A COMBINED CELL-CYCLE AND METABOLIC MODEL FOR THE GROWTH OF HYBRIDOMACELLS IN STEADY-STATE CONTINUOUS-CULTURE

The model presented in this work demonstrates the combination of a cel l-cycle model with a model describing the growth and conversion kineti cs of hybridoma cells in a steady-state continuous culture. The cell-c ycle model is based upon a population balance model as described by Ca zzador et al. and assumes the existence of a cycling-and apoptotic-cel l population, which together form the viable-cell population. In this part the fraction of apoptotic cells, the age distribution of the cycl ing-and apoptotic-cell population, the mean volume and biomass content per cell of the cycling, apoptotic, and viable cells, and the specifi c growth and death rates of the cells are calculated. The metabolic pa rt consists of a Monod-type growth equation, four elemental balances, an equation assuming a constant yield of ammonia on glutamine, an equa tion for product formation, and the relation of Glacken for energy pro duction. Furthermore, a maintenance-energy model for the consumption o f glucose and glutamine is introduced, which combines the approaches o f Herbert and Pirt into one model in a way similar to Beeftink et al. For energy consumption a Pirt model is assumed. The model is capable o f predicting trends in steady-state values of a large number of variab les of interest like specific growth rate, specific death rate, viabil ity, cell numbers, mean viable-cell volume, and concentrations and con version rates of product, glucose, glutamine, lactate, and ammonia. Al so the concentrations and conversion rates of oxygen and carbon dioxid e are qualitatively predicted. The values of the model predictions are generally close to experimental data obtained from literature. (C) 19 95 John Wiley & Sons, Inc.