Abstract
Microbial cells in industrial large-scale bioreactors are exposed to fluctuating conditions, e.g., nutrient concentration, dissolved oxygen, temperature, and pH. These inhomogeneities can influence the cell physiology and metabolism, e.g., decelerate cell growth and product formation. Microfluidic systems offer new opportunities to study such effects in great detail by examining responses to varying environmental conditions at single-cell level. However, the possibility to reproduce large-scale bioreactor conditions in microscale cultivation systems has not yet been systematically investigated. Hence, we apply computational fluid dynamics (CFD) simulations to analyze and compare three commonly used microfluidic single-cell trapping and cultivation devices that are based on (i) mother machines (MM), (ii) monolayer growth chambers (MGC), and (iii) negative dielectrophoresis (nDEP). Several representative time-variant nutrient concentration profiles are applied at the chip entry. Responses to these input signals within the studied microfluidic devices are comparatively evaluated at the positions of the cultivated cells. The results are comprehensively presented in a Bode diagram that illustrates the degree of signal damping depending on the frequency of change in the inlet concentration. As a key finding, the MM can accurately reproduce signal changes that occur within 1 s or slower, which are typical for the environmental conditions observed by single cells in large-scale bioreactors, while faster changes are levelled out. In contrast, the nDEP and MGC are found to level out signal changes occurring within 10 s or faster, which can be critical for the proposed application.
Highlights
Industrial bioprocesses, for example the production of the antibiotic penicillin by the fungal species Penicillium chrysogenum, typically involve suspension cultivation of the microorganisms in stirred large-scale bioreactors with working volumes up to several hundred cubic meters [1]
In this contribution we study if the dynamics of environmental conditions typically encountered by individual cells in large-scale bioreactors can be reproduced in the trapping zones of microfluidic chips
The mother machines (MM) can reproduce the signal within 1 s, which is the response time required for reproducing large-scale bioreactor conditions
Summary
Industrial bioprocesses, for example the production of the antibiotic penicillin by the fungal species Penicillium chrysogenum, typically involve suspension cultivation of the microorganisms in stirred large-scale bioreactors with working volumes up to several hundred cubic meters [1]. Within those large-scale bioreactors, spatial gradients and highly dynamic inhomogeneous conditions are caused by imperfect mixing due to limited power input and the cultivated microorganisms are exposed to fluctuating pH, temperature, nutrients and dissolved oxygen [2,3]. Microbes have further been reported to metabolically react to glucose pulses after only 2 s by forming significantly high amounts of by-products such as acetate and formate under aerobic and anaerobic conditions [4]
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