A Framework for the Development of Integrated and Computationally Feasible Models of Large-Scale Mammalian Cell Bioreactors

Abstract

Industrialization of bioreactors has been achieved by applying several core concepts of science and engineering. Modeling has deepened the understanding of biological and physical phenomena. In this paper, the state of existing cell culture models is summarized. A framework for development of dynamic and computationally feasible models that capture the interactions of hydrodynamics and cellular activities is proposed. Operating conditions are described by impeller rotation speed, gas sparging flowrate, and liquid fill level. A set of admissible operating states is defined over discretized process parameters. The burden on a dynamic solver is reduced by assuming hydrodynamics at its fully developed state and implementation of compartmental modeling. A change in the conditions of operation is followed by hydrodynamics switching instantaneously to the steady state that would be reached under new conditions. Finally, coupling the model with optimization solvers leads to improvements in operation.

Comprehensive modeling of cell culture profile using Raman spectroscopy and machine learning

“…To further improve model accuracy, it is worth considering incorporating information other than Raman spectra into the model. Previous studies have proposed models that combine the computational fluid dynamics models 38 or include process-related impurities and kinetics of each cultivation data 39 , suggesting that combining this information with Raman spectral data may lead to even higher accuracy models. Additionally, improving the model construction methods is expected to further enhance model accuracy.…”

Integration Approaches to Model Bioreactor Hydrodynamics and Cellular Kinetics for Advancing Bioprocess Optimisation

“…If the impact of process parameter gradients on cellular behaviour can be predicted for the entire duration of the production process, significant leads can be gained for the development of strategies to enhance productivity [37], increase efficiency [38], and reduce costs [81], contributing to the goals of process intensification. In one of the studies, for optimisation of vanillin production from ferulic acid using recombinant Escherichia coli cells, Yeoh et al [37] evaluated the impact of mass transfer and aeration rate on the process performance.…”

“…The Eulerian approach is computationally less expensive and more suited for transient simulations. The integration of CFD-CRK for transient analysis of the system has the potential to provide real-time and predictive insights into the dynamic cellular responses, enabling quick decision-making in biomanufacturing processes [38]. It also allows for the creation of digital twins (virtual representations of the bioprocess), enabling simulation and prediction of the impact of various parameters on cellular behaviour.…”

Special Issue: Methods in Computational Biology

“…Pool et al [5] studies intra-and extracellular processes associated with cholesterol and lipoprotein metabolism and how intervention strategies such as statins or diet can influence metabolism. Farzan and Ierapetritou [6] report on multicellular scale systems and analyze interactions between mammalian cells and the bioreactor environment with the ultimate goal of optimizing bioprocess applications. Norton et al [2] study systems on the cellular and tissue scales and examine the interactions between tumor cells, host immune cells and local microenvironments.…”

“…These gradients lead to spatial distributions of cell types and often enhanced system robustness. Farzan and Ierapetritou [6] consider the interface of mammalian cells and convective transport processes which ultimately influence the local chemical, thermal and mechanical environments. The work also discusses computational optimization and selection of solvers for these types of modeling applications.…”