Cell Migration with Microfluidic Chips

  • Jinxin Dou
  • Jin-Ming Lin
Part of the Integrated Analytical Systems book series (ANASYS)


Cell migration plays important roles for a variety of physiological and pathological processes including but not limited to host defense, cancer metastasis and embryogenesis, wound healing and inflammation, most of which can be guided by diverse biochemical and biophysical factors. A detailed understanding of individual factor or integrated factors in controlled condition that induces directed cell migration is essential for studying the dynamic and complex behaviors in vivo and capable of improved tissue engineering and therapeutic strategies. Based on this, a number of in vitro assays have been developed to study the complex guiding mechanisms for cell migration. However, those assays are typically end-point detection which is limited by the inability to sustain the stimuli for a long time. Another limitation with traditional assays is high through-put detection. Recently, the design of the standard cell migration assay has incorporated microfluidic platforms, which have opened up new possibilities for exploring the migration in a better control of cellular microenvironment. Cell-attractive and cell-repellant factors involved in cell migration, single or integrated, can be precisely studied in microfluidic devices, some of which have already been developed for medical and commercial applications. In this part, we present recent developments in microfluidic-based cell migration studies and potential trends in this field.


Microfluidics Cell migration Chemotaxis Electrotaxis 


  1. 1.
    Young EW, Beebe DJ (2010) Fundamentals of microfluidic cell culture in controlled microenvironments. Chem Soc Rev 39(3):1036–1048. doi: 10.1039/b909900j CrossRefGoogle Scholar
  2. 2.
    Discher DE, Mooney DJ, Zandstra PW (2009) Growth factors, matrices, and forces combine and control stem cells. Science 324(5935):1673–1677. doi: 10.1126/science.1171643 CrossRefGoogle Scholar
  3. 3.
    Fidler IJ (2002) The organ microenvironment and cancer metastasis. Differentiation 70(70):498–505. doi: 10.1046/j.1432-0436.2002.700904.x CrossRefGoogle Scholar
  4. 4.
    Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118(Pt 21):4917–4919. doi: 10.1242/jcs.02662 CrossRefGoogle Scholar
  5. 5.
    Berzat A, Hall A (2010) Cellular responses to extracellular guidance cues. EMBO J 29(16):2734–2745. doi: 10.1038/emboj.2010.170 CrossRefGoogle Scholar
  6. 6.
    Jin T, Xu X, Hereld D (2008) Chemotaxis, chemokine receptors and human disease. Cytokine 44(1):1–8. doi: 10.1016/j.cyto.2008.06.017 CrossRefGoogle Scholar
  7. 7.
    Zhao M (2009) Electrical fields in wound healing-An overriding signal that directs cell migration. Semin Cell Dev Biol 20(6):674–682. doi: 10.1016/j.semcdb.2008.12.009 CrossRefGoogle Scholar
  8. 8.
    Campbell JJ, Butcher EC (2000) Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 12(3):336–341. doi: 10.1016/S0952-7915(00)00096-0 CrossRefGoogle Scholar
  9. 9.
    Sallusto F, Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392(6676):565–568. doi: 10.1038/33340 CrossRefGoogle Scholar
  10. 10.
    Wolf K, Wu YI, Liu Y, Geiger J, Tam E, Overall C, Stack MS, Friedl P (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9(8):893–904. doi: 10.1038/ncb1616 CrossRefGoogle Scholar
  11. 11.
    Kim HD, Guo TW, Wu AP, Wells A, Gertler FB, Lauffenburger DA (2008) Epidermal growth factor-induced enhancement of glioblastoma cell migration in 3D arises from an intrinsic increase in speed but an extrinsic matrix- and proteolysis-dependent increase in persistence. Mol Biol Cell 19(10):4249–4259. doi: 10.1091/mbc.E08-05-0501 CrossRefGoogle Scholar
  12. 12.
    Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R, Sixt M (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453(7191):51–55. doi: 10.1038/nature06887 CrossRefGoogle Scholar
  13. 13.
    Ilina O, Bakker G-J, Vasaturo A, Hoffman RM, Friedl P (2011) Two-photon laser-generated microtracks in 3D collagen lattices: principles of MMP-dependent and -independent collective cancer cell invasion. Phys Biol 8(2):029501. doi: 10.1088/1478-3975/8/2/029501 CrossRefGoogle Scholar
  14. 14.
    Roussos ET, Condeelis JS, Patsialou A (2011) Chemotaxis in cancer. Nat Rev Cancer 11(8):573–587. doi: 10.1038/nrc3078 CrossRefGoogle Scholar
  15. 15.
    Cukierman E, Bassi DE (2010) Physico-mechanical aspects of extracellular matrix influences on tumorigenic behaviors. Semin Cancer Biol 20(3):139–145. doi: 10.1016/j.semcancer.2010.04.004 CrossRefGoogle Scholar
  16. 16.
    Fraley SI, Feng Y, Krishnamurthy R, Kim DH, Celedon A, Longmore GD, Wirtz D (2010) A distinctive role for focal adhesion proteins in three-dimensional cell motility. Nat Cell Biol 12(6):598–604. doi: 10.1038/ncb2062 CrossRefGoogle Scholar
  17. 17.
    Griffith LG, Swartz MA (2006) Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol 7(3):211–224. doi: 10.1038/nrm1858 CrossRefGoogle Scholar
  18. 18.
    Patel DD, Koopmann W, Imai T, Whichard LP, Yoshie O, Krangel MS (2001) Chemokines have diverse abilities to form solid phase gradients. Clin Immunol 99(1):43–52. doi: 10.1006/clim.2000.4997 CrossRefGoogle Scholar
  19. 19.
    Petrie RJ, Doyle AD, Yamada KM (2009) Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10(8):538–549. doi: 10.1038/nrm2729 CrossRefGoogle Scholar
  20. 20.
    †PAD, Quinn JA, Albelda SM, Lauffenburger DA (1992) Measurement of individual cell migration parameters for human tissue cells. Aiche J 38(7):1092–1104. doi: 10.1002/aic.690380712
  21. 21.
    He X, Shen Y (1999) Vascular endothelial growth factor induced endothelial cell migration and proliferation depend on a nitric oxide mediated decrease in protein kinase C activity. Circ Res 85(3):247–256. doi: 10.1083/jcb.140.4.947 CrossRefGoogle Scholar
  22. 22.
    Rojas JD, Sennoune SR, Maiti D, Bakunts K, Reuveni M, Sanka SC, Martinez GM, Seftor EA, Meininger CJ, Wu G, Wesson DE, Hendrix MJ, Martinez-Zaguilan R (2006) Vacuolar-type H + -ATPases at the plasma membrane regulate pH and cell migration in microvascular endothelial cells. Am J Physiol Heart Circ Physiol 291(3):H1147–1157. doi: 10.1152/ajpheart.00166.2006 CrossRefGoogle Scholar
  23. 23.
    Sagnella SM, Kligman F, Anderson EH, King JE, Murugesan G, Marchant RE, Kottke-Marchant K (2004) Human microvascular endothelial cell growth and migration on biomimetic surfactant polymers. Biomaterials 25(7–8):1249–1259. doi: 10.1016/s0142-9612(03)00634-3 CrossRefGoogle Scholar
  24. 24.
    Boyden S (1962) The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J Exp Med 115(115):453–466. doi: 10.1084/jem.115.3.453 CrossRefGoogle Scholar
  25. 25.
    Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, Mcewan RN (1987) A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 47(47):3239–3245Google Scholar
  26. 26.
    Zigmond SH (1977) Ability of polymorphonuclear leukocytes to orient in gradients of chemotactic factors. J Cell Biol 75(75):606–616CrossRefGoogle Scholar
  27. 27.
    Zicha D, Dunn GA, Brown AF (1991) A new direct-viewing chemotaxis chamber. J Cell Sci 99(Pt 4) (4):769–775Google Scholar
  28. 28.
    Servant G, Weiner OD, Herzmark P, Balla T, Sedat JW, Bourne HR (2000) Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287(5455):1037–1040. doi: 10.1126/science.287.5455.1037 CrossRefGoogle Scholar
  29. 29.
    Wong K, Pertz O, Hahn K, Bourne H (2006) Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. Proc Natl Acad Sci U S A 103(10):3639–3644. doi: 10.1073/pnas.0600092103 CrossRefGoogle Scholar
  30. 30.
    Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2(2):329–333. doi: 10.1038/nprot.2007.30 CrossRefGoogle Scholar
  31. 31.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi: 10.1016/j.cell.2011.02.013 CrossRefGoogle Scholar
  32. 32.
    Beebe DJ, Mensing GA, Walker GM (2002) Physics and applications of microfluidics in biology. Annu Rev Biomed Eng 4:261–286. doi: 10.1146/annurev.bioeng.4.112601.125916 CrossRefGoogle Scholar
  33. 33.
    Mehling M, Tay S (2014) Microfluidic cell culture. Curr Opin Biotechnol 25:95–102. doi: 10.1016/j.copbio.2013.10.005 CrossRefGoogle Scholar
  34. 34.
    Chung BG, Choo J (2010) Microfluidic gradient platforms for controlling cellular behavior. Electrophoresis 31(18):3014–3027. doi: 10.1002/elps.201000137 CrossRefGoogle Scholar
  35. 35.
    Lohof AM, Quillan M, Dan Y, Poo MM (1992) Asymmetric modulation of cytosolic cAMP activity induces growth cone turning. J Neurosci 12(4):1253–1261Google Scholar
  36. 36.
    Nelson RD, Quie PG, Simmons RL (1975) Chemotaxis under agarose: a new and simple method for measuring chemotaxis and spontaneous migration of human polymorphonuclear leukocytes and monocytes. J Immunol 115(6):1650–1656Google Scholar
  37. 37.
    Kim S, Kim HJ, Jeon NL (2010) Biological applications of microfluidic gradient devices. Integr Biol (Camb) 2(11–12):584–603. doi: 10.1039/c0ib00055h CrossRefGoogle Scholar
  38. 38.
    Chicurel M (2002) Cell migration research is on the move. Science 295(5555):606–609. doi: 10.1126/science.295.5555.606 CrossRefGoogle Scholar
  39. 39.
    Selmeczi D, Mosler S, Hagedorn PH, Larsen NB, Flyvbjerg H (2005) Cell motility as persistent random motion: theories from experiments. Biophys J 89(2):912–931. doi: 10.1529/biophysj.105.061150 CrossRefGoogle Scholar
  40. 40.
    Li Jeon N, Baskaran H, Dertinger SK, Whitesides GM, Van de Water L, Toner M (2002) Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nat Biotechnol 20(8):826–830. doi: 10.1038/nbt712
  41. 41.
    Chung BG, Flanagan LA, Rhee SW, Schwartz PH, Lee AP, Monuki ES, Jeon NL (2005) Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab Chip 5(4):401–406. doi: 10.1039/b417651k CrossRefGoogle Scholar
  42. 42.
    Tourovskaia A, Figueroa-Masot X, Folch A (2005) Differentiation-on-a-chip: a microfluidic platform for long-term cell culture studies. Lab Chip 5(1):14–19. doi: 10.1039/b405719h CrossRefGoogle Scholar
  43. 43.
    Rafael Gómezsjöberg, † AAL, ‡ DMP, And CSC, ‡, † SRQ (2007) Versatile, fully automated, microfluidic cell culture system. Anal Chem 79(22):8557–8563. doi: 10.1021/ac071311w
  44. 44.
    Frisk T, Rydholm S, Liebmann T, Svahn HA, Stemme G, Brismar H (2007) A microfluidic device for parallel 3-D cell cultures in asymmetric environments. Electrophoresis 28(24):4705–4712. doi: 10.1002/elps.200700342 CrossRefGoogle Scholar
  45. 45.
    Saadi W, Rhee SW, Lin F, Vahidi B, Chung BG, Jeon NL (2007) Generation of stable concentration gradients in 2D and 3D environments using a microfluidic ladder chamber. Biomed Microdevices 9(5):627–635. doi: 10.1007/s10544-007-9051-9 CrossRefGoogle Scholar
  46. 46.
    Chang YC, Funamoto S, Firtel RA (2001) Signaling pathways controlling cell polarity and chemotaxis. Trends Biochem Sci 26(9):557–566. doi: 10.1016/S0968-0004(01)01934-X CrossRefGoogle Scholar
  47. 47.
    Horwitz AR, Parsons JT (1999) Cell migration–movin’ on. Science 286(5442):1102–1103. doi: 10.1126/science.286.5442.1102 CrossRefGoogle Scholar
  48. 48.
    Doerr ME, Jones JI (1996) The roles of integrins and extracellular matrix proteins in the insulin-like growth factor I-stimulated chemotaxis of human breast cancer cells. J Biol Chem 271(5):2443–2447. doi: 10.1074/jbc.271.5.2443 CrossRefGoogle Scholar
  49. 49.
    Keenan TM, Folch A (2008) Biomolecular gradients in cell culture systems. Lab Chip 8(1):34–57. doi: 10.1039/b711887b CrossRefGoogle Scholar
  50. 50.
    Meyvantsson I, Beebe DJ (2008) Cell culture models in microfluidic systems. Annu Rev Anal Chem (Palo Alto Calif) 1:423–449. doi: 10.1146/annurev.anchem.1.031207.113042 CrossRefGoogle Scholar
  51. 51.
    Terry K, Williams SM, Connolly L, Ottemann KM (2005) Chemotaxis plays multiple roles during Helicobacter pylori animal infection. Infect Immun 73(2):803–811. doi: 10.1128/IAI.73.2.803-811.2005 CrossRefGoogle Scholar
  52. 52.
    Hawes MC, Smith LY (1989) Requirement for chemotaxis in pathogenicity of Agrobacterium tumefaciens on roots of soil-grown pea plants. J Bacteriol 171(10):5668–5671. doi: 10.1128/jb.171.10.5668-5671.1989 CrossRefGoogle Scholar
  53. 53.
    Stocker R, Seymour JR, Samadani A, Hunt DE, Polz MF (2008) Rapid chemotactic response enables marine bacteria to exploit ephemeral microscale nutrient patches. Proc Natl Acad Sci U S A 105(11):4209–4214. doi: 10.1073/pnas.0709765105 CrossRefGoogle Scholar
  54. 54.
    Atencia J, Morrow J, Locascio LE (2009) The microfluidic palette: a diffusive gradient generator with spatio-temporal control. Lab Chip 9(18):2707–2714. doi: 10.1039/b902113b CrossRefGoogle Scholar
  55. 55.
    Luster AD, Alon R, von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6(12):1182–1190. doi: 10.1038/ni1275 CrossRefGoogle Scholar
  56. 56.
    Baggiolini M, Dewald B, Moser B (1997) Human chemokines: an update. Annu Rev Immunol 15(1):675–705. doi: 10.1146/annurev.immunol.15.1.675 CrossRefGoogle Scholar
  57. 57.
    Yonekawa K, Harlan JM (2005) Targeting leukocyte integrins in human diseases. J Leukoc Biol 77(2):129–140. doi: 10.1189/jlb.0804460 CrossRefGoogle Scholar
  58. 58.
    Jeon NL, Dertinger SKW, Chiu DT, Choi IS, And ADS, Whitesides GM (2000) Generation of solution and surface gradients using microfluidic systems. Langmuir 16(22):8311–8316. doi: 10.1021/la000600b
  59. 59.
    Gao Y, Sun J, Lin WH, Webb D, Li D (2012) A compact microfluidic gradient generator using passive pumping. Microfluid Nanofluid 12(6):887–895. doi: 10.1007/s10404-011-0908-0 CrossRefGoogle Scholar
  60. 60.
    Du Y, Shim J, Vidula M, Hancock MJ, Lo E, Chung BG, Borenstein JT, Khabiry M, Cropek DM, Khademhosseini A (2009) Rapid generation of spatially and temporally controllable long-range concentration gradients in a microfluidic device. Lab Chip 9(6):761–767. doi: 10.1039/b815990d CrossRefGoogle Scholar
  61. 61.
    Xu Z, Huang X, Wang P, Wang H, Weitz DA (2016) Optimization and development of a universal flow-based microfluidic gradient generator. Microfluid Nanofluid 20(6). doi: 10.1007/s10404-016-1749-7
  62. 62.
    Dertinger SKW, Chiu DT, Jeon NL, Whitesides GM (2001) Generation of gradients having complex shapes using microfluidic networks. Anal Chem 73(6):1240–1246. doi: 10.1021/ac001132d CrossRefGoogle Scholar
  63. 63.
    Campbell K, Groisman A (2007) Generation of complex concentration profiles in microchannels in a logarithmically small number of steps. Lab Chip 7(2):264–272. doi: 10.1039/b610011b CrossRefGoogle Scholar
  64. 64.
    Cooksey GA, Sip CG, Folch A (2009) A multi-purpose microfluidic perfusion system with combinatorial choice of inputs, mixtures, gradient patterns, and flow rates. Lab Chip 9(3):417–426. doi: 10.1039/b806803h CrossRefGoogle Scholar
  65. 65.
    Lee K, Kim C, Kim Y, Ahn B, Bang J, Kim J, Panchapakesan R, Yoon Y-K, Kang JY, Oh KW (2011) Microfluidic concentration-on-demand combinatorial dilutions. Microfluid Nanofluid 11(1):75–86. doi: 10.1007/s10404-011-0775-8 CrossRefGoogle Scholar
  66. 66.
    Wu J, Hillier C, Komenda P, Lobato de Faria R, Levin D, Zhang M, Lin F (2015) A microfluidic platform for evaluating neutrophil chemotaxis induced by sputum from COPD patients. PLoS ONE 10(5):e0126523. doi: 10.1371/journal.pone.0126523 CrossRefGoogle Scholar
  67. 67.
    Cheng JY, Yen MH, Kuo CT, Young TH (2008) A transparent cell-culture microchamber with a variably controlled concentration gradient generator and flow field rectifier. Biomicrofluidics 2(2):24105. doi: 10.1063/1.2952290 CrossRefGoogle Scholar
  68. 68.
    Abhyankar VV, Lokuta MA, Huttenlocher A, Beebe DJ (2006) Characterization of a membrane-based gradient generator for use in cell-signaling studies. Lab Chip 6(3):389–393. doi: 10.1039/b514133h CrossRefGoogle Scholar
  69. 69.
    Kim M, Kim T (2010) Diffusion-based and long-range concentration gradients of multiple chemicals for bacterial chemotaxis assays. Anal Chem 82(22):9401–9409. doi: 10.1021/ac102022q CrossRefGoogle Scholar
  70. 70.
    Berthier E, Surfus J, Verbsky J, Huttenlocher A, Beebe D (2010) An arrayed high-content chemotaxis assay for patient diagnosis. Integr Biol (Camb) 2(11–12):630–638. doi: 10.1039/c0ib00030b CrossRefGoogle Scholar
  71. 71.
    Kong Q, Majeska RJ, Vazquez M (2011) Migration of connective tissue-derived cells is mediated by ultra-low concentration gradient fields of EGF. Exp Cell Res 317(11):1491–1502. doi: 10.1016/j.yexcr.2011.04.003 CrossRefGoogle Scholar
  72. 72.
    Irimia D, Charras G, Agrawal N, Mitchison T, Toner M (2007) Polar stimulation and constrained cell migration in microfluidic channels. Lab Chip 7(12):1783–1790. doi: 10.1039/b710524j CrossRefGoogle Scholar
  73. 73.
    Zou H, Yue W, Yu WK, Liu D, Fong CC, Zhao J, Yang M (2015) Microfluidic platform for studying chemotaxis of adhesive cells revealed a gradient-dependent migration and acceleration of cancer stem cells. Anal Chem 87(14):7098–7108. doi: 10.1021/acs.analchem.5b00873 CrossRefGoogle Scholar
  74. 74.
    Lee SS, Horvath P, Pelet S, Hegemann B, Lee LP, Peter M (2012) Quantitative and dynamic assay of single cell chemotaxis. Integr Biol (Camb) 4(4):381–390. doi: 10.1039/c2ib00144f CrossRefGoogle Scholar
  75. 75.
    Keenan TM, Frevert CW, Wu A, Wong V, Folch A (2010) A new method for studying gradient-induced neutrophil desensitization based on an open microfluidic chamber. Lab Chip 10(1):116–122. doi: 10.1039/b913494h CrossRefGoogle Scholar
  76. 76.
    Kim D, Liu A, Diller E, Sitti M (2012) Chemotactic steering of bacteria propelled microbeads. Biomed Microdevices 14(6):1009–1017. doi: 10.1007/s10544-012-9701-4 CrossRefGoogle Scholar
  77. 77.
    Cheng SY, Heilman S, Wasserman M, Archer S, Shuler ML, Wu M (2007) A hydrogel-based microfluidic device for the studies of directed cell migration. Lab Chip 7(6):763–769. doi: 10.1039/b618463d CrossRefGoogle Scholar
  78. 78.
    Choi HI, Kim JY, Kwak HS, Sung YJ, Sim SJ (2016) Quantitative analysis of the chemotaxis of a green alga, Chlamydomonas reinhardtii, to bicarbonate using diffusion-based microfluidic device. Biomicrofluidics 10(1):014121. doi: 10.1063/1.4942756 CrossRefGoogle Scholar
  79. 79.
    Chung BG, Lin F, Jeon NL (2006) A microfluidic multi-injector for gradient generation. Lab Chip 6(6):764–768. doi: 10.1039/b512667c CrossRefGoogle Scholar
  80. 80.
    Qasaimeh MA, Gervais T, Juncker D (2011) Microfluidic quadrupole and floating concentration gradient. Nat Commun 2:464. doi: 10.1038/ncomms1471 CrossRefGoogle Scholar
  81. 81.
    Wright GA, Costa L, Terekhov A, Jowhar D, Hofmeister W, Janetopoulos C (2012) On-chip open microfluidic devices for chemotaxis studies. Microsc Microanal 18(4):816–828. doi: 10.1017/S1431927612000475 CrossRefGoogle Scholar
  82. 82.
    Moussavi-Harami SF, Pezzi HM, Huttenlocher A, Beebe DJ (2015) Simple microfluidic device for studying chemotaxis in response to dual gradients. Biomed Microdevices 17(3):9955. doi: 10.1007/s10544-015-9955-8 CrossRefGoogle Scholar
  83. 83.
    Paguirigan A, Beebe DJ (2006) Gelatin based microfluidic devices for cell culture. Lab Chip 6(3):407–413. doi: 10.1039/b517524k CrossRefGoogle Scholar
  84. 84.
    Kothapalli CR, van Veen E, de Valence S, Chung S, Zervantonakis IK, Gertler FB, Kamm RD (2011) A high-throughput microfluidic assay to study neurite response to growth factor gradients. Lab Chip 11(3):497–507. doi: 10.1039/c0lc00240b CrossRefGoogle Scholar
  85. 85.
    Srinivasan P, Zervantonakis IK, Kothapalli CR (2014) Synergistic effects of 3D ECM and chemogradients on neurite outgrowth and guidance: a simple modeling and microfluidic framework. PLoS ONE 9(6):e99640. doi: 10.1371/journal.pone.0099640 CrossRefGoogle Scholar
  86. 86.
    Kothapalli CR, Honarmandi P (2014) Theoretical and experimental quantification of the role of diffusive chemogradients on neuritogenesis within three-dimensional collagen scaffolds. Acta Biomater 10(8):3664–3674. doi: 10.1016/j.actbio.2014.05.009 CrossRefGoogle Scholar
  87. 87.
    Haessler U, Kalinin Y, Swartz MA, Wu M (2009) An agarose-based microfluidic platform with a gradient buffer for 3D chemotaxis studies. Biomed Microdevices 11(4):827–835. doi: 10.1007/s10544-009-9299-3 CrossRefGoogle Scholar
  88. 88.
    Herzmark P, Campbell K, Wang F, Wong K, El-Samad H, Groisman A, Bourne HR (2007) Bound attractant at the leading vs. the trailing edge determines chemotactic prowess. Proc Natl Acad Sci U S A 104(33):13349–13354. doi: 10.1073/pnas.0705889104 CrossRefGoogle Scholar
  89. 89.
    Mosadegh B, Saadi W, Wang SJ, Jeon NL (2008) Epidermal growth factor promotes breast cancer cell chemotaxis in CXCL12 gradients. Biotechnol Bioeng 100(6):1205–1213. doi: 10.1002/bit.21851 CrossRefGoogle Scholar
  90. 90.
    Ricart BG, John B, Lee D, Hunter CA, Hammer DA (2011) Dendritic cells distinguish individual chemokine signals through CCR7 and CXCR4. J Immunol 186(1):53–61. doi: 10.4049/jimmunol.1002358 CrossRefGoogle Scholar
  91. 91.
    Wang SJ, Saadi W, Lin F, Minh-Canh Nguyen C, Li Jeon N (2004) Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis. Exp Cell Res 300(1):180–189. doi: 10.1016/j.yexcr.2004.06.030 CrossRefGoogle Scholar
  92. 92.
    Chen YC, Allen SG, Ingram PN, Buckanovich R, Merajver SD, Yoon E (2015) Single-cell migration chip for chemotaxis-based microfluidic selection of heterogeneous cell populations. Sci Rep 5:9980. doi: 10.1038/srep09980 CrossRefGoogle Scholar
  93. 93.
    Ng CP, Hinz B, Swartz MA (2005) Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J Cell Sci 118(Pt 20):4731–4739. doi: 10.1242/jcs.02605 CrossRefGoogle Scholar
  94. 94.
    Shamloo A, Ma N, Poo MM, Sohn LL, Heilshorn SC (2008) Endothelial cell polarization and chemotaxis in a microfluidic device. Lab Chip 8(8):1292–1299. doi: 10.1039/b719788h CrossRefGoogle Scholar
  95. 95.
    Walker GM, Zeringue HC, Beebe DJ (2004) Microenvironment design considerations for cellular scale studies. Lab Chip 4(2):91–97. doi: 10.1039/b311214d CrossRefGoogle Scholar
  96. 96.
    Lee P, Lin R, Moon J, Lee LP (2006) Microfluidic alignment of collagen fibers for in vitro cell culture. Biomed Microdevices 8(1):35–41. doi: 10.1007/s10544-006-6380-z CrossRefGoogle Scholar
  97. 97.
    Beta C, Frohlich T, Bodeker HU, Bodenschatz E (2008) Chemotaxis in microfluidic devices–a study of flow effects. Lab Chip 8(7):1087–1096. doi: 10.1039/b801331d CrossRefGoogle Scholar
  98. 98.
    Haessler U, Pisano M, Wu M, Swartz MA (2011) Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. Proc Natl Acad Sci U S A 108(14):5614–5619. doi: 10.1073/pnas.1014920108 CrossRefGoogle Scholar
  99. 99.
    Suh S, Traore MA, Behkam B (2016) Bacterial chemotaxis-enabled autonomous sorting of nanoparticles of comparable sizes. Lab Chip 16(7):1254–1260. doi: 10.1039/c6lc00059b CrossRefGoogle Scholar
  100. 100.
    Walsh DI 3rd, Lalli ML, Kassas JM, Asthagiri AR, Murthy SK (2015) Cell chemotaxis on paper for diagnostics. Anal Chem 87(11):5505–5510. doi: 10.1021/acs.analchem.5b00726 CrossRefGoogle Scholar
  101. 101.
    McCaig CD, Rajnicek AM, Song B, Zhao M (2005) Controlling cell behavior electrically: current views and future potential. Physiol Rev 85(3):943–978. doi: 10.1152/physrev.00020.2004 CrossRefGoogle Scholar
  102. 102.
    Yao L, Pandit A, Yao S, McCaig CD (2011) Electric field-guided neuron migration: a novel approach in neurogenesis. Tissue Eng Part B Rev 17(3):143–153. doi: 10.1089/ten.TEB.2010.0561 CrossRefGoogle Scholar
  103. 103.
    Jin T, Hereld D (eds) (2009) Chemotaxis: methods and protocols. Humana Press, New YorkGoogle Scholar
  104. 104.
    Robinson KR, Messerli MA (2003) Left/right, up/down: the role of endogenous electrical fields as directional signals in development, repair and invasion. BioEssays 25(8):759–766. doi: 10.1002/bies.10307 CrossRefGoogle Scholar
  105. 105.
    Cooper MS, Keller RE (1984) Perpendicular orientation and directional migration of amphibian neural crest cells in dc electrical fields. Proc Natl Acad Sci 81(1):160–164CrossRefGoogle Scholar
  106. 106.
    Guo A, Song B, Reid B, Gu Y, Forrester JV, Jahoda CA, Zhao M (2010) Effects of physiological electric fields on migration of human dermal fibroblasts. J Invest Dermatol 130(9):2320–2327. doi: 10.1038/jid.2010.96 CrossRefGoogle Scholar
  107. 107.
    Finkelstein E, Chang W, Chao P-HG, Gruber D, Minden A, Hung CT, Bulinski JC (2004) Roles of microtubules, cell polarity and adhesion in electric-field-mediated motility of 3T3 fibroblasts. J Cell Sci 117(8):1533–1545. doi: 10.1242/jcs.00986 CrossRefGoogle Scholar
  108. 108.
    Jennings J, Chen D, Feldman D (2008) Transcriptional response of dermal fibroblasts in direct current electric fields. Bioelectromagnetics 29(5):394–405. doi: 10.1002/bem.20408 CrossRefGoogle Scholar
  109. 109.
    Mba D, Mycielska M, Madeja Z, Fraser SP, Korohoda W (2001) Directional movement of rat prostate cancer cells in direct-current electric field: involvement of voltagegated Na + channel activity. J Cell Sci 114(Pt 14):2697–2705Google Scholar
  110. 110.
    Zhao M, Agius-Fernandez A, Forrester JV, McCaig CD (1996) Directed migration of corneal epithelial sheets in physiological electric fields. Invest Ophth Vis Sci 37(13):2548–2558Google Scholar
  111. 111.
    Zhao M, Agius-Fernandez A, Forrester JV, Mccaig CD (1996) Orientation and directed migration of cultured corneal epithelial cells in small electric fields are serum dependent. J Cell Sci 109(Pt 6) (6):1405–1414Google Scholar
  112. 112.
    Rapp B, De B-CA, Gruler H (1988) Galvanotaxis of human granulocytes. Eur Biophys J Biophy 16(5):313–319. doi: 10.1007/BF00254068 CrossRefGoogle Scholar
  113. 113.
    Zhao M, Bai H, Wang E, Forrester JV, Mccaig CD (2004) Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J Cell Sci 117(3):397–405. doi: 10.1242/jcs.00868 CrossRefGoogle Scholar
  114. 114.
    Biber TUL, Sanders ML (1973) Influence of transepithelial potential difference on the sodium uptake at the outer surface of the isolated frog skin. J Gen Physiol 61(5):529–551. doi: 10.1085/jgp.61.5.529 CrossRefGoogle Scholar
  115. 115.
    Jaffe LF (1977) Electrophoresis along cell membranes. Nature 265(5595):600–602. doi: 10.1038/265600a0 CrossRefGoogle Scholar
  116. 116.
    McLaughlin S, Poo MM (1981) The role of electro-osmosis in the electric-field-induced movement of charged macromolecules on the surfaces of cells. Biophys J 34(1):85–93. doi: 10.1016/S0006-3495(81)84838-2 CrossRefGoogle Scholar
  117. 117.
    Mycielska ME, Djamgoz MB (2004) Cellular mechanisms of direct-current electric field effects: galvanotaxis and metastatic disease. J Cell Sci 117(Pt 9):1631–1639. doi: 10.1242/jcs.01125 CrossRefGoogle Scholar
  118. 118.
    Zhao M, Song B, Pu J et al (2006) Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature 442(7101):457–460. doi: 10.1038/nature04925 CrossRefGoogle Scholar
  119. 119.
    Song B, Gu Y, Pu J, Reid B, Zhao Z, Zhao M (2007) Application of direct current electric fields to cells and tissues in vitro and modulation of wound electric field in vivo. Nat Protoc 2(6):1479–1489. doi: 10.1038/nprot.2007.205 CrossRefGoogle Scholar
  120. 120.
    Li X, Kolega J (2002) Effects of direct current electric fields on cell migration and actin filament distribution in bovine vascular endothelial cells. J Vasc Res 39(5):391–404. doi: 10.1159/000064517 CrossRefGoogle Scholar
  121. 121.
    Sato MJ, Ueda M, Takagi H, Watanabe TM, Yanagida T, Ueda M (2007) Input–output relationship in galvanotactic response of Dictyostelium cells. Biosystems 88(3):261–272. doi: 10.1016/j.biosystems.2006.06.008 CrossRefGoogle Scholar
  122. 122.
    Lin F, Baldessari F, Gyenge CC, Sato T, Chambers RD, Santiago JG, Butcher EC (2008) Lymphocyte electrotaxis in vitro and in vivo. J Immunol 181(4):2465–2471. doi: 10.4049/jimmunol.181.4.2465 CrossRefGoogle Scholar
  123. 123.
    Li J, Nandagopal S, Wu D, Romanuik SF, Paul K, Thomson DJ, Lin F (2011) Activated T lymphocytes migrate toward the cathode of DC electric fields in microfluidic devices. Lab Chip 11(7):1298–1304. doi: 10.1039/C0LC00371A CrossRefGoogle Scholar
  124. 124.
    Rezai P, Siddiqui A, Selvaganapathy PR, Gupta BP (2010) Electrotaxis of Caenorhabditis elegans in a microfluidic environment. Lab Chip 10(2):220–226. doi: 10.1039/B917486A CrossRefGoogle Scholar
  125. 125.
    Zhao S, Zhu K, Zhang Y, Zhu Z, Xu Z, Zhao M, Pan T (2014) ElectroTaxis-on-a-Chip (ETC): an integrated quantitative high-throughput screening platform for electrical field-directed cell migration. Lab Chip 14(22):4398–4405. doi: 10.1039/C4LC00745J CrossRefGoogle Scholar
  126. 126.
    Huang CW, Cheng JY, Yen MH, Young TH (2009) Electrotaxis of lung cancer cells in a multiple-electric-field chip. Biosens Bioelectron 24(12):3510–3516. doi: 10.1016/j.bios.2009.05.001 CrossRefGoogle Scholar
  127. 127.
    Tsai H-F, Peng S-W, Wu C-Y, Chang H-F, Cheng J-Y (2012) Electrotaxis of oral squamous cell carcinoma cells in a multiple-electric-field chip with uniform flow field. Biomicrofluidics 6(3):034116. doi: 10.1063/1.4749826 CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of ChemistryTsinghua UniversityBeijingPeople’s Republic of China

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