Skip to main content

At the Interface: Advanced Microfluidic Assays for Study of Cell Function

  • Chapter
BioMEMS and Biomedical Nanotechnology

Abstract

Understanding basic biology and disease mechanisms, testing drug safety and efficacy, engineering tissues and cell-based biosensors all require methods to study and manipulate mammalian cell function. A convenient method that has been developed over the past century for these purposes is in vitro cell culture where cells are taken out of their normal physiological environment inside the body and kept alive in a dish. Although in vitro cell culture is powerful, there is increasing evidence that cellular responses in culture dishes do not necessarily reflect how cells may behave in vivo. This discrepancy is due, at least in part, to the fact that much of what happens in living organisms is affected by microscale patterns and heterogeneity which are not well controlled in traditional macroscopic culture systems. Cells, which are micron-sized, determine their behavior based on cues from their microenvironment. Cellular behaviors such as subcellular signaling, chemotaxis (directed migration towards a chemical), growth, differentiation, and death, for example, are determined by subcellular stimulation, microscale chemical gradients, and adhesive micro- & nanopatterns. Microfluidics and other microscale phenomena dominate at this level making microtechnology crucial to the understanding of the cellular basis of life.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. C.D. Bain.Motion of liquids on surfaces. Chemphyschem, 2(10):580–582, 2001.

    Google Scholar 

  2. S.L.R. Barker, D. Ross et al.Control of flowdirection in microfluidic devices with polyelectrolyte multilayers. Analytical Chemistry, 72(24):5925–5929, 2000.

    Article  Google Scholar 

  3. A. Bernard, B. Michel, and E. Delamarche. Micromosaic immunoassays. Anal. Chem., 73(1):8–12, 2001.

    Article  Google Scholar 

  4. K. Bhadriraju and C.S. Chen. Engineering cellular microenvironments to cell-based drug testing improve. Drug Discovery Today, 7(11):612–620, 2002.

    Article  Google Scholar 

  5. R. Bharadwaj, J.G. Santiago et al. Design and optimization of on-chip capillary electrophoresis. Electrophoresis, 23(16):2729–2744, 2002.

    Article  Google Scholar 

  6. F. Bradke and C.G. Dotti. The role of local actin instability in axon formation. Science, 283(5409):1931–1934, 1999.

    Article  Google Scholar 

  7. R. Brock and T.M. Jovin. Heterogeneity of signal transduction at the subcellular level: microsphere-based focal EGF receptor activation and stimulation of Shc translocation. J. Cell Sci., 114(13):2437–2447, 2001.

    Google Scholar 

  8. A.D. Carroll, L. Scampavia, D. Luo, A. Lernmark, and J. Ruzicka. Bead injection ELISA for the determination of antibodies implicated in type 1 diabetes mellitus. Analyst., 128(9):1157–1162, Sep. 2003.

    Article  Google Scholar 

  9. N.H. Chiem and D.J. Harrison. Monoclonal antibody binding affinity determined by microchip-based capillary electrophoresis. Electrophoresis, 19(16–17):3040–3044, Nov. 1998.

    Article  Google Scholar 

  10. D.T. Chiu, N.L. Jeon et al. Patterned Deposition of Cells and Proteins onto Surfaces by Using Threedimensional Microfluidic Systems. Proceedings of the National Academy of Sciences of the United States of America. 97(6), pp. 2408–2413, 2000.

    Article  Google Scholar 

  11. B.S. Cho, T.G. Schuster et al. Passively driven integrated microfluidic system for separation of motile sperm. Analytical Chemistry, 75(7):1671–1675, 2003.

    Article  Google Scholar 

  12. S.K. Cho, H.J. Moon et al. Creating, transporting, cutting, and merging liquid droplets by electrowettingbased actuation for digital microfluidic circuits. J. Microelectromech. Systems, 12(1):70–80, 2003.

    Article  Google Scholar 

  13. T. Chovan and A. Guttman. Microfabricated devices in biotechnology and biochemical processing. Trends in Biotechnology, 20(3):116–122, 2002.

    Article  Google Scholar 

  14. A.A. Darhuber, J.P. Valentino et al. Thermocapillary actuation of droplets on chemically patterned surfaces by programmable microheater arrays. J. Microelectromech. Systems 12(6):873–879, 2003.

    Article  Google Scholar 

  15. J.M. Davis and S.M. Troian. Influence of attractive van der Waals interactions on the optimal excitations in thermocapillary-driven spreading. Physical Review E, 67(1), 2003.

    Google Scholar 

  16. E. Delamarche, A. Bernard et al. Patterned delivery of immunoglobulins to surfaces using microfluidic networks. Science, 276(5313):779–781, 1997.

    Article  Google Scholar 

  17. E. Delamarche, A. Bernard, H. Schmidt, A. Bietsch, B. Michel, and H. Biebuyck. Microfluidic networks for chemical patterning of substrates: design and application to bioassays. J. Am. chem. soc., 120:500–508, 1998.

    Article  Google Scholar 

  18. S.K.W. Dertinger, X.Y. Jiang et al. Gradients of Substrate-Bound Laminin Orient Axonal Specification of Neurons. Proceedings of the National Academy of Sciences of the United States of America 99(20): pp. 12542–12547, 2002.

    Article  Google Scholar 

  19. E. Diamandis and T.K. Christopoulos. Immunoassay. A. P. Inc. San Diego, 1996.

    Google Scholar 

  20. H. Ding, K. Chakrabarty et al. Scheduling of microfluidic operations for reconfigurable two-dimensional electrowetting arrays. Ieee Transactions on Computer-Aided Design of Integrated Circuits and Systems, 20(12):1463–1468, 2001.

    Article  Google Scholar 

  21. D.C. Duffy, J.C. McDonald, O.J. Schueller, A., and G.M. Whitesides. Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal. Chem., 70:4974–4984, 1998.

    Article  Google Scholar 

  22. A. Folch and M. Toner. Microengineering of cellular interactions. Annual Review of Biomedical Engineering, 2:227-+, 2000.

    Article  Google Scholar 

  23. A. Folch and M. Toner. Cellular micropatterns on biocompatible materials. Biotechnology Progress, 14(3):388–392, 1998.

    Article  Google Scholar 

  24. A.Y. Fu, C. Spence et al. A microfabricated fluorescence-activated cell sorter. Nat. Biotechnol., 17(11):1109–1111, 1999.

    Article  Google Scholar 

  25. B.S. Gallardo, V.K. Gupta et al. ELectrochemical principles for active control of liquids on submillimeter scales. Science, 283(5398):57–60, 1999.

    Article  Google Scholar 

  26. B.D. Gates and G.M. Whitesides. Replication of vertical features smaller than 2 nm by soft lithography. J. Am. Chem. Soc., 125(49):14986–14987, 2003.

    Article  Google Scholar 

  27. I. German and R.T. Kennedy. Reversed-phase capillary liquid chromatography coupled on-line to capillary electrophoresis immunoassays. Anal Chem., 72(21):5365–5372, 1 Nov. 2000.

    Article  Google Scholar 

  28. J.T. Groves, S.G. Boxer et al. Electric Field-Induced Reorganization of Two-component Supported Bilayer Membranes. Proceedings of the National Academy of Sciences of the United States of America 94(25): pp. 13390–13395, 1997.

    Article  Google Scholar 

  29. J.T. Groves, N. Ulman et al. Micropatterning fluid lipid bilayers on solid supports. Science, 275(5300):651–653, 1997.

    Article  Google Scholar 

  30. A. Hatch, E. Garcia et al. Diffusion-based Analysis of Molecular Interactions in Microfluidic Devices. Proceedings of the Ieee, 92(1):126–139, 2004.

    Article  Google Scholar 

  31. A. Hatch, A.E. Kamholz et al.Arapid diffusion immunoassay in aT-sensor. Nature Biotechnology, 19(5):461–465, 2001.

    Article  Google Scholar 

  32. R.A. Hayes and B.J. Feenstra.Video-speed electronic paper based on electrowetting. Nature, 425(6956):383–385, 2003.

    Article  Google Scholar 

  33. M.A. Hayes, T.N. Polson, A.N. Phayre, and A.A. Garcia. Flow-based microimmunoassay. Anal. Chem., 73(24):5896–5902, 15 Dec. 2001.

    Google Scholar 

  34. H. Hisamoto, T. Saito, M. Tokeshi, A. Hibara, and T. Kitamori. Fast and high conversion phase-transfer synthesis exploiting the liquid-liquid interface formed in a microchannel chip. Chemical Communications 24:2662–2663, 2001.

    Article  Google Scholar 

  35. D. Huh, A.H. Tkaczyk et al. Reversible switching of high-speed air-liquid two-phase flows using electrowetting-assisted flow-pattern change. J. Am. Chem. Soc., 125(48):14678–14679, 2003.

    Article  Google Scholar 

  36. D. Huh, Y.C. Tung et al. Use of air-liquid two-phase flowin hydrophobic microfluidic channels for disposable flow cytometers. Biomedical Microdevices, 4(2):141–149, 2002.

    Article  Google Scholar 

  37. D. Huh, H.H. Wei et al. Development of Stable and Tunable High-Speed Liquid Jets in Microscale for Miniaturized and Disposable Flow Cytometry. Proceedings of 2nd IEEE-EMBS Special Topics Conference on Microtechnologies in Medicine & Biology: pp. 449–452, 2002.

    Google Scholar 

  38. R.F. Ismagilov, A.D. Stroock et al. Experimental and theoretical scaling laws for transverse diffusive broadening in two-phase laminar flows in microchannels. App. Phys. Lett., 76(17):2376–2378, 2000.

    Article  Google Scholar 

  39. K.F. Jensen. Microchemical systems: Status, challenges, and opportunities. Aiche J., 45(10):2051–2054, 1999.

    Article  Google Scholar 

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

    Google Scholar 

  41. X. Jiang, J.M. Ng, A.D. Stroock, S.K. Dertinger, and G.M. Whitesides. A miniaturized, parallel, serially diluted immunoassay for analyzing multiple antigens. J. Am. Chem. Soc., 125(18):5294–5295, 7 May 2003.

    Article  Google Scholar 

  42. T.J. Johnson, D. Ross et al. Rapid microfluidic mixing. Anal. Chem., 74(1):45–51, 2002.

    Article  Google Scholar 

  43. P.J.A. Kenis, R.F. Ismagilov et al. Microfabrication inside capillaries using multiphase laminar flow patterning. Science, 285(5424):83–85, 1999.

    Article  Google Scholar 

  44. L.B. Koutny, D. Schmalzing, T.A. Taylor, and M. Fuchs. Microchip electrophoretic immunoassay for serum cortisol. Anal. Chem., 68(1):18–22, 1 Jan 1996.

    Article  Google Scholar 

  45. K. Kurokawa, N. Mochizuki, Y. Ohba, H. Mizuno, A. Miyawaki, and M. Matsuda. A pair of fluorescent resonance energy transfer-based probes for tyrosine phosphorylation of the Crk11 adaptor protein in vivo. J. Biol. Chem., 276:31305–31310, 2001.

    Article  Google Scholar 

  46. P. Lam, K.J. Wynne et al. Surface-tension-confined microfluidics. Langmuir, 18(3):948–951, 2002.

    Article  Google Scholar 

  47. J. Lee, H. Moon et al. Electrowetting and electrowetting-on-dielectric for microscale liquid handling. Sensors and Actuators a-Physical 95(2–3):259–268, 2002.

    Article  Google Scholar 

  48. P.C.H. Li and D.J. Harrison. Transport, manipulation, and reaction of biological cells on-chip using electrokinetic effects. Anal. Chem. 69(8):1564–1568, 1997.

    Article  Google Scholar 

  49. V. Linder, H.K. Wu et al. Rapid prototyping of 2D structures with feature sizes larger than 8 mu m. Anal. Chem. 75(10):2522–2527, 2003.

    Article  Google Scholar 

  50. J.C., W.D. Love, H.O. Jacobs, and G.M. Whitesides. Microscope projection photolithography for rapid prototyping of masters with micron-scale features for use in soft lithography. Langmuir, 17:6005–6012, 2001.

    Article  Google Scholar 

  51. M. Madou. Fundamentals of Microfabrication, 2002.

    Google Scholar 

  52. J. McDonald, D.C. Duffy, J.R., D.T., C., H.W. Anderson, O.J. Schueller, G.M. Whitesides. Fabrication of microfluidic system in poly(dimethysiloxane). Electrophoresis, 21:27–40, 2000.

    Article  Google Scholar 

  53. J.C. McDonald and G.M. Whitesides. Poly(dimethylsiloxane) as a material for fabricating microfluidic devices. Accounts of Chemical Research, 35(7):491–499, 2002.

    Article  Google Scholar 

  54. R. Miyake, H. Ohki et al. Investigation of sheath flow chambers for flow cytometers—(Micro machined flow chamber with low pressure loss). Jsme Int. J. Series B-Fluids and Thermal Eng. 40(1):106–113, 1997.

    Google Scholar 

  55. R. Miyake, H. Ohki et al. Flow cytometric analysis by using micro-machined flow chamber. Jsme Int. J. Series B-Fluids and Thermal Eng., 43(2):219–224, 2000.

    Google Scholar 

  56. N. Mochizuki, S. Yamashita, K. Kurokawa, Y. Ohba, T. Nagai, A. Miyawaki, and M. Matsuda. Spatiotemporal images of growth-factor-induced activation of Ras and Rap1. Nature, 411:1065–1068, 2001.

    Article  Google Scholar 

  57. P. Paik, V.K. Pamula et al. Electrowetting-based droplet mixers for microfluidic systems. Lab on a Chip, 3(1):28–33, 2003.

    Article  Google Scholar 

  58. A. Papra, A. Bernard et al. Microfluidic networks made of poly(dimethylsiloxane), Si, and Au coated with polyethylene glycol for patterning proteins onto surfaces. Langmuir, 17(13):4090–4095, 2001.

    Article  Google Scholar 

  59. M.G. Pollack, R.B. Fair et al. Electrowetting-based actuation of liquid droplets for microfluidic applications. App. Phys. Lett., 77(11):1725–1726, 2000.

    Article  Google Scholar 

  60. A.R. Reynolds, C. Tischer, P.J. Verveer, O. Rocks, and P.I. Bastiaens. EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation. Nat. Cell Biol., 5(5):447–453, May 2003.

    Article  Google Scholar 

  61. M. Roberts and R.A. Durst. Investigation of liposome based immunomigration sensor for the detection of polychlorinated-biphenyls. Anal. Chem., 67:482–491, 1995.

    Article  Google Scholar 

  62. P. Roos and C.D. Skinner. A two bead immunoassay in a micro fluidic device using a flat laser intensity profile for illumination. Analyst., 128(6):527–531, Jun 2003.

    Article  Google Scholar 

  63. J. Rossier and H.H. Girault. Enzyme linked immunosorbent assay on a microchip with electrochemical detection. Lab on a chip, 1:153–157, 2001.

    Article  Google Scholar 

  64. K. Sato, A. Hibara et al. Microchip-based chemical and biochemical analysis systems. Advanced Drug Delivery Reviews, 55(3):379–391, 2003.

    Article  Google Scholar 

  65. K. Sato, A. Hibara, M. Tokeshi, H. Hisamoto, and T. Kitamori. Integration of chemical and biochemical analysis systems into a glass microchip. Analytical Sciences, 19:15–22, 2003.

    Article  Google Scholar 

  66. A. Sawano, S. Takayama, M. Matsuda, and A. Miyawaki. Lateral propagation of EGF signaling after local stimulation is dependent on receptor density. Developmental Cell, 3:245–257, 2002.

    Article  Google Scholar 

  67. J.A. Schwartz, J.V. Vykoukal et al. Droplet-based chemistry on a programmable micro-chip. Lab on a Chip, 4(1):11–17, 2004.

    Article  Google Scholar 

  68. P.V. Schwartz. Meniscus force nanografting: Nanoscopic patterning of DNA. Langmuir, 17(19):5971–5977, 2001.

    Article  Google Scholar 

  69. B. Schweitzer, S. Wiltshire, J. Lambert, S. O’Malley, K. Kukanskis, Z. Zhu, and S.F. Kingsmore. Inaugural article: immunoassays with rolling circle DNA amplification: a versatile platform for ultrasensitive antigen detection. Proc. Natl. Acad. Sci. USA, 97(18):10113–10119, 29 Aug 2000.

    Article  Google Scholar 

  70. B. Schweitzer, S. Roberts, B. Grimwade, W. Shao, M. Wang, Q. Fu, Q. Shu, I. Laroche I, Z. Zhou, V.T. Tchernev, J. Christiansen, M. Velleca, S.F. Kingsmore, P.M. Lizardi, and D.C. Ward. Multiplexed protein profiling on microarrays by rolling-circle amplification. Nat. Biotechnol., 20(4):359–365, Apr. 2002.

    Article  Google Scholar 

  71. H.M. Shapiro. Practical Flow Cytometry. New York, Wiley-Liss, 1995.

    Google Scholar 

  72. J. Shim, T.F. Bersano-Begey, X. Zhu, A.H. Tkaczyk, J.J. Linderman, and S. Takayama. Micro-and Nanotechnologies for studying cellular function. Current Topics in Medicinal Chemistry, 3:687–703, 2003.

    Article  Google Scholar 

  73. S.K. Sia and G.M. Whitesides. Microfluidic devices fabricated in poly(dimethylsiloxane) for biological studies. Electrophoresis, 24(21):3563–3576, 2003.

    Article  Google Scholar 

  74. D. Sobek, A.M. Young et al. A Microfabricated Flow Chamber for Optical Measurement in Fluids. Proceedings of MEMS’ 93: pp. 219–224, 1993.

    Google Scholar 

  75. H.A. Stone and S. Kim. Microfluidics: Basic issues, applications, and hallenges. Aiche J., 47(6):1250–1254, 2001.

    Article  Google Scholar 

  76. A.D. Stroock, S.K.W. Dertinger et al. Chaotic mixer for microchannels. Science, 295(5555):647–651, 2002.

    Article  Google Scholar 

  77. A.D. Stroock, M. Weck et al. Patterning electro-osmotic flowwith patterned surface charge (vol. 84, pg. 3314, 2000). Phys. Rev. Lett., 86(26):6050–6050, 2001.

    Google Scholar 

  78. A.D. Stroock and G.M. Whitesides. Controlling flows in microchannels with patterned surface charge and topography. Acc. Chem. Res. 36(8):597–604, 2003.

    Article  Google Scholar 

  79. S.A. Sundberg. High-throughput and ultra-high-throughput screening: solution-and cell-based approaches. Curr. Opin. Biotechnol. 11(1):47–53, 2000.

    Article  Google Scholar 

  80. S. Takayama, J.C. McDonald et al. Patterning cells and their Environments using Multiple Laminar Fluid Flows in Capillary Networks. Proceedings of the National Academy of Sciences of the United States of America 96(10): pp. 5545–5548, 1999.

    Article  Google Scholar 

  81. S. Takayama, E. Ostuni et al. Laminar flows—Subcellular positioning of small molecules. Nature, 411(6841):1016–1016, 2001.

    Article  Google Scholar 

  82. S. Takayama, E. Ostuni et al. Selective chemical treatment of cellular microdomains using multiple laminar streams. Chem. Biol., 10(2):123–130, 2003.

    Article  Google Scholar 

  83. S. Takayama, E. Ostuni et al. Topographical micropatterning of poly(dimethylsiloxane) using laminar flows of liquids in capillaries. Advanc. Mater. 13(8):570-+, 2001.

    Article  Google Scholar 

  84. A.M. Taylor, S.W. Rhee et al. Microfluidic multicompartment device for neuroscience research. Langmuir, 19(5):1551–1556, 2003.

    Article  Google Scholar 

  85. M. Unger, H.P. Chou, T. Thorsen, A. Scherer, and S.R. Quake. Monolithic microfabricated valves and pumps by multilayer soft lithography. Science, 288(5463):113–116, 2000.

    Article  Google Scholar 

  86. F. von Heeren, E. Verpoorte, A. Manz, and W. Thormann. Micellar electrokinetic chromatography separations and analyses of biological samples on a cyclic planar microstructure. Anal. Chem., 68(13):2044–2053, 1 Jul. 1996.

    Google Scholar 

  87. A. van Oudenaarden and S.G. Boxer. Brownian ratchets: Molecular separations in lipid bilayers supported on patterned arrays. Science, 285(5430):1046–1048, 1999.

    Article  Google Scholar 

  88. B.H. Weigl and P. Yager. Microfluidics—Microfluidic diffusion-based separation and detection. Science, 283(5400):346–347, 1999.

    Article  Google Scholar 

  89. G.M. Whitesides, E. Ostuni et al. Soft lithography in biology and biochemistry. Annual Review of Biomedical Engineering, 3:335–373, 2001.

    Article  Google Scholar 

  90. H. Wu, T.W. Odom, D.T. Chiu, and G.M. Whitesides. Fabrication of complex three-dimensional microchannel systems in PDMS. J. Am. Chem. Soc., 125(2):554–559, 2003.

    Article  Google Scholar 

  91. T.L. Yang, E.E. Simanek et al. Creating addressable aqueous microcompartments above solid supported phospholipid bilayers using lithographically patterned poly(dimethylsiloxane) molds. Anal. Chem., 72(11):2587–2589, 2000.

    Article  Google Scholar 

  92. B. Zhao, J.S. Moore et al. Surface-directed liquid flowinside microchannels. Science, 291(5506):1023–1026, 2001.

    Article  Google Scholar 

  93. B. Zhao, J.S. Moore et al. Principles of surface-directed liquid flow in microfluidic channels. Anal. Chem. 74(16):4259–4268, 2002.

    Article  Google Scholar 

  94. B. Zhao, N.O.L. Viernes et al. Control and applications of immiscible liquids in microchannels. J. Am. Chem. Soc., 124(19):5284–5285, 2002.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Kamotani, Y., Huh, D., Futai, N., Takayama, S. (2006). At the Interface: Advanced Microfluidic Assays for Study of Cell Function. In: Ferrari, M., Desai, T., Bhatia, S. (eds) BioMEMS and Biomedical Nanotechnology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-25844-7_4

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-25844-7_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-25565-1

  • Online ISBN: 978-0-387-25844-7

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics