Review of microfluidic microbioreactor technology for high-throughput submerged microbiological cultivation.

Microbial fermentation process development is pursuing a high production yield. This requires a high throughput screening and optimization of the microbial strains, which is nowadays commonly achieved by applying slow and labor-intensive submerged cultivation in shake flasks or microtiter plates. These methods are also limited towards end-point measurements, low analytical data output, and control over the fermentation process. These drawbacks could be overcome by means of scaled-down microfluidic microbioreactors (μBR) that allow for online control over cultivation data and automation, hence reducing cost and time. This review goes beyond previous work not only by providing a detailed update on the current μBR fabrication techniques but also the operation and control of μBRs is compared to large scale fermentation reactors.

[1]  Ingo Klimant,et al.  Modeling of Mixing in 96‐Well Microplates Observed with Fluorescence Indicators , 2002, Biotechnology progress.

[2]  Stephanus Büttgenbach,et al.  Microfluidic reactor for continuous cultivation of Saccharomyces cerevisiae , 2010, Biotechnology progress.

[3]  A J J Straathof,et al.  Liquid–liquid extraction of fermentation inhibiting compounds in lignocellulose hydrolysate , 2009, Biotechnology and bioengineering.

[4]  Gwo-Bin Lee,et al.  A microfluidic system for automatic cell culture , 2007, TRANSDUCERS 2007 - 2007 International Solid-State Sensors, Actuators and Microsystems Conference.

[5]  Krist V. Gernaey,et al.  Development of a single-use microbioreactor for cultivation of microorganisms , 2010 .

[6]  Kwang Ho Song,et al.  Immobilized cell microchannel bioreactor for evaluating fermentation characteristics of mixed substrate consumption and product formation , 2012 .

[7]  Steve C. C. Shih,et al.  Integrated microbioreactor for culture and analysis of bacteria, algae and yeast , 2011, Biomedical microdevices.

[8]  S. Quake,et al.  Long-Term Monitoring of Bacteria Undergoing Programmed Population Control in a Microchemostat , 2005, Science.

[9]  C. Hewitt,et al.  Physiological responses to mixing in large scale bioreactors. , 2001, Journal of biotechnology.

[10]  Nicolas Szita,et al.  A well‐mixed, polymer‐based microbioreactor with integrated optical measurements , 2006, Biotechnology and bioengineering.

[11]  Gerardo Perozziello,et al.  Microchemostat-microbial continuous culture in a polymer-based, instrumented microbioreactor. , 2006, Lab on a chip.

[12]  Holger Becker,et al.  Polymer microfabrication technologies for microfluidic systems , 2008, Analytical and bioanalytical chemistry.

[13]  Gürkan Sin,et al.  Application of mechanistic models to fermentation and biocatalysis for next-generation processes. , 2010, Trends in biotechnology.

[14]  Chunxiong Luo,et al.  An automatic microturbidostat for bacterial culture at constant density , 2010, Biomedical microdevices.

[15]  J. Heijnen,et al.  Improving mixing in microbioreactors , 2008 .

[16]  Nicolas Szita,et al.  Development of a multiplexed microbioreactor system for high-throughput bioprocessing. , 2005, Lab on a chip.

[17]  Ingo Klimant,et al.  PH-sensing 96-well microtitre plates for the characterization of acid production by dairy starter cultures. , 2003, The Journal of dairy research.

[18]  Marcel Ottens,et al.  Lab‐scale fermentation tests of microchip with integrated electrochemical sensors for pH, temperature, dissolved oxygen and viable biomass concentration , 2008, Biotechnology and bioengineering.

[19]  Dirk Weuster-Botz,et al.  Parallel-operated stirred-columns for microbial process development , 2002 .

[20]  Rajeev J Ram,et al.  Microfluidic chemostat and turbidostat with flow rate, oxygen, and temperature control for dynamic continuous culture. , 2011, Lab on a chip.

[21]  Nicolas Szita,et al.  Membrane‐aerated microbioreactor for high‐throughput bioprocessing , 2004, Biotechnology and bioengineering.

[22]  Krist V. Gernaey,et al.  Embedded resistance wire as a heating element for temperature control in microbioreactors , 2010 .

[23]  Charles S Henry,et al.  Culturing and investigation of stress-induced lipid accumulation in microalgae using a microfluidic device , 2011, Analytical and bioanalytical chemistry.

[24]  Martin L Yarmush,et al.  Living-cell microarrays. , 2009, Annual review of biomedical engineering.

[25]  Pedro Fernandes,et al.  Microlitre/millilitre shaken bioreactors in fermentative and biotransformation processes – a review , 2006 .

[26]  U. Sauer.  High-throughput phenomics: experimental methods for mapping fluxomes. , 2004, Current opinion in biotechnology.

[27]  Gary J. Lye,et al.  An automated microscale technique for the quantitative and parallel analysis of microfiltration operations , 2006 .

[28]  Anders Blomberg,et al.  Automated screening in environmental arrays allows analysis of quantitative phenotypic profiles in Saccharomyces cerevisiae , 2003, Yeast.

[29]  Harry L. T. Lee,et al.  Microbioreactor arrays with integrated mixers and fluid injectors for high-throughput experimentation with pH and dissolved oxygen control. , 2006, Lab on a chip.

[30]  Ingo Klimant,et al.  Integrated optical sensing of dissolved oxygen in microtiter plates: A novel tool for microbial cultivation , 2003, Biotechnology and bioengineering.

[31]  G J Lye,et al.  Scale‐up of Escherichia coli growth and recombinant protein expression conditions from microwell to laboratory and pilot scale based on matched kLa , 2008, Biotechnology and bioengineering.

[32]  Robert Hermann,et al.  Methods for Intense Aeration, Growth, Storage, and Replication of Bacterial Strains in Microtiter Plates , 2000, Applied and Environmental Microbiology.

[33]  G. Whitesides,et al.  Solvent compatibility of poly(dimethylsiloxane)-based microfluidic devices. , 2003, Analytical chemistry.

[34]  Martina Micheletti,et al.  Microscale bioprocess optimisation. , 2006, Current opinion in biotechnology.

[35]  Jay D Keasling,et al.  Microbioreactor arrays with parametric control for high‐throughput experimentation , 2004, Biotechnology and bioengineering.

[36]  Yu-Hsiang Hsu,et al.  Microbioreactor designed for integration with piezoelectric transducers for cellular diagnostics , 2011 .

[37]  Wilfried Mokwa,et al.  Microbioreactors with microfluidic control and a user-friendly connection to the actuator hardware , 2009 .

[38]  Matthias Reuss,et al.  Dynamic Behavior of Microbial Populations in Stirred Bioreactors Simulated with Euler−Lagrange Methods: Traveling along the Lifelines of Single Cells† , 2004 .

[39]  Elmar Heinzle,et al.  On-line oxygen uptake rate and culture viability measurement of animal cell culture using microplates with integrated oxygen sensors , 2004, Biotechnology Letters.

[40]  G. Whitesides,et al.  Poly(dimethylsiloxane) as a material for fabricating microfluidic devices. , 2002, Accounts of chemical research.

[41]  Johannes G.E. Gardeniers,et al.  Application of direct fluid flow oscillations to improve mixing in microbioreactors , 2009 .

[42]  R Krull,et al.  Disposable parallel poly(dimethylsiloxane) microbioreactor with integrated readout grid for germination screening of Aspergillus ochraceus. , 2011, Biomicrofluidics.

[43]  D. DeVoe,et al.  Bonding of thermoplastic polymer microfluidics , 2009 .

[44]  Jonathan I. Betts,et al.  Miniature bioreactors: current practices and future opportunities , 2006, Microbial cell factories.

[45]  G. Khayati,et al.  In situ recovery of 2,3-butanediol from fermentation by liquid–liquid extraction , 2009, Journal of Industrial Microbiology & Biotechnology.

[46]  Andreas Neyer,et al.  PDMS microfluidic chip with integrated waveguides for optical detection , 2006 .

[47]  K. Jensen,et al.  Differential Gene Expression Profiles and Real‐Time Measurements of Growth Parameters in Saccharomyces cerevisiae Grown in Microliter‐Scale Bioreactors Equipped with Internal Stirring , 2006, Biotechnology progress.

[48]  Han Gardeniers,et al.  Aerobic batch cultivation in micro bioreactor with integrated electrochemical sensor array , 2009, Biotechnology progress.

[49]  K. Jensen,et al.  In situ measurement of bioluminescence and fluorescence in an integrated microbioreactor. , 2006, Biotechnology and bioengineering.

[50]  J Büchs,et al.  Characterisation of operation conditions and online monitoring of physiological culture parameters in shaken 24-well microtiter plates , 2005, Bioprocess and biosystems engineering.

[51]  Stephen Wiggins,et al.  Introduction: mixing in microfluidics , 2004, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[52]  Seng-Tiong Ho,et al.  Traveling wave electro-optic phase modulators based on intrinsically polar self-assembled chromophoric superlattices , 2001 .

[53]  S. Haswell,et al.  Design and characterization of a microfluidic packed bed system for protein breakthrough and dynamic binding capacity determination , 2009, Biotechnology progress.

[54]  Amy Q. Shen,et al.  A Portable Anaerobic Microbioreactor Reveals Optimum Growth Conditions for the Methanogen Methanosaeta concilii , 2007, Applied and Environmental Microbiology.