Multi-scale modeling of heterogeneities in mammalian cell culture processes

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 G₁/G₀, S, and G₂/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.