Abstract
The performance of currently available minibioreactors with volumes below about 100 ml is reviewed. Bioreactors are characterized by their area of application, by mass transfer and mixing characteristics and by their suitability for on-line monitoring and control. The review comprises shaken bioreactors such as shake-flasks, microtiter plates and test-tubes, stirred bioreactors including spinner-flasks for the cultivation of mammalian cells and various special reactors particularly involving on-line monitoring as e.g. membrane inlet mass spectrometry and NMR.
References
Arroyo M, Guzman RT, Mata I, Castillon MP, Acebal C (2000) Activation and stabilization of penicillin V acylase from Streptomyces lavendulae in the presence of glycerol and glycols. Biotechol. Prog. 16: 368–371.
Balcarcel RR, Clark LM (2003) Metabolic screening of mammalian cell cultures using well plate. Biotechnol. Prog. 19: 98–108.
Blanch HW, Clark DS (1996) Biochemical Engineering: Basic Concepts, 2nd edn. New York: Marcel Dekker Inc.
Bochner BR (2003) New technologies to assess genotype-phenotype relationships. Nat. Rev. Genet. 4: 309–314.
Bochner BR, Gadzinski P, Panomitros E (2001) Phenotype microarrays for high-throughput phenotypic testing and assay of gene function. Genome Res. 11: 1246–1255.
Bonarius HPJ, Özemre A, Timmerarends B, Skrabal P, Tramper J, Schmid G, Heinzle E (2001) Metabolic-flux analysis of continuously cultured hybridoma cells using 13 Cox mass spectrometry in combination with 13C-lactate nuclear magnetic resonance spectroscopy and metabolite balancing. Biotechnol. Bioeng. 74: 528–538.
Büchs J (2001) Introduction to advantages and problems of shaken cultures. Biochem. Eng. J. 7: 91–98.
Büchs J, Lotter S, Milbradt C (2001) Out-of-phase operating conditions, a hitherto unknown phenomenon in shaking bioreactors. Biochem. Eng. J. 7: 135–141.
Büchs J, Maier U, Milbradt C, Zoels B (2000) Power consumption in shaking flasks on rotary shaking machines: I. power consumption measurement in unbaffled flasks at low liquid viscosity. Biotechnol. Bioeng. 68: 589–593.
Bushell ME, Dunstan GL, Wilson GC (1997) Effect of small-scale culture vessel type on hyphal fragment size and erythromycin production in Saccaropolyspora erythraea. Biotechnol. Lett. 19: 849–852.
Chattopadhyay S, Srivastava AK, Bisaria VS (2002) Optimization of culture parameters for production of podophyllotoxin in suspension culture of Podophyllum hexandrum. Appl. Biochem. Biotechnol. 102: 381–393.
Chu L, Robinson DK (2001) Industrial choices for protein production by large-scale cell culture. Curr. Opin. Biotechnol. 12: 180–187.
Clerval R, Kühner M, Li Z, Minas W, Fjällman A, Witholt B, Duetz WA (2000) The come-back of high-throughput screening of wild-type microbial strains through the use of miniaturised growth systems and LC-MS. Bioworld 6: 24–26.
Collins CP, Miller WM, Papoutsakis ET (1998) Stirred culture of peripheral and cord blood hematopoietic cells offers advantages over traditional static systems for clinically relevant applications. Biotechnol. Bioeng. 59: 534–543.
Connon SA, Giovannoni SJ (2002) High-throughput methods for culturing microorganism in very-low-nutrient media yield diverse new marine isolates. Appl. Environ. Microbiol. 68: 3878–3885.
Czirbik RJ, Rosen SM, Trunfio DM, Ellyn W. Bender F, Palmer SM (1996) Factors affecting antibody production efficiency in hollow-fiber bioreactors. IVD Technology Magazine pp. 56.
Dilsen S, Paul W, Herforth D, Sandgathe A, Altenbach-Rehm J, Freudl R, Wandrey C, Weuster-Botz D (2001) Evaluation of parallel operated small-scale bubble columns for microbial process development using Staphylococcus carnosus. J. Biotechnol. 88: 77–84.
Doig SD, Pickering SCR, Lye G, Woodley JM (2002) The use of microscale processing technologies for quantification of biocatalytic Baeyer-Villiger oxidation kinetics. Biotechnol. Bioeng. 80: 42–49.
Duetz WA, Witholt B (2001) Effectiveness of orbital shaking for the aeration of suspended bacteria in square-deep well microtiter plates. Biochem. Eng. J. 7: 113–115.
Duetz WA, Witholt B (2003) Oxygen transfer by orbital shaking of square vessels and deepwell microtiter plates of various dimensions. Biochem. Eng. J., in press.
Duetz WA, Minas W, Kühner M, Clerval R, Li Z, Fjällman AHM, Witholt B (2001) Miniaturized microbial growth systems for screening for secondary metabolites and enzymes. Bioworld 2: 8–10.
Duetz WA, Rüedi L, Hermann R, Connor KO, Büchs J, Witholt B (2000) Methods for intense aeration, growth, storage and replication of bacterial strains in microtitre plates. Appl. Environ. Microbiol. 66: 2641–2646.
Falkenberg FW, Weichert H, Krane M, Bartels I, Palme M, Nagels HO, Fiebig H (1995) In vitro production of monoclonal antibodies in high concentration in a new and easy to handle modular minifermenter. J. Immunol. Meth. 179: 13–29.
Girard P, Jordan M, Tsao M, Wurm FM (2001) Small-scale bioreactor system for process development and optimization. Biochem. Eng. J. 7: 117–119.
Glaever G et al. (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418: 387–391.
Glicklis, R, Mills D, Sitton D, Stortelder W, Merchuk JC (1998) Polysaccharide production by plant cells in suspension: experiments and mathematical modelling. Biotechnol. Bioeng. 57: 732–740.
Gramer MJ, Britton TL (2000) Selection and isolation of cells for optimal growth in hollow fiber bioreactors. Hybridoma 19: 407–412.
Gramer MJ, Britton TL (2002) Antibody production by a hybridoma cell line at high cell density is limited by two independent mechanisms. Biotechnol. Bioeng. 79: 277–283.
Gramer MJ, Poeschl DM, Conroy MJ, Hammer BE (1999) Effect of harvesting protocol on performance of a hollow fiber bioreactor. Biotechnol. Bioeng. 65: 334–340.
Griffiths JB (1995) Core culture systems. In: Doyle A, Griffiths JB, eds. Mammalian Cell Culture. Essential Techniques. Chichester: John Wiley & Sons Ltd., pp. 105–117.
Guilmanov V, Ballistreri A, Impallomeni G, Gross RA (2002) Oxygen transfer rate and sophorose lipid production by Candida bombicola. Biotechnol. Bioeng. 79: 490–494.
Hans MA, Heinzle E, Wittmann C (2003) Free intracellular amino acid pools during autonomous oscillations in Saccharomyces cerevisiae. Biotechnol. Bioeng. 82: 143–151.
Heinzle E (1987) Mass spectrometry for on-line monitoring of biotechnological processes. Adv. Biochem. Eng. 35: 2–45.
Henzler HJ, Schedel M (1991) Suitability of the shaking flask for oxygen supply to microbiological cultures. Bioprocess Eng. 7: 123–131.
Hermann R, Lehmann M, Büchs J (2003) Characterization of gasliquid mass transfer phenomena in microtiter plates. Biotechnol. Bioeng. 81: 178–186.
Hopwood DA, Bibb MJ, Chater KF, Kieser T, Bruton CJ, Kieser HM, Lydiate KJ, Simt CP, Ward JM, Schrempf H (1995) Genetic Manipulation of Streptomyces, A Laboratory Manual. Norwich, UK: The John Innes Foundation.
Ibarra RU, Edwards JS, Palson BO (2002) E. coli K-12 undergoes adaptive evolution to achieve in silico predicted optimal growth. Nature 420: 186–189.
Jackson LR, Trudel LJ, Lipman NS (1999) Small-scale monoclonal antibody production in vitro: methods and resources. Lab. Anim. 28: 38–50.
John GT, Heinzle E (2001) Quantitative screening method for hydrolases in microtiter plates using pH indicators: determination of kinetic parameters by dynamic pH monitoring. Biotechnol. Bioeng. 72: 620–627.
John GT, Klimant I, Wittmann C, Heinzle E (2003a) Integrated optical sensing of dissolved oxygen in microtiter plates: a novel tool for microbial cultivation. Biotechnol. Bioeng. 81: 829–836.
John G, Goelling D, Klimant I, Schneider H, Heinzle E (2003b) pH-Sensing 96-well micrtotiter plates for the characterisation of acid production by dairy starter cultures. J. Dairy Res. 70: 327–333.
Johnson RC, Cooks RG, Allen TM, Cisper ME, Hemberger PH (2000) Membrane introduction mass spectrometry: trends and applications. Mass Spectrom. Rev. 19: 1–37.
Kato I, Tanaka H (1998a) Influence of CO2 ventilation on microbial cultivation in shake-flasks. Biotechnol. Tech. 12: 325–328.
Kato I, Tanaka H (1998b) Development of novel box-shaped shake flask with efficient gas exchange capacity. J. Ferment. Bioeng. 85: 404–409.
Knazek RA, Guillino PM, Kohler PO, Dedrick RL (1972) Cell culture on artificial capillaries: an approach to tissue growth in vitro. Science 178: 65–67.
Kostov Y, Harms P, Eichhorn LR, Rao G (2001) Low-cost microbioreactor for high-through put bioprocessing. Biotechnol. Bioeng. 72: 346–352.
Lambert C, Weuster-Botz D, Wichenhain R, Kreutz EW, deGraaf AA, Schoberth SM (2002) Monitoring of inorganic polyphosphate dynamics in Corynebacterium glutamicum using a novel oxygen sparger fo real time 31P in vivo NMR. Acta Biotechnol. 22: 245–260.
Liu CM, Hong LN (2001) Development of a shaking bioreactor system for animal cell cultures. Biochem. Eng. J. 7: 121–125.
Lloyd JR, Hirst TR, Bunch AW (1997) Hollow-fibre bioreactors compared to batch and chemostat culture for the production of a recombinant toxoid by a marine Vibrio. Appl. Microbiol. Biotechnol. 48: 155–161.
Lueking A, Horn M, Eickhoff H, Buessow K, Lehrach H, Walter G (1999) Protein microarrays for gene expression and antibody screening. Anal. Biochem. 270: 103–111.
Maier U, Büchs J (2001) Characterization of the gas-liquid mass transfer in shaking bioreactors. Biochem. Eng. J. 7: 99–106.
Málek I, Beran K, Hospodka J (1964) Continuous Cultivation of Microorganisms: Proceedings of the 2nd Symposium, Prague, June 18-23, 1962. Prague: Czechoslovak Academy of Sciences.
Man BG, Prasad SD (1996) A miniature bioreactor for sensing toxicity using recombinant bioluminescent E. coli cells. Biotechnol. Prog. 12: 393–397.
Marteijn RCL, Jurrius O, Dhont J, Gooijer CD, Tramper J, Martens DE (2003) Optimization of a feed medium for fed-batch culture of insect cells using a genetic algorithm. Biotechnol. Bioeng. 81: 269–278.
Meyer B, Heinzle E (1998) Dynamic determination of anaerobic acetate kinetics using membrane mass spectrometry. Biotechnol. Bioeng. 57: 127–135.
Minas W, Bailey JE, Duetz WA (2000) Streptomycetes in microcultures: growth, production of secondary metabolites, and storage and retrieval in the 96-well format. Antonie van Leeuwenhoek 78: 297–305
Mrotzek C, Anderlei T, Henzler HJ, Büchs J (2001) Mass transfer resistance of sterile plugs in shaking bioreactors. Biochem. Eng. J. 7: 107–112.
Nagel A, Koch S, Valley U, Emmrich F, Marx U (1999) Membrane-based cell culture systems-an alternative to in vivo production of monoclonal antibodies. Dev. Biol. Stand. 101: 57–64.
Nakayama GRI (1998) Microplate assays for high-throughput screening. Curr. Opin. Drug Discov. Develop. 1: 85–91.
Oezemre A, Heinzle E (2001) Measurement of oxygen uptake and carbon dioxide production rates of mammalian cells using membrane mass spectrometry. Cytotechnology 37: 153–162.
Ohashi R, Mochizuki E, Suzuki T (1999) A mini-scale mass production and separation system for secretory heterologous proteins by perfusion culture of recombinant Pichia pastoris using a shaken ceramic membrane flask. J. Biosci. Bioeng. 87: 655–660.
Payne GF, Davison SW, Tate JT (1990) Experimental constraints to studying the effects of dissolved oxygen and dissolved carbon dioxide on plant cell growth. Develop. Ind. Microbiol. 31: 293–301.
Riet K, Tramper J (1991) Basic Bioreactor Design. New York: Marcel Dekker Inc.
Robert H, Mathias L, Jöchen B (2003) Characterization of gas-liquid mass transfer phenomena in microtiter plates. Biotechnol. Bioeng. 81: 178–186.
Sangdun C, Creelman RA, Mullet JE, Wing RA (1995) Construction and characterization of a bacterial artificial chromosome library of Arabidopsis thaliana. Weeds World 2: 17–20.
Shin HS, Lim HJ, Cha HJ (2003) Quantitative monitoring for secreted production of human interleukin-2 in stable insect Drosophila S2 cells using a green fluorescent protein fusion partner. Biotechnol. Prog. 19: 152–157
Shuler ML, Kargi F (2002) Bioprocessing Engineering: Basic Concepts. NJ: Upper Saddle River, Prentice-Hall Inc.
Sielaff TD, Hu MY, Amiot B, Rollins MD, Rao S, McGuire B, Bloomer JR, Hu WS, Cerra FB (1995) Gel-entrapment bioartificial liver therapy in galactosamine hepatitis. J. Surg. Res. 59: 179–184.
Stitt DT, Nagar MS, Haq TA, Timmins MR (2002) Determination of growth rate of microorganisms in broth from oxygen-sensitive fluorescence plate reader measurements. Biotechniques 32: 684–689.
Szita N, Zannotto A, Boccazzi P, Sinskey AJ, Schmidt MA, Jensen KF (2002) Monitoring of cell growth, oxygen and pH in microfermenters. In: Proceedings of µTAS 2002 Symposium on Micro Total Analysis Systems, November 3-7, 2002. Nara, Japan, pp. 7-9.
Tanaka H, Nakanishi M, Ogbonna JC, Ashiara Y (1993) Development of an apparatus for cultivation of anaerobic microorganisms. Biotechnol. Tech. 7: 189–192.
Tolosa L, Kostov Y, Harms P, Rao G (2002) Non-invasive measurement of dissolved oxygen in shake-flasks. Biotechnol. Bioeng. 80: 594–597.
Tsotsou GE, Cass AEG, Gianfranco G (2002) High throughput assay for cytochrome P450 BM3 for screening libraries of substrates and combinatorial mutants. Biosens. Bioelectron. 17: 119–131.
Veglio F, Beolchini F, Ubaldini S (1998) Empirical models for oxygen mass transfer: a comparison between shake flask and labscale fermenter and application to manganiferous or bioleaching. Proc. Biochem. 33: 367–376.
Wang MD, Yang M, Huzel N, Butler M (2002) Erythropoietin production from CHO cells grown by continuous culture in a fluidized-bed bioreactor. Biotechnol. Bioeng. 77: 194–203.
Weiss S, John, GT, Klimant I, Heinzle E (2002) Modelling of mixing in 96-well microplates observed with fluorescence indicators. Biotechnol. Prog. 18: 821–830.
Weuster-Botz D (2002) Parallele Reaktorsysteme zur Bioprozessentwicklung. Chem. Ing. Tech. 12: 1762–1766.
Weuster-Botz D, Rehm JA, Arnold M (2001a) Parallel substrate feeding and pH-control in shaking-flasks. Biochem. Eng. J. 7: 163–170.
Weuster-Botz D, Altenbach-Rehm J, Hawrylenko A (2001b) Process-engineering characterization of small-scale bubble columns for microbial process development. Bioproc. Biosys. Eng. 24: 3–11.
Weuster-Botz D, Stevens S, Hawrylenko A (2002) Parallel-operated stirred-columns for microbial process development. Biochem. Eng. J. 11: 69–71.
Wittmann C, Heinzle E (2001) Application of MALDI-TOF MS to lysine-producing Corynebacterium glutamicum-A novel approach for metabolic flux analysis. Eur. J. Biochem. 268: 2441–2455.
Wittmann C, Heinzle E (2002) Genealogy profiling through strain improvement by using metabolic network analysis: metabolic flux genealogy of several generations of lysine-producing corynebacteria. Appl. Environ. Microbiol. 68: 5843–5859.
Wittmann C, Kim HM, John G, Heinzle E (2003a) Characterization and application of an optical sensor for quantification of dissolved O2in shake-flasks. Biotechnol. Lett. 25: 377–380.
Wittmann C, Kim HM, Heinzle E (2003b) Metabolic network analysis at a miniaturized scale. Biotechnol. Bioeng., in press.
Wittmann C, Yang T, Kochems I, Heinzle E (2001) Dynamic respiratory measurements with Corynebacterium glutamicum using membrane mass spectrometry. J. Microbiol. Biotechnol. 11: 40–49.
Yang TH, Wittmann H, Heinzle E (2003a) Membrane inlet mass spectrometry for process-near analysis of metabolic fluxes: application to lysin producing Corynebacterium glutamicum. Chem. Ing. Tech. 75: 1359–1364.
Yang TH, Wittmann C, Heinzle E (2003b) Dynamic calibration and dissolved gas analysis using membrane inlet mass spectrometry for the quantification of cell respiration. Rapid Comm. Mass Spectrom., in press.
Zimmermann HF, John GT, Trauthwein H, Dingerdissen U, Huthmacher K (2003) Rapid evaluation of oxygen and water permeation through microplate sealing tapes. Biotechnol. Prog. 9: 1061–1063.
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Kumar, S., Wittmann, C. & Heinzle, E. Review: Minibioreactors. Biotechnology Letters 26, 1–10 (2004). https://doi.org/10.1023/B:BILE.0000009469.69116.03
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DOI: https://doi.org/10.1023/B:BILE.0000009469.69116.03