Monday, May 5, 2008
9-28

Environmental oscillations occurring in small and large-scale bioreactors during an Escherichia coli BL21 fed-batch culture

Frank Delvigne, Aldric Jean-Marc, Destain Jacqueline, and Thonart Philippe. Bio-industries, Faculté Universitaire des Sciences Agronomiques de Gembloux, Passage des Déportés, 2, Gembloux, 5030, Belgium

Escherichia coli BL21 is widely used as a recombinant microorganism for the production of several foreign proteins. The metabolic characteristics of the strain impose a strict control of the environmental conditions of the cultivation reactor. A lot of previous works have dealt with the glucose and dissolved oxygen feeding strategies to apply in order to avoid undesired metabolic states, such as overflow metabolism and mixed acid fermentation. In the present work, two strategies for the glucose addition have been investigated: exponential feed control and dissolved oxygen feed control. The results show that, even at small scale, the controller induces a lot of oscillations at the level of the environmental factors, i.e. the substrate level and the dissolved oxygen concentration, which can affect the microbial growth and further the recombinant protein synthesis. However, little is known about the evolution of these environmental oscillations at larger scale. The scale-up effect on the oscillating behavior of the process has been first studied by using a structured hydrodynamic model. This model has been elaborated to take into account the homogeneity efficiency of the bioreactor. In a second time, the large-scale environmental oscillations have been reproduced in a scale-down reactor. The results suggest that the scale-up process induces some variability at the level of the characteristic frequencies of the glucose and dissolved oxygen oscillations. In front of these results, a stochastic model has been proposed in order to capture this variability and to predict the efficiency of the E. coli BL21 fed-batch process at large-scale.

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