An energetically structured model of mammalian cell metabolism. 1. Model development and application to steady-state hybridoma cell growth in continuous culture.

Incomplete understanding of mammalian cell culture kinetics hinders the ability of the biochemical engineer or biologist to design and control mammalian cell culture systems and to develop operating strategies. To address this problem, a mechanistic, structured mathematical model has been developed to simulate mammalian cell culture kinetics under a variety of bioreactor operating conditions. An important feature of in vitro mammalian cell metabolism in conventional cell culture media is the partial substitutability of the substrates glucose and glutamine for provision of energy in the cell. The utilization of glucose and glutamine by cells can therefore vary substantially, and these changes can profoundly affect the culture behavior. The model developed here specifically addresses the dynamics of substrate consumption and energy metabolism in mammalian cell culture. This energetically structured (ES) model is also distinguished by the consideration of changes in the specific cell mass with specific growth rate and the consideration of essential amino acids as potentially growth rate limiting. The model is applied here to simulate literature data on the growth and metabolism of a murine hybridoma in continuous culture.