Multi-Scale Modeling of Heterogeneities in Mammalian Cell Culture Processes

Abstract

Conventionally cell cultures are modeled using either structured/unstructured average cell models to capture the intracellular processes or population balance models (PBM) to account for the cell cycle propagation. The former is based on average cell population behavior and cannot describe the heterogeneities within, whereas the latter cannot alone probe into the detailed phenomena of intracellular metabolism. In this work, a multiscale modeling approach is proposed to unify the understanding of intracellular metabolism and the probabilistic nature of intercellular heterogeneities arising because of cell cycle apportioning. As a first step, average culture dynamics are described using an unstructured model encompassing cell growth, cell death, nutrient consumption, metabolite, and protein production and their dependency on various environmental factors. The model parameter identification is performed on the data obtained from the batch Chinese Hamster Ovary (CHO) cell cultures in spinner flasks. Then, a one-dimensional age-based PBM is formulated with three flow-cytometry identifiable cell cycle phases G 1 /G 0 , S, and G 2 /M. The cell metabolism for each cell cycle phase is considered to be different to account for the heterogeneity arising from cell cycle propagation and cycle specific intracellular activities. Simulated annealing is used for PBM specific parameter identification. It is found that the PBM combined with average cell model can explain the CHO cell cultures accurately in different aspects of cell cycle apportioning, culture media concentration dynamics, and protein production.

Kinetic Modeling of Mammalian Cell Culture Bioprocessing: The Quest to Advance Biomanufacturing

“…Recently, Kar et al presented a whole cell model of Mycoplasma genitalium which combines 900 pre‐existing models for various individual cellular processes with more than 1900 parameters . Such multi‐scale modeling has also been used to develop kinetic models of mammalian cells as well, but in a much narrower scope due to their cellular complexity . Reconstructing such a multi‐scale model to a mammalian cell line such as CHO cells with more than 21 000 genes, as opposed to 525 in M. genitalium , will introduce much more parameters and severely increase the complexity.…”

A novel quantitative model of cell cycle progression based on cyclin-dependent kinases activity and population balances

“…In addition, cell cycle is the crucial process that regulates cell growth and its proliferation during in vitro cell cultivation. Mammalian cells are usually cultured to produce high-value biopharmaceutical products such as monoclonal antibodies and vaccines (Sidoli et al, 2006;Liu et al, 2007;Karra et al, 2010) and to synthesize ex vivo biological tissues through stem cells differentiation for regenerative medicine (Lanza et al, 1996), as well as to expand specialized cells for tissue engineering (Horch, 2006). For all these reasons, the cell division cycle is one of the most intensively studied biological processes, while, on the other hand, in spite of such a great effort, many questions still remain open (Tyers, 2004).…”

A novel population balance model to investigate the kinetics of in vitro cell proliferation: Part I. model development

“…Nowadays mammalian cells are routinely cultured to produce high‐value biopharmaceutical products as monoclonal antibodies and vaccines (cf. Karra et al, 2010; Liu et al, 2007; Sidoli et al, 2006) and to synthesize ex vivo biological tissues, like stem cells expansion, and differentiation for regenerative medicine (cf. Lanza et al, 1997).…”