Review Article | Published:

The present and future role of microfluidics in biomedical research

Nature volume 507, pages 181189 (13 March 2014) | Download Citation

Abstract

Microfluidics, a technology characterized by the engineered manipulation of fluids at the submillimetre scale, has shown considerable promise for improving diagnostics and biology research. Certain properties of microfluidic technologies, such as rapid sample processing and the precise control of fluids in an assay, have made them attractive candidates to replace traditional experimental approaches. Here we analyse the progress made by lab-on-a-chip microtechnologies in recent years, and discuss the clinical and research areas in which they have made the greatest impact. We also suggest directions that biologists, engineers and clinicians can take to help this technology live up to its potential.

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References

  1. 1.

    , & Physics and application of microfluidics in biology. Annu. Rev. Biomed. Eng. 4, 261–286 (2002)

  2. 2.

    & Microfluidics in structural biology: smaller, faster…better. Curr. Opin. Struct. Biol. 13, 538–544 (2003)

  3. 3.

    et al. Microfluidic diagnostic technologies for global public health. Nature 442, 412–418 (2006)

  4. 4.

    , & Cells on chips. Nature 442, 403–411 (2006)

  5. 5.

    The origins and the future of microfluidics. Nature 442, 368–373 (2006)

  6. 6.

    , & Miniaturized total chemical-analysis systems — a novel concept for chemical sensing. Sens. Actuators B 1, 244–248 (1990)

  7. 7.

    , , & Micro total analysis systems. 1. Introduction, theory, and technology. Anal. Chem. 74, 2623–2636 (2002)This pioneering publication described the concept of a µTAS device.

  8. 8.

    A passive pumping method for microfluidic devices. Lab Chip 2, 131–134 (2002)Describes a method to passively pump fluids within microchannels using only a micropipette.

  9. 9.

    et al. Capillary based patterning of cellular communities in laterally open channels. Anal. Chem. 82, 2900–2906 (2010)

  10. 10.

    , & Streamlining immunoassays with immiscible filtrations assisted by surface tension. Anal. Chem. 84, 5518–5523 (2012)

  11. 11.

    , & Formation of dispersions using ‘flow focusing’ in microchannels. Appl. Phys. Lett. 82, 364–366 (2003)

  12. 12.

    Cool, or simple and cheap? Why not both? Lab Chip 13, 11–13 (2012)

  13. 13.

    Microfluidics: in search of a killer application. Nature Methods 4, 665–670 (2007)

  14. 14.

    Hype, hope and hubris: the quest for the killer application in microfluidics. Lab Chip 9, 2119–2122 (2009)

  15. 15.

    The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J. Exp. Med. 115, 453–466 (1962)

  16. 16.

    Ability of polymorphonuclear leukocytes to orient in gradients of chemotactic factors. J. Cell Biol. 75, 606–616 (1977)

  17. 17.

    , & A new direct-viewing chemotaxis chamber. J. Cell Sci. 99, 769–775 (1991)

  18. 18.

    , , & An improved chamber for direct visualisation of chemotaxis. PLoS ONE 5, e15309 (2010)

  19. 19.

    & Biomolecular gradients in cell culture systems. Lab Chip 8, 34–57 (2008)A detailed review of microfluidic chemical gradient generators.

  20. 20.

    Microfluidic technologies for temporal perturbations of chemotaxis. Annu. Rev. Biomed. Eng. 12, 259–284 (2010)

  21. 21.

    & Theoretical analysis of molecular diffusion in pressure-driven laminar flow in microfluidic channels. Biophys. J. 80, 155–160 (2001)

  22. 22.

    et al. Generation of solution and surface gradients using microfluidic systems. Langmuir 16, 8311–8316 (2000)

  23. 23.

    , & Universal microfluidic gradient generator. Anal. Chem. 78, 3472–3477 (2006)

  24. 24.

    & Microfluidics meet cell biology: bridging the gap by validation and application of microscale techniques for cell biological assays. Bioessays 30, 811–821 (2008)

  25. 25.

    et al. Burn injury reduces neutrophil directional migration speed in microfluidic devices. PLoS ONE 5, e11921 (2010)

  26. 26.

    et al. Microfluidic kit-on-a-lid: a versatile platform for neutrophil chemotaxis assays. Blood 120, e45–e53 (2012)

  27. 27.

    , , , & Open access microfluidic device for the study of cell migration during chemotaxis. Integr. Biol. 2, 648–658 (2010)

  28. 28.

    Miniaturized electronic circuits. US Patent 3,138, 743 (issued, 23 June 1964)

  29. 29.

    Semiconductor device-and-lead structure. US Patent 2,981, 877 (issued, 25 April 1961)

  30. 30.

    , & A piezoelectric micropump based on micromachining of silicon. Sens. Actuators 15, 153–167 (1988)

  31. 31.

    , , , & Capillary electrophoresis and sample injection systems integrated on a planar glass chip. Anal. Chem. 64, 1926–1932 (1992)

  32. 32.

    , , & Submicrometer resolution replication of relief patterns for integrated optics. J. Appl. Phys. 45, 4557–4562 (1974)An early example of replicating microfluidic structures with elastomer materials.

  33. 33.

    , & Novel method of cell fusion in field constriction area in fluid integrated circuit. IEEE Trans. Ind. Appl. 25, 732–737 (1989)

  34. 34.

    , , & Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal. Chem. 70, 4974–4984 (1998)

  35. 35.

    , & Engineers are from PDMS-land, Biologists are from Polystyrenia. Lab Chip 12, 1224–1237 (2012)

  36. 36.

    & Direct measurement of interfacial interactions between semispherical lenses and flat sheets of poly(dimethylsiloxane) and their chemical derivatives. Langmuir 7, 1013–1025 (1991)

  37. 37.

    et al. On the aging of oxygen plasma-treated polydimethylsiloxane surfaces. J. Colloid Interface Sci. 137, 11–24 (1990)

  38. 38.

    , , , & Assaying stem cell mechanobiology on microfabricated elastomeric substrates with geometrically modulated rigidity. Nature Protocols 6, 187–213 (2011)

  39. 39.

    , & Engineered materials and the cellular microenvironment: a strengthening interface between cell biology and bioengineering. Trends Cell Biol. 20, 705–714 (2010)

  40. 40.

    From micro- to nanofabrication with soft materials. Science 290, 1536–1540 (2000)

  41. 41.

    Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288, 113–116 (2000)

  42. 42.

    et al. Biological implications of polydimethylsiloxane-based microfluidic cell culture. Lab Chip 9, 2132–2139 (2009)A study that details the biological implications of using PDMS in cell biology research.

  43. 43.

    , & Solvent compatibility of poly(dimethylsiloxane)-based microfluidic devices. Anal. Chem. 75, 6544–6554 (2003)

  44. 44.

    & PDMS absorption of small molecules and consequences in microfluidic applications. Lab Chip 6, 1484–1486 (2006)

  45. 45.

    , , & Managing evaporation for more robust microscale assays. Part 1. Volume loss in high throughput assays. Lab Chip 8, 852–859 (2008)

  46. 46.

    , , & The effect of hyperosmotic pressure on antibody production and gene expression in the GS-NS0 cell line. Biotechnol. Appl. Biochem. 40, 41–46 (2004)

  47. 47.

    , & Effects of CO2 and osmolality on hybridoma cells: growth, metabolism and monoclonal antibody production. Cytotechnology 28, 213–227 (1998)

  48. 48.

    et al. Characterization and resolution of evaporation-mediated osmolality shifts that constrain microfluidic cell culture in poly(dimethylsiloxane) devices. Anal. Chem. 79, 1126–1134 (2007)

  49. 49.

    , , & Handheld recirculation system and customized media for microfluidic cell culture. Lab Chip 6, 149–154 (2006)

  50. 50.

    , , , & Poly (dimethylsiloxane)(PDMS) and silicon hybrid biochip for bacterial culture. Biomed. Microdevices 5, 281–290 (2003)

  51. 51.

    It’s the economy… Lab Chip. 9, 2759–2762 (2009)

  52. 52.

    When PDMS isn’t the best. Anal. Chem. 79, 3248–3253 (2007)

  53. 53.

    et al. Microfluidics-based diagnostics of infectious diseases in the developing world. Nature Med. 17, 1015–1019 (2011)A study that diagnosed HIV from blood samples in Rwanda using a simple microfluidic chip.

  54. 54.

    et al. Surface modification of poly(methyl methacrylate) used in the fabrication of microanalytical devices. Anal. Chem. 72, 5331–5337 (2000)

  55. 55.

    , , , & A rapid prototyping method for polymer microfluidics with fixed aspect ratio and 3D tapered channels. Lab Chip 9, 2941–2946 (2009)

  56. 56.

    & Hot embossing as a method for the fabrication of polymer high aspect ratio structures. Sens. Actuators A 83, 130–135 (2000)

  57. 57.

    et al. Fabrication of plastic microfluid channels by imprinting methods. Anal. Chem. 69, 4783–4789 (1997)

  58. 58.

    , , , & Hot embossing of plastic microfluidic devices using poly(dimethylsiloxane) molds. J. Micromech. Microeng. 21, 017002 (2011)

  59. 59.

    et al. Rapid prototyping of arrayed microfluidic systems in polystyrene for cell-based assays. Anal. Chem. 83, 1408–1417 (2011)

  60. 60.

    et al. Benchtop micromolding of polystyrene by soft lithography. Lab Chip 11, 3089–3097 (2011)

  61. 61.

    , & Assessment of enhanced autofluorescence and impact on cell microscopy for microfabricated thermoplastic devices. Anal. Chem. 85, 44–49 (2013)

  62. 62.

    et al. Flexible microfluidic cloth-based analytical devices using a low-cost wax patterning technique. Lab Chip 12, 209–218 (2011)

  63. 63.

    Point-of-care immunotesting: approaching the analytical performance of central laboratory methods. Clin. Biochem. 38, 591–606 (2005)

  64. 64.

    , , & Diagnostics for the developing world: microfluidic paper-based analytical devices. Anal. Chem. 82, 3–10 (2010)

  65. 65.

    , & Understanding wax printing: a simple micropatterning process for paper-based microfluidics. Anal. Chem. 81, 7091–7095 (2009)

  66. 66.

    , , , & FLASH: A rapid method for prototyping paper-based microfluidic devices. Lab Chip 8, 2146–2150 (2008)

  67. 67.

    , & Inkjet-printed microfluidic multianalyte chemical sensing paper. Anal. Chem. 80, 6928–6934 (2008)

  68. 68.

    , & Flexographically printed fluidic structures in paper. Anal. Chem. 82, 10246–10250 (2010)

  69. 69.

    et al. Two-dimensional paper network format that enables simple multistep assays for use in low-resource settings in the context of malaria antigen detection. Anal. Chem. 84, 4574–4579 (2012)

  70. 70.

    , & Three-dimensional microfluidic devices fabricated in layered paper and tape. Proc. Natl Acad. Sci. USA 105, 19606–19611 (2008)A review of advancements in µPAD devices for diagnostics in developing regions.

  71. 71.

    , , , & Development of automated paper-based devices for sequential multistep sandwich enzyme-linked immunosorbent assays using inkjet printing. Lab Chip 13, 126–135 (2012)

  72. 72.

    et al. Microfluidic CD4+ and CD8+ T lymphocyte counters for point-of-care HIV diagnostics using whole blood. Sci. Transl. Med. 5, 214ra170 (2013)

  73. 73.

    et al. Microfluidics-based diagnostics of infectious diseases in the developing world. Nature Med. 17, 1015–1019 (2011)

  74. 74.

    et al. Clinical microfluidics for neutrophil genomics and proteomics. Nature Med. 16, 1042–1047 (2010)This study investigated the relationship between protein/genetic information and the clinical condition of burn patients using a simple microfluidic device.

  75. 75.

    et al. Microfluidics-based capture of human neutrophils for expression analysis in blood and bronchoalveolar lavage. Lab. Invest. 91, 1787–1795 (2011)

  76. 76.

    & Single-step separation of red blood cells, granulocytes and mononuclear leukocytes on discontinuous density gradients of Ficoll-Hypaque. Exp. Cell Res. 61, 387–396 (1970)

  77. 77.

    , & One-step purification of nucleic acid for gene expression analysis via Immiscible Filtration Assisted by Surface Tension (IFAST). Lab Chip 11, 1747–1753 (2011)

  78. 78.

    , , , & Purification of cell subpopulations via immiscible filtration assisted by surface tension (IFAST). Biomed. Microdevices 13, 1033–1042 (2011)

  79. 79.

    Pfizer slashes R&D. Nature 470, 154 (2011)

  80. 80.

    , & The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151–185 (2003)

  81. 81.

    Traditional drug-discovery model ripe for reform. Nature 471, 17–18 (2011)

  82. 82.

    et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nature Rev. Drug Discov. 9, 203–214 (2010)

  83. 83.

    Academia and big pharma united. Sci. Transl. Med. 6, 217ed1 (2014)

  84. 84.

    , , , & An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models. Lab Chip 8, 741–746 (2008)

  85. 85.

    et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010)

  86. 86.

    et al. In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology. J. Clin. Invest. 122, 408–418 (2012)This study utilized precisely patterned microvessels to diagnose vasco-occlusions in patient samples.

  87. 87.

    , , & Tubeless microfluidic angiogenesis assay with three-dimensional endothelial-lined microvessels. Biomaterials 34, 1471–1477 (2013)

  88. 88.

    & Fluid forces control endothelial sprouting. Proc. Natl Acad. Sci. USA 108, 15342–15347 (2011)

  89. 89.

    et al. A multipurpose microfluidic device designed to mimic microenvironment gradients and develop targeted cancer therapeutics. Lab Chip 9, 545–554 (2009)

  90. 90.

    et al. Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc. Natl Acad. Sci. USA 109, 13515–13520 (2012)This study describes a system that more closely mimics tumour cell intravasation in vitro compared to standard cell biology techniques such as modified Transwell assays.

  91. 91.

    et al. Transition to invasion in breast cancer: a microfluidic in vitro model enables examination of spatial and temporal effects. Integr. Biol. 3, 439–450 (2011)

  92. 92.

    & A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells. Lab Chip 10, 36–42 (2010)

  93. 93.

    , & From 3D cell culture to organs-on-chips. Trends Cell Biol. 21, 745–754 (2011)

  94. 94.

    , , , & A biophysical indicator of vaso-occlusive risk in sickle cell disease. Sci. Transl. Med. 4, 123ra26 (2012)

  95. 95.

    , & Pipette-friendly laminar flow patterning for cell-based assays. Lab Chip 11, 2060–2065 (2011)

  96. 96.

    et al. Centrifugal microfluidics for biomedical applications. Lab Chip 10, 1758–1773 (2010)

  97. 97.

    et al. Kit-On-A-Lid-Assays for accessible self-contained cell assays. Lab Chip 13, 424–431 (2013)

  98. 98.

    , , & Three options for citation tracking: Google Scholar, Scopus and Web of Science. Biomed. Digit. Libr 10.1186/1742-5581-3-7 (2006)

  99. 99.

    , , & Comparison of PubMed, Scopus, Web of Science, and Google Scholar: strengths and weaknesses. FASEB J. 22, 338–342 (2008)

  100. 100.

    , & et al. Crossing the endothelial barrier during metastasis. Nature Rev. Cancer 13, 858–870 (2013)

  101. 101.

    & Fabrication of biofunctionalized microfluidic structures by low-temperature wax bonding. Anal. Chem. 84, 7838–7844 (2012)

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Acknowledgements

We thank S. Berry, B. Casavant, P. Thomas and L. Strotman for discussions during the preparation of this manuscript.

Author information

Affiliations

  1. Materials Science Program, Department of Biomedical Engineering, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, Wisconsin 53705-2275, USA

    • Eric K. Sackmann
  2. Wendt Commons Library, University of Wisconsin-Madison, 215 North Randall Avenue, Madison, Wisconsin 53706, USA

    • Anna L. Fulton
  3. Department of Biomedical Engineering, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Room 6009, Madison, Wisconsin 53705-2275, USA

    • David J. Beebe

Authors

  1. Search for Eric K. Sackmann in:

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Contributions

E.K.S. and D.J.B. wrote the manuscript. A.L.F. contributed to the design and execution of the literature searches that measured the quantity of microfluidic publications in various categories.

Competing interests

E.K.S. and D.J.B. have patent applications pending on technology cited in this work. D.J.B. has ownership in Ratio, Inc., BellBrook Labs, LLC and Salus Discovery, LLC. E.K.S. has ownership in Salus Discovery, LLC.

Corresponding author

Correspondence to David J. Beebe.

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https://doi.org/10.1038/nature13118

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