Miniature bioreactors: current practices and future opportunities

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Abstract

This review focuses on the emerging field of miniature bioreactors (MBRs), and examines the way in which they are used to speed up many areas of bioprocessing. MBRs aim to achieve this acceleration as a result of their inherent high-throughput capability, which results from their ability to perform many cell cultivations in parallel. There are several applications for MBRs, ranging from media development and strain improvement to process optimisation. The potential of MBRs for use in these applications will be explained in detail in this review. MBRs are currently based on several existing bioreactor platforms such as shaken devices, stirred-tank reactors and bubble columns. This review will present the advantages and disadvantages of each design together with an appraisal of prototype and commercialised devices developed for parallel operation. Finally we will discuss how MBRs can be used in conjunction with automated robotic systems and other miniature process units to deliver a fully-integrated, high-throughput (HT) solution for cell cultivation process development.

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Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation.

M. Jordan, A Schallhorn, F. M. Wurm (1996)

DNA-calcium phosphate co-precipitates arise spontaneously in supersaturated solutions. Highly effective precipitates for transfection purposes, however, can be generated only in a very narrow range of physico-chemical conditions that control the initiation and growth of precipitate complexes. The concentrations of calcium and phosphate are the main factors influencing characteristics of the precipitate complex, but other parameters, such as temperature, DNA concentration and reaction time are important as well. An example for this is the finding that almost all of the soluble DNA in the reaction mix can be bound into an insoluble complex with calcium phosphate in <1 min. Extending the reaction time to 20 min results in aggregation and/or growth of particles and reduces the level of expression. With improved protocols we gained better reproducibility and higher efficiencies both for transient and for stable transfections. Up to 60% of cells stained positive for beta-gal and transient production of secreted proteins was improved 5- to 10-fold over results seen with transfections using standard procedures. Similar improvements in efficiency (number of recombinant cell colonies) were observed with stable transfections, using co-transfected marker plasmids for selection. Transient expression levels 2 days after DNA transfer and titers obtained from stable cell lines, emerging weeks later, showed strong correlation.

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High cell-density culture of Escherichia coli.

S Lee (1996)

Escherichia coli is the most widely used prokaryotic system for the synthesis of heterologous proteins. Once an optimal expression system has been constructed, protein production can be enhanced by increasing the production of protein per cell per unit time (specific productivity), or by increasing the cell concentration per unit time (cell productivity). Various high cell-density culture (HCDC) techniques have been developed for growing recombinant and non-recombinant E. coli strains in fed-batch cultures at concentrations greater than 100 grams (dry cell weight) per liter. This article reviews the problems encountered in HCDC of E. coli, and discusses various solutions. Feeding strategies for HCDC of E. coli, and the results obtained using them, are also described.

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Methods for intense aeration, growth, storage, and replication of bacterial strains in microtiter plates.

Timothy O'Connor, R Hermann, W Duetz … (2000)

Miniaturized growth systems for heterogeneous culture collections are not only attractive in reducing demands for incubation space and medium but also in making the parallel handling of large numbers of strains more practicable. We report here on the optimization of oxygen transfer rates in deep-well microtiter plates and the development of a replication system allowing the simultaneous and reproducible sampling of 96 frozen glycerol stock cultures while the remaining culture volume remains frozen. Oxygen transfer rates were derived from growth curves of Pseudomonas putida and from rates of oxygen disappearance due to the cobalt-catalyzed oxidation of sulfite. Maximum oxygen transfer rates (38 mmol liter(-1) h(-1), corresponding to a mass transfer coefficient of 188 h(-1)) were measured during orbital shaking at 300 rpm at a shaking diameter of 5 cm and a culture volume of 0.5 ml. A shaking diameter of 2.5 cm resulted in threefold-lower values. These high oxygen transfer rates allowed P. putida to reach a cell density of approximately 9 g (dry weight) liter(-1) during growth on a glucose mineral medium at culture volumes of up to 1 ml. The growth-and-replication system was evaluated for a culture collection consisting of aerobic strains, mainly from the genera Pseudomonas, Rhodococcus, and Alcaligenes, using mineral media and rich media. Cross-contamination and excessive evaporation during vigorous aeration were adequately prevented by the use of a sandwich cover of spongy silicone and cotton wool on top of the microtiter plates.

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Journal

Journal ID (nlm-ta): Microb Cell Fact

Title: Microbial Cell Factories

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2859

Publication date Collection: 2006

Publication date (Electronic): 25 May 2006

Volume: 5

Page: 21

Affiliations

[1 ]The Advanced Centre for Biochemical Engineering, Department of Biochemical Engineering, University College London, Torrington Place, London, WC1E 7JE, UK

Article

Publisher ID: 1475-2859-5-21

DOI: 10.1186/1475-2859-5-21

PMC ID: 1523360

PubMed ID: 16725043

SO-VID: 65654ad1-9b35-4f04-9715-f17d475eff4d

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Miniature bioreactors: current practices and future opportunities

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Genome Engineering using CRISPR

Most cited references 76

Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation.

High cell-density culture of Escherichia coli.

Methods for intense aeration, growth, storage, and replication of bacterial strains in microtiter plates.

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