Flux analysis of mammalian cell culture

Animal cells are used for the production of vaccines and pharmaceutical proteins. The increase in demand for these products requires an increase in volumetric productivity of animal cell culture processes, which can be attained through an increase in biomass concentration and/or specific productivity. At the same time, the correct glycosylation pattern must be preserved to guarantee the correct biological activity of the protein. To optimize the volumetric productivity and to keep the desired glycosylation pattern of the protein, knowledge of cell physiology including cell metabolism is essential. The metabolism of animal cells is complex; because metabolism is distributed over different compartments, animal cells have complex nutritional demands and substantial waste metabolism occurs. Metabolic flux modeling can be a useful tool to reduce this complexity and to obtain a better understanding of cell metabolism. The models can be used to obtain fundamental understanding of metabolism, design media, and processes and for process control. For these applications, it would be useful to further develop genome-scale models for mammalian cells. In this article, first, the theory and concepts of metabolic flux analysis are treated using a simplified example of mammalian cell catabolism. Subjects that are discussed are as follows: model construction and simplification, methods to calculate fluxes, underdetermined systems, consistency testing, and rate balancing. Next, a comprehensive metabolic network model for mammalian cells is presented and specific problems associated with flux analysis in mammalian cells, such as the different underdetermined parts, are discussed. Finally, applications for metabolic network models in animal cell culture are briefly discusse