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Microbioreactors

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Microsystems for Pharmatechnology

Abstract

In the last decade, microbioreactor (MBR) technology has allowed for rapid advances in biotechnology process development and the investigation of various biological systems from the industrial biotechnology and pharmaceutical biotechnology. Many of the devices that have been reported in the literature are being applied for early-stage bioprocess research. This research makes it possible to perform comprehensive experiments with very expensive substances that are only available in limited quantities.

Microtechnologically fabricated MBRs range in complexity from simple microtiter-based systems to complex automated parallel bioreactors designed to allow meaningful scaling up/scaling down of conventional pilot and large-scale bioprocesses. MBR technology and the capability to monitor cultivation process variables in situ, such as the optical density, dissolved oxygen, pH and fluorescent protein expression, provide real-time and quantitative data from a microliter cultivation broth. Currently, the majority of MBR systems have been designed for batch and fed-batch processing; there are a few efforts directed at developing MBRs for continuous chemostat mode operation.

This overview of microtechnologically fabricated MBRs, their design and application presents the advantages, different strategies for manufacturing and biotechnological applications of these tiny devices in different operation modes. The report discusses the possibility of design versatility and maintaining key aspects, for example, single-use and fluidic connections, as well as the application of MBRs in versatile and different biotechnological fields.

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References

  1. Al-Halhouli A, Demming S, Waldschik A, Büttgenbach S (2014) Implementation of synchronous micromotor in developing integrated microfluidic systems. Micromachines 5:442–456

    Article  Google Scholar 

  2. Allain M, Berthier J, Basrour S, Pouteau P (2010) Electrically actuated sacrificial membranes for valving in microsystems. J Micromech Microeng 20:035006

    Article  Google Scholar 

  3. Amirouche F, Zhou Y, Johnson T (2009) Current micropump technologies and their biomedical applications. Microsyst Technol 15:647–666

    Article  Google Scholar 

  4. Atencia J, Cooksey GA, Jahn A, Zook JM, Vreeland WN, Locascio LE (2010) Magnetic connectors for microfluidic applications. Lab Chip 10:246–249

    Article  Google Scholar 

  5. Au AK, Lai H, Utela BR, Folch A (2011) Microvalves and micropumps for BioMEMS. Micromachines 2:179–220

    Article  Google Scholar 

  6. Balagaddé FK, You L, Hansen CL, Arnold FH, Quake SR (2005) Long-term monitoring of bacteria undergoing programmed population control in a microchemostat. Science 309:137–140

    Article  Google Scholar 

  7. Bechert T, Steinrücke P, Guggenbichler JP (2000) A new method for screening anti-infective biomaterials. Nat Med 6:1053–1056

    Article  Google Scholar 

  8. Beebe DJ, Mensing GA, Walker GM (2002) Physics and applications of microfluidics in biology. Annu Rev Biomed Eng 4:261–286

    Article  Google Scholar 

  9. Betts JI, Baganz F (2006) Miniature bioreactors: current practices and future opportunities. Microb Cell Fact 5:21

    Article  Google Scholar 

  10. Bhagat AAS, Kuntaegowdanahalli SS, Papautsky I (2008) Continuous particle separation in spiral microchannels using dean flows and differential migration. Lab Chip 8:1906–1914

    Article  Google Scholar 

  11. Boccazzi P, Zhang Z, Kurosawa K, Szita N, Bhattacharya S, Jensen KF, Sinskey AJ (2006) Differential gene expression profiles and real-time measurements of growth parameters in Saccharomyces cerevisiae grown in microliter-scale bioreactors equipped with internal stirring. Biotechnol Prog 22:710–717

    Article  Google Scholar 

  12. Boxshall K, Wu M, Cui Z, Cui Z, Watts JF, Baker MA (2005) Simple surface treatments to modify protein adsorption and cell attachment properties within a poly(dimethylsiloxane) micro-bioreactor. Surf Interface Anal 38:198–201

    Article  Google Scholar 

  13. Breslauer DN, Lee PJ, Lee LP (2006) Microfluidics-based systems biology. Mol Biosyst 2:97–112

    Article  Google Scholar 

  14. Bridle H, Millingen M, Jesorka A (2008) On-chip fabrication to add temperature control to a microfluidic solution exchange system. Lab Chip 8:480–483

    Article  Google Scholar 

  15. Brody JP, Yager P, Goldstein RE, Austin RH (1996) Biotechnology at low Reynolds numbers. Biophys J 71:3430–3441

    Article  Google Scholar 

  16. Büttgenbach S (2014) Electromagnetic micromotors—design, fabrication and applications. Micromachines 5:929–942

    Article  Google Scholar 

  17. Carregal-Romero E, Fernández-Sánchez C, Eguizabal A, Demming S, Büttgenbach S, Llobera A (2012) Development and integration of xerogel polymeric absorbance micro-filters into lab-on-chip systems. Opt Express 20:23700–19

    Article  Google Scholar 

  18. Chen A, Chitta R, Chang D, Amanullah A (2009) Twenty-four well plate miniature bioreactor system as a scale-down model for cell culture process development. Biotechnol Bioeng 102:148–160

    Article  Google Scholar 

  19. Chen H, Acharya D, Gajraj A, Meiners J (2003) Robust interconnects and packaging for microfluidic elastomeric chips. Anal Chem 75:5287–5291

    Article  Google Scholar 

  20. Choi H, Boccazzi P, Laibinis PE, Sinskey AJ, Jensen KF (2003) Poly(ethylene glycol) (PEG)-modified poly(dimethylsiloxane) (PDMS) for protein- and cell-resistant surfaces in microbioreactor. In: 7th International conference on miniaturized chemical and biochemical analysts systems, Squaw Valley, CA, USA, pp 1105–1108

    Google Scholar 

  21. Chung SK, Zhao Y, Cho SK (2008) On-chip creation and elimination of microbubbles for a micro-object manipulator. J Micromech Microeng 18:1–13

    Google Scholar 

  22. Demming S (2011) Disposable lab-on-chip systems for biotechnological screening. In: Büttgenbach S (ed) Berichte aus der Mikro- und Feinwerktechnik, vol 30. Ph.D. Thesis, Technische Universität Braunschweig, Shaker-Verlag, Aachen

    Google Scholar 

  23. Demming S, Hahn A, Edlich A, Franco-Lara E, Krull R, Barcikowski S, Büttgenbach S (2010) Softlithographic partial integration of surface-active nanoparticles in a PDMS matrix for microfluidic biodevices. Phys Status Solidi A Appl Mater Sci 207:898–903

    Article  Google Scholar 

  24. Demming S, Peterat G, Llobera A, Schmolke H, Bruns A, Kohlstedt M, Al-Halhouli A, Klages C-P, Krull R, Büttgenbach S (2012) Vertical microbubble column-A photonic lab-on-chip for cultivation and online analysis of yeast cell cultures. Biomicrofluidics 6:34106

    Article  Google Scholar 

  25. Demming S, Sommer B, Llobera A, Rasch D, Krull R, Büttgenbach S (2011) Disposable parallel poly(dimethylsiloxane) microbioreactor with integrated readout grid for germination screening of Aspergillus ochraceus. Biomicrofluidics 5:14104

    Article  Google Scholar 

  26. Demming S, Vila-Planas J, Aliasghar Zadeh S, Edlich A, Franco-Lara E, Radespiel R, Büttgenbach S, Llobera A (2011) Poly(dimethylsiloxane) photonic microbioreactors based on segmented waveguides for local absorbance measurement. Electrophoresis 32:431–439

    Article  Google Scholar 

  27. Di Carlo D, Irimia D, Tompkins RG, Toner M (2007) Continuous inertial focusing, ordering, and separation of particles in microchannels. Proc Natl Acad Sci U S A 104:18892–18897

    Article  Google Scholar 

  28. Doig SD, Diep A, Baganz F (2005) Characterisation of a novel miniaturised bubble column bioreactor for high throughput cell cultivation. Biochem Eng J 23:97–105

    Article  Google Scholar 

  29. Doig SD, Ortiz-Ochoa K, Ward JM, Baganz F (2005) Characterization of oxygen transfer in miniature and lab-scale bubble column bioreactors and comparison of microbial growth performance based on constant k L a. Biotechnol Prog 21:1175–82

    Article  Google Scholar 

  30. Duffy DC, McDonald JC, Schueller OJ, Whitesides GM (1998) Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal Chem 70:4974–4984

    Article  Google Scholar 

  31. Edlich A (2010) Entwicklung eines Mikroreaktors als Screening-Instrument für biologische Prozesse. In: Wittmann C (ed) ibvt-Schriftenreihe, vol 51. Ph.D. Thesis, Technische Universität Braunschweig, Cuvillier-Verlag, Göttingen

    Google Scholar 

  32. Edlich A, Magdanz V, Rasch D, Demming S, Aliasghar Zadeh S, Segura R, Kähler C, Radespiel R, Büttgenbach S, Franco-Lara E, Krull R (2010) Microfluidic reactor for continuous cultivation of Saccharomyces cerevisiae. Biotechnol Prog 26:1259–1270

    Article  Google Scholar 

  33. El-Ali J, Sorger PK, Jensen KF (2006) Cells on chips. Nature 442:403–411

    Article  Google Scholar 

  34. Feldmann M, Buttgenbach S (2007) Novel microrobots and micromotors using Lorentz force driven linear microactuators based on polymer magnets. IEEE Trans Magn 43:3891–3895

    Article  Google Scholar 

  35. Fernández-Sánchez C, Cadarso VJ, Darder M, Domínguez C, Llobera A (2008) Patterning high-aspect-ratio sol–gel structures by microtransfer molding. Chem Mater 20:2662–2668

    Article  Google Scholar 

  36. Furno F, Morley KS, Wong B, Sharp BL, Arnold PL, Howdle SM, Bayston R, Brown PD, Winship PD, Reid HJ (2004) Silver nanoparticles and polymeric medical devices: a new approach to prevention of infection? J Antimicrob Chemother 54:1019–1024

    Article  Google Scholar 

  37. Garcia-Ochoa F, Gomez E (2009) Bioreactor scale-up and oxygen transfer rate in microbial processes: an overview. Biotechnol Adv 27:153–176

    Article  Google Scholar 

  38. Geng Z, Cui D, Wang H, Chen X (2006) Disposable PDMS diaphragm micropump actuated by PZT. In: 1st IEEE International conference on nano/micro engineered and molecular systems, IEEE, Zhuhai, China, pp 1436–1439

    Google Scholar 

  39. Gravesen P, Branebjerg J, Jensen OS (1993) Microfluidics—a review. J Micromech Microeng 3:168–182

    Article  Google Scholar 

  40. Groisman A, Lobo C, Cho H, Campbell JK, Dufour YS, Stevens AM, Levchenko A (2005) A microfluidic chemostat for experiments with bacterial and yeast cells. Nat Methods 2:685–689

    Article  Google Scholar 

  41. Gruenberger A, Probst C, Heyer A, Wiechert W, Frunzke J, Kohlheyer D (2013) Microfluidic picoliter bioreactor for microbial single-cell analysis: fabrication, system setup, and operation. J Vis Exp 82:50560

    Google Scholar 

  42. Grünberger A, Paczia N, Probst C, Schendzielorz G, Eggeling L, Noack S, Wiechert W, Kohlheyer D (2012) A disposable picolitre bioreactor for cultivation and investigation of industrially relevant bacteria on the single cell level. Lab Chip 12:2060–2068

    Article  Google Scholar 

  43. Grünberger A, Wiechert W, Kohlheyer D (2014) Single-cell microfluidics: opportunity for bioprocess development. Curr Opin Biotechnol 29C:15–23

    Article  Google Scholar 

  44. Harrison DJ, Manz A, Fan Z, Luedi H, Widmer HM (1992) Capillary electrophoresis and sample injection systems integrated on a planar glass chip. Anal Chem 64:1926–1932

    Article  Google Scholar 

  45. Hegab HM, Elmekawy A, Stakenborg T (2013) Review of microfluidic microbioreactor technology for high-throughput submerged microbiological cultivation. Biomicrofluidics 7:21502

    Article  Google Scholar 

  46. Hemmerich J, Adelantado N, Barrigón JM, Ponte X, Hörmann A, Ferrer P, Kensy F, Valero F (2014) Comprehensive clone screening and evaluation of fed-batch strategies in a microbioreactor and lab scale stirred tank bioreactor system: application on Pichia pastoris producing Rhizopus oryzae lipase. Microb Cell Fact 13:36

    Article  Google Scholar 

  47. Hench LL, West JK (1990) The sol-gel process. Chem Rev 90:33–72

    Article  Google Scholar 

  48. Hessel V, Löwe H, Schönfeld F (2005) Micromixers—a review on passive and active mixing principles. Chem Eng Sci 60:2479–2501

    Article  Google Scholar 

  49. Hu S, Ren X, Bachman M, Sims CE, Li GP, Allbritton N (2002) Surface modification of poly(dimethylsiloxane) microfluidic devices by ultraviolet polymer grafting. Anal Chem 74:4117–4123

    Article  Google Scholar 

  50. Huber R, Ritter D, Hering T, Hillmer A-K, Kensy F, Müller C, Wang L, Büchs J (2009) Robo-Lector—a novel platform for automated high-throughput cultivations in microtiter plates with high information content. Microb Cell Fact 8:42

    Article  Google Scholar 

  51. Hung PJ, Lee PJ, Sabounchi P, Lin R, Lee LP (2004) Continuous perfusion microfluidic cell culture array for high-throughput cell-based assays. Biotechnol Bioeng 89:1–8

    Article  Google Scholar 

  52. Inman W, Domansky K, Serdy J, Owens B, Trumper D, Griffith LG (2007) Design, modeling and fabrication of a constant flow pneumatic micropump. J Micromech Microeng 17:891–899

    Article  Google Scholar 

  53. Jeong OC, Park SW, Yang SS, Pak JJ (2005) Fabrication of a peristaltic PDMS micropump. Sensors Actuators A Phys 123–124:453–458

    Article  Google Scholar 

  54. Jones KD, Kompala DS (1999) Cybernetic model of the growth dynamics of Saccharomyces cerevisiae in batch and continuous cultures. J Biotechnol 71:105–131

    Article  Google Scholar 

  55. Kang JH, Kim YC, Park JK (2007) Analysis of pressure-driven air bubble elimination in a microfluidic device. Lab Chip 8:176–178

    Article  Google Scholar 

  56. Kardous F, Yahiaoui R, Aoubiza B, Manceau JF (2014) Acoustic mixer using low frequency vibration for biological and chemical applications. Sensors Actuators A Phys 211:19–26

    Article  Google Scholar 

  57. Kim BJ, Zhao T, Young L, Zhou P, Shuler ML (2012) Batch, fed-batch, and microcarrier cultures with CHO cell lines in a pressure-cycle driven miniaturized bioreactor. Biotechnol Bioeng 109:137–45

    Article  Google Scholar 

  58. Kim J, Kang M, Jensen EC, Mathies RA (2012) Lifting gate polydimethylsiloxane microvalves and pumps for microfluidic control. Anal Chem 84:2067–2071

    Article  Google Scholar 

  59. Kim JH, Na KH, Kang CJ, Kim YS (2005) A disposable thermopneumatic-actuated micropump stacked with PDMS layers and ITO-coated glass. Sensors Actuators A Phys 120:365–369

    Article  Google Scholar 

  60. Kirk TV, Szita N (2013) Oxygen transfer characteristics of miniaturized bioreactor systems. Biotechnol Bioeng 110:1005–1019

    Article  Google Scholar 

  61. Kliche S, Räuchle K, Bertau M, Reschetilowski W (2009) Ganzzell-Biokatalyse mittels Saccharomyces cerevisiae im Mikroreaktor. Chem Ing Tech 81:343–347

    Article  Google Scholar 

  62. Korivi NS, Jiang L (2007) A generic chip-to-world fluidic interconnect system for microfluidic devices. In: 39th Southeastern symposium on system theory, IEEE, Macon, GA, USA, pp 176–180

    Google Scholar 

  63. Kostov Y, Harms P, Randers-Eichhorn L, Rao G (2001) Low-cost microbioreactor for high-throughput bioprocessing. Biotechnol Bioeng 72:346–352

    Article  Google Scholar 

  64. Kovarik ML, Gach PC, Ornoff DM, Wang Y, Balowski J, Farrag L, Allbritton NL (2012) Micro total analysis systems for cell biology and biochemical assays. Anal Chem 84:516–540

    Article  Google Scholar 

  65. Kuhlmann W, Meyer H-D, Bellgardt KH, Schügerl K (1984) On-line analysis of yeast growth and alcohol production. J Biotechnol 1:171–185

    Article  Google Scholar 

  66. Kunze M, Lattermann C, Diederichs S, Kroutil W, Büchs J (2014) Minireactor-based high-throughput temperature profiling for the optimization of microbial and enzymatic processes. J Biol Eng 8:22

    Article  Google Scholar 

  67. Lamping SR, Zhang H, Allen B, Ayazi Shamlou P (2003) Design of a prototype miniature bioreactor for high throughput automated bioprocessing. Chem Eng Sci 58:747–758

    Article  Google Scholar 

  68. Lara AR, Galindo E, Ramírez OT, Palomares LA (2006) Living with heterogeneities in bioreactors: understanding the effects of environmental gradients on cells. Mol Biotechnol 34:355–381

    Article  Google Scholar 

  69. Lattermann C, Büchs J (2015) Microscale and miniscale fermentation and screening. Curr Opin Biotechnol 35:1–6

    Article  Google Scholar 

  70. Lee HLT, Boccazzi P, Ram RJ, Sinskey AJ (2006) Microbioreactor arrays with integrated mixers and fluid injectors for high-throughput experimentation with pH and dissolved oxygen control. Lab Chip 6:1229–1235

    Article  Google Scholar 

  71. Lee KS, Boccazzi P, Sinskey AJ, Ram RJ (2011) Microfluidic chemostat and turbidostat with flow rate, oxygen, and temperature control for dynamic continuous culture. Lab Chip 11:1730–1739

    Article  Google Scholar 

  72. Lee PJ, Hung PJ, Rao VM, Lee LP (2005) Nanoliter scale microbioreactor array for quantitative cell biology. Biotechnol Bioeng 94:5–14

    Article  Google Scholar 

  73. Lewis G, Taylor IW, Nienow AW, Hewitt CJ (2004) The application of multi-parameter flow cytometry to the study of recombinant Escherichia coli batch fermentation processes. J Ind Microbiol Biotechnol 31:311–322

    Article  Google Scholar 

  74. Li L, Wang W, Zhang S, Chen S, Guo S, Français O, Cheng J-K, Huang W-H (2011) Integrated microdevice for long-term automated perfusion culture without shear stress and real-time electrochemical monitoring of cells. Anal Chem 83:9524–9530

    Article  Google Scholar 

  75. Liu C-H, Lee G-B (2013) A micropump using amplified deformation of resilient membranes through oil hydraulics. Microfluid Nanofluid 17:393–400

    Article  Google Scholar 

  76. Llobera A, Cadarso VJ, Darder M, Domínguez C, Fernández-Sánchez C (2008) Full-field photonic biosensors based on tunable bio-doped sol-gel glasses. Lab Chip 8:1185–1190

    Article  Google Scholar 

  77. Llobera A, Demming S, Joensson HN, Vila-Planas J, Andersson-Svahn H, Büttgenbach S (2010) Monolithic PDMS passband filters for fluorescence detection. Lab Chip 10:1987–1992

    Article  Google Scholar 

  78. Llobera A, Wilke R, Büttgenbach S (2004) Poly(dimethylsiloxane) hollow Abbe prism with microlenses for detection based on absorption and refractive index shift. Lab Chip 4:24–27

    Article  Google Scholar 

  79. Lo R, Meng E (2008) Integrated and reusable in-plane microfluidic interconnects. Sensors Actuators B Chem 132:531–539

    Article  Google Scholar 

  80. Long Z, Nugent E, Javer A, Cicuta P, Sclavi B, Cosentino Lagomarsino M, Dorfman KD (2013) Microfluidic chemostat for measuring single cell dynamics in bacteria. Lab Chip 13:947–954

    Article  Google Scholar 

  81. Lorenz H, Despont M, Fahrni N, Brugger J, Vettiger P, Renaud P (1998) High-aspect-ratio, ultrathick, negative-tone near-UV photoresist and its applications for MEMS. Sensors Actuators A Phys 64:33–39

    Article  Google Scholar 

  82. Loverich J, Kanno I, Kotera H (2006) Single-step replicable microfluidic check valve for rectifying and sensing low Reynolds number flow. Microfluid Nanofluid 3:427–435

    Article  Google Scholar 

  83. Lucas N, Demming S, Jordan A, Sichler P, Büttgenbach S (2008) An improved method for double-sided moulding of PDMS. J Micromech Microeng 18:075037

    Article  Google Scholar 

  84. Maharbiz MM, Holtz WJ, Howe RT, Keasling JD (2004) Microbioreactor arrays with parametric control for high-throughput experimentation. Biotechnol Bioeng 85:376–381

    Article  Google Scholar 

  85. Mandal S, Rouillard JM, Srivannavit O, Gulari E (2007) Cytophobic surface modification of microfluidic arrays for in situ parallel peptide synthesis and cell adhesion assays. Biotechnol Prog 23:972–978

    Article  Google Scholar 

  86. Mansur EA, Ye M, Wang Y, Dai Y (2008) A state-of-the-art review of mixing in microfluidic mixers. Chin J Chem Eng 16:503–516

    Article  Google Scholar 

  87. Manz A, Graber N, Widmer HM (1990) Miniaturized total chemical analysis systems: a novel concept for chemical sensing. Sensors Actuators B Chem 1:244–248

    Article  Google Scholar 

  88. Matsubara Y, Murakami Y, Kobayashi M, Morita Y, Tamiya E (2003) Application of on-chip cell cultures for the detection of allergic response. Biosens Bioelectron 19:741–747

    Article  Google Scholar 

  89. McDonald JC, Duffy DC, Anderson JR, Chiu DT, Wu H, Schueller OJ, Whitesides GM (2000) Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis 21:27–40

    Article  Google Scholar 

  90. McDonald JC, Whitesides GM (2002) Poly(dimethylsiloxane) as a material for fabricating microfluidic devices. Acc Chem Res 35:491–499

    Article  Google Scholar 

  91. Meyvantsson I, Beebe DJ (2008) Cell culture models in microfluidic systems. Annu Rev Anal Chem (Palo Alto CA, USA) 1:423–449

    Article  Google Scholar 

  92. Moffitt JR, Lee JB, Cluzel P (2012) The single-cell chemostat: an agarose-based, microfluidic device for high-throughput, single-cell studies of bacteria and bacterial communities. Lab Chip 12:1487–1494

    Article  Google Scholar 

  93. Mohan R, Schudel BR, Desai AV, Yearsley JD, Apblett CA, Kenis PJA (2011) Design considerations for elastomeric normally closed microfluidic valves. Sensors Actuators B Chem 160:1216–1223

    Article  Google Scholar 

  94. Moncada-Hernández H, Lapizco-Encinas BH (2010) Simultaneous concentration and separation of microorganisms: insulator-based dielectrophoretic approach. Anal Bioanal Chem 396:1805–1816

    Article  Google Scholar 

  95. Moon H, Nam Y, Jae CP, Jung H (2009) Dielectrophoretic separation of airborne microbes and dust particles using a microfluidic channel for real-time bioaerosol monitoring. Environ Sci Technol 43:5857–5863

    Article  Google Scholar 

  96. Morones JR, Elechiguerra JL, Camacho A, Holt K, Kouri JB, Ramírez JT, Yacaman MJ (2005) The bactericidal effect of silver nanoparticles. Nanotechnology 16:2346–2353

    Article  Google Scholar 

  97. Morris CJ, Forster FK (2003) Low-order modeling of resonance for fixed-valve micropumps based on first principles. J Microelectromech Syst 12:325–334

    Article  Google Scholar 

  98. Muñoz-Berbel X, Rodríguez-Rodríguez R, Vigués N, Demming S, Mas J, Büttgenbach S, Verpoorte E, Ortiz P, Llobera A (2013) Monolithically integrated biophotonic lab-on-a-chip for cell culture and simultaneous pH monitoring. Lab Chip 13:4239–4247

    Article  Google Scholar 

  99. Nazrul M, Zainal H, Gernaey KV (2012) Overview on design considerations for development of disposable microbiorector prototypes. J Teknol Sci Eng 59:53–60

    Google Scholar 

  100. Nguyen NT, Wu Z (2005) Micromixers—a review. J Micromech Microeng 15:R1–R16

    Article  Google Scholar 

  101. Nisar A, Afzulpurkar N, Mahaisavariya B, Tuantranont A (2008) MEMS-based micropumps in drug delivery and biomedical applications. Sensors Actuators B Chem 130:917–942

    Article  Google Scholar 

  102. Niu X, Liu L, Wen W, Sheng P (2007) Microfluidic manipulation in lab-chips using electrorheological fluid. J Intell Mater Syst Struct 18:1187–1190

    Article  Google Scholar 

  103. Oh KW, Ahn CH (2006) A review of microvalves. J Micromech Microeng 16:R13–R39

    Article  Google Scholar 

  104. Ostrovidov S, Jiang J, Sakai Y, Fujii T (2004) Membrane-based PDMS microbioreactor for perfused 3D primary rat hepatocyte cultures. Biomed Microdevices 6:279–287

    Article  Google Scholar 

  105. Palme O, Comanescu G, Stoineva I, Radel S, Benes E, Develter D, Wray V, Lang S (2010) Sophorolipids from Candida bombicola: cell separation by ultrasonic particle manipulation. Eur J Lipid Sci Technol 112:663–673

    Article  Google Scholar 

  106. Park J, Wu J, Polymenis M, Han A (2013) Microchemostat array with small-volume fraction replenishment for steady-state microbial culture. Lab Chip 13:4217

    Article  Google Scholar 

  107. Pečar B, Križaj D, Vrtačnik D, Resnik D, Dolžan T, Možek M (2014) Piezoelectric peristaltic micropump with a single actuator. J Micromech Microeng 24:105010

    Article  Google Scholar 

  108. Peng XY, Li PCH (2004) A three-dimensional flow control concept for single-cell experiments on a microchip. 1. Cell selection, cell retention, cell culture, cell balancing, and cell scanning. Anal Chem 76:5273–5281

    Article  Google Scholar 

  109. Perozziello G, Bundgaard F, Geschke O (2008) Fluidic interconnections for microfluidic systems: a new integrated fluidic interconnection allowing plug“n”play functionality. Sensors Actuators B Chem 130:947–953

    Article  Google Scholar 

  110. Peterat G (2014) Prozesstechnik und reaktionskinetische Analysen in einem mehrphasigen Mikrobioreaktorsystem. In: Krull R (ed) ibvt-Schriftenreihe, vol 75. Ph.D. Thesis, Technische Universität Braunschweig, Cuvillier-Verlag, Göttingen

    Google Scholar 

  111. Peterat G, Schmolke H, Lorenz T, Llobera A, Rasch D, Al-Halhouli AT, Dietzel A, Büttgenbach S, Klages C-P, Krull R (2014) Characterization of oxygen transfer in vertical microbubble columns for aerobic biotechnological processes. Biotechnol Bioeng 111:1809–1819

    Article  Google Scholar 

  112. Probst C, Grünberger A, Braun N, Helfrich S, Nöh K, Wiechert W, Kohlheyer D (2014) Rapid inoculation of single bacteria into parallel picoliter fermentation chambers. Anal Methods 7:91–98

    Article  Google Scholar 

  113. Prokop A, Prokop Z, Schaffer D, Kozlov E, Wikswo J, Cliffel D, Baudenbacher F (2004) NanoLiterBioReactor: long-term mammalian cell culture at nanofabricated scale. Biomed Microdevices 6:325–339

    Article  Google Scholar 

  114. Puskeiler R, Kusterer A, John GT, Weuster-Botz D (2005) Miniature bioreactors for automated high-throughput bioprocess design (HTBD): reproducibility of parallel fed-batch cultivations with Escherichia coli. Biotechnol Appl Biochem 42:227–235

    Article  Google Scholar 

  115. Quaglio M, Canavese G, Giuri E, Marasso SL, Perrone D, Cocuzza M, Pirri CF (2008) Evaluation of different PDMS interconnection solutions for silicon, Pyrex and COC microfluidic chips. J Micromech Microeng 18:055012

    Article  Google Scholar 

  116. Quake SR (2000) From micro- to nanofabrication with soft materials. Science 290:1536–1540

    Article  Google Scholar 

  117. Rhee SW, Taylor AM, Tu CH, Cribbs DH, Cotman CW, Jeon NL (2004) Patterned cell culture inside microfluidic devices. Lab Chip 5:102–7

    Article  Google Scholar 

  118. Rodriguez-Rodriguez R, Muñoz-Berbel X, Demming S, Büttgenbach S, Herrera MD, Llobera A (2012) Cell-based microfluidic device for screening anti-proliferative activity of drugs in vascular smooth muscle cells. Biomed Microdevices 14:1129–1140

    Article  Google Scholar 

  119. Ryu KS, Shaikh K, Goluch E, Fan Z, Liu C (2004) Micro magnetic stir-bar mixer integrated with parylene microfluidic channels. Lab Chip 4:608–613

    Article  Google Scholar 

  120. Sabourin D, Snakenborg D, Dufva M (2009) Interconnection blocks: a method for providing reusable, rapid, multiple, aligned and planar microfluidic interconnections. J Micromech Microeng 19:035021

    Article  Google Scholar 

  121. Satoh W, Takahashi S, Sassa F, Fukuda J, Suzuki H (2009) On-chip culturing of hepatocytes and monitoring their ammonia metabolism. Lab Chip 9:35–37

    Article  Google Scholar 

  122. Schäpper D (2010) Continuous culture microbioreactors. Ph.D. Thesis, Technical University of Denmark (DTU)

    Google Scholar 

  123. Schäpper D, Alam MN, Szita N, Eliasson Lantz A, Gernaey KV (2009) Application of microbioreactors in fermentation process development: a review. Anal Bioanal Chem 395:679–695

    Article  Google Scholar 

  124. Schäpper D, Stocks SM, Szita N, Lantz AE, Gernaey KV (2010) Development of a single-use microbioreactor for cultivation of microorganisms. Chem Eng J 160:891–898

    Article  Google Scholar 

  125. Schlichting H, Gersten K (2006) Grenzschichttheorie, 10th edn. Springer, Berlin

    Google Scholar 

  126. Schmid L, Weitz DA, Franke T (2014) Sorting drops and cells with acoustics: acoustic microfluidic fluorescence-activated cell sorter. Lab Chip 14:3710–3718

    Article  Google Scholar 

  127. Schmolke H (2013) Funktionale Polyelektrolytschichten für mikrofluidische Systeme. Ph.D. Thesis, Technische Universität Braunschweig

    Google Scholar 

  128. Schmolke H, Demming S, Edlich A, Magdanz V, Büttgenbach S, Franco-Lara E, Krull R, Klages CP (2010) Polyelectrolyte multilayer surface functionalization of poly(dimethylsiloxane) (PDMS) for reduction of yeast cell adhesion in microfluidic devices. Biomicrofluidics 4:44113

    Article  Google Scholar 

  129. Sharma V, Dhayal M, Shivaprasad SM, Jain SC (2007) Surface characterization of plasma-treated and PEG-grafted PDMS for micro fluidic applications. Vacuum 81:1094–1100

    Article  Google Scholar 

  130. Skelley AM, Voldman J (2008) An active, integrated bubble trap and debubbler for microfluidic applications. In: 12th International conference on miniaturized systems for chemistry and life sciences, San Diego, CA, USA, pp 1360–1362

    Google Scholar 

  131. Soares FO, Correia JH (2000) Bioreactor-on-a-chip: application to baker’s yeast fermentation. In: 1st Annual international IEEE-EMBS special topic conference on microtechnologies in medicine and biology, IEEE, Lyon, pp 45–48

    Google Scholar 

  132. Spence DM, Torrence NJ, Kovarik ML, Martin RS (2004) Amperometric determination of nitric oxide derived from pulmonary artery endothelial cells immobilized in a microchip channel. Analyst 129:995–1000

    Article  Google Scholar 

  133. Suh YK, Kang S (2010) A review on mixing in microfluidics. Micromachines 1:82–111

    Article  Google Scholar 

  134. Szita N, Boccazzi P, Zhang Z, Boyle P, Sinskey AJ, Jensen KF (2005) Development of a multiplexed microbioreactor system for high-throughput bioprocessing. Lab Chip 5:819–826

    Article  Google Scholar 

  135. Tehranirokh M, Kouzani AZ, Francis PS, Kanwar JR (2013) Microfluidic devices for cell cultivation and proliferation. Biomicrofluidics 7:51502

    Article  Google Scholar 

  136. Thompson DM, King KR, Wieder KJ, Toner M, Yarmush ML, Jayaraman A (2004) Dynamic gene expression profiling using a microfabricated living cell array. Anal Chem 76:4098–4103

    Article  Google Scholar 

  137. Toh YC, Lim TC, Tai D, Xiao G, van Noort D, Yu H (2009) A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip 9:2026–2035

    Article  Google Scholar 

  138. Vila-Planas J, Fernández-Rosas E, Ibarlucea B, Demming S, Nogués C, Plaza JA, Domínguez C, Büttgenbach S, Llobera A (2011) Cell analysis using a multiple internal reflection photonic lab-on-a-chip. Nat Protoc 6:1642–1655

    Article  Google Scholar 

  139. Von Meyenburg K (1969) Energetics of the budding cycle of Saccharomyces cerevisiae during glucose limited aerobic growth. Arch Mikrobiol 66:289–303

    Article  Google Scholar 

  140. Walker GM, Zeringue HC, Beebe DJ (2004) Microenvironment design considerations for cellular scale studies. Lab Chip 4:91–97

    Article  Google Scholar 

  141. Wang YC, Ho CC (2004) Micropatterning of proteins and mammalian cells on biomaterials. FASEB J 18:525–527

    Google Scholar 

  142. Weigl BH, Bardell RL, Cabrera CR (2003) Lab-on-a-chip for drug development. Adv Drug Deliv Rev 55:349–377

    Article  Google Scholar 

  143. Wenk P, Hemmerich J, Müller C, Kensy F (2012) Hochparallele Bioprozessentwicklung in geschüttelten Mikrobioreaktoren. Chem Ing Tech 84:704–714

    Article  Google Scholar 

  144. Weuster-Botz D, Altenbach-Rehm J, Hawrylenko A (2001) Process-engineering characterization of small-scale bubble columns for microbial process development. Bioprocess Biosyst Eng 24:3–11

    Article  Google Scholar 

  145. Whitesides GM, Ostuni E, Takayama S, Jiang X, Ingber DE (2001) Soft lithography in biology and biochemistry. Annu Rev Biomed Eng 3:335–73

    Article  Google Scholar 

  146. Wilming A, Bähr C, Kamerke C, Büchs J (2014) Fed-batch operation in special microtiter plates: a new method for screening under production conditions. J Ind Microbiol Biotechnol 41:513–525

    Article  Google Scholar 

  147. Wu MH, Huang SB, Cui Z, Cui Z, Lee GB (2008) A high throughput perfusion-based microbioreactor platform integrated with pneumatic micropumps for three-dimensional cell culture. Biomed Microdevices 10:309–319

    Article  Google Scholar 

  148. Wu MH, Huang SB, Lee GB (2010) Microfluidic cell culture systems for drug research. Lab Chip 10:939–956

    Article  Google Scholar 

  149. Wu MH, Urban JPG, Cui Z, Cui ZF (2006) Development of PDMS microbioreactor with well-defined and homogenous culture environment for chondrocyte 3-D culture. Biomed Microdevices 8:331–340

    Article  Google Scholar 

  150. Wu Z, Hjort K (2009) Surface modification of PDMS by gradient-induced migration of embedded Pluronic. Lab Chip 9:1500–1503

    Article  Google Scholar 

  151. Xia Y, Whitesides GM (1998) Soft lithography. Annu Rev Mater Sci 28:153–184

    Article  Google Scholar 

  152. Xia Y, Whitesides GM (1998) Soft lithography. Angew Chem Int Ed 37:550–575

    Article  Google Scholar 

  153. Yamamoto T, Fujii T, Nojima T (2002) PDMS-glass hybrid microreactor array with embedded temperature control device. Application to cell-free protein synthesis. Lab Chip 2:197–202

    Article  Google Scholar 

  154. Yang B, Lin Q (2009) A latchable phase-change microvalve with integrated heaters. J Microelectromech Syst 18:860–867

    Article  Google Scholar 

  155. Yang YN, Hsiung SK, Lee GB (2008) A pneumatic micropump incorporated with a normally closed valve capable of generating a high pumping rate and a high back pressure. Microfluid Nanofluid 6:823–833

    Article  Google Scholar 

  156. Yuen PK (2008) SmartBuild-a truly plug-n-play modular microfluidic system. Lab Chip 8:1374–1378

    Article  Google Scholar 

  157. Zainal Alam MNH, Gernaey KV (2012) Overview on design considerations for development of disposable microbioreactor prototypes. J Teknol 59:53–60

    Google Scholar 

  158. Zanzotto A, Szita N, Boccazzi P, Lessard P, Sinskey AJ, Jensen KF (2004) Membrane-aerated microbioreactor for high-throughput bioprocessing. Biotechnol Bioeng 87:243–254

    Article  Google Scholar 

  159. Zeng Q, Guo F, Yao L, Zhu HW, Zheng L, Guo ZX, Liu W, Chen Y, Guo SS, Zhao XZ (2011) Milliseconds mixing in microfluidic channel using focused surface acoustic wave. Sensors Actuators B Chem 160:1552–1556

    Article  Google Scholar 

  160. Zhang W, Lin S, Wang C, Hu J, Li C, Zhuang Z, Zhou Y, Mathies R, Yang CJ (2009) PMMA/PDMS valves and pumps for disposable microfluidics. Lab Chip 9:3088–3094

    Article  Google Scholar 

  161. Zhang Z, Boccazzi P, Choi H-G, Perozziello G, Sinskey AJ, Jensen KF (2006) Microchemostat-microbial continuous culture in a polymer-based, instrumented microbioreactor. Lab Chip 6:906–913

    Article  Google Scholar 

  162. Zhang Z, Boccazzi P, Choi HG, Szita N, Sinskey AJ, Jensen KF (2004) A microchemostat-continuous cell culture in microbioreactors. In: 8th International conference on miniaturized systems for chemistry and life sciences, Royal Society of Chemistry, Malmo, Sweden, pp 231–233

    Google Scholar 

  163. Zhang Z, Perozziello G, Boccazzi P, Sinskey AJ, Geschke O, Jensen KF (2007) Microbioreactors for bioprocess development. J Assoc Lab Autom 12:143–151

    Article  Google Scholar 

  164. Zhang Z, Szita N, Boccazzi P, Sinskey AJ, Jensen KF (2005) A well-mixed, polymer-based microbioreactor with integrated optical measurements. Biotechnol Bioeng 93:286–296

    Article  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the financial support provided by the German Research Foundation (DFG) in the Research Unit 856 mikroPART—Microsystems for particulate Life-Science-Products at the Technische Universität Braunschweig, Germany. R. Krull has also received funding from the People Programme (Marie Curie Actions, Multi-ITN) of the European Union’s Seventh Framework Programme for research, technological development and demonstration within the project EUROMBR—European network for innovative microbioreactor applications in bioprocess development (Project ID 608104). S. Büttgenbach gratefully acknowledges additional financial support from the Volkswagen Foundation.

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Krull, R., Lladó‐Maldonado, S., Lorenz, T., Demming, S., Büttgenbach, S. (2016). Microbioreactors. In: Dietzel, A. (eds) Microsystems for Pharmatechnology. Springer, Cham. https://doi.org/10.1007/978-3-319-26920-7_4

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