Microfluidic single-cell scale-down systems: introduction, application, and future challenges.

Performance losses during the scaling-up of bioprocesses from the laboratory to the production scale are common obstacles caused by the formation of concentration gradients in bioreactors. To overcome these obstacles, so-called scale-down bioreactors are used to analyze selected large-scale conditions and are one of the most important predictive tools for the successful transfer of bioprocesses from the lab to the industrial scale. In this regard, cellular behavior is usually measured as an averaged value, neglecting possible cell-to-cell heterogeneity within the culture. In contrast, microfluidic single-cell cultivation (MSCC) systems offer the possibility of understanding cellular processes on a single-cell level. To date, most MSCC systems have a limited choice of cultivation parameters that are not representative of bioprocess-relevant environmental conditions. Herein, we critically review recent advances in MSCC that allow the cultivation and analysis of cells under dynamic (bioprocess-relevant) environmental conditions. Finally, we discuss what technological advances and efforts are needed to bridge the gap between current MSCC systems and the use of these systems as single-cell scale-down devices.