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Control and detection of chemical reactions in microfluidic systems

Nature volume 442, pages 394–402 (2006)Cite this article

Abstract

Recent years have seen considerable progress in the development of microfabricated systems for use in the chemical and biological sciences. Much development has been driven by a need to perform rapid measurements on small sample volumes. However, at a more primary level, interest in miniaturized analytical systems has been stimulated by the fact that physical processes can be more easily controlled and harnessed when instrumental dimensions are reduced to the micrometre scale. Such systems define new operational paradigms and provide predictions about how molecular synthesis might be revolutionized in the fields of high-throughput synthesis and chemical production.

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Figure 1: Microfluidic approaches for mixing in continuous flow.
Figure 2: Formation of microdroplets in microchannels.
Figure 3: Schematic view of three-dimensional microchannel circuit for performing parallel combinatorial chemistry.
Figure 4: Microfluidic reactor for nanoparticle production.
Figure 5: Integrated microfluidic bioprocessor.
Figure 6: Schematic representation of a chemical reaction circuit used to synthesize 2-deoxy-2-fluoro-D-glucose.

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References

  1. Wöhler, F. Grundriß der Organischen Chemie (Duncker und Humblot, Berlin, 1848).

    Google Scholar 

  2. Levenspiel, O. Chemical Reaction Engineering (Wiley & Sons, Chichester, 1999).

    Google Scholar 

  3. Nguyen, N. T. & Wu, Z. Micromixers — a review. J. Micromech. Microeng. 15, R1–R16 (2005).

    Google Scholar 

  4. Ottino, J. M., Wiggins, S. Introduction: mixing in microfluidics. Phil. Trans. R. Soc. Lond. A 362, 923–935 (2004).

    MathSciNet  MATH  ADS  Google Scholar 

  5. Shastry, M. C. R., Luck, S. D. & Roder, H. A Continuous-flow capillary mixing method to monitor reactions on the microsecond time scale. Biophys. J. 74, 2714–2721 (1998).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  6. Knight, J. B., Vishwanath, A., Brody, J. P. & Austin, R. H. Hydrodynamic focusing on a silicon chip: mixing nanoliters in microseconds. Phys. Rev. Lett. 80, 3863–3866 (1998).

    CAS  ADS  Google Scholar 

  7. Ottino, J. M. The mixing of fluids. Sci. Am. 260, 56–67 (1989).

    ADS  Google Scholar 

  8. Ottino, J. M. Mixing, chaotic advection, and turbulence. Ann. Rev. Fluid Mech. 22, 207–254 (1990).

    MathSciNet  ADS  Google Scholar 

  9. Mengeaud, V., Josserand, J. & Girault, H. H. Mixing processes in a zigzag microchannel: finite element simulation and optical study. Anal. Chem. 74, 4279–4286 (2002).

    CAS  PubMed  Google Scholar 

  10. Chen, H. & Meiners, J. C. Topologic mixing on a microfluidic chip. Appl. Phys. Lett. 84, 2193–2195 (2004).

    CAS  ADS  Google Scholar 

  11. Liu, R. H. et al. Passive mixing in a three-dimensional serpentine microchannel. J. Microelectromech. Syst. 9, 190–197 (2000).

    Google Scholar 

  12. Stroock, A. D. et al. Chaotic mixer for microchannels. Science 295, 647–651 (2002).

    CAS  ADS  PubMed  Google Scholar 

  13. Biddiss, E., Erickson, D. & Li, D. Q. Heterogeneous surface charge enhanced micromixing for electrokinetic flows. Anal. Chem. 76, 3208–3213 (2004).

    CAS  PubMed  Google Scholar 

  14. Burns, M. A. et al. An integrated nanoliter DNA analysis device. Science 282, 484–487 (1998).

    CAS  ADS  PubMed  Google Scholar 

  15. Taniguchi, T., Torii, T. & Higuchi, T. Chemical reactions in microdroplets by electrostatic manipulation of droplets in liquid media. Lab Chip 2, 19–23 (2002).

    CAS  PubMed  Google Scholar 

  16. Bringer, M. R., Gerdts, C. J., Song, H., Tice, J. D. & Ismagilov, R. F. Microfluidic systems for chemical kinetics that rely on chaotic mixing in droplets. Phil. Trans. R. Soc. Lond. A 362, 1087–1104 (2004).

    CAS  ADS  Google Scholar 

  17. Tice, J. D., Song, H., Lyon, A. D. & Ismagilov, R. F. Formation of droplets and mixing in multiphase microfluidics at low values of the Reynolds and the capillary numbers. Langmuir 19, 9127–9133 (2003).

    CAS  Google Scholar 

  18. Song, H., Tice, J. D. & Ismagilov, R. F. A microfluidic system for controlling reaction networks in time. Angew. Chem. Int. Edn 42, 768–772 (2003).

    CAS  Google Scholar 

  19. Song, H. & Ismagilov, R. F. Millisecond kinetics on a microfluidic chip using nanoliters of reagents. J. Am. Chem. Soc. 125, 14613–14619 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chambers, R. D. & Spink, R. C. H. Microreactors for elemental fluorine. Chem. Commun. 883–884 (1999).

  21. Chambers, R. D., Holling, D., Spink, R. C. H. & Sandford, G. Elemental fluorine Part 13. Gas–liquid thin film microreactors for selective direct fluorination. Lab Chip 1, 132–137 (2001).

    CAS  PubMed  Google Scholar 

  22. Chambers, R. D., Fox, M. A. & Sandford, G. Elemental fluorine Part 18. Selective direct fluorination of 1,3-ketoesters and 1,3-diketones using gas/liquid microreactor technology. Lab Chip 5, 1132–1139 (2005).

    CAS  PubMed  Google Scholar 

  23. Mitchell, M. C., Spikmans, V. & deMello, A. J. Microchip-based synthesis and analysis: control of multicomponent reaction products and intermediates. Analyst 126, 24–27 (2001).

    CAS  ADS  PubMed  Google Scholar 

  24. Kawaguchi, T., Miyata, H., Ataka, K., Mae, K. & Yoshida, J. Room-temperature Swern oxidations by using a microscale flow system. Angew. Chem. Int. Edn 44, 2413–2416 (2005).

    CAS  Google Scholar 

  25. Salimi-Moosavi, H., Tang, T. & Harrison, D. J. Electroosmotic pumping of organic solvents and reagents in microfabricated reactor chips. J. Am. Chem. Soc. 119, 8716–8717 (1997).

    CAS  Google Scholar 

  26. Wootton, R. C. R., Fortt, R. & de Mello, A. J. On chip generation and reaction of unstable intermediates — monolithic nanoreactors for diazonium chemistry: azo dyes. Lab Chip 2, 5–7 (2002).

    CAS  PubMed  Google Scholar 

  27. Ducry, L. & Roberge, D. M. Controlled autocatalytic nitration of phenol in a microreactor. Angew. Chem. 117, 8186–8189 (2005).

    Google Scholar 

  28. Iles, A., Fortt, R. & de Mello, A. J. Thermal optimisation of the Reimer–Tiemann reaction using thermochromic liquid crystals on a microfluidic reactor. Lab Chip 5, 550–554 (2005).

    Google Scholar 

  29. Miller, P. W. et al. Rapid formation of amides via carbonylative coupling reactions using a microfluidic device. Chem. Commun. 546–548 (2006).

  30. Besser, R. S., Ouyang, X. & Surangalikar, H. Hydrocarbon hydrogenation and dehydrogenation reactions in microfabricated catalytic reactors. Chem. Eng. Sci. 58, 19–26 (2003).

    CAS  Google Scholar 

  31. Greenway, G. M., Haswell, S. J., Morgan, D. O., Skelton, V. & Styring, P. The use of a novel microreactor for high throughput continuous-flow organic synthesis. Sens. Actuators B 63, 153–158 (2000).

    CAS  Google Scholar 

  32. Schwesinger, N., Pieper, G. & Wurziger, H. Method for carrying out a metathesis reaction of unsaturated organic compounds. World Patent WO0170387 (2001).

  33. Lu, H., Schmidt, M. A. & Jensen, K. F. Photochemical reactions and on-line UV detection in microfabricated reactors. Lab Chip 1, 22–28 (2001).

    CAS  PubMed  Google Scholar 

  34. Wootton, R. C. R., Fortt, R. & de Mello, A. J. A microfabricated nanoreactor for safe, continuous generation and use of singlet oxygen. Org. Proc. Res. Dev. 6, 187–189 (2002).

    CAS  Google Scholar 

  35. Watts, P. & Haswell, S. J. Continuous-flow reactors for drug discovery. Drug Discov. Today 8, 586–593 (2003).

    CAS  PubMed  Google Scholar 

  36. Jhähnisch, K., Hessel, V., Löwe, H. & Baerns, M. Chemistry in microstructured reactors. Angew. Chem. Int. Edn 43, 406–446 (2004).

    Google Scholar 

  37. Brivio, M., Verboom, W. & Reinhoudt, D. N. Miniaturized continuous-flow reaction vessels: influence on chemical reactions. Lab Chip 6, 329–344 (2006).

    CAS  PubMed  Google Scholar 

  38. Watts, P. & Haswell, S. J. The application of microreactors for small-scale organic synthesis. Chem. Eng. Technol. 28, 290–301 (2005).

    CAS  Google Scholar 

  39. Jensen, K. F. Microreaction engineering — is small better? Chem. Eng. Sci. 56, 293–303 (2001).

    CAS  Google Scholar 

  40. Geysen, H. M., Schoenen, F., Wagner, D. & Wagner, R. Combinatorial compound libraries for drug discovery: an ongoing challenge. Nature Rev. Drug Discov. 2, 222–230 (2003).

    Google Scholar 

  41. Dittrich, P. S. & Manz, A. Lab-on-a-chip: microfluidics in drug discovery Nature Rev. Drug Discov. 5, 211–218 (2006).

    Google Scholar 

  42. Mitchell, M. C., Spikmans, V., Manz, A. & deMello, A. J. Microchip-based synthesis and total analysis system (µSYNTAS): chemical microprocessing for generation and analysis of compound libraries. J. Chem. Soc. Perkin Trans. 1 514–518 (2001).

  43. Garcia-Egido, E., Wong, S. Y. F. & Warrington, B. H. A Hantzsch synthesis of 2-aminothiazoles performed in a heated microreactor system. Lab Chip 2, 31–33 (2002).

    CAS  PubMed  Google Scholar 

  44. Fernandez-Suarez, M., Wong, S. Y. F. & Warrington, B. H. Synthesis of a three-member array of cycloadducts in a glass microchip under pressure driven flow. Lab Chip 2, 170–174 (2002).

    CAS  PubMed  Google Scholar 

  45. Garcia-Egido, E., Spikmans, V., Wong, S. Y. F. & Warrington, B. H. Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system. Lab Chip 3, 73–76 (2003).

    CAS  PubMed  Google Scholar 

  46. Kikutani, Y. et al. Glass microchip with three-dimensional microchannel network for 2 × 2 parallel synthesis. Lab Chip 2, 188–192 (2002).

    CAS  PubMed  Google Scholar 

  47. Kobayashi, J. et al. A microfluidic device for conducting gas–liquid–solid hydrogenation reactions. Science 304, 1305–1308 (2004).

    CAS  ADS  PubMed  Google Scholar 

  48. Fredrickson, C. K. & Fan, Z. H. Macro-to-micro interfaces for microfluidic devices. Lab Chip 4, 526–533 (2004).

    CAS  PubMed  Google Scholar 

  49. Alivisatos, A. P. Semiconductor clusters, nanocrystals, and quantum dots. Science 271, 933–937 (1996).

    CAS  ADS  Google Scholar 

  50. LaMer, V. K. & Dinegar, R. H. Theory, production and mechanism of formation of monodispersed hydrosols. J. Am. Chem. Soc. 72, 4847–4854 (1950).

    CAS  Google Scholar 

  51. Murray, C. B., Kagan, C. R. & Bawendi, M. G. Synthesis and characterization of monodisperse nanocrystals and close-packed nanocrystal assemblies. Annu. Rev. Mater. Sci. 30, 545–610 (2000).

    CAS  ADS  Google Scholar 

  52. deMello, J. & deMello, A. Microscale reactors: nanoscale products. Lab Chip 4, 11N–15N (2004).

    CAS  PubMed  Google Scholar 

  53. Edel, J. B., Fortt, R., deMello, J. C. & deMello, A. J. Microfluidic routes to the controlled production of nanoparticles. Chem. Commun. 1136–1137 (2002).

  54. Hung, L. -H. et al. Alternating droplet generation and controlled dynamic droplet fusion in microfluidic device for CdS nanoparticle synthesis. Lab Chip 6, 174–178 (2006).

    CAS  PubMed  Google Scholar 

  55. Krishnadasan, S., Tovilla, J., Vilar, R., deMello, A. J. & deMello, J. C. On-line analysis of CdSe nanoparticle formation in a continuous-flow chip-based microreactor. J. Mater. Chem. 14, 2655–2660 (2004).

    CAS  Google Scholar 

  56. Yen, B. K. H., Stott, N. E., Jensen, K. F. & Bawendi, M. G. A continuous-flow microcapillary reactor for the preparation of a size series of CdSe nanocrystals. Adv. Mater. 15, 1858–1862 (2003).

    CAS  Google Scholar 

  57. Song, Y., Kumar, C. S. S. R. & Hormes, J. Synthesis of Pd nanoparticles using a continuous-flow polymeric micro reactor. J. Nanosci. Nanotech. 4, 788–793 (2004).

    CAS  Google Scholar 

  58. He, S. et al. Effects of interior wall on continuous fabrication of silver nanoparticles in microcapillary reactor. Chem. Lett. 34, 748–749 (2005).

    CAS  Google Scholar 

  59. Lin, X. Z., Terepka, A. D. & Yang, H. Synthesis of silver nanoparticles in a continuous-flow tubular microreactor. Nano Lett. 4, 2227–2232 (2004).

    CAS  ADS  Google Scholar 

  60. Wagner, J., Kirner, T., Mayer, G., Albert, J. A. & Köhler, J. M. Generation of metal nanoparticles in a microchannel reactor. Chem. Eng. J. 101, 251–260 (2004).

    CAS  Google Scholar 

  61. Song, Y. et al. Investigations into sulfobetaine-stabilized Cu nanoparticle formation: toward development of a microfluidic synthesis. J. Phys. Chem. B 109, 9330–9338 (2005).

    CAS  PubMed  Google Scholar 

  62. Wang, H., Nakamura, H., Uehara, M., Miyazaki, M. & Maeda, H. Preparation of titania particles utilizing the insoluble phase interface in a microchannel reactor. Chem. Commun. 1462–1463 (2002).

  63. Wang, H. et al. Continuous synthesis of CdSe–ZnS composite nanoparticles in a microfluidic reactor. Chem. Commun. 48–49 (2004).

  64. Shestopalov, I., Tice, J. D. & Ismagilov, R. F. Multi-step synthesis of nanoparticles performed on millisecond time scale in a microfluidic droplet-based system. Lab Chip 4, 316–321 (2004).

    CAS  PubMed  Google Scholar 

  65. Chan, E. M., Alivisatos, A. P. & Mathies, R. A. High-temperature microfluidic synthesis of CdSe nanocrystals in nanoliter droplet. J. Am. Chem. Soc. 127, 13854–13861 (2005).

    CAS  PubMed  Google Scholar 

  66. Yen, B. K. H., Günther, A., Schmidt, M. A., Jensen, K. F. & Bawendi, M. G. A microfabricated gas–liquid segmented flow reactor for high-temperature synthesis: the case of CdSe quantum dots. Angew. Chem. Int. Edn 44, 5447–5451 (2005).

    CAS  Google Scholar 

  67. Millman, J. R., Bhatt, K. H., Prevo, B. G. & Velev, O. D. Anisotropic particle synthesis in dielectrophoretically controlled microdroplet reactors. Nature Mater. 4, 98–102 (2004).

    ADS  Google Scholar 

  68. Lagally, E. T. & Mathies, R. A. Integrated genetic analysis microsystems. J. Phys. D 37, R245–R261 (2004).

    CAS  ADS  Google Scholar 

  69. Beebe, D. J., Mensing, G. A. & Walker, G. M. Physics and applications of microfluidics in biology. Annu. Rev. Biomed. Eng. 4, 261–286 (2002).

    CAS  PubMed  Google Scholar 

  70. Auroux, P.-A., Koç, Y., deMello, A., Manz, A. & Day, P. J. R. Miniaturised nucleic acid analysis. Lab Chip 4, 534–546 (2004).

    CAS  PubMed  Google Scholar 

  71. Jakeway, S. C., de Mello, A. J. & Russell, E. Miniaturized total analysis systems for biological analysis. Fresenius J. Anal. Chem. 366, 525–539 (2000).

    CAS  PubMed  Google Scholar 

  72. Mullis, K. B. et al. Specific enzymatic amplification of DNA in vitro: the polymerase chain reaction. Cold Spring Harb. Symp. Quant. Biol. 51, 263–273 (1986).

    CAS  PubMed  Google Scholar 

  73. Oda, R. P. et al. Infrared-mediated thermocycling for ultrafast polymerase chain reaction amplification of DNA. Anal. Chem. 70, 4361–4368 (1998).

    CAS  PubMed  Google Scholar 

  74. Fermér, C., Nilsson, P. & Larhed, M. Microwave-assisted high-speed PCR. Eur. J. Pharm. Sci. 18, 129–132 (2003).

    PubMed  Google Scholar 

  75. Hu, G. et al. Electrokinetically controlled real-time polymerase chain reaction in microchannel using Joule heating effect. Anal. Chim. Acta 557, 146–151 (2006).

    CAS  Google Scholar 

  76. Woolley, A. T. et al. Functional integration of PCR amplification and capillary electrophoresis in a microfabricated DNA analysis device. Anal. Chem. 68, 4081–4086 (1996).

    CAS  PubMed  Google Scholar 

  77. Krishnan, M., Ugaz, V. M. & Burns, M. A. PCR in a Rayleigh–Benard convection cell. Science 298, 793 (2003).

    Google Scholar 

  78. Kopp, M. U., deMello, A. J. & Manz, A. Chemical amplification: continuous-flow PCR on a chip. Science 280, 1046–1048 (1998).

    CAS  ADS  PubMed  Google Scholar 

  79. Obeid, P. J., Christopoulos, T. K., Crabtree, H. J. & Backhouse, C. J. Microfabricated device for DNA and RNA amplification by continuous-flow polymerase chain reaction and reverse transcription-polymerase chain reaction with cycle number selection. Anal. Chem. 75, 288–295 (2003).

    CAS  PubMed  Google Scholar 

  80. Marcus, J. S., Anderson, W. F. & Quake, S. R. Parallel picoliter RT-PCR assays using microfluidics. Anal. Chem. 78, 956–958 (2006).

    CAS  PubMed  Google Scholar 

  81. Liu, R. H., Yang, J., Lenigk, R., Bonanno, J. & Grodzinski, P. Self-contained, fully integrated biochip for sample preparation, polymerase chain reaction amplification, and DNA microarray detection. Anal. Chem. 76, 1824–1831 (2004).

    CAS  PubMed  Google Scholar 

  82. Lagally, E. T. et al. Integrated portable genetic analysis microsystem for pathogen/infectious disease detection. Anal. Chem. 76, 3162–3170 (2004).

    CAS  PubMed  Google Scholar 

  83. Blazej, R. G., Kumaresan, P. & Mathies, R. A. Microfabricated bioprocessor for integrated nanoliter-scale Sanger DNA sequencing. Proc. Natl Acad. Sci. USA 103, 7240–7245 (2006).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  84. Schwarz, M. A. & Hauser, P. C. Recent developments in detection methods for microfabricated analytical devices. Lab Chip 1, 1–6 (2001).

    CAS  PubMed  Google Scholar 

  85. Dittrich, P. S. & Manz, A. Single-molecule fluorescence detection in microfluidic channels — the holy Grail in µTAS? Anal. Bioanal. Chem. 382, 1771–1782 (2005).

    CAS  PubMed  Google Scholar 

  86. Dertinger, S. K. W., Chiu, D. T., Jeon, N. L. & Whitesides, G. M. Generation of gradients having complex shapes using microfluidic networks. Anal. Chem. 73, 1240–1246 (2001).

    CAS  Google Scholar 

  87. Jeon, N. L. et al. Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nature Biotechnol. 20, 826–830 (2002).

    CAS  Google Scholar 

  88. Mao, H., Yang, T. & Cremer, P. S. A microfluidic device with a linear temperature gradient for parallel and combinatorial measurements. J. Am. Chem. Soc. 124, 4432–4435 (2002).

    CAS  PubMed  Google Scholar 

  89. Cabrera, C. R., Finlayson, B. & Yager, P. Formation of natural pH gradients in a microfluidic device under flow conditions: model and experimental validation. Anal. Chem. 73, 658–666 (2001).

    CAS  PubMed  Google Scholar 

  90. Ratner, D. M. et al. Microreactor-based reaction optimization in organic chemistry — glycosylation as a challenge. Chem. Commun. 578–580 (2005).

  91. Leung, S. -A., Winkle, R. F., Wootton, R. C. R. & deMello, A. J. A method for rapid reaction optimisation in continuous-flow microfluidic reactors using online Raman spectroscopic detection. Analyst 130, 46–52 (2005).

    CAS  ADS  PubMed  Google Scholar 

  92. Hatakeyama, T., Chen, D. L. & Ismagilov, R. F. Microgram-scale testing of reaction conditions in solution using nanoliter plugs in microfluidics with detection by MALDI-MS. J. Am. Chem. Soc. 128, 2518–2519 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Chambers, R. D. et al. Elemental fluorine Part 16. Versatile thin-film gas–liquid multi-channel microreactors for effective scale-out. Lab Chip 5, 191–198 (2005).

    CAS  PubMed  Google Scholar 

  94. Lee, C. C. et al. Multistep synthesis of a radiolabeled imaging probe using integrated microfluidics. Science 16, 1793–1796 (2005).

    ADS  Google Scholar 

  95. Kikutani, Y. et al. Pile-up glass microreactor. Lab Chip 2, 193–196 (2002).

    CAS  PubMed  Google Scholar 

  96. Pennemann, H., Watts, P., Haswell, S. J., Hessel, V. & Lowe, H. Benchmarking of microreactor applications. Org. Proc. Res. Dev. 8, 422–439 (2004).

    CAS  Google Scholar 

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I would like to thank C. deMello and T. deMello for help in preparing the manuscript.

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    Andrew J. deMello

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deMello, A. Control and detection of chemical reactions in microfluidic systems. Nature 442, 394–402 (2006). https://doi.org/10.1038/nature05062

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