Large-scale production of yeast (Saccharomyces cerevisiae) is difficult to control, considering the drop of mixing and mass transfer efficiency during scale-up. The drop of hydrodynamic efficiency in large-scale bioreactors induces the formation of heterogeneities, i.e. mainly substrate and dissolved oxygen in process conditions. These extracellular fluctuations have several impacts at the level of the physiology of microorganisms, from metabolic shift to specific gene expression (stress response). Microbial cell responses to extracellular fluctuations are actually not fully understood. In this work, we propose to reproduce the main extracellular fluctuations at the level of a mini bioreactor platform. These mini-reactors are shake flasks equipped with dissolved oxygen probes. The cultures are realized with different fed-batch control strategies. A scale-down approach has been developed by considering slow release techniques and intermittent feeding, in order to reproduce the glucose and dissolved oxygen fluctuations experienced in large-scale reactors. The mini-reactor has been used to screen the response of several green fluorescent protein (GFP) reporter strains (adh2, tps2, pdc6 and hxt2). The GFP content of cells has been determined by flow cytometry in order to take into account population heterogeneity. In front of these results, the methodology presented in this work can be proposed as a scale-down tool.
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