Annals of Biomedical Engineering

, Volume 38, Issue 6, pp 2056–2067 | Cite as

Current Application of Micro/Nano-Interfaces to Stimulate and Analyze Cellular Responses

  • Yoon-Kyoung Cho
  • Heungjoo Shin
  • Sung Kuk Lee
  • Taesung Kim


Microfabrication technologies have a high potential for novel approaches to access living cells at a cellular or even at a molecular level. In the course of reviewing and discussing the current application of microinterface systems including nanointerfaces to stimulate and analyze cellular responses with subcellular resolution, this article focuses on interfaces based on microfluidics, nanoparticles, and scanning electrochemical microscopy (SECM). Micro/nanointerface systems provide a novel, attractive means for cell study because they are capable of regulating and monitoring cellular signals simultaneously and repeatedly, leading us to an enhanced understanding and interpretation of cellular responses. Therefore, it is hoped that the integrated micro/nanointerfaces presented in this review will contribute to future developments of cell biology and facilitate advanced biomedical applications.


Micro/nanointerfaces Microfabrication Microfluidics Nanoparticles Scanning electrochemical microscopy Interfacing biology 



This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) (2009-0076534), and WCU (World Class University) program through the NRF of Korea funded by the MEST (R32-2008-000-20054-0).


  1. 1.
    Abbou, J., C. Demaille, M. Druet, and J. Moiroux. Fabrication of submicrometer-sized gold electrodes of controlled geometry for scanning electrochemical-atomic force microscopy. Anal. Chem. 74:6355–6363, 2002.CrossRefPubMedGoogle Scholar
  2. 2.
    Altinoglu, E. I., T. J. Russin, J. M. Kaiser, B. M. Barth, P. C. Eklund, M. Kester, and J. H. Adair. Near-infrared emitting fluorophore-doped calcium phosphate nanoparticles for in vivo imaging of human breast cancer. ACS Nano 2:2075–2084, 2008.CrossRefPubMedGoogle Scholar
  3. 3.
    Ashe, H. L., and J. Briscoe. The interpretation of morphogen gradients. Development 133:385–394, 2006.CrossRefPubMedGoogle Scholar
  4. 4.
    Atencia, J., J. Morrow, and L. E. Locascio. The microfluidic palette: a diffusive gradient generator with spatio-temporal control. Lab Chip 9:2707–2714, 2009.CrossRefPubMedGoogle Scholar
  5. 5.
    Balaban, N. Q., J. Merrin, R. Chait, L. Kowalik, and S. Leibler. Bacterial persistence as a phenotypic switch. Science 305:1622–1625, 2004.CrossRefPubMedGoogle Scholar
  6. 6.
    Bard, A. J., F. R. F. Fan, J. Kwak, and O. Lev. Scanning electrochemical microscopy—introduction and principles. Anal. Chem. 61:132–138, 1989.CrossRefGoogle Scholar
  7. 7.
    Bard, A. J., X. Li, and W. Zhan. Chemically imaging living cells by scanning electrochemical microscopy. Biosens. Bioelectron. 22:461–472, 2006.CrossRefPubMedGoogle Scholar
  8. 8.
    Bennett, M. R., and J. Hasty. Modelling microfluidic devices for measuring gene network dynamics in single cells. Nat. Rev. Genet. 10:628–638, 2009.CrossRefPubMedGoogle Scholar
  9. 9.
    Boedicker, J. Q., M. E. Vincent, and R. F. Ismagilov. Microfluidic confinement of single cells of bacteria in small volumes initiates high-density behavior of quorum sensing and growth and reveals its variability. Angew. Chem. Int. Ed. 48:5908–5911, 2009.CrossRefGoogle Scholar
  10. 10.
    Brehm-Stecher, B. F., and E. A. Johnson. Single-cell microbiology: tools, technologies, and applications. Microbiol. Mol. Biol. Rev. 68:538–559, 2004.CrossRefPubMedGoogle Scholar
  11. 11.
    Carano, M., K. B. Holt, and A. J. Bard. Scanning electrochemical microscopy. 49. Gas-phase scanning electrochemical microscopy measurements with a clark oxygen ultramicroelectrode. Anal. Chem. 75:5071–5079, 2003.CrossRefGoogle Scholar
  12. 12.
    Chen, Z., S. B. Xie, L. Shen, Y. Du, S. L. He, Q. Li, Z. W. Liang, X. Meng, B. Li, X. D. Xu, H. W. Ma, Y. Y. Huang, and Y. H. Shao. Investigation of the interactions between silver nanoparticles and Hela cells by scanning electrochemical microscopy. Analyst 133:1221–1228, 2008.CrossRefPubMedGoogle Scholar
  13. 13.
    Chithrani, B. D., A. A. Ghazani, and W. C. W. Chan. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 6:662–668, 2006.CrossRefPubMedGoogle Scholar
  14. 14.
    Chueh, B. H., D. G. Huh, C. R. Kyrtsos, T. Houssin, N. Futai, and S. Takayama. Leakage-free bonding of porous membranes into layered microfluidic array systems. Anal. Chem. 79:3504–3508, 2007.CrossRefPubMedGoogle Scholar
  15. 15.
    Chung, B. G., L. A. Flanagan, S. W. Rhee, P. H. Schwartz, A. P. Lee, E. S. Monuki, and N. L. Jeon. Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab Chip 5:401–406, 2005.CrossRefPubMedGoogle Scholar
  16. 16.
    Ciobanu, M., D. E. Taylor, J. P. Wilburn, and D. E. Cliffel. Glucose and lactate biosensors for scanning electrochemical microscopy imaging of single live cells. Anal. Chem. 80:2717–2727, 2008.CrossRefPubMedGoogle Scholar
  17. 17.
    Davis, M. E., Z. Chen, and D. M. Shin. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7:771–782, 2008.CrossRefPubMedGoogle Scholar
  18. 18.
    Davoodi, A., J. Pan, C. Leygraf, and S. Norgren. Integrated AFM and SECM for in situ studies of localized corrosion of Al alloys. Electrochim. Acta 52:7697–7705, 2007.CrossRefGoogle Scholar
  19. 19.
    Dertinger, S. K. W., D. T. Chiu, N. L. Jeon, and G. M. Whitesides. Generation of gradients having complex shapes using microfluidic networks. Anal. Chem. 73:1240–1246, 2001.CrossRefGoogle Scholar
  20. 20.
    Diakowski, P. M., and Z. F. Ding. Interrogation of living cells using alternating current scanning electrochemical microscopy (AC-SECM). Phys. Chem. Chem. Phys. 9:5966–5974, 2007.CrossRefPubMedGoogle Scholar
  21. 21.
    Dobson, P. S., J. M. R. Weaver, D. P. Burt, M. N. Holder, N. R. Wilson, P. R. Unwin, and J. V. Macpherson. Electron beam lithographically-defined scanning electrochemical-atomic force microscopy probes: fabrication method and application to high resolution imaging on heterogeneously active surfaces. Phys. Chem. Chem. Phys. 8:3909–3914, 2006.CrossRefPubMedGoogle Scholar
  22. 22.
    El-Ali, J., P. K. Sorger, and K. F. Jensen. Cells on chips. Nature 442:403–411, 2006.CrossRefPubMedGoogle Scholar
  23. 23.
    Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nat. Rev. Cancer 5:161–171, 2005.CrossRefPubMedGoogle Scholar
  24. 24.
    Frasch, M., T. Hoey, C. Rushlow, H. Doyle, and M. Levine. Characterization and localization of the even-skipped protein of Drosophila. EMBO J. 6:749–759, 1987.PubMedGoogle Scholar
  25. 25.
    Gao, N., X. L. Wang, L. Li, X. L. Zhang, and W. R. Jin. Scanning electrochemical microscopy coupled with intracellular standard addition method for quantification of enzyme activity in single intact cells. Analyst 132:1139–1146, 2007.CrossRefPubMedGoogle Scholar
  26. 26.
    Ghim, C.-M., T. Kim, R. J. Mitchell, and S. K. Lee. Synthetic biology for biofuels: building designer microbes from the scratch. Biotechnol. Bioprocess Eng. 15, 2010. doi: 10.1007/s12257-009-3065-5.
  27. 27.
    Gullo, M. R., P. L. T. M. Frederix, T. Akiyama, A. Engel, N. F. deRooij, and U. Staufer. Characterization of microfabricated probes for combined atomic force and high-resolution scanning electrochemical microscopy. Anal. Chem. 78:5436–5442, 2006.CrossRefPubMedGoogle Scholar
  28. 28.
    Gurdon, J. B., and P. Y. Bourillot. Morphogen gradient interpretation. Nature 413:797–803, 2001.CrossRefPubMedGoogle Scholar
  29. 29.
    Guzman, L. M., D. Belin, M. J. Carson, and J. Beckwith. Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD Promoter. J. Bacteriol. 177:4121–4230, 1995.PubMedGoogle Scholar
  30. 30.
    Hatch, A., A. E. Kamholz, K. R. Hawkins, M. S. Munson, E. A. Schilling, B. H. Weigl, and P. Yager. A rapid diffusion immunoassay in a T-sensor. Nat. Biotechnol. 19:461–465, 2001.CrossRefPubMedGoogle Scholar
  31. 31.
    Hauck, T. S., A. A. Ghazani, and W. C. W. Chan. Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small 4:153–159, 2008.CrossRefPubMedGoogle Scholar
  32. 32.
    Helmke, B. P., and A. R. Minerick. Designing a nano-interface in a microfluidic chip to probe living cells: challenges and perspectives. Proc. Natl Acad. Sci. USA 103:6419–6424, 2006.CrossRefPubMedGoogle Scholar
  33. 33.
    Honda, A., H. Komatsu, D. Kato, A. Ueda, K. Maruyama, Y. Iwasaki, T. Ito, O. Niwa, and K. Suzuki. Newly developed chemical probes and nano-devices for cellular analysis. Anal. Sci. 24:55–66, 2008.CrossRefPubMedGoogle Scholar
  34. 34.
    Irimia, D., and M. Toner. Spontaneous migration of cancer cells under conditions of mechanical confinement. Integr. Biol. 1:506–512, 2009.CrossRefGoogle Scholar
  35. 35.
    Ismagilov, R. F., and M. M. Maharbiz. Can we build synthetic, multicelullar systems by controlling developmental signaling in space and time? Curr. Opin. Chem. Biol. 11:604–611, 2007.CrossRefPubMedGoogle Scholar
  36. 36.
    Jeon, N. L., H. Baskaran, S. K. W. Dertinger, G. M. Whitesides, L. Van de Water, and M. Toner. Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nat. Biotechnol. 20:826–830, 2002.Google Scholar
  37. 37.
    Jeon, N. L., S. K. W. Dertinger, D. T. Chiu, I. S. Choi, A. D. Stroock, and G. M. Whitesides. Generation of solution and surface gradients using microfluidic systems. Langmuir 16:8311–8316, 2000.CrossRefGoogle Scholar
  38. 38.
    Jiang, W., B. Y. S. Kim, J. T. Rutka, and W. C. W. Chan. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotechnol. 3:145–150, 2008.CrossRefPubMedGoogle Scholar
  39. 39.
    Katemann, B. B., A. Schulte, and W. Schuhmann. Constant-distance mode scanning electrochemical microscopy (SECM). Part I. Adaptation of a non-optical shear-force-based positioning mode for SECM tips. Chem. Eur. J. 9:2025–2033, 2003.CrossRefGoogle Scholar
  40. 40.
    Keenan, T. M., and A. Folch. Biomolecular gradients in cell culture systems. Lab Chip 8:34–57, 2008.CrossRefPubMedGoogle Scholar
  41. 41.
    Kim, T., M. Pinelis, and M. M. Maharbiz. Generating steep, shear-free gradients of small molecules for cell culture. Biomed. Microdevices 11:65–73, 2009.CrossRefPubMedGoogle Scholar
  42. 42.
    King, K. R., S. Wang, A. Jayaraman, M. L. Yarmush, and M. Toner. Microfluidic flow-encoded switching for parallel control of dynamic cellular microenvironments. Lab Chip 8:107–116, 2008.CrossRefPubMedGoogle Scholar
  43. 43.
    Kranz, C., G. Friedbacher, and B. Mizaikoff. Integrating an ultramicroelectrode in an AFM cantilever: combined technology for enhanced information. Anal. Chem. 73:2491–3500, 2001.CrossRefPubMedGoogle Scholar
  44. 44.
    Kueng, A., C. Kranz, A. Lugstein, E. Bertagnolli, and B. Mizaikoff. AFM-tip-integrated amperometric microbiosensors: high-resolution imaging of membrane transport. Angew. Chem. Int. Ed. 44:3419–3422, 2005.CrossRefGoogle Scholar
  45. 45.
    Kueng, A., C. Kranz, and B. Mizaikoff. Imaging of ATP membrane transport with dual micro-disk electrodes and scanning electrochemical microscopy. Biosens. Bioelectron. 21:346–353, 2005.CrossRefPubMedGoogle Scholar
  46. 46.
    Lander, A. D. Morpheus unbound: reimagining the morphogen gradient. Cell 128:245–256, 2007.CrossRefPubMedGoogle Scholar
  47. 47.
    Laurent, S., D. Forge, M. Port, A. Roch, C. Robic, L. V. Elst, and R. N. Muller. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev. 108:2064–2110, 2008.CrossRefPubMedGoogle Scholar
  48. 48.
    Lee, S. K., H. H. Chou, B. F. Pfleger, J. D. Newman, Y. Yoshikuni, and J. D. Keasling. Directed evolution of Arac for improved compatibility of arabinose- and lactose-inducible promoters. Appl. Environ. Microbiol. 73:5711–5715, 2007.CrossRefPubMedGoogle Scholar
  49. 49.
    Lee, Y., Z. F. Ding, and A. J. Bard. Combined scanning electrochemical/optical microscopy with shear force and current feedback. Anal. Chem. 74:3634–3643, 2002.CrossRefPubMedGoogle Scholar
  50. 50.
    Lee, Y.-E. K., R. Smith, and R. Kopelman. Nanoparticle pebble sensors in live cells and in vivo. Annu. Rev. Anal. Chem. 2:57–76, 2009.PubMedCrossRefGoogle Scholar
  51. 51.
    Li, K., J. Pan, S.-S. Feng, A. W. Wu, K.-Y. Pu, Y. Liu, and B. Liu. Generic strategy of preparing fluorescent conjugated-polymer-loaded Poly(dl-lactide-co-Glycolide) nanoparticles for targeted cell imaging. Adv. Funct. Mater. 19:3535–3542, 2009.CrossRefGoogle Scholar
  52. 52.
    Lucchetta, E. M., J. H. Lee, L. A. Fu, N. H. Patel, and R. F. Ismagilov. Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics. Nature 434:1134–1138, 2005.CrossRefPubMedGoogle Scholar
  53. 53.
    Lucchetta, E. M., M. S. Munson, and R. F. Ismagilov. Characterization of the local temperature in space and time around a developing Drosophila embryo in a microfluidic device. Lab Chip 6:185–190, 2006.CrossRefPubMedGoogle Scholar
  54. 54.
    Macpherson, J. V., and P. R. Unwin. Noncontact electrochemical imaging with combined scanning electrochemical atomic force microscopy. Anal. Chem. 73:550–557, 2001.CrossRefPubMedGoogle Scholar
  55. 55.
    Macpherson, J. V., P. R. Unwin, A. C. Hillier, and A. J. Bard. In-situ imaging of ionic crystal dissolution using an integrated electrochemical/AFM probe. J. Am. Chem. Soc. 118:6445–6452, 1996.CrossRefGoogle Scholar
  56. 56.
    Martin-Orozco, N., N. Touret, M. L. Zaharik, E. Park, R. Kopelman, S. Miller, B. B. Finlay, P. Gros, and S. Grinstein. Visualization of vacuolar acidification-induced transcription of genes of pathogens inside macrophages. Mol. Biol. Cell 17:498–510, 2006.CrossRefPubMedGoogle Scholar
  57. 57.
    Meyvantsson, I., and D. J. Beebe. Cell culture models in microfluidic systems. Annu. Rev. Anal. Chem. 1:423–449, 2008.CrossRefGoogle Scholar
  58. 58.
    Paguirigan, A. L., and D. J. Beebe. From the cellular perspective: exploring differences in the cellular baseline in macroscale and microfluidic cultures. Integr. Biol. 1:182–195, 2009.CrossRefGoogle Scholar
  59. 59.
    Park, J., T. Bansal, M. Pinelis, and M. M. Maharbiz. A microsystem for sensing and patterning oxidative microgradients during cell culture. Lab Chip 6:611–622, 2006.CrossRefPubMedGoogle Scholar
  60. 60.
    Park, E. J., M. Brasuel, C. Behrend, M. A. Philbert, and R. Kopelman. Ratiometric optical pebble nanosensors for real-time magnesium ion concentrations inside viable cells. Anal. Chem. 75:3784–3791, 2003.CrossRefPubMedGoogle Scholar
  61. 61.
    Parthasarathy, M., S. Singh, S. Hazra, and V. K. Pillai. Imaging the stomatal physiology of somatic embryo-derived peanut leaves by scanning electrochemical microscopy. Anal. Bioanal. Chem. 391:2227–2233, 2008.CrossRefPubMedGoogle Scholar
  62. 62.
    Rao, J. Shedding light on tumors using nanoparticles. ACS Nano 2:1984–1986, 2008.CrossRefPubMedGoogle Scholar
  63. 63.
    Saadi, W., S. J. Wang, F. Lin, and N. L. Jeon. A parallel-gradient microfluidic chamber for quantitative analysis of breast cancer cell chemotaxis. Biomed. Microdevices 8:109–118, 2006.CrossRefPubMedGoogle Scholar
  64. 64.
    Schrock, D. S., and J. E. Baur. Chemical imaging with voltammetry-scanning microscopy. Anal. Chem. 79:7053–7061, 2007.CrossRefPubMedGoogle Scholar
  65. 65.
    Schrock, D. S., D. O. Wipf, and J. E. Baur. Feedback effects in combined fast-scan cyclic voltammetry-scanning electrochemical microscopy. Anal. Chem. 79:4931–4941, 2007.CrossRefPubMedGoogle Scholar
  66. 66.
    Schulte, A., and W. Schuhmann. Single-cell microelectrochemistry. Angew. Chem. Int. Ed. 46:8760–8777, 2007.CrossRefGoogle Scholar
  67. 67.
    Shiku, H., M. Takeda, T. Murata, U. Akiba, F. Hamada, and T. Matsue. Development of electrochemical reporter assay using Hela cells transfected with vector plasmids encoding various responsive elements. Anal. Chim. Acta 640:87–92, 2009.CrossRefPubMedGoogle Scholar
  68. 68.
    Shin, H., P. J. Hesketh, B. Mizaikofff, and C. Kranz. Development of wafer-level batch fabrication for combined atomic force-scanning electrochemical microscopy (AFM-SECM) probes. Sens. Actuators B Chem. 134:488–495, 2008.CrossRefGoogle Scholar
  69. 69.
    Siegele, D. A., and J. C. Hu. Gene expression from plasmids containing the araBAD promoter at subsaturating inducer concentrations represents mixed populations. Proc. Natl Acad. Sci. USA 94:8168–8172, 1997.CrossRefPubMedGoogle Scholar
  70. 70.
    Sun, P., F. O. Laforge, and M. V. Mirkin. Scanning electrochemical microscopy in the 21st century. Phys. Chem. Chem. Phys. 9:802–823, 2007.CrossRefPubMedGoogle Scholar
  71. 71.
    Takahashi, Y., T. Miyamoto, H. Shiku, R. Asano, T. Yasukawa, I. Kumagai, and T. Matsue. Electrochemical detection of epidermal growth factor receptors on a single living cell surface by scanning electrochemical microscopy. Anal. Chem. 81:2785–2790, 2009.CrossRefPubMedGoogle Scholar
  72. 72.
    Takayama, S., E. Ostuni, P. LeDuc, K. Naruse, D. E. Ingber, and G. M. Whitesides. Laminar flows-subcellular positioning of small molecules. Nature 411:1016, 2001.CrossRefPubMedGoogle Scholar
  73. 73.
    Tholouli, E., E. Sweeney, E. Barrow, V. Clay, J. A. Hoyland, and R. J. Byers. Quantum dots light up pathology. J. Pathol. 216:275–285, 2008.CrossRefPubMedGoogle Scholar
  74. 74.
    Torisawa, Y. S., B. H. Chueh, D. Huh, P. Ramamurthy, T. M. Roth, K. F. Barald, and S. Takayama. Efficient formation of uniform-sized embryoid bodies using a compartmentalized microchannel device. Lab Chip 7:770–776, 2007.CrossRefPubMedGoogle Scholar
  75. 75.
    Torisawa, Y. S., B. Mosadegh, G. D. Luker, M. Morell, K. S. O’Shea, and S. Takayama. Microfluidic hydrodynamic cellular patterning for systematic formation of co-culture spheroids. Integr. Biol. 1:649–654, 2009.CrossRefGoogle Scholar
  76. 76.
    Torisawa, Y. S., N. Ohara, K. Nagamine, S. Kasai, T. Yasukawa, H. Shiku, and T. Matsue. Electrochemical monitoring of cellular signal transduction with a secreted alkaline phosphatase reporter system. Anal. Chem. 78:7625–7631, 2006.CrossRefPubMedGoogle Scholar
  77. 77.
    Tyner, K. M., R. Kopelman, and M. A. Philbert. “Nanosized voltmeter” enables cellular-wide electric field mapping. Biophys. J. 93:1163–1174, 2007.CrossRefPubMedGoogle Scholar
  78. 78.
    Yasukawa, T., T. Kaya, and T. Matsue. Characterization and imaging of single cells with scanning electrochemical microscopy. Electroanalysis 12:653–659, 2000.CrossRefGoogle Scholar
  79. 79.
    Zhan, D. P., X. Li, W. Zhan, F. R. F. Fan, and A. J. Bard. Scanning electrochemical microscopy. 58. Application of a micropipet-supported ITIES tip to detect Ag+ and study its effect on fibroblast cells. Anal. Chem. 79:5225–5231, 2007.CrossRefPubMedGoogle Scholar
  80. 80.
    Zhu, L. L., N. Gao, X. L. Zhang, and W. R. Jin. Accurately measuring respiratory activity of single living cells by scanning electrochemical microscopy. Talanta 77:804–808, 2008.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2010

Authors and Affiliations

  • Yoon-Kyoung Cho
    • 1
    • 2
  • Heungjoo Shin
    • 1
    • 2
  • Sung Kuk Lee
    • 1
    • 3
  • Taesung Kim
    • 1
    • 2
  1. 1.School of Nano-Biotechnology and Chemical EngineeringUlsan National Institute of Science and Technology (UNIST)UlsanKorea
  2. 2.School of Mechanical and Advanced Materials EngineeringUlsan National Institute of Science and Technology (UNIST)UlsanKorea
  3. 3.School of Energy EngineeringUlsan National Institute of Science and Technology (UNIST)UlsanKorea

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