A model for cellulase production from Trichoderma reesei in an airlift reactor.
ABSTRACT A mathematical model for cellulase production by Trichoderma reesei RUT-C30 grown in a cellulose medium with lactose as fed batch in an airlift reactor is proposed. To describe adequately the mass transfer between the air bubbles and the broth, it uses computational fluid dynamics (CFD) including multiphase Eulerian-Eulerian formulation, with a detailed description of the bubble size distribution through the use of the population balance model (PBM) and the class method (CM). The kinetics of the biomass growth is further coupled to the fluid flow conditions using partial differential equations for all the species involved, providing detailed information of important reactor conditions such as the distribution of oxygen, cellulose, and the shear stress within the reactor over the entire period of fermentation. Predicted results agree well with the available overall measurements for a typical fed-batch operation and detailed profiles of the predicted concentration fields are discussed from an engineering viewpoint.
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ABSTRACT: Penicillin is one of the best known pharmaceuticals and is also an important member of the β-lactam antibiotics. Over the years, ambitious yields, titers, productivities, and low costs in the production of the β-lactam antibiotics have been stepwise realized through successive rounds of strain improvement and process optimization. Penicillium chrysogenum was proven to be an ideal cell factory for the production of penicillin, and successful approaches were exploited to elevate the production titer. However, the industrial production of penicillin faces the serious challenge that environmental gradients, which are caused by insufficient mixing and mass transfer limitations, exert a considerably negative impact on the ultimate productivity and yield. Scale-down studies regarding diverse environmental gradients have been carried out on bacteria, yeasts, and filamentous fungi as well as animal cells. In accordance, a variety of scale-down devices combined with fast sampling and quenching protocols have been established to acquire the true snapshots of the perturbed cellular conditions. The perturbed metabolome information stemming from scale-down studies contributed to the comprehension of the production process and the identification of improvement approaches. However, little is known about the influence of the flow field and the mechanisms of intracellular metabolism. Consequently, it is still rather difficult to realize a fully rational scale-up. In the future, developing a computer framework to simulate the flow field of the large-scale fermenters is highly recommended. Furthermore, a metabolically structured kinetic model directly related to the production of penicillin will be further coupled to the fluid flow dynamics. A mathematical model including the information from both computational fluid dynamics and chemical reaction dynamics will then be established for the prediction of detailed information over the entire period of the fermentation process and thereby for the optimization of penicillin production, and subsequently also benefiting other fermentation products.Applied Microbiology and Biotechnology 01/2014; 98(6). DOI:10.1007/s00253-013-5497-2 · 3.81 Impact Factor
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ABSTRACT: Scale-up of bioprocesses is hampered by open questions, mostly related to poor mixing and mass transfer limitations. Concentration gradients of substrate, carbon dioxide, and oxygen in time and space, especially in large-scale high-cell density fed-batch processes, are likely induced as the mixing time of the fermentor is usually longer than the relevant cellular reaction time. Cells in the fermentor are therefore repeatedlyexposedtodynamicenvironmentsorperturbations.Asaconsequence,the heterogeneityinindustrialpracticesoftendecreaseseitheryield,titer,orproductivity, or combinations thereof and increases by-product formation as compared to well- mixed small-scale bioreactors, which is summarized as scale-up effects. Identiﬁcation of response mechanisms of the microorganism to various external perturbations is of great importance for pinpointing metabolic bottlenecks and targets for metabolic engineering. In this review, pulse response experimentation is proposed as an ideal way of obtaining kinetic information in combination with scale-down approaches for in-depth understanding of dynamic response mechanisms. As an emerging tool, computational ﬂuid dynamics is able to draw a holistic picture of the ﬂuid ﬂow and concentration ﬁelds in the fermentor and ﬁnds its use in the optimization of fermentor design and process strategy. In the future, directed strain improvement and fermentor redesign are expected to largely depend on models, in which both microbial kinetics and ﬂuid dynamics are thoroughly integrated.Engineering in Life Sciences 01/2015; 15(1). DOI:10.1002/elsc.201400172 · 1.89 Impact Factor
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ABSTRACT: Population balance modeling is undergoing phenomenal growth in its applications, and this growth is accompanied by multifarious reviews. This review aims to fortify the model's fundamental base, as well as point to a variety of new applications, including modeling of crystal morphology, cell growth and differentiation, gene regulatory processes, and transfer of drug resistance. This is accomplished by presenting the many faces of population balance equations that arise in the foregoing applications. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering Volume 5 is June 07, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.Annual Review of Chemical and Biomolecular Engineering 03/2014; 5. DOI:10.1146/annurev-chembioeng-060713-040241 · 8.11 Impact Factor