Daniel Schäpper

Application of microbioreactors in fermentation process development: A review

Biotechnology process development involves strain testing and improvement steps aimed at increasing yields and productivity. This necessitates the high-throughput screening of many potential strain candidates, a task currently mainly performed in shake flasks or microtiter plates. However, these methods have some drawbacks, such as the low data density (usually only end-point measurements) and the lack of control over cultivation conditions in standard shake flasks. Microbioreactors can offer the flexibility and controllability of bench-scale reactors and thus deliver results that are more comparable to large-scale fermentations, but with the additional advantages of small size, availability of online cultivation data and the potential for automation. Current microbioreactor technology is analyzed in this review paper, focusing on its industrial applicability, and directions for future research are presented.

Experimental methods and modeling techniques for description of cell population heterogeneity

With the continuous development, in the last decades, of analytical techniques providing complex information at single cell level, the study of cell heterogeneity has been the focus of several research projects within analytical biotechnology. Nonetheless, the complex interplay between environmental changes and cellular responses is yet not fully understood, and the integration of this new knowledge into the strategies for design, operation and control of bioprocesses is far from being an established reality. Indeed, the impact of cell heterogeneity on productivity of large scale cultivations is acknowledged but seldom accounted for. In order to include population heterogeneity mechanisms in the development of novel bioprocess control strategies, a reliable mathematical description of such phenomena has to be developed. With this review, we search to summarize the potential of currently available methods for monitoring cell population heterogeneity as well as model frameworks suitable for describing dynamic heterogeneous cell populations. We will furthermore underline the highly important coordination between experimental and modeling efforts necessary to attain a reliable quantitative description of cell heterogeneity, which is a necessity if such models are to contribute to the development of improved control of bioprocesses.

Topology optimized microbioreactors

This article presents the fusion of two hitherto unrelated fields—microbioreactors and topology optimization. The basis for this study is a rectangular microbioreactor with homogeneously distributed immobilized brewers yeast cells (Saccharomyces cerevisiae) that produce a recombinant protein. Topology optimization is then used to change the spatial distribution of cells in the reactor in order to optimize for maximal product flow out of the reactor. This distribution accounts for potentially negative effects of, for example, by‐product inhibition. We show that the theoretical improvement in productivity is at least fivefold compared with the homogeneous reactor. The improvements obtained by applying topology optimization are largest where either nutrition is scarce or inhibition effects are pronounced. Biotechnol. Bioeng. 2011; 108:786–796.

Embedded resistance wire as a heating element for temperature control in microbioreactors

This paper presents the technical realization of a low-cost heating element consisting of a resistance wire in a microbioreactor, as well as the implementation and performance assessment of an on/off controller for temperature control of the microbioreactor content based on this heating element. The microbioreactor (working volume of 100 µL) is designed to work bubble-free, and is fabricated out of the polymers poly(methylmethacrylate) (PMMA) and poly(dimethylsiloxane) (PDMS). The temperature is measured with a Pt 100 sensor, and the resistance wires are embedded in the polymer such that they either surround the reactor chamber or are placed underneath it. The latter can achieve an even temperature distribution across the reactor chamber and direct heating of the reactor content. We show that an integrated resistance wire coupled to a simple on/off controller results in accurate temperature control of the reactor (±0.1 °C of the set point value) and provides a good disturbance rejection capability (corrective action for a sudden temperature drop of 2.5 °C at an operating temperature of 50 °C takes less than 30 s). Finally, we also demonstrate the workability of the established temperature control in a batch Saccharomyces cerevisiae cultivation in a microbioreactor.