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Mechanical and Electrical Principles for Separation of Rare Cells

  • Elisa M. WassonEmail author
  • Temple A. Douglas
  • Rafael V. Davalos
Chapter

Abstract

Early detection of disease has long been a goal of many research projects and public health initiatives, as prevention from disease advancement is one of the most effective cures. Many diseases that are difficult to treat in late stage such as melanoma, pancreatic cancer, and highly metastatic tumors are treatable with a much better prognosis in early stage. One method of interest in early cancer detection has been the isolation of circulating tumor cells (CTCs) from the blood. By isolating CTCs, we can determine the presence of cancer from only a blood sample rather than requiring multiple screening modalities be performed on a patient. In addition, cancers without effective screening modalities, such as pancreatic cancer, may produce CTCs while the patient is asymptomatic, allowing for a much earlier start to treatment and improved prognosis [1]. In this chapter, we present several approaches that employ microfluidics to separate rare cells of interest. We start with a basic overview of fluid dynamics that includes scaling analysis and several solutions to the Navier-Stokes equations. We then introduce mechanical and electrical separation techniques along with an overview of their respective theories and several examples of each.

Keywords

Inertial microfluidics Dielectrophoresis DEP Circulating tumor cells (CTCs) 

References

  1. 1.
    Tjensvoll K, Nordgård O, Smaaland R (2014) Circulating tumor cells in pancreatic cancer patients: methods of detection and clinical implications. Int J Cancer 134:1–8. doi: 10.1002/ijc.28134 CrossRefPubMedGoogle Scholar
  2. 2.
    Alix-Panabieres C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14:623–631CrossRefPubMedGoogle Scholar
  3. 3.
    Nagrath S, Sequist LV, Maheswaran S et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450:1235–1239. doi: 10.1038/nature06385 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Stott SL, Hsu C, Tsukrov DI et al (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A 107:18392–18397. doi: 10.1073/pnas.1012539107 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wlodkowic D, Cooper JM (2010) Tumors on chips: oncology meets microfluidics. Curr Opin Chem Biol 14:556–567. doi: 10.1016/j.cbpa.2010.08.016 CrossRefPubMedGoogle Scholar
  6. 6.
    Shelby JP, White J, Ganesan K et al (2003) A microfluidic model for single-cell capillary obstruction by Plasmodium falciparum-infected erythrocytes. Proc Natl Acad Sci U S A 100:14618–14622. doi: 10.1073/pnas.2433968100 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gascoyne P, Satayavivad J, Ruchirawat M (2004) Microfluidic approaches to malaria detection. Acta Trop 89:357–369. doi: 10.1016/j.actatropica.2003.11.009 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hou HW, Bhagat AAS, Chong AGL et al (2010) Deformability based cell margination—a simple microfluidic design for malaria-infected erythrocyte separation. Lab Chip 10:2605–2613. doi: 10.1039/c003873c CrossRefPubMedGoogle Scholar
  9. 9.
    Cheng X, Irimia D, Dixon M et al (2007) A microfluidic device for practical label-free CD4(+) T cell counting of HIV-infected subjects. Lab Chip 7:170–178. doi: 10.1039/b612966h CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lee WG, Kim Y, Geun B et al (2010) Nano/microfluidics for diagnosis of infectious diseases in developing countries. Adv Drug Deliv Rev 62:449–457. doi: 10.1016/j.addr.2009.11.016 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yang BD, Niu X, Liu Y et al (2008) Electrospun nanofibrous membranes: a novel solid substrate for microfluidic immunoassays for HIV. Adv Mater 20:4770–4775. doi: 10.1002/adma.200801302 CrossRefGoogle Scholar
  12. 12.
    Baker CA, Duong CT, Grimley A, Roper MG (2009) Recent advances in microfluidic detection systems. Bioanalysis 1:967–975. doi: 10.4155/bio.09.86 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chin CD, Laksanasopin T, Cheung YK et al (2011) Microfluidics-based diagnostics of infectious diseases in the developing world. Nat Med 17:1015–1019. doi: 10.1038/nm.2408 CrossRefPubMedGoogle Scholar
  14. 14.
    Yager P, Domingo GJ, Gerdes J (2008) Point-of-care diagnostics for global health. Annu Rev Biomed Eng 10:107–144. doi: 10.1146/annurev.bioeng.10.061807.160524 CrossRefPubMedGoogle Scholar
  15. 15.
    Chung TD, Kim HC (2007) Recent advances in miniaturized microfluidic flow cytometry for clinical use. Electrophoresis 28:4511–4520. doi: 10.1002/elps.200700620 CrossRefPubMedGoogle Scholar
  16. 16.
    Dimov IK, Basabe-Desmonts L, Garcia-Cordero JL et al (2011) Stand-alone self-powered integrated microfluidic blood analysis system (SIMBAS). Lab Chip 11:845–850. doi: 10.1039/c0lc00403k CrossRefPubMedGoogle Scholar
  17. 17.
    Gad-el-Hak M (2001) Flow physics. MEMS Handb. doi: 10.1201/9781420050905.ch4 CrossRefGoogle Scholar
  18. 18.
    Bruus H (2008) Theoretical microfluidics. Physics (College Park Md) 18:363. doi: 10.1111/j.1574-6968.2009.01808.x Google Scholar
  19. 19.
    Lei H, Fedosov DA, Caswell B, Karniadakis GE (2013) Blood flow in small tubes: quantifying the transition to the non-continuum regime. J Fluid Mech 722:214–239. doi: 10.1017/jfm.2013.91 CrossRefGoogle Scholar
  20. 20.
    Ali Beskok GEK (1999) report: a model for flows in channels, pipes, and ducts at micro and nano scales. Microscale Thermophys Eng 3:43–77. doi: 10.1080/108939599199864 CrossRefGoogle Scholar
  21. 21.
    Thompson P, Troian SM (1997) A general boundary condition for liquid flow at solid surfaces. Nature 389:360–362. doi: 10.1038/38686 CrossRefGoogle Scholar
  22. 22.
    Ghosh A (2011) Mechanics over micro and nano scales. In: Chakraborty S (ed). Springer, New York, pp 61–94Google Scholar
  23. 23.
    Pianka ER, Vitt LJ (2003) Lizards: windows to the evolution of diversity. University of California Press, Berkeley, CAGoogle Scholar
  24. 24.
    Trimmer W, Stroud R (2001) Scaling of micromechanical devices. MEMS Handb. doi: 10.1201/9781420050905.ch2 Google Scholar
  25. 25.
    Munson B, Young D, Okiishi T, Huebsch W (2009) Fundamentals of fluid mechanics, 6th edn. John Wiley & Sons Inc., New YorkGoogle Scholar
  26. 26.
    Sia SK, Whitesides GM (2003) Microfluidic devices fabricated in poly(dimethylsiloxane) for biological studies. Electrophoresis 24:3563–3576. doi: 10.1002/elps.200305584 CrossRefPubMedGoogle Scholar
  27. 27.
    Kirby B (2010) Micro- and nanoscale fluid mechanics. Cambridge University Press, New YorkCrossRefGoogle Scholar
  28. 28.
    Panton RL (2013) Flow at low Reynolds numbers. In: Incompressible flow. Wiley, New York, pp 607–649Google Scholar
  29. 29.
    Squires TM, Quake SRSR (2005) Microfluidics: fluid physics at the nanoliter scale. Rev Mod Phys 77:977–1026CrossRefGoogle Scholar
  30. 30.
    Asmolov ES (1999) The inertial lift on a spherical particle in a plane Poiseuille flow at large channel Reynolds number. J Fluid Mech 381:63–87. doi: 10.1017/S0022112098003474 CrossRefGoogle Scholar
  31. 31.
    Di Carlo D (2009) Inertial microfluidics. Lab Chip 9:3038–3046. doi: 10.1039/b912547g CrossRefPubMedGoogle Scholar
  32. 32.
    Dean WR (1928) Fluid motion in a curved channel. Proc R Soc A Math Phys Eng Sci 121:402–420. doi: 10.1098/rspa.1928.0205 CrossRefGoogle Scholar
  33. 33.
    Berger SA, Talbot L, Yao LS (1983) Flow in curved pipes. Annu Rev Fluid Mech 15:461–512. doi: 10.1146/annurev.fl.15.010183.002333 CrossRefGoogle Scholar
  34. 34.
    Bergman TL, Lavine AS, Incropera FP, Dewitt DP (2011) Fundamentals of heat and mass transfer, 7th edn. John Wiley & Sons, Inc., New YorkGoogle Scholar
  35. 35.
    Brody JP, Yager P (1997) Diffusion-based extraction in a microfabricated device. Sensors Actuators A Phys 58:13–18. doi: 10.1016/S0924-4247(97)80219-1 CrossRefGoogle Scholar
  36. 36.
    Morgan H, Green NG (2003) Fluid dynamics. In: Pethig R (ed) AC electrokinetics: colloids nanoparticles. Institute of Physics Publishing, UK, pp 65–80Google Scholar
  37. 37.
    Lei U, Yang CY, Wu KC (2006) Viscous torque on a sphere under arbitrary rotation. Appl Phys Lett 89:20–23. doi: 10.1063/1.2372704 Google Scholar
  38. 38.
    Panton RL (2013) Ideal Flows in a plane. In: Incompressible flow. Wiley, New York, pp 438–501Google Scholar
  39. 39.
    Zeng L, Balachandar S, Fischer P (2005) Wall-induced forces on a rigid sphere at finite Reynolds number. J Fluid Mech 536:1–25. doi: 10.1017/S0022112005004738 CrossRefGoogle Scholar
  40. 40.
    Rubinow SI, Keller JB (1961) The transverse force on a spinning sphere moving in a viscous fluid. J Fluid Mech 11:447. doi: 10.1017/S0022112061000640 CrossRefGoogle Scholar
  41. 41.
    Segré G, Silberberg A (1961) Radial particle displacements in Poiseuille flow of suspensions. Nature 189:209–210. doi: 10.1038/189209a0 CrossRefGoogle Scholar
  42. 42.
    Chun B, Ladd AJC (2006) Inertial migration of neutrally buoyant particles in a square duct: an investigation of multiple equilibrium positions. Phys Fluids 18:3–6. doi: 10.1063/1.2176587 CrossRefGoogle Scholar
  43. 43.
    Ho BP, Leal LG (1976) Migration of rigid spheres in a two-dimensional unidirectional shear flow of a second-order fluid. J Fluid Mech 76:783. doi: 10.1017/S002211207600089X CrossRefGoogle Scholar
  44. 44.
    Cox RG, Brenner H (1968) The lateral migration of solid particles in Poiseuille flow—I: Theory. Chem Eng Sci 23:147–173. doi: 10.1016/0301-9322(77)90001-5 CrossRefGoogle Scholar
  45. 45.
    Matas J-P, Morris JF, Guazzelli É (2004) Inertial migration of rigid spherical particles in Poiseuille flow. J Fluid Mech 515:171–195. doi: 10.1017/S0022112004000254 CrossRefGoogle Scholar
  46. 46.
    Schonberg JA, Hinch EJ (1989) Inertial migration of a sphere in Poiseuille flow. J Fluid Mech 203:517–524CrossRefGoogle Scholar
  47. 47.
    Di Carlo D, Edd JF, Humphry KJ et al (2009) Particle segregation and dynamics in confined flows. Phys Rev Lett 102:1–4. doi: 10.1103/PhysRevLett.102.094503 Google Scholar
  48. 48.
    Di Carlo D, Irimia D, Tompkins RG, Toner M (2007) Continuous inertial focusing, ordering, and separation of particles in microchannels. Proc Natl Acad Sci U S A 104:18892–18897. doi: 10.1073/pnas.0704958104 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhou J, Giridhar PV, Kasper S, Papautsky I (2013) Modulation of aspect ratio for complete separation in an inertial microfluidic channel. Lab Chip 13:1919–1929. doi: 10.1039/c3lc50101a CrossRefPubMedGoogle Scholar
  50. 50.
    Bhagat AAS, Kuntaegowdanahalli SS, Papautsky I (2008) Enhanced particle filtration in straight microchannels using shear-modulated inertial migration. Phys Fluids 20:101702. doi: 10.1063/1.2998844 CrossRefGoogle Scholar
  51. 51.
    Bhagat AAS, Kuntaegowdanahalli SS, Papautsky I (2009) Inertial microfluidics for continuous particle filtration and extraction. Microfluid Nanofluid 7:217–226. doi: 10.1007/s10404-008-0377-2 CrossRefGoogle Scholar
  52. 52.
    Hur SC, Brinckerhoff TZ, Walthers CM et al (2012) Label-free enrichment of adrenal cortical progenitor cells using inertial microfluidics. PLoS One 7:e46550. doi: 10.1371/journal.pone.0046550 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wang X, Zandi M, Ho C-C et al (2015) Single stream inertial focusing in a straight microchannel. Lab Chip 15:1812–1821. doi: 10.1039/C4LC01462F CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Zhou J, Kasper S, Papautsky I (2013) Enhanced size-dependent trapping of particles using microvortices. Microfluid Nanofluid 15:611–623. doi: 10.1007/s10404-013-1176-y CrossRefGoogle Scholar
  55. 55.
    Hur SC, Mach AJ, Di Carlo D (2011) High-throughput size-based rare cell enrichment using microscale vortices. Biomicrofluidics 5:1–10. doi: 10.1063/1.3576780 CrossRefGoogle Scholar
  56. 56.
    Sollier E, Go DE, Che J et al (2014) Size-selective collection of circulating tumor cells using Vortex technology. Lab Chip 14:63–77. doi: 10.1039/c3lc50689d CrossRefPubMedGoogle Scholar
  57. 57.
    Che J, Mach AJ, Go DE et al (2013) Microfluidic purification and concentration of malignant pleural effusions for improved molecular and cytomorphological diagnostics. PLoS One 8:e78194. doi: 10.1371/journal.pone.0078194 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wang X, Zhou J, Papautsky I (2013) Vortex-aided inertial microfluidic device for continuous particle separation with high size-selectivity, efficiency, and purity. Biomicrofluidics 7:22–25. doi: 10.1063/1.4818906 Google Scholar
  59. 59.
    Wang X, Papautsky I (2015) Size-based microfluidic multimodal microparticle sorter. Lab Chip 15:1350–1359. doi: 10.1039/c4lc00803k CrossRefPubMedGoogle Scholar
  60. 60.
    Gossett DR, Di Carlo D (2009) Particle focusing mechanisms in curving confined flows. Anal Chem 81:8459–8465. doi: 10.1021/ac901306y CrossRefPubMedGoogle Scholar
  61. 61.
    Matas JP, Morris JF, Guazzelli E (2004) Lateral forces on a sphere. Oil Gas Sci Technol Rev IFP 59:59–70CrossRefGoogle Scholar
  62. 62.
    Lee MG, Shin JH, Bae CY et al (2013) Label-free cancer cell separation from human whole blood using inertial micro fluidics at low shear stress. Anal Chem 85(13):6213–6218CrossRefPubMedGoogle Scholar
  63. 63.
    Lee MG, Choi S, Park J-K (2009) Three-dimensional hydrodynamic focusing with a single sheath flow in a single-layer microfluidic device. Lab Chip 9:3155–3160. doi: 10.1039/b910712f CrossRefPubMedGoogle Scholar
  64. 64.
    Zhang J, Li M, Li WH, Alici G (2013) Inertial focusing in a straight channel with asymmetrical expansion–contraction cavity arrays using two secondary flows. J Micromech Microeng 23:085023. doi: 10.1088/0960-1317/23/8/085023 CrossRefGoogle Scholar
  65. 65.
    Hou HW, Warkiani ME, Khoo BL et al (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep 3:1259. doi: 10.1038/srep01259 PubMedPubMedCentralGoogle Scholar
  66. 66.
    Nivedita N, Papautsky I (2013) Continuous separation of blood cells in spiral microfluidic devices. Biomicrofluidics 7:1–14. doi: 10.1063/1.4819275 CrossRefGoogle Scholar
  67. 67.
    Sun J, Liu C, Li M et al (2013) Size-based hydrodynamic rare tumor cell separation in curved microfluidic channels. Biomicrofluidics 7:1–11. doi: 10.1063/1.4774311 CrossRefGoogle Scholar
  68. 68.
    Xiang N, Yi H, Chen K et al (2013) High-throughput inertial particle focusing in a curved microchannel: insights into the flow-rate regulation mechanism and process model. Biomicrofluidics 7:1–10. doi: 10.1063/1.4818445 Google Scholar
  69. 69.
    Tallapragada P, Hasabnis N, Katuri K et al (2015) Scale invariant hydrodynamic focusing and sorting of inertial particles by size in spiral micro channels. J Micromech Microeng 25:084013. doi: 10.1088/0960-1317/25/8/084013 CrossRefGoogle Scholar
  70. 70.
    Xiang N, Chen K, Dai Q et al (2015) Inertia-induced focusing dynamics of microparticles throughout a curved microfluidic channel. Microfluid Nanofluid 18:29–39. doi: 10.1007/s10404-014-1395-x CrossRefGoogle Scholar
  71. 71.
    Reece AE, Kaastrup K, Sikes HD, Oakey J (2015) Staged inertial microfluidic focusing for complex fluid enrichment. RSC Adv 5:53857–53864. doi: 10.1039/C5RA10634F CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Pethig R (2013) Dielectrophoresis: an assessment of its potential to aid the research and practice of drug discovery and delivery. Adv Drug Deliv Rev 65:1589–1599. doi: 10.1016/j.addr.2013.09.003 CrossRefPubMedGoogle Scholar
  73. 73.
    Pethig R (2010) Review article-dielectrophoresis: status of the theory, technology, and applications. Biomicrofluidics 4:1–35. doi: 10.1063/1.3456626 Google Scholar
  74. 74.
    Martinez-Duarte R, Camacho-Alanis F, Renaud P, Ros A (2013) Dielectrophoresis of lambda-DNA using 3D carbon electrodes. Electrophoresis 34:1113–1122. doi: 10.1002/elps.201200447 CrossRefPubMedGoogle Scholar
  75. 75.
    Moncada-Hernandez H, Nagler E, Minerick AR (2014) Theoretical and experimental examination of particle-particle interaction effects on induced dipole moments and dielectrophoretic responses of multiple particle chains. Electrophoresis 35:1803–1813. doi: 10.1002/elps.201300636 CrossRefPubMedGoogle Scholar
  76. 76.
    Gascoyne PRC, Vykoukal J (2002) Particle separation by dielectrophoresis. Electrophoresis 23:1973–1983. doi: 10.1002/1522-2683(200207)23:13<1973::AID-ELPS1973>3.0.CO;2-1 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Salmanzadeh A, Romero L, Shafiee H et al (2012) Isolation of prostate tumor initiating cells (TICs) through their dielectrophoretic signature. Lab Chip 12:182–189. doi: 10.1039/c1lc20701f CrossRefPubMedGoogle Scholar
  78. 78.
    Wang X, Becker FF, Gascoyne PRC (2002) Membrane dielectric changes indicate induced apoptosis in HL-60 cells more sensitively than surface phosphatidylserine expression or DNA fragmentation. Biochim Biophys Acta 1564:412–420CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Abdallah BG, Chao T-C, Kupitz C et al (2013) Dielectrophoretic sorting of membrane protein nanocrystals. ACS Nano 7:9129–9137. doi: 10.1021/nn403760q CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Jones PV, Staton SJR, Hayes MA (2011) Blood cell capture in a sawtooth dielectrophoretic microchannel. Anal Bioanal Chem 401:2103–2111. doi: 10.1007/s00216-011-5284-9 CrossRefPubMedGoogle Scholar
  81. 81.
    Shafiee H, Sano MB, Henslee EA et al (2010) Selective isolation of live/dead cells using contactless dielectrophoresis (cDEP). Lab Chip 10:438–445. doi: 10.1039/b920590j CrossRefPubMedGoogle Scholar
  82. 82.
    Pethig R, Kell DB (1987) The passive electrical properties of biological systems: their significance in physiology, biophysics and biotechnology. Phys Med Biol 32:933–970. doi: 10.1088/0031-9155/32/8/001 CrossRefPubMedGoogle Scholar
  83. 83.
    Cemažar J, Kotnik T (2012) Dielectrophoretic field-flow fractionation of electroporated cells. Electrophoresis 33:2867–2874. doi: 10.1002/elps.201200265 CrossRefPubMedGoogle Scholar
  84. 84.
    Chan KL, Gascoyne PR, Becker FF, Pethig R (1997) Electrorotation of liposomes: verification of dielectric multi-shell model for cells. Biochim Biophys Acta 1349:182–196CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Nejad HR, Chowdhury OZ, Buat MD, Hoorfar M (2013) Characterization of the geometry of negative dielectrophoresis traps for particle immobilization in digital microfluidic platforms. Lab Chip 13:1823–1830. doi: 10.1039/c3lc41292j CrossRefPubMedGoogle Scholar
  86. 86.
    Puttaswamy SV, Sivashankar S, Chen R-J et al (2010) Enhanced cell viability and cell adhesion using low conductivity medium for negative dielectrophoretic cell patterning. Biotechnol J 5:1005–1015. doi: 10.1002/biot.201000194 CrossRefPubMedGoogle Scholar
  87. 87.
    Leonard KM, Minerick AR (2011) Explorations of ABO-Rh antigen expressions on erythrocyte dielectrophoresis: changes in cross-over frequency. Electrophoresis 32:2512–2522. doi: 10.1002/elps.201100077 CrossRefPubMedGoogle Scholar
  88. 88.
    Sano MB, Salmanzadeh A, Davalos RV (2012) Multilayer contactless dielectrophoresis: theoretical considerations. Electrophoresis 33:1938–1946. doi: 10.1002/elps.201100677 CrossRefPubMedGoogle Scholar
  89. 89.
    Jones TB (1995) Electromechanics of particles. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  90. 90.
    Camacho-Alanis F, Gan L, Ros A (2012) Transitioning streaming to trapping in DC insulator-based dielectrophoresis for biomolecules. Sens Actuators B Chem 173:668–675. doi: 10.1016/j.snb.2012.07.080 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Elisa M. Wasson
    • 1
    • 2
    Email author
  • Temple A. Douglas
    • 1
    • 2
  • Rafael V. Davalos
    • 1
    • 2
  1. 1.Bioelectromechanical Systems Lab, Department of Mechanical EngineeringVirginiaUSA
  2. 2.Tech—Wake Forest UniversitySchool of Biomedical Engineering and SciencesBlacksburgUSA

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