig.…”