Recent Development of Cell Analysis on Microfludics

Chapter
Part of the Integrated Analytical Systems book series (ANASYS)

Abstract

Cells are basic structural and functional units of living organisms. Understanding the composition, structure and function of cells, and exploring cellular activities, are quite important for the cognition of phenomena and rules of life. Microfluidics, combined with advanced molecular, imaging and bioinformatics techniques, constitute a robust ‘toolbox’ and revolutionize the way for cell biology researches. In microfluidic systems, small amounts of fluids are manipulated using precisely designed channels with dimensions at micrometer level. Various chemical and biological processes can be transferred and integrated in a small single device, achieving multiple chemical and biological functions. Microfluidic technology displays a number of unique merits over conventional approaches, and has been extensively applied to various fields of cell research. In this chapter, we will review the recent developments and outstanding achievements of microfluidic technology in cell researches. Based on the cell study procedure, the main content is divided into four parts: cell culture, cell manipulation, cell stimulation and cell analysis. This review will also discuss the challenges and directions of microfluidic-based cell analysis, providing important references and ideas for the development of biological and medical researches and applications.

Keywords

Microfluidics Cell analysis Cell culture Cell manipulation Cell stimulation 

References

  1. 1.
    Barthes J, Ozcelik H, Hindie M, Ndreu-Halili A, Hasan A, Vrana NE (2014) Cell microenvironment engineering and monitoring for tissue engineering and regenerative medicine: the recent advances. Biomed Res Int 2014:921905. doi: 10.1155/2014/921905 CrossRefGoogle Scholar
  2. 2.
    El-Ali J, Sorger PK, Jensen KF (2006) Cells on chips. Nature 442(7101):403–411. doi: 10.1038/nature05063 CrossRefGoogle Scholar
  3. 3.
    Gattazzo F, Urciuolo A, Bonaldo P (2014) Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta 1840(8):2506–2519. doi: 10.1016/j.bbagen.2014.01.010 CrossRefGoogle Scholar
  4. 4.
    Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423–1437. doi: 10.1038/nm.3394 CrossRefGoogle Scholar
  5. 5.
    Sun Y, Chen CS, Fu J (2012) Forcing stem cells to behave: a biophysical perspective of the cellular microenvironment. Annu Rev Biophys 41:519–542. doi: 10.1146/annurev-biophys-042910-155306 CrossRefGoogle Scholar
  6. 6.
    Whitesides GM (2006) The origins and the future of microfluidics. Nature 442(7101):368–373. doi: 10.1038/nature05058 CrossRefGoogle Scholar
  7. 7.
    Sackmann EK, Fulton AL, Beebe DJ (2014) The present and future role of microfluidics in biomedical research. Nature 507(7491):181–189. doi: 10.1038/nature13118 CrossRefGoogle Scholar
  8. 8.
    Mark D, Haeberle S, Roth G, von Stetten F, Zengerle R (2010) Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications. Chem Soc Rev 39(3):1153–1182. doi: 10.1039/b820557b CrossRefGoogle Scholar
  9. 9.
    Nge PN, Rogers CI, Woolley AT (2013) Advances in microfluidic materials, functions, integration, and applications. Chem Rev 113(4):2550–2583. doi: 10.1021/cr300337x CrossRefGoogle Scholar
  10. 10.
    Livak-Dahl E, Sinn I, Burns M (2011) Microfluidic chemical analysis systems. Annu Rev Chem Biomol Eng 2:325–353. doi: 10.1146/annurev-chembioeng-061010-114215 CrossRefGoogle Scholar
  11. 11.
    Salieb-Beugelaar GB, Simone G, Arora A, Philippi A, Manz A (2010) Latest developments in microfluidic cell biology and analysis systems. Anal Chem 82(12):4848–4864. doi: 10.1021/ac1009707 CrossRefGoogle Scholar
  12. 12.
    Zhuang Q-C, Ning R-Z, Ma Y, Lin J-M (2016) Recent developments in microfluidic chip for in vitro cell-based research. Chin J Anal Chem 44(4):522–532. doi: 10.1016/s1872-2040(16)60919-2 CrossRefGoogle Scholar
  13. 13.
    Andersson H, van den Berg A (2003) Microfluidic devices for cellomics: a review. Sens Actuators B: Chem 92(3):315–325. doi: 10.1016/s0925-4005(03)00266-1 CrossRefGoogle Scholar
  14. 14.
    Xiong B, Ren K, Shu Y, Chen Y, Shen B, Wu H (2014) Recent developments in microfluidics for cell studies. Adv Mater 26(31):5525–5532. doi: 10.1002/adma.201305348 CrossRefGoogle Scholar
  15. 15.
    Duncombe TA, Tentori AM, Herr AE (2015) Microfluidics: reframing biological enquiry. Nat Rev Mol Cell Biol 16(9):554–567. doi: 10.1038/nrm4041 CrossRefGoogle Scholar
  16. 16.
    Priest C (2010) Surface patterning of bonded microfluidic channels. Biomicrofluidics 4(3):32206. doi: 10.1063/1.3493643 CrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    Lucchetta EM, Lee JH, Fu LA, Patel NH, Ismagilov RF (2005) Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics. Nature 434(7037):1134–1138. doi: 10.1038/nature03509 CrossRefGoogle Scholar
  19. 19.
    Araci IE, Brisk P (2014) Recent developments in microfluidic large scale integration. Curr Opin Biotechnol 25:60–68. doi: 10.1016/j.copbio.2013.08.014 CrossRefGoogle Scholar
  20. 20.
    Melin J, Quake SR (2007) Microfluidic large-scale integration: the evolution of design rules for biological automation. Annu Rev Biophys Biomol Struct 36:213–231. doi: 10.1146/annurev.biophys.36.040306.132646 CrossRefGoogle Scholar
  21. 21.
    Wu J, He Z, Chen Q, Lin J-M (2016) Biochemical analysis on microfluidic chips. TrAC Trends Anal Chem 80:213–231. doi: 10.1016/j.trac.2016.03.013 CrossRefGoogle Scholar
  22. 22.
    Kellogg RA, Gomez-Sjoberg R, Leyrat AA, Tay S (2014) High-throughput microfluidic single-cell analysis pipeline for studies of signaling dynamics. Nat Protoc 9(7):1713–1726. doi: 10.1038/nprot.2014.120 CrossRefGoogle Scholar
  23. 23.
    Shembekar N, Chaipan C, Utharala R, Merten CA (2016) Droplet-based microfluidics in drug discovery, transcriptomics and high-throughput molecular genetics. Lab Chip 16(8):1314–1331. doi: 10.1039/c6lc00249h CrossRefGoogle Scholar
  24. 24.
    Joensson HN, Andersson Svahn H (2012) Droplet microfluidics—a tool for single-cell analysis. Angew Chem Int Ed Engl 51(49):12176–12192. doi: 10.1002/anie.201200460 CrossRefGoogle Scholar
  25. 25.
    Rothbauer M, Wartmann D, Charwat V, Ertl P (2015) Recent advances and future applications of microfluidic live-cell microarrays. Biotechnol Adv 33(6 Pt 1):948–961. doi: 10.1016/j.biotechadv.2015.06.006 CrossRefGoogle Scholar
  26. 26.
    Willaert R, Goossens K (2015) Microfluidic bioreactors for cellular microarrays. Fermentation 1(1):38–78. doi: 10.3390/fermentation1010038 CrossRefGoogle Scholar
  27. 27.
    Mehling M, Tay S (2014) Microfluidic cell culture. Curr Opin Biotechnol 25:95–102. doi: 10.1016/j.copbio.2013.10.005 CrossRefGoogle Scholar
  28. 28.
    Halldorsson S, Lucumi E, Gomez-Sjoberg R, Fleming RM (2015) Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices. Biosens Bioelectron 63:218–231. doi: 10.1016/j.bios.2014.07.029 CrossRefGoogle Scholar
  29. 29.
    Shields CW, Reyes CD, Lopez GP (2015) Microfluidic cell sorting: a review of the advances in the separation of cells from debulking to rare cell isolation. Lab Chip 15(5):1230–1249. doi: 10.1039/c4lc01246a CrossRefGoogle Scholar
  30. 30.
    Pappas D (2016) Microfluidics and cancer analysis: cell separation, cell/tissue culture, cell mechanics, and integrated analysis systems. Analyst 141(2):525–535. doi: 10.1039/c5an01778e CrossRefGoogle Scholar
  31. 31.
    Ertl P, Sticker D, Charwat V, Kasper C, Lepperdinger G (2014) Lab-on-a-chip technologies for stem cell analysis. Trends Biotechnol 32(5):245–253. doi: 10.1016/j.tibtech.2014.03.004 CrossRefGoogle Scholar
  32. 32.
    Mach AJ, Adeyiga OB, Di Carlo D (2013) Microfluidic sample preparation for diagnostic cytopathology. Lab Chip 13(6):1011–1026. doi: 10.1039/c2lc41104k CrossRefGoogle Scholar
  33. 33.
    Eicher D, Merten CA (2011) Microfluidic devices for diagnostic applications. Expert Rev Mol Diagn 11(5):505–519. doi: 10.1586/ERM.11.25 CrossRefGoogle Scholar
  34. 34.
    Dittrich PS, Manz A (2006) Lab-on-a-chip: microfluidics in drug discovery. Nat Rev Drug Discov 5(3):210–218. doi: 10.1038/nrd1985 CrossRefGoogle Scholar
  35. 35.
    Neuzi P, Giselbrecht S, Lange K, Huang TJ, Manz A (2012) Revisiting lab-on-a-chip technology for drug discovery. Nat Rev Drug Discov 11(8):620–632. doi: 10.1038/nrd3799 CrossRefGoogle Scholar
  36. 36.
    Choi NW, Cabodi M, Held B, Gleghorn JP, Bonassar LJ, Stroock AD (2007) Microfluidic scaffolds for tissue engineering. Nat Mater 6(11):908–915. doi: 10.1038/nmat2022 CrossRefGoogle Scholar
  37. 37.
    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
  38. 38.
    Tehranirokh M, Kouzani AZ, Francis PS, Kanwar JR (2013) Microfluidic devices for cell cultivation and proliferation. Biomicrofluidics 7(5):51502. doi: 10.1063/1.4826935 CrossRefGoogle Scholar
  39. 39.
    Gao D, Liu H, Jiang Y, Lin J-M, Gao D, Liu H, Jiang Y (2012) Recent developments in microfluidic devices for in vitro cell culture for cell-biology research. TrAC Trends Anal Chem 35:150–164. doi: 10.1016/j.trac.2012.02.008 CrossRefGoogle Scholar
  40. 40.
    Gupta N, Liu JR, Patel B, Solomon DE, Vaidya B, Gupta V (2016) Microfluidics-based 3D cell culture models: utility in novel drug discovery and delivery research. Bioeng Transl Med 1(1):63–81. doi: 10.1002/btm2.10013 Google Scholar
  41. 41.
    Shamir ER, Ewald AJ (2014) Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol 15(10):647–664. doi: 10.1038/nrm3873 CrossRefGoogle Scholar
  42. 42.
    Ravi M, Paramesh V, Kaviya SR, Anuradha E, Solomon FD (2015) 3D cell culture systems: advantages and applications. J Cell Physiol 230(1):16–26. doi: 10.1002/jcp.24683 CrossRefGoogle Scholar
  43. 43.
    Edmondson R, Broglie JJ, Adcock AF, Yang L (2014) Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol 12(4):207–218. doi: 10.1089/adt.2014.573 CrossRefGoogle Scholar
  44. 44.
    van Duinen V, Trietsch SJ, Joore J, Vulto P, Hankemeier T (2015) Microfluidic 3D cell culture: from tools to tissue models. Curr Opin Biotechnol 35:118–126. doi: 10.1016/j.copbio.2015.05.002 CrossRefGoogle Scholar
  45. 45.
    Lee DH, Bae CY, Kwon S, Park JK (2015) User-friendly 3D bioassays with cell-containing hydrogel modules: narrowing the gap between microfluidic bioassays and clinical end-users’ needs. Lab Chip 15(11):2379–2387. doi: 10.1039/c5lc00239g CrossRefGoogle Scholar
  46. 46.
    Li XJ, Valadez AV, Zuo P, Nie Z (2012) Microfluidic 3D cell culture: potential application for tissue-based bioassays. Bioanalysis 4(12):1509–1525. doi: 10.4155/bio.12.133 CrossRefGoogle Scholar
  47. 47.
    Sung KE, Su X, Berthier E, Pehlke C, Friedl A, Beebe DJ (2013) Understanding the impact of 2D and 3D fibroblast cultures on in vitro breast cancer models. PLoS ONE 8(10):e76373. doi: 10.1371/journal.pone.0076373 CrossRefGoogle Scholar
  48. 48.
    Chen Q, Utech S, Chen D, Prodanovic R, Lin JM, Weitz DA (2016) Controlled assembly of heterotypic cells in a core-shell scaffold: organ in a droplet. Lab Chip 16(8):1346–1349. doi: 10.1039/c6lc00231e CrossRefGoogle Scholar
  49. 49.
    Griffin DR, Weaver WM, Scumpia PO, Di Carlo D, Segura T (2015) Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat Mater 14(7):737–744. doi: 10.1038/nmat4294 CrossRefGoogle Scholar
  50. 50.
    Frey O, Misun PM, Fluri DA, Hengstler JG, Hierlemann A (2014) Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis. Nat Commun 5:4250. doi: 10.1038/ncomms5250 CrossRefGoogle Scholar
  51. 51.
    Misun PM, Rothe J, Schmid YRF, Hierlemann A, Frey O (2016) Multi-analyte biosensor interface for real-time monitoring of 3D microtissue spheroids in hanging-drop networks. Microsyst Nanoeng 2:16022. doi: 10.1038/micronano.2016.22 CrossRefGoogle Scholar
  52. 52.
    Chen YC, Lou X, Zhang Z, Ingram P, Yoon E (2015) High-throughput cancer cell sphere formation for characterizing the efficacy of photo dynamic therapy in 3D cell cultures. Sci Rep 5:12175. doi: 10.1038/srep12175 CrossRefGoogle Scholar
  53. 53.
    Tsutsui H, Yu E, Marquina S, Valamehr B, Wong I, Wu H, Ho CM (2010) Efficient dielectrophoretic patterning of embryonic stem cells in energy landscapes defined by hydrogel geometries. Ann Biomed Eng 38(12):3777–3788. doi: 10.1007/s10439-010-0108-1 CrossRefGoogle Scholar
  54. 54.
    Physiology in perspective: cell-cell interactions: the physiological basis of communication (2014) Physiology (Bethesda) 29(4):220–221. doi: 10.1152/physiol.00031.2014
  55. 55.
    Kim SH, Turnbull J, Guimond S (2011) Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol 209(2):139–151. doi: 10.1530/JOE-10-0377 CrossRefGoogle Scholar
  56. 56.
    Zervantonakis IK, Kothapalli CR, Chung S, Sudo R, Kamm RD (2011) Microfluidic devices for studying heterotypic cell-cell interactions and tissue specimen cultures under controlled microenvironments. Biomicrofluidics 5(1):13406. doi: 10.1063/1.3553237 CrossRefGoogle Scholar
  57. 57.
    Guo F, French JB, Li P, Zhao H, Chan CY, Fick JR, Benkovic SJ, Huang TJ (2013) Probing cell-cell communication with microfluidic devices. Lab Chip 13(16):3152–3162. doi: 10.1039/c3lc90067c CrossRefGoogle Scholar
  58. 58.
    Delamarche E, Tonna N, Lovchik RD, Bianco F, Matteoli M (2013) Pharmacology on microfluidics: multimodal analysis for studying cell-cell interaction. Curr Opin Pharmacol 13(5):821–828. doi: 10.1016/j.coph.2013.07.005 CrossRefGoogle Scholar
  59. 59.
    Nahavandi S, Tang SY, Baratchi S, Soffe R, Nahavandi S, Kalantar-zadeh K, Mitchell A, Khoshmanesh K (2014) Microfluidic platforms for the investigation of intercellular signalling mechanisms. Small 10(23):4810–4826. doi: 10.1002/smll.201401444 CrossRefGoogle Scholar
  60. 60.
    Jeon JS, Bersini S, Gilardi M, Dubini G, Charest JL, Moretti M, Kamm RD (2015) Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc Natl Acad Sci U S A 112(1):214–219. doi: 10.1073/pnas.1417115112 CrossRefGoogle Scholar
  61. 61.
    Zervantonakis IK, Hughes-Alford SK, Charest JL, Condeelis JS, Gertler FB, Kamm RD (2012) Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc Natl Acad Sci U S A 109(34):13515–13520. doi: 10.1073/pnas.1210182109 CrossRefGoogle Scholar
  62. 62.
    Kimura H, Yamamoto T, Sakai H, Sakai Y, Fujii T (2008) An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models. Lab Chip 8(5):741–746. doi: 10.1039/b717091b CrossRefGoogle Scholar
  63. 63.
    Chen Q, Wu J, Zhuang Q, Lin X, Zhang J, Lin JM (2013) Microfluidic isolation of highly pure embryonic stem cells using feeder-separated co-culture system. Sci Rep 3:2433. doi: 10.1038/srep02433 CrossRefGoogle Scholar
  64. 64.
    Liu W, Li L, Wang X, Ren L, Wang X, Wang J, Tu Q, Huang X, Wang J (2010) An integrated microfluidic system for studying cell-microenvironmental interactions versatilely and dynamically. Lab Chip 10(13):1717–1724. doi: 10.1039/c001049a CrossRefGoogle Scholar
  65. 65.
    Lin X, Chen Q, Liu W, Zhang J, Wang S, Lin Z, Lin JM (2015) Oxygen-induced cell migration and on-line monitoring biomarkers modulation of cervical cancers on a microfluidic system. Sci Rep 5:9643. doi: 10.1038/srep09643 CrossRefGoogle Scholar
  66. 66.
    Tumarkin E, Tzadu L, Csaszar E, Seo M, Zhang H, Lee A, Peerani R, Purpura K, Zandstra PW, Kumacheva E (2011) High-throughput combinatorial cell co-culture using microfluidics. Integr Biol (Camb) 3(6):653–662. doi: 10.1039/c1ib00002k CrossRefGoogle Scholar
  67. 67.
    Ricoult SG, Goldman JS, Stellwagen D, Juncker D, Kennedy TE (2012) Generation of microisland cultures using microcontact printing to pattern protein substrates. J Neurosci Methods 208(1):10–17. doi: 10.1016/j.jneumeth.2012.04.016 CrossRefGoogle Scholar
  68. 68.
    Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26(1):120–126. doi: 10.1038/nbt1361 CrossRefGoogle Scholar
  69. 69.
    Cho CH, Park J, Tilles AW, Berthiaume F, Toner M, Yarmush ML (2010) Layered patterning of hepatocytes in co-culture systems using microfabricated stencils. Biotechniques 48(1):47–52. doi: 10.2144/000113317 CrossRefGoogle Scholar
  70. 70.
    Edahiro J, Sumaru K, Ooshima Y, Kanamori T (2009) Selective separation and co-culture of cells by photo-induced enhancement of cell adhesion (PIECA). Biotechnol Bioeng 102(4):1278–1282. doi: 10.1002/bit.22124 CrossRefGoogle Scholar
  71. 71.
    Gao Y, Broussard J, Haque A, Revzin A, Lin T (2016) Functional imaging of neuron–astrocyte interactions in a compartmentalized microfluidic device. Microsyst Nanoeng 2:15045. doi: 10.1038/micronano.2015.45 CrossRefGoogle Scholar
  72. 72.
    Shin Y, Han S, Jeon JS, Yamamoto K, Zervantonakis IK, Sudo R, Kamm RD, Chung S (2012) Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels. Nat Protoc 7(7):1247–1259. doi: 10.1038/nprot.2012.051 CrossRefGoogle Scholar
  73. 73.
    Dura B, Dougan SK, Barisa M, Hoehl MM, Lo CT, Ploegh HL, Voldman J (2015) Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing. Nat Commun 6:5940. doi: 10.1038/ncomms6940 CrossRefGoogle Scholar
  74. 74.
    Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotechnol 32(8):760–772. doi: 10.1038/nbt.2989 CrossRefGoogle Scholar
  75. 75.
    Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs-on-chips. Trends Cell Biol 21(12):745–754. doi: 10.1016/j.tcb.2011.09.005 CrossRefGoogle Scholar
  76. 76.
    Lee E, Song HG, Chen CS (2016) Biomimetic on-a-chip platforms for studying cancer metastasis. Curr Opin Chem Eng 11:20–27. doi: 10.1016/j.coche.2015.12.001 CrossRefGoogle Scholar
  77. 77.
    Esch EW, Bahinski A, Huh D (2015) Organs-on-chips at the frontiers of drug discovery. Nat Rev Drug Discov 14(4):248–260. doi: 10.1038/nrd4539 CrossRefGoogle Scholar
  78. 78.
    Chrobak KM, Potter DR, Tien J (2006) Formation of perfused, functional microvascular tubes in vitro. Microvasc Res 71(3):185–196. doi: 10.1016/j.mvr.2006.02.005 CrossRefGoogle Scholar
  79. 79.
    Tsai M, Kita A, Leach J, Rounsevell R, Huang JN, Moake J, Ware RE, Fletcher DA, Lam WA (2012) In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology. J Clin Invest 122(1):408–418. doi: 10.1172/JCI58753 CrossRefGoogle Scholar
  80. 80.
    Cho H, Seo JH, Wong KH, Terasaki Y, Park J, Bong K, Arai K, Lo EH, Irimia D (2015) Three-dimensional blood-brain barrier model for in vitro studies of neurovascular pathology. Sci Rep 5:15222. doi: 10.1038/srep15222 CrossRefGoogle Scholar
  81. 81.
    Toh YC, Lim TC, Tai D, Xiao G, van Noort D, Yu H (2009) A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip 9(14):2026–2035. doi: 10.1039/b900912d CrossRefGoogle Scholar
  82. 82.
    Carraro A, Hsu WM, Kulig KM, Cheung WS, Miller ML, Weinberg EJ, Swart EF, Kaazempur-Mofrad M, Borenstein JT, Vacanti JP, Neville C (2008) In vitro analysis of a hepatic device with intrinsic microvascular-based channels. Biomed Microdevices 10(6):795–805. doi: 10.1007/s10544-008-9194-3 CrossRefGoogle Scholar
  83. 83.
    Huh D, Fujioka H, Tung YC, Futai N, Paine R 3rd, Grotberg JB, Takayama S (2007) Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems. Proc Natl Acad Sci U S A 104(48):18886–18891. doi: 10.1073/pnas.0610868104 CrossRefGoogle Scholar
  84. 84.
    Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, Thorneloe KS, McAlexander MA, Ingber DE (2012) A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med 4(159):159ra147. doi: 10.1126/scitranslmed.3004249
  85. 85.
    Jang KJ, Suh KY (2010) A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells. Lab Chip 10(1):36–42. doi: 10.1039/b907515a CrossRefGoogle Scholar
  86. 86.
    Wilmer MJ, Ng CP, Lanz HL, Vulto P, Suter-Dick L, Masereeuw R (2016) Kidney-on-a-chip technology for drug-induced nephrotoxicity screening. Trends Biotechnol 34(2):156–170. doi: 10.1016/j.tibtech.2015.11.001 CrossRefGoogle Scholar
  87. 87.
    Agarwal A, Goss JA, Cho A, McCain ML, Parker KK (2013) Microfluidic heart on a chip for higher throughput pharmacological studies. Lab Chip 13(18):3599–3608. doi: 10.1039/c3lc50350j CrossRefGoogle Scholar
  88. 88.
    Grosberg A, Alford PW, McCain ML, Parker KK (2011) Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. Lab Chip 11(24):4165–4173. doi: 10.1039/c1lc20557a CrossRefGoogle Scholar
  89. 89.
    Park SH, Sim WY, Min BH, Yang SS, Khademhosseini A, Kaplan DL (2012) Chip-based comparison of the osteogenesis of human bone marrow- and adipose tissue-derived mesenchymal stem cells under mechanical stimulation. PLoS ONE 7(9):e46689. doi: 10.1371/journal.pone.0046689 CrossRefGoogle Scholar
  90. 90.
    Grosberg A, Nesmith AP, Goss JA, Brigham MD, McCain ML, Parker KK (2012) Muscle on a chip: in vitro contractility assays for smooth and striated muscle. J Pharmacol Toxicol Methods 65(3):126–135. doi: 10.1016/j.vascn.2012.04.001 CrossRefGoogle Scholar
  91. 91.
    Zheng Y, Chen J, Craven M, Choi NW, Totorica S, Diaz-Santana A, Kermani P, Hempstead B, Fischbach-Teschl C, Lopez JA, Stroock AD (2012) In vitro microvessels for the study of angiogenesis and thrombosis. Proc Natl Acad Sci U S A 109(24):9342–9347. doi: 10.1073/pnas.1201240109 CrossRefGoogle Scholar
  92. 92.
    Huh D, Kim HJ, Fraser JP, Shea DE, Khan M, Bahinski A, Hamilton GA, Ingber DE (2013) Microfabrication of human organs-on-chips. Nat Protoc 8(11):2135–2157. doi: 10.1038/nprot.2013.137 CrossRefGoogle Scholar
  93. 93.
    Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (2010) Reconstituting organ-level lung functions on a chip. Science 328(5986):1662–1668. doi: 10.1126/science.1188302 CrossRefGoogle Scholar
  94. 94.
    Benam KH, Villenave R, Lucchesi C, Varone A, Hubeau C, Lee HH, Alves SE, Salmon M, Ferrante TC, Weaver JC, Bahinski A, Hamilton GA, Ingber DE (2016) Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat Methods 13(2):151–157. doi: 10.1038/nmeth.3697 CrossRefGoogle Scholar
  95. 95.
    Young EW (2013) Cells, tissues, and organs on chips: challenges and opportunities for the cancer tumor microenvironment. Integr Biol (Camb) 5(9):1096–1109. doi: 10.1039/c3ib40076j CrossRefGoogle Scholar
  96. 96.
    Fan Y, Nguyen DT, Akay Y, Xu F, Akay M (2016) Engineering a brain cancer chip for high-throughput drug screening. Sci Rep 6:25062. doi: 10.1038/srep25062 CrossRefGoogle Scholar
  97. 97.
    Albanese A, Lam AK, Sykes EA, Rocheleau JV, Chan WC (2013) Tumour-on-a-chip provides an optical window into nanoparticle tissue transport. Nat Commun 4:2718. doi: 10.1038/ncomms3718 CrossRefGoogle Scholar
  98. 98.
    Zheng F, Fu F, Cheng Y, Wang C, Zhao Y, Gu Z (2016) Organ-on-a-chip systems: microengineering to biomimic living systems. Small 12(17):2253–2282. doi: 10.1002/smll.201503208 CrossRefGoogle Scholar
  99. 99.
    Yi C, Li C-W, Ji S, Yang M (2006) Microfluidics technology for manipulation and analysis of biological cells. Anal Chim Acta 560(1–2):1–23. doi: 10.1016/j.aca.2005.12.037 CrossRefGoogle Scholar
  100. 100.
    Mu X, Zheng W, Sun J, Zhang W, Jiang X (2013) Microfluidics for manipulating cells. Small 9(1):9–21. doi: 10.1002/smll.201200996 CrossRefGoogle Scholar
  101. 101.
    Yarmush ML, King KR (2009) Living-cell microarrays. Annu Rev Biomed Eng 11:235–257. doi: 10.1146/annurev.bioeng.10.061807.160502 CrossRefGoogle Scholar
  102. 102.
    Jonczyk R, Kurth T, Lavrentieva A, Walter JG, Scheper T, Stahl F (2016) Living cell microarrays: an overview of concepts. Microarrays (Basel) 5(2). doi: 10.3390/microarrays5020011
  103. 103.
    Chung J, Kim YJ, Yoon E (2011) Highly-efficient single-cell capture in microfluidic array chips using differential hydrodynamic guiding structures. Appl Phys Lett 98(12):123701. doi: 10.1063/1.3565236 CrossRefGoogle Scholar
  104. 104.
    Lin L, Chu YS, Thiery JP, Lim CT, Rodriguez I (2013) Microfluidic cell trap array for controlled positioning of single cells on adhesive micropatterns. Lab Chip 13(4):714–721. doi: 10.1039/c2lc41070b CrossRefGoogle Scholar
  105. 105.
    Chung K, Kim Y, Kanodia JS, Gong E, Shvartsman SY, Lu H (2011) A microfluidic array for large-scale ordering and orientation of embryos. Nat Methods 8(2):171–176. doi: 10.1038/nmeth.1548 CrossRefGoogle Scholar
  106. 106.
    Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, Engstrom A, Zhu H, Sundaresan TK, Miyamoto DT, Luo X, Bardia A, Wittner BS, Ramaswamy S, Shioda T, Ting DT, Stott SL, Kapur R, Maheswaran S, Haber DA, Toner M (2015) A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods 12(7):685–691. doi: 10.1038/nmeth.3404 CrossRefGoogle Scholar
  107. 107.
    Lecault V, Vaninsberghe M, Sekulovic S, Knapp DJ, Wohrer S, Bowden W, Viel F, McLaughlin T, Jarandehei A, Miller M, Falconnet D, White AK, Kent DG, Copley MR, Taghipour F, Eaves CJ, Humphries RK, Piret JM, Hansen CL (2011) High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays. Nat Methods 8(7):581–586. doi: 10.1038/nmeth.1614 CrossRefGoogle Scholar
  108. 108.
    Novo P, Dell’Aica M, Janasek D, Zahedi RP (2016) High spatial and temporal resolution cell manipulation techniques in microchannels. Analyst 141(6):1888–1905. doi: 10.1039/c6an00027d CrossRefGoogle Scholar
  109. 109.
    Dudani JS, Gossett DR, Tse HT, Di Carlo D (2013) Pinched-flow hydrodynamic stretching of single-cells. Lab Chip 13(18):3728–3734. doi: 10.1039/c3lc50649e CrossRefGoogle Scholar
  110. 110.
    McGrath J, Jimenez M, Bridle H (2014) Deterministic lateral displacement for particle separation: a review. Lab Chip 14(21):4139–4158. doi: 10.1039/c4lc00939h CrossRefGoogle Scholar
  111. 111.
    Qian C, Huang H, Chen L, Li X, Ge Z, Chen T, Yang Z, Sun L (2014) Dielectrophoresis for bioparticle manipulation. Int J Mol Sci 15(10):18281–18309. doi: 10.3390/ijms151018281 CrossRefGoogle Scholar
  112. 112.
    Lim B, Reddy V, Hu X, Kim K, Jadhav M, Abedini-Nassab R, Noh YW, Lim YT, Yellen BB, Kim C (2014) Magnetophoretic circuits for digital control of single particles and cells. Nat Commun 5:3846. doi: 10.1038/ncomms4846 Google Scholar
  113. 113.
    Ahmed D, Ozcelik A, Bojanala N, Nama N, Upadhyay A, Chen Y, Hanna-Rose W, Huang TJ (2016) Rotational manipulation of single cells and organisms using acoustic waves. Nat Commun 7:11085. doi: 10.1038/ncomms11085 CrossRefGoogle Scholar
  114. 114.
    Zhang H, Liu KK (2008) Optical tweezers for single cells. J R Soc Interface 5(24):671–690. doi: 10.1098/rsif.2008.0052 CrossRefGoogle Scholar
  115. 115.
    Warkiani ME, Khoo BL, Wu L, Tay AK, Bhagat AA, Han J, Lim CT (2016) Ultra-fast, label-free isolation of circulating tumor cells from blood using spiral microfluidics. Nat Protoc 11(1):134–148. doi: 10.1038/nprot.2016.003 CrossRefGoogle Scholar
  116. 116.
    Karabacak NM, Spuhler PS, Fachin F, Lim EJ, Pai V, Ozkumur E, Martel JM, Kojic N, Smith K, Chen PI, Yang J, Hwang H, Morgan B, Trautwein J, Barber TA, Stott SL, Maheswaran S, Kapur R, Haber DA, Toner M (2014) Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat Protoc 9(3):694–710. doi: 10.1038/nprot.2014.044 CrossRefGoogle Scholar
  117. 117.
    Collins DJ, Morahan B, Garcia-Bustos J, Doerig C, Plebanski M, Neild A (2015) Two-dimensional single-cell patterning with one cell per well driven by surface acoustic waves. Nat Commun 6:8686. doi: 10.1038/ncomms9686 CrossRefGoogle Scholar
  118. 118.
    Voldman J (2006) Electrical forces for microscale cell manipulation. Annu Rev Biomed Eng 8:425–454. doi: 10.1146/annurev.bioeng.8.061505.095739 CrossRefGoogle Scholar
  119. 119.
    Yasukawa T, Nagamine K, Horiguchi Y, Shiku H, Koide M, Itayama T, Shiraishi F, Matsue T (2008) Electrophoretic cell manipulation and electrochemical gene-function analysis based on a yeast two-hybrid system in a microfluidic device. Anal Chem 80(10):3722–3727. doi: 10.1021/ac800143t CrossRefGoogle Scholar
  120. 120.
    Park K, Suk HJ, Akin D, Bashir R (2009) Dielectrophoresis-based cell manipulation using electrodes on a reusable printed circuit board. Lab Chip 9(15):2224–2229. doi: 10.1039/b904328d CrossRefGoogle Scholar
  121. 121.
    Glawdel T, Ren CL (2009) Electro-osmotic flow control for living cell analysis in microfluidic PDMS chips. Mech Res Commun 36(1):75–81. doi: 10.1016/j.mechrescom.2008.06.015 CrossRefGoogle Scholar
  122. 122.
    Geng T, Lu C (2013) Microfluidic electroporation for cellular analysis and delivery. Lab Chip 13(19):3803–3821. doi: 10.1039/c3lc50566a CrossRefGoogle Scholar
  123. 123.
    Wu W, Qu Y, Hu N, Zeng Y, Yang J, Xu H, Yin ZQ (2015) A cell electrofusion chip for somatic cells reprogramming. PLoS ONE 10(7):e0131966. doi: 10.1371/journal.pone.0131966 CrossRefGoogle Scholar
  124. 124.
    Pethig R (2010) Review article-dielectrophoresis: status of the theory, technology, and applications. Biomicrofluidics 4(2). doi: 10.1063/1.3456626
  125. 125.
    Mazutis L, Gilbert J, Ung WL, Weitz DA, Griffiths AD, Heyman JA (2013) Single-cell analysis and sorting using droplet-based microfluidics. Nat Protoc 8(5):870–891. doi: 10.1038/nprot.2013.046 CrossRefGoogle Scholar
  126. 126.
    Yarmush ML, Golberg A, Sersa G, Kotnik T, Miklavcic D (2014) Electroporation-based technologies for medicine: principles, applications, and challenges. Annu Rev Biomed Eng 16:295–320. doi: 10.1146/annurev-bioeng-071813-104622 CrossRefGoogle Scholar
  127. 127.
    Movahed S, Li D (2010) Microfluidics cell electroporation. Microfluid Nanofluid 10(4):703–734. doi: 10.1007/s10404-010-0716-y CrossRefGoogle Scholar
  128. 128.
    Garcia PA, Ge Z, Moran JL, Buie CR (2016) Microfluidic screening of electric fields for electroporation. Sci Rep 6:21238. doi: 10.1038/srep21238 CrossRefGoogle Scholar
  129. 129.
    Qu B, Eu YJ, Jeong WJ, Kim DP (2012) Droplet electroporation in microfluidics for efficient cell transformation with or without cell wall removal. Lab Chip 12(21):4483–4488. doi: 10.1039/c2lc40360a CrossRefGoogle Scholar
  130. 130.
    Kang W, Giraldo-Vela JP, Nathamgari SS, McGuire T, McNaughton RL, Kessler JA, Espinosa HD (2014) Microfluidic device for stem cell differentiation and localized electroporation of postmitotic neurons. Lab Chip 14(23):4486–4495. doi: 10.1039/c4lc00721b CrossRefGoogle Scholar
  131. 131.
    Ogle BM, Cascalho M, Platt JL (2005) Biological implications of cell fusion. Nat Rev Mol Cell Biol 6(7):567–575. doi: 10.1038/nrm1678 CrossRefGoogle Scholar
  132. 132.
    Hu N, Yang J, Joo SW, Banerjee AN, Qian S (2013) Cell electrofusion in microfluidic devices: a review. Sens Actuators B: Chem 178:63–85. doi: 10.1016/j.snb.2012.12.034 CrossRefGoogle Scholar
  133. 133.
    Skelley AM, Kirak O, Suh H, Jaenisch R, Voldman J (2009) Microfluidic control of cell pairing and fusion. Nat Methods 6(2):147–152. doi: 10.1038/nmeth.1290 CrossRefGoogle Scholar
  134. 134.
    Takayama S, Ostuni E, LeDuc P, Naruse K, Ingber DE, Whitesides GM (2001) Subcellular positioning of small molecules. Nature 411(6841):1016. doi: 10.1038/35082637 CrossRefGoogle Scholar
  135. 135.
    Takayama S, Ostuni E, LeDuc P, Naruse K, Ingber DE, Whitesides GM (2003) Selective chemical treatment of cellular microdomains using multiple laminar streams. Chem Biol 10(2):123–130. doi: 10.1016/s1074-5521(03)00019-x CrossRefGoogle Scholar
  136. 136.
    Lee CY, Romanova EV, Sweedler JV (2013) Laminar stream of detergents for subcellular neurite damage in a microfluidic device: a simple tool for the study of neuroregeneration. J Neural Eng 10(3):036020. doi: 10.1088/1741-2560/10/3/036020 CrossRefGoogle Scholar
  137. 137.
    Au AK, Lai H, Utela BR, Folch A (2011) Microvalves and micropumps for BioMEMS. Micromachines 2(4):179–220. doi: 10.3390/mi2020179 CrossRefGoogle Scholar
  138. 138.
    Ogden S, Klintberg L, Thornell G, Hjort K, Bodén R (2013) Review on miniaturized paraffin phase change actuators, valves, and pumps. Microfluid Nanofluid 17(1):53–71. doi: 10.1007/s10404-013-1289-3 CrossRefGoogle Scholar
  139. 139.
    Iverson BD, Garimella SV (2008) Recent advances in microscale pumping technologies: a review and evaluation. Microfluid Nanofluid 5(2):145–174. doi: 10.1007/s10404-008-0266-8 CrossRefGoogle Scholar
  140. 140.
    Shen J, Cai C, Yu Z, Pang Y, Zhou Y, Qian L, Wei W, Huang Y (2015) A microfluidic live cell assay to study anthrax toxin induced cell lethality assisted by conditioned medium. Sci Rep 5:8651. doi: 10.1038/srep08651 CrossRefGoogle Scholar
  141. 141.
    Taylor RJ, Falconnet D, Niemisto A, Ramsey SA, Prinz S, Shmulevich I, Galitski T, Hansen CL (2009) Dynamic analysis of MAPK signaling using a high-throughput microfluidic single-cell imaging platform. Proc Natl Acad Sci U S A 106(10):3758–3763. doi: 10.1073/pnas.0813416106 CrossRefGoogle Scholar
  142. 142.
    Nguyen EH, Schwartz MP, Murphy WL (2011) Biomimetic approaches to control soluble concentration gradients in biomaterials. Macromol Biosci 11(4):483–492. doi: 10.1002/mabi.201000448 CrossRefGoogle Scholar
  143. 143.
    Dhumpa R, Roper MG (2012) Temporal gradients in microfluidic systems to probe cellular dynamics: a review. Anal Chim Acta 743:9–18. doi: 10.1016/j.aca.2012.07.006 CrossRefGoogle Scholar
  144. 144.
    Chung BG, Choo J (2010) Microfluidic gradient platforms for controlling cellular behavior. Electrophoresis 31(18):3014–3027. doi: 10.1002/elps.201000137 CrossRefGoogle Scholar
  145. 145.
    Toh AGG, Wang ZP, Yang C, Nguyen N-T (2013) Engineering microfluidic concentration gradient generators for biological applications. Microfluid Nanofluid 16(1–2):1–18. doi: 10.1007/s10404-013-1236-3 Google Scholar
  146. 146.
    Lin F, Butcher EC (2006) T cell chemotaxis in a simple microfluidic device. Lab Chip 6(11):1462–1469. doi: 10.1039/b607071j CrossRefGoogle Scholar
  147. 147.
    Englert DL, Manson MD, Jayaraman A (2010) Investigation of bacterial chemotaxis in flow-based microfluidic devices. Nat Protoc 5(5):864–872. doi: 10.1038/nprot.2010.18 CrossRefGoogle Scholar
  148. 148.
    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
  149. 149.
    Dertinger SK, Jiang X, Li Z, Murthy VN, Whitesides GM (2002) Gradients of substrate-bound laminin orient axonal specification of neurons. Proc Natl Acad Sci U S A 99(20):12542–12547. doi: 10.1073/pnas.192457199 CrossRefGoogle Scholar
  150. 150.
    Gao D, Li H, Wang N, Lin JM (2012) Evaluation of the absorption of methotrexate on cells and its cytotoxicity assay by using an integrated microfluidic device coupled to a mass spectrometer. Anal Chem 84(21):9230–9237. doi: 10.1021/ac301966c Google Scholar
  151. 151.
    Wu J, Wu X, Lin F (2013) Recent developments in microfluidics-based chemotaxis studies. Lab Chip 13(13):2484–2499. doi: 10.1039/c3lc50415h CrossRefGoogle Scholar
  152. 152.
    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
  153. 153.
    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
  154. 154.
    Nguyen DH, Stapleton SC, Yang MT, Cha SS, Choi CK, Galie PA, Chen CS (2013) Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc Natl Acad Sci U S A 110(17):6712–6717. doi: 10.1073/pnas.1221526110 CrossRefGoogle Scholar
  155. 155.
    Chabaud M, Heuze ML, Bretou M, Vargas P, Maiuri P, Solanes P, Maurin M, Terriac E, Le Berre M, Lankar D, Piolot T, Adelstein RS, Zhang Y, Sixt M, Jacobelli J, Benichou O, Voituriez R, Piel M, Lennon-Dumenil AM (2015) Cell migration and antigen capture are antagonistic processes coupled by myosin II in dendritic cells. Nat Commun 6:7526. doi: 10.1038/ncomms8526 CrossRefGoogle Scholar
  156. 156.
    Boneschansker L, Yan J, Wong E, Briscoe DM, Irimia D (2014) Microfluidic platform for the quantitative analysis of leukocyte migration signatures. Nat Commun 5:4787. doi: 10.1038/ncomms5787 CrossRefGoogle Scholar
  157. 157.
    Vanapalli SA, Duits MH, Mugele F (2009) Microfluidics as a functional tool for cell mechanics. Biomicrofluidics 3(1):12006. doi: 10.1063/1.3067820 CrossRefGoogle Scholar
  158. 158.
    Tee SY, Bausch AR, Janmey PA (2009) The mechanical cell. Curr Biol 19(17):R745–R748. doi: 10.1016/j.cub.2009.06.034 CrossRefGoogle Scholar
  159. 159.
    Polacheck WJ, Li R, Uzel SG, Kamm RD (2013) Microfluidic platforms for mechanobiology. Lab Chip 13(12):2252–2267. doi: 10.1039/c3lc41393d CrossRefGoogle Scholar
  160. 160.
    Jain A, Graveline A, Waterhouse A, Vernet A, Flaumenhaft R, Ingber DE (2016) A shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function. Nat Commun 7:10176. doi: 10.1038/ncomms10176 CrossRefGoogle Scholar
  161. 161.
    Sundd P, Gutierrez E, Koltsova EK, Kuwano Y, Fukuda S, Pospieszalska MK, Groisman A, Ley K (2012) ‘Slings’ enable neutrophil rolling at high shear. Nature 488(7411):399–403. doi: 10.1038/nature11248 CrossRefGoogle Scholar
  162. 162.
    Sundd P, Gutierrez E, Pospieszalska MK, Zhang H, Groisman A, Ley K (2010) Quantitative dynamic footprinting microscopy reveals mechanisms of neutrophil rolling. Nat Methods 7(10):821–824. doi: 10.1038/nmeth.1508 CrossRefGoogle Scholar
  163. 163.
    Miura S, Sato K, Kato-Negishi M, Teshima T, Takeuchi S (2015) Fluid shear triggers microvilli formation via mechanosensitive activation of TRPV6. Nat Commun 6:8871. doi: 10.1038/ncomms9871 CrossRefGoogle Scholar
  164. 164.
    Humphrey JD, Dufresne ER, Schwartz MA (2014) Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15(12):802–812. doi: 10.1038/nrm3896 CrossRefGoogle Scholar
  165. 165.
    Hsieh HY, Camci-Unal G, Huang TW, Liao R, Chen TJ, Paul A, Tseng FG, Khademhosseini A (2014) Gradient static-strain stimulation in a microfluidic chip for 3D cellular alignment. Lab Chip 14(3):482–493. doi: 10.1039/c3lc50884f CrossRefGoogle Scholar
  166. 166.
    Kollmannsperger A, Sharei A, Raulf A, Heilemann M, Langer R, Jensen KF, Wieneke R, Tampe R (2016) Live-cell protein labelling with nanometre precision by cell squeezing. Nat Commun 7:10372. doi: 10.1038/ncomms10372 CrossRefGoogle Scholar
  167. 167.
    Si F, Li B, Margolin W, Sun SX (2015) Bacterial growth and form under mechanical compression. Sci Rep 5:11367. doi: 10.1038/srep11367 CrossRefGoogle Scholar
  168. 168.
    Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47(4):1394–1400. doi: 10.1002/hep.22193 CrossRefGoogle Scholar
  169. 169.
    Sundararaghavan HG, Monteiro GA, Firestein BL, Shreiber DI (2009) Neurite growth in 3D collagen gels with gradients of mechanical properties. Biotechnol Bioeng 102(2):632–643. doi: 10.1002/bit.22074 CrossRefGoogle Scholar
  170. 170.
    Garcia S, Sunyer R, Olivares A, Noailly J, Atencia J, Trepat X (2015) Generation of stable orthogonal gradients of chemical concentration and substrate stiffness in a microfluidic device. Lab Chip 15(12):2606–2614. doi: 10.1039/c5lc00140d CrossRefGoogle Scholar
  171. 171.
    Polacheck WJ, Chen CS (2016) Measuring cell-generated forces: a guide to the available tools. Nat Methods 13(5):415–423. doi: 10.1038/nmeth.3834 CrossRefGoogle Scholar
  172. 172.
    Tan JL, Tien J, Pirone DM, Gray DS, Bhadriraju K, Chen CS (2003) Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc Natl Acad Sci U S A 100(4):1484–1489. doi: 10.1073/pnas.0235407100 CrossRefGoogle Scholar
  173. 173.
    du Roure O, Saez A, Buguin A, Austin RH, Chavrier P, Silberzan P, Ladoux B (2005) Force mapping in epithelial cell migration. Proc Natl Acad Sci U S A 102(7):2390–2395. doi: 10.1073/pnas.0408482102 CrossRefGoogle Scholar
  174. 174.
    Fu J, Wang YK, Yang MT, Desai RA, Yu X, Liu Z, Chen CS (2010) Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat Methods 7(9):733–736. doi: 10.1038/nmeth.1487 CrossRefGoogle Scholar
  175. 175.
    Ghassemi S, Meacci G, Liu S, Gondarenko AA, Mathur A, Roca-Cusachs P, Sheetz MP, Hone J (2012) Cells test substrate rigidity by local contractions on submicrometer pillars. Proc Natl Acad Sci U S A 109(14):5328–5333. doi: 10.1073/pnas.1119886109 CrossRefGoogle Scholar
  176. 176.
    Trichet L, Le Digabel J, Hawkins RJ, Vedula SR, Gupta M, Ribrault C, Hersen P, Voituriez R, Ladoux B (2012) Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness. Proc Natl Acad Sci U S A 109(18):6933–6938. doi: 10.1073/pnas.1117810109 CrossRefGoogle Scholar
  177. 177.
    Zare RN, Kim S (2010) Microfluidic platforms for single-cell analysis. Annu Rev Biomed Eng 12:187–201. doi: 10.1146/annurev-bioeng-070909-105238 CrossRefGoogle Scholar
  178. 178.
    Chen Y, Li P, Huang PH, Xie Y, Mai JD, Wang L, Nguyen NT, Huang TJ (2014) Rare cell isolation and analysis in microfluidics. Lab Chip 14(4):626–645. doi: 10.1039/c3lc90136j CrossRefGoogle Scholar
  179. 179.
    Autebert J, Coudert B, Bidard FC, Pierga JY, Descroix S, Malaquin L, Viovy JL (2012) Microfluidic: an innovative tool for efficient cell sorting. Methods 57(3):297–307. doi: 10.1016/j.ymeth.2012.07.002 CrossRefGoogle Scholar
  180. 180.
    Gao Y, Li W, Pappas D (2013) Recent advances in microfluidic cell separations. Analyst 138(17):4714–4721. doi: 10.1039/c3an00315a CrossRefGoogle Scholar
  181. 181.
    Gossett DR, Weaver WM, Mach AJ, Hur SC, Tse HT, Lee W, Amini H, Di Carlo D (2010) Label-free cell separation and sorting in microfluidic systems. Anal Bioanal Chem 397(8):3249–3267. doi: 10.1007/s00216-010-3721-9 CrossRefGoogle Scholar
  182. 182.
    Plouffe BD, Murthy SK (2014) Perspective on microfluidic cell separation: a solved problem? Anal Chem 86(23):11481–11488. doi: 10.1021/ac5013283 CrossRefGoogle Scholar
  183. 183.
    Bhagat AA, Bow H, Hou HW, Tan SJ, Han J, Lim CT (2010) Microfluidics for cell separation. Med Biol Eng Comput 48(10):999–1014. doi: 10.1007/s11517-010-0611-4 CrossRefGoogle Scholar
  184. 184.
    Warkiani ME, Wu L, Tay AK, Han J (2015) Large-volume microfluidic cell sorting for biomedical applications. Annu Rev Biomed Eng 17:1–34. doi: 10.1146/annurev-bioeng-071114-040818 CrossRefGoogle Scholar
  185. 185.
    Stott SL, Hsu CH, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, Rothenberg SM, Shah AM, Smas ME, Korir GK, Floyd FP Jr, Gilman AJ, Lord JB, Winokur D, Springer S, Irimia D, Nagrath S, Sequist LV, Lee RJ, Isselbacher KJ, Maheswaran S, Haber DA, Toner M (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A 107(43):18392–18397. doi: 10.1073/pnas.1012539107 CrossRefGoogle Scholar
  186. 186.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584. doi: 10.1126/science.1228522 CrossRefGoogle Scholar
  187. 187.
    Chen Q, Wu J, Zhang Y, Lin Z, Lin JM (2012) Targeted isolation and analysis of single tumor cells with aptamer-encoded microwell array on microfluidic device. Lab Chip 12(24):5180–5185. doi: 10.1039/c2lc40858a CrossRefGoogle Scholar
  188. 188.
    Herzenberg LA, Parks D, Sahaf B, Perez O, Roederer M, Herzenberg LA (2002) The history and future of the fluorescence activated cell sorter and flow cytometry: a view from Stanford. Clin Chem 48(10):1819–1827Google Scholar
  189. 189.
    Lenshof A, Laurell T (2010) Continuous separation of cells and particles in microfluidic systems. Chem Soc Rev 39(3):1203–1217. doi: 10.1039/b915999c CrossRefGoogle Scholar
  190. 190.
    Yao B, Luo GA, Feng X, Wang W, Chen LX, Wang YM (2004) A microfluidic device based on gravity and electric force driving for flow cytometry and fluorescence activated cell sorting. Lab Chip 4(6):603–607. doi: 10.1039/b408422e CrossRefGoogle Scholar
  191. 191.
    Baret JC, Miller OJ, Taly V, Ryckelynck M, El-Harrak A, Frenz L, Rick C, Samuels ML, Hutchison JB, Agresti JJ, Link DR, Weitz DA, Griffiths AD (2009) Fluorescence-activated droplet sorting (FADS): efficient microfluidic cell sorting based on enzymatic activity. Lab Chip 9(13):1850–1858. doi: 10.1039/b902504a CrossRefGoogle Scholar
  192. 192.
    Sun Y, Lim CS, Liu AQ, Ayi TC, Yap PH (2007) Design, simulation and experiment of electroosmotic microfluidic chip for cell sorting. Sens Actuators A: Phys 133(2):340–348. doi: 10.1016/j.sna.2006.06.047 CrossRefGoogle Scholar
  193. 193.
    Austin Suthanthiraraj PP, Piyasena ME, Woods TA, Naivar MA, Lomicronpez GP, Graves SW (2012) One-dimensional acoustic standing waves in rectangular channels for flow cytometry. Methods 57(3):259–271. doi: 10.1016/j.ymeth.2012.02.013 CrossRefGoogle Scholar
  194. 194.
    Johansson L, Nikolajeff F, Johansson S, Thorslund S (2009) On-chip fluorescence-activated cell sorting by an integrated miniaturized ultrasonic transducer. Anal Chem 81(13):5188–5196. doi: 10.1021/ac802681r CrossRefGoogle Scholar
  195. 195.
    Wu TH, Chen Y, Park SY, Hong J, Teslaa T, Zhong JF, Di Carlo D, Teitell MA, Chiou PY (2012) Pulsed laser triggered high speed microfluidic fluorescence activated cell sorter. Lab Chip 12(7):1378–1383. doi: 10.1039/c2lc21084c CrossRefGoogle Scholar
  196. 196.
    Yung CW, Fiering J, Mueller AJ, Ingber DE (2009) Micromagnetic-microfluidic blood cleansing device. Lab Chip 9(9):1171–1177. doi: 10.1039/b816986a CrossRefGoogle Scholar
  197. 197.
    Hoshino K, Huang YY, Lane N, Huebschman M, Uhr JW, Frenkel EP, Zhang X (2011) Microchip-based immunomagnetic detection of circulating tumor cells. Lab Chip 11(20):3449–3457. doi: 10.1039/c1lc20270g CrossRefGoogle Scholar
  198. 198.
    Xia N, Hunt TP, Mayers BT, Alsberg E, Whitesides GM, Westervelt RM, Ingber DE (2006) Combined microfluidic-micromagnetic separation of living cells in continuous flow. Biomed Microdevices 8(4):299–308. doi: 10.1007/s10544-006-0033-0 CrossRefGoogle Scholar
  199. 199.
    Kim S, Han SI, Park MJ, Jeon CW, Joo YD, Choi IH, Han KH (2013) Circulating tumor cell microseparator based on lateral magnetophoresis and immunomagnetic nanobeads. Anal Chem 85(5):2779–2786. doi: 10.1021/ac303284u CrossRefGoogle Scholar
  200. 200.
    Brown RB, Audet J (2008) Current techniques for single-cell lysis. J R Soc Interface 5(Suppl 2):S131–S138. doi: 10.1098/rsif.2008.0009.focus CrossRefGoogle Scholar
  201. 201.
    Nan L, Jiang Z, Wei X (2014) Emerging microfluidic devices for cell lysis: a review. Lab Chip 14(6):1060–1073. doi: 10.1039/c3lc51133b CrossRefGoogle Scholar
  202. 202.
    Hosic S, Murthy SK, Koppes AN (2016) Microfluidic sample preparation for single cell analysis. Anal Chem 88(1):354–380. doi: 10.1021/acs.analchem.5b04077 CrossRefGoogle Scholar
  203. 203.
    Yun SS, Yoon SY, Song MK, Im SH, Kim S, Lee JH, Yang S (2010) Handheld mechanical cell lysis chip with ultra-sharp silicon nano-blade arrays for rapid intracellular protein extraction. Lab Chip 10(11):1442–1446. doi: 10.1039/b925244d CrossRefGoogle Scholar
  204. 204.
    Kim J, Hee Jang S, Jia G, Zoval JV, Da Silva NA, Madou MJ (2004) Cell lysis on a microfluidic CD (compact disc). Lab Chip 4(5):516–522. doi: 10.1039/b401106f CrossRefGoogle Scholar
  205. 205.
    Siegrist J, Gorkin R, Bastien M, Stewart G, Peytavi R, Kido H, Bergeron M, Madou M (2010) Validation of a centrifugal microfluidic sample lysis and homogenization platform for nucleic acid extraction with clinical samples. Lab Chip 10(3):363–371. doi: 10.1039/b913219h CrossRefGoogle Scholar
  206. 206.
    Mellors JS, Jorabchi K, Smith LM, Ramsey JM (2010) Integrated microfluidic device for automated single cell analysis using electrophoretic separation and electrospray ionization mass spectrometry. Anal Chem 82(3):967–973. doi: 10.1021/ac902218y CrossRefGoogle Scholar
  207. 207.
    Jokilaakso N, Salm E, Chen A, Millet L, Guevara CD, Dorvel B, Reddy B Jr, Karlstrom AE, Chen Y, Ji H, Chen Y, Sooryakumar R, Bashir R (2013) Ultra-localized single cell electroporation using silicon nanowires. Lab Chip 13(3):336–339. doi: 10.1039/c2lc40837f CrossRefGoogle Scholar
  208. 208.
    Lee C-Y, Lee G-B, Lin J-L, Huang F-C, Liao C-S (2005) Integrated microfluidic systems for cell lysis, mixing/pumping and DNA amplification. J Micromech Microeng 15(6):1215–1223. doi: 10.1088/0960-1317/15/6/011 CrossRefGoogle Scholar
  209. 209.
    Sarkar A, Kolitz S, Lauffenburger DA, Han J (2014) Microfluidic probe for single-cell analysis in adherent tissue culture. Nat Commun 5:3421. doi: 10.1038/ncomms4421 CrossRefGoogle Scholar
  210. 210.
    Yang W, Woolley AT (2010) Integrated multi-process microfluidic systems for automating analysis. JALA Charlottesv Va 15(3):198–209. doi: 10.1016/j.jala.2010.01.008 Google Scholar
  211. 211.
    Cui F, Rhee M, Singh A, Tripathi A (2015) Microfluidic sample preparation for medical diagnostics. Annu Rev Biomed Eng 17:267–286. doi: 10.1146/annurev-bioeng-071114-040538 CrossRefGoogle Scholar
  212. 212.
    Wu D, Qin J, Lin B (2008) Electrophoretic separations on microfluidic chips. J Chromatogr A 1184(1–2):542–559. doi: 10.1016/j.chroma.2007.11.119 CrossRefGoogle Scholar
  213. 213.
    Cong H, Xu X, Yu B, Yuan H, Peng Q, Tian C (2015) Recent progress in preparation and application of microfluidic chip electrophoresis. J Micromech Microeng 25(5):053001. doi: 10.1088/0960-1317/25/5/053001 CrossRefGoogle Scholar
  214. 214.
    Karlinsey JM (2012) Sample introduction techniques for microchip electrophoresis: a review. Anal Chim Acta 725:1–13. doi: 10.1016/j.aca.2012.02.052 CrossRefGoogle Scholar
  215. 215.
    Liu P, Yeung SH, Crenshaw KA, Crouse CA, Scherer JR, Mathies RA (2008) Real-time forensic DNA analysis at a crime scene using a portable microchip analyzer. Forensic Sci Int Genet 2(4):301–309. doi: 10.1016/j.fsigen.2008.03.009 CrossRefGoogle Scholar
  216. 216.
    Lin X, Chen Q, Liu W, Yi L, Li H, Wang Z, Lin JM (2015) Assay of multiplex proteins from cell metabolism based on tunable aptamer and microchip electrophoresis. Biosens Bioelectron 63:105–111. doi: 10.1016/j.bios.2014.07.013 CrossRefGoogle Scholar
  217. 217.
    Smejkal P, Bottenus D, Breadmore MC, Guijt RM, Ivory CF, Foret F, Macka M (2013) Microfluidic isotachophoresis: a review. Electrophoresis 34(11):1493–1509. doi: 10.1002/elps.201300021 CrossRefGoogle Scholar
  218. 218.
    Schoch RB, Ronaghi M, Santiago JG (2009) Rapid and selective extraction, isolation, preconcentration, and quantitation of small RNAs from cell lysate using on-chip isotachophoresis. Lab Chip 9(15):2145–2152. doi: 10.1039/b903542g CrossRefGoogle Scholar
  219. 219.
    Tetala KK, Vijayalakshmi MA (2016) A review on recent developments for biomolecule separation at analytical scale using microfluidic devices. Anal Chim Acta 906:7–21. doi: 10.1016/j.aca.2015.11.037 CrossRefGoogle Scholar
  220. 220.
    Wu R, Hu L, Wang F, Ye M, Zou H (2008) Recent development of monolithic stationary phases with emphasis on microscale chromatographic separation. J Chromatogr A 1184(1–2):369–392. doi: 10.1016/j.chroma.2007.09.022 CrossRefGoogle Scholar
  221. 221.
    Lin SL, Lin TY, Fuh MR (2014) Microfluidic chip-based liquid chromatography coupled to mass spectrometry for determination of small molecules in bioanalytical applications: an update. Electrophoresis 35(9):1275–1284. doi: 10.1002/elps.201300415 CrossRefGoogle Scholar
  222. 222.
    Chen ZW, Fuchs K, Sieghart W, Townsend RR, Evers AS (2012) Deep amino acid sequencing of native brain GABAA receptors using high-resolution mass spectrometry. Mol Cell Proteomics 11(1):M111 011445Google Scholar
  223. 223.
    Hwang KY, Kwon SH, Jung SO, Namkoong K, Jung WJ, Kim JH, Suh KY, Huh N (2012) Solid phase DNA extraction with a flexible bead-packed microfluidic device to detect methicillin-resistant Staphylococcus aureus in nasal swabs. Anal Chem 84(18):7912–7918. doi: 10.1021/ac3016533 CrossRefGoogle Scholar
  224. 224.
    Kumar S, Sahore V, Rogers CI, Woolley AT (2016) Development of an integrated microfluidic solid-phase extraction and electrophoresis device. Analyst 141(5):1660–1668. doi: 10.1039/c5an02352a CrossRefGoogle Scholar
  225. 225.
    Ramsey JD, Collins GE (2005) Integrated microfluidic device for solid-phase extraction coupled to micellar electrokinetic chromatography separation. Anal Chem 77(20):6664–6670. doi: 10.1021/ac0507789 CrossRefGoogle Scholar
  226. 226.
    Mao S, Zhang J, Li H, Lin JM (2013) Strategy for signaling molecule detection by using an integrated microfluidic device coupled with mass spectrometry to study cell-to-cell communication. Anal Chem 85(2):868–876. doi: 10.1021/ac303164b CrossRefGoogle Scholar
  227. 227.
    Zhang J, Wu J, Li H, Chen Q, Lin JM (2015) An in vitro liver model on microfluidic device for analysis of capecitabine metabolite using mass spectrometer as detector. Biosens Bioelectron 68:322–328. doi: 10.1016/j.bios.2015.01.013 CrossRefGoogle Scholar
  228. 228.
    Gao D, Liu H, Lin JM, Wang Y, Jiang Y (2013) Characterization of drug permeability in Caco-2 monolayers by mass spectrometry on a membrane-based microfluidic device. Lab Chip 13(5):978–985. doi: 10.1039/c2lc41215b CrossRefGoogle Scholar
  229. 229.
    Hagan KA, Meier WL, Ferrance JP, Landers JP (2009) Chitosan-coated silica as a solid phase for RNA purification in a microfluidic device. Anal Chem 81(13):5249–5256. doi: 10.1021/ac900820z CrossRefGoogle Scholar
  230. 230.
    Tia S, Herr AE (2009) On-chip technologies for multidimensional separations. Lab Chip 9(17):2524–2536. doi: 10.1039/b900683b CrossRefGoogle Scholar
  231. 231.
    Emrich CA, Medintz IL, Chu WK, Mathies RA (2007) Microfabricated two-dimensional electrophoresis device for differential protein expression profiling. Anal Chem 79(19):7360–7366. doi: 10.1021/ac0711485 CrossRefGoogle Scholar
  232. 232.
    Choi JR, Song H, Sung JH, Kim D, Kim K (2016) Microfluidic assay-based optical measurement techniques for cell analysis: a review of recent progress. Biosens Bioelectron 77:227–236. doi: 10.1016/j.bios.2015.07.068 CrossRefGoogle Scholar
  233. 233.
    Chrimes AF, Khoshmanesh K, Stoddart PR, Mitchell A, Kalantar-Zadeh K (2013) Microfluidics and Raman microscopy: current applications and future challenges. Chem Soc Rev 42(13):5880–5906. doi: 10.1039/c3cs35515b CrossRefGoogle Scholar
  234. 234.
    Perro A, Lebourdon G, Henry S, Lecomte S, Servant L, Marre S (2016) Combining microfluidics and FT-IR spectroscopy: towards spatially resolved information on chemical processes. React Chem Eng. doi: 10.1039/c6re00127k Google Scholar
  235. 235.
    Kuswandi B, Nuriman, Huskens J, Verboom W (2007) Optical sensing systems for microfluidic devices: a review. Anal Chim Acta 601(2):141–155. doi: 10.1016/j.aca.2007.08.046 CrossRefGoogle Scholar
  236. 236.
    Rackus DG, Shamsi MH, Wheeler AR (2015) Electrochemistry, biosensors and microfluidics: a convergence of fields. Chem Soc Rev 44(15):5320–5340. doi: 10.1039/c4cs00369a CrossRefGoogle Scholar
  237. 237.
    Kiilerich-Pedersen K, Rozlosnik N (2012) Cell-Based biosensors: electrical sensing in microfluidic devices. Diagnostics (Basel) 2(4):83–96. doi: 10.3390/diagnostics2040083 CrossRefGoogle Scholar
  238. 238.
    D’hahan NP (2011) Live cell analysis: when electric detection interfaces microfluidics. J Biochips Tissue Chips 01(01). doi: 10.4172/2153-0777.s1-001
  239. 239.
    Rossier J, Reymond F, Michel PE (2002) Polymer microfluidic chips for electrochemical and biochemical analyses. Electrophoresis 23(6):858–867. doi: 10.1002/1522-2683(200203)23:6<858:AID-ELPS858>3.0.CO;2-3 CrossRefGoogle Scholar
  240. 240.
    Wang X, Yi L, Mukhitov N, Schrell AM, Dhumpa R, Roper MG (2015) Microfluidics-to-mass spectrometry: a review of coupling methods and applications. J Chromatogr A 1382:98–116. doi: 10.1016/j.chroma.2014.10.039 CrossRefGoogle Scholar
  241. 241.
    Gao D, Liu H, Jiang Y, Lin JM (2013) Recent advances in microfluidics combined with mass spectrometry: technologies and applications. Lab Chip 13(17):3309–3322. doi: 10.1039/c3lc50449b CrossRefGoogle Scholar
  242. 242.
    Feng X, Liu BF, Li J, Liu X (2015) Advances in coupling microfluidic chips to mass spectrometry. Mass Spectrom Rev 34(5):535–557. doi: 10.1002/mas.21417 CrossRefGoogle Scholar
  243. 243.
    Mao X, Huang TJ (2012) Microfluidic diagnostics for the developing world. Lab Chip 12(8):1412–1416. doi: 10.1039/c2lc90022j CrossRefGoogle Scholar
  244. 244.
    Chen J, Li J, Sun Y (2012) Microfluidic approaches for cancer cell detection, characterization, and separation. Lab Chip 12(10):1753–1767. doi: 10.1039/c2lc21273k CrossRefGoogle Scholar
  245. 245.
    Giobbe GG, Michielin F, Luni C, Giulitti S, Martewicz S, Dupont S, Floreani A, Elvassore N (2015) Functional differentiation of human pluripotent stem cells on a chip. Nat Methods 12(7):637–640. doi: 10.1038/nmeth.3411 CrossRefGoogle Scholar
  246. 246.
    Lewis DM, Gerecht S (2016) Microfluidics and biomaterials to study angiogenesis. Curr Opin Chem Eng 11:114–122. doi: 10.1016/j.coche.2016.02.005 CrossRefGoogle Scholar
  247. 247.
    Huang Y, Agrawal B, Sun D, Kuo JS, Williams JC (2011) Microfluidics-based devices: new tools for studying cancer and cancer stem cell migration. Biomicrofluidics 5(1):13412. doi: 10.1063/1.3555195 CrossRefGoogle Scholar
  248. 248.
    Chung S, Sudo R, Vickerman V, Zervantonakis IK, Kamm RD (2010) Microfluidic platforms for studies of angiogenesis, cell migration, and cell-cell interactions. Ann Biomed Eng 38(3):1164–1177. doi: 10.1007/s10439-010-9899-3 CrossRefGoogle Scholar
  249. 249.
    Kim C, Kasuya J, Jeon J, Chung S, Kamm RD (2015) A quantitative microfluidic angiogenesis screen for studying anti-angiogenic therapeutic drugs. Lab Chip 15(1):301–310. doi: 10.1039/c4lc00866a CrossRefGoogle Scholar
  250. 250.
    Haandbaek N, Burgel SC, Heer F, Hierlemann A (2014) Characterization of subcellular morphology of single yeast cells using high frequency microfluidic impedance cytometer. Lab Chip 14(2):369–377. doi: 10.1039/c3lc50866h CrossRefGoogle Scholar
  251. 251.
    Kim J, Johnson M, Hill P, Gale BK (2009) Microfluidic sample preparation: cell lysis and nucleic acid purification. Integr Biol (Camb) 1(10):574–586. doi: 10.1039/b905844c CrossRefGoogle Scholar
  252. 252.
    Chang CM, Chang WH, Wang CH, Wang JH, Mai JD, Lee GB (2013) Nucleic acid amplification using microfluidic systems. Lab Chip 13(7):1225–1242. doi: 10.1039/c3lc41097h CrossRefGoogle Scholar
  253. 253.
    Wu J, Kodzius R, Cao W, Wen W (2013) Extraction, amplification and detection of DNA in microfluidic chip-based assays. Microchim Acta 181(13–14):1611–1631. doi: 10.1007/s00604-013-1140-2 Google Scholar
  254. 254.
    Mauk MG, Liu C, Song J, Bau HH (2015) Integrated microfluidic nucleic acid isolation, isothermal amplification, and amplicon quantification. Microarrays (Basel) 4(4):474–489. doi: 10.3390/microarrays4040474 CrossRefGoogle Scholar
  255. 255.
    Zhang R, Li X, Ramaswami G, Smith KS, Turecki G, Montgomery SB, Li JB (2014) Quantifying RNA allelic ratios by microfluidic multiplex PCR and sequencing. Nat Methods 11(1):51–54. doi: 10.1038/nmeth.2736 CrossRefGoogle Scholar
  256. 256.
    Fang X, Chen H, Xu L, Jiang X, Wu W, Kong J (2012) A portable and integrated nucleic acid amplification microfluidic chip for identifying bacteria. Lab Chip 12(8):1495–1499. doi: 10.1039/c2lc40055c CrossRefGoogle Scholar
  257. 257.
    Liu P, Mathies RA (2009) Integrated microfluidic systems for high-performance genetic analysis. Trends Biotechnol 27(10):572–581. doi: 10.1016/j.tibtech.2009.07.002 CrossRefGoogle Scholar
  258. 258.
    Foudeh AM, Fatanat Didar T, Veres T, Tabrizian M (2012) Microfluidic designs and techniques using lab-on-a-chip devices for pathogen detection for point-of-care diagnostics. Lab Chip 12(18):3249–3266. doi: 10.1039/c2lc40630f CrossRefGoogle Scholar
  259. 259.
    Horsman KM, Bienvenue JM, Blasier KR, Landers JP (2007) Forensic DNA analysis on microfluidic devices: a review. J Forensic Sci 52(4):784–799. doi: 10.1111/j.1556-4029.2007.00468.x CrossRefGoogle Scholar
  260. 260.
    Zheng GX, Lau BT, Schnall-Levin M, Jarosz M, Bell JM, Hindson CM, Kyriazopoulou-Panagiotopoulou S, Masquelier DA, Merrill L, Terry JM, Mudivarti PA, Wyatt PW, Bharadwaj R, Makarewicz AJ, Li Y, Belgrader P, Price AD, Lowe AJ, Marks P, Vurens GM, Hardenbol P, Montesclaros L, Luo M, Greenfield L, Wong A, Birch DE, Short SW, Bjornson KP, Patel P, Hopmans ES, Wood C, Kaur S, Lockwood GK, Stafford D, Delaney JP, Wu I, Ordonez HS, Grimes SM, Greer S, Lee JY, Belhocine K, Giorda KM, Heaton WH, McDermott GP, Bent ZW, Meschi F, Kondov NO, Wilson R, Bernate JA, Gauby S, Kindwall A, Bermejo C, Fehr AN, Chan A, Saxonov S, Ness KD, Hindson BJ, Ji HP (2016) Haplotyping germline and cancer genomes with high-throughput linked-read sequencing. Nat Biotechnol 34(3):303–311. doi: 10.1038/nbt.3432 CrossRefGoogle Scholar
  261. 261.
    Ting DT, Wittner BS, Ligorio M, Vincent Jordan N, Shah AM, Miyamoto DT, Aceto N, Bersani F, Brannigan BW, Xega K, Ciciliano JC, Zhu H, MacKenzie OC, Trautwein J, Arora KS, Shahid M, Ellis HL, Qu N, Bardeesy N, Rivera MN, Deshpande V, Ferrone CR, Kapur R, Ramaswamy S, Shioda T, Toner M, Maheswaran S, Haber DA (2014) Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep 8(6):1905–1918. doi: 10.1016/j.celrep.2014.08.029 CrossRefGoogle Scholar
  262. 262.
    Kimmerling RJ, Lee Szeto G, Li JW, Genshaft AS, Kazer SW, Payer KR, de Riba Borrajo J, Blainey PC, Irvine DJ, Shalek AK, Manalis SR (2016) A microfluidic platform enabling single-cell RNA-seq of multigenerational lineages. Nat Commun 7:10220. doi: 10.1038/ncomms10220 CrossRefGoogle Scholar
  263. 263.
    Sanchez-Freire V, Ebert AD, Kalisky T, Quake SR, Wu JC (2012) Microfluidic single-cell real-time PCR for comparative analysis of gene expression patterns. Nat Protoc 7(5):829–838. doi: 10.1038/nprot.2012.021 CrossRefGoogle Scholar
  264. 264.
    Streets AM, Zhang X, Cao C, Pang Y, Wu X, Xiong L, Yang L, Fu Y, Zhao L, Tang F, Huang Y (2014) Microfluidic single-cell whole-transcriptome sequencing. Proc Natl Acad Sci U S A 111(19):7048–7053. doi: 10.1073/pnas.1402030111 CrossRefGoogle Scholar
  265. 265.
    Shalek AK, Satija R, Shuga J, Trombetta JJ, Gennert D, Lu D, Chen P, Gertner RS, Gaublomme JT, Yosef N, Schwartz S, Fowler B, Weaver S, Wang J, Wang X, Ding R, Raychowdhury R, Friedman N, Hacohen N, Park H, May AP, Regev A (2014) Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature 510(7505):363–369. doi: 10.1038/nature13437 Google Scholar
  266. 266.
    Cao Z, Chen C, He B, Tan K, Lu C (2015) A microfluidic device for epigenomic profiling using 100 cells. Nat Methods 12(10):959–962. doi: 10.1038/nmeth.3488 CrossRefGoogle Scholar
  267. 267.
    Bennett MR, Hasty J (2009) Microfluidic devices for measuring gene network dynamics in single cells. Nat Rev Genet 10(9):628–638. doi: 10.1038/nrg2625 CrossRefGoogle Scholar
  268. 268.
    Toriello NM, Douglas ES, Thaitrong N, Hsiao SC, Francis MB, Bertozzi CR, Mathies RA (2008) Integrated microfluidic bioprocessor for single-cell gene expression analysis. Proc Natl Acad Sci U S A 105(51):20173–20178. doi: 10.1073/pnas.0806355106 CrossRefGoogle Scholar
  269. 269.
    Busch W, Moore BT, Martsberger B, Mace DL, Twigg RW, Jung J, Pruteanu-Malinici I, Kennedy SJ, Fricke GK, Clark RL, Ohler U, Benfey PN (2012) A microfluidic device and computational platform for high-throughput live imaging of gene expression. Nat Methods 9(11):1101–1106. doi: 10.1038/nmeth.2185 CrossRefGoogle Scholar
  270. 270.
    Yu J, Zhou J, Sutherland A, Wei W, Shin YS, Xue M, Heath JR (2014) Microfluidics-based single-cell functional proteomics for fundamental and applied biomedical applications. Annu Rev Anal Chem (Palo Alto Calif) 7:275–295. doi: 10.1146/annurev-anchem-071213-020323 CrossRefGoogle Scholar
  271. 271.
    Sun J, Masterman-Smith MD, Graham NA, Jiao J, Mottahedeh J, Laks DR, Ohashi M, DeJesus J, Kamei K, Lee KB, Wang H, Yu ZT, Lu YT, Hou S, Li K, Liu M, Zhang N, Wang S, Angenieux B, Panosyan E, Samuels ER, Park J, Williams D, Konkankit V, Nathanson D, van Dam RM, Phelps ME, Wu H, Liau LM, Mischel PS, Lazareff JA, Kornblum HI, Yong WH, Graeber TG, Tseng HR (2010) A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. Cancer Res 70(15):6128–6138. doi: 10.1158/0008-5472.CAN-10-0076 CrossRefGoogle Scholar
  272. 272.
    Nguyen CQ, Ogunniyi AO, Karabiyik A, Love JC (2013) Single-cell analysis reveals isotype-specific autoreactive B cell repertoires in Sjogren’s syndrome. PLoS ONE 8(3):e58127. doi: 10.1371/journal.pone.0058127 CrossRefGoogle Scholar
  273. 273.
    Bailey RC, Kwong GA, Radu CG, Witte ON, Heath JR (2007) DNA-encoded antibody libraries: a unified platform for multiplexed cell sorting and detection of genes and proteins. J Am Chem Soc 129(7):1959–1967. doi: 10.1021/ja065930i CrossRefGoogle Scholar
  274. 274.
    Xue M, Wei W, Su Y, Kim J, Shin YS, Mai WX, Nathanson DA, Heath JR (2015) Chemical methods for the simultaneous quantitation of metabolites and proteins from single cells. J Am Chem Soc 137(12):4066–4069. doi: 10.1021/jacs.5b00944 CrossRefGoogle Scholar
  275. 275.
    Ma C, Fan R, Ahmad H, Shi Q, Comin-Anduix B, Chodon T, Koya RC, Liu CC, Kwong GA, Radu CG, Ribas A, Heath JR (2011) A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells. Nat Med 17(6):738–743. doi: 10.1038/nm.2375 CrossRefGoogle Scholar
  276. 276.
    Poovathingal SK, Kravchenko-Balasha N, Shin YS, Levine RD, Heath JR (2016) Critical points in Tumorigenesis: a carcinogen-initiated phase transition analyzed via single-cell proteomics. Small 12(11):1425–1431. doi: 10.1002/smll.201501178 CrossRefGoogle Scholar
  277. 277.
    He M, Herr AE (2010) Automated microfluidic protein immunoblotting. Nat Protoc 5(11):1844–1856. doi: 10.1038/nprot.2010.142 CrossRefGoogle Scholar
  278. 278.
    Hughes AJ, Herr AE (2012) Microfluidic Western blotting. Proc Natl Acad Sci U S A 109(52):21450–21455. doi: 10.1073/pnas.1207754110 CrossRefGoogle Scholar
  279. 279.
    Hughes AJ, Spelke DP, Xu Z, Kang CC, Schaffer DV, Herr AE (2014) Single-cell western blotting. Nat Methods 11(7):749–755. doi: 10.1038/nmeth.2992 CrossRefGoogle Scholar
  280. 280.
    Kang CC, Yamauchi KA, Vlassakis J, Sinkala E, Duncombe TA, Herr AE (2016) Single cell-resolution western blotting. Nat Protoc 11(8):1508–1530. doi: 10.1038/nprot.2016.089 CrossRefGoogle Scholar
  281. 281.
    Lee JR, Bechstein DJ, Ooi CC, Patel A, Gaster RS, Ng E, Gonzalez LC, Wang SX (2016) Magneto-nanosensor platform for probing low-affinity protein-protein interactions and identification of a low-affinity PD-L1/PD-L2 interaction. Nat Commun 7:12220. doi: 10.1038/ncomms12220 CrossRefGoogle Scholar
  282. 282.
    Lee J, Soper SA, Murray KK (2009) Microfluidic chips for mass spectrometry-based proteomics. J Mass Spectrom 44(5):579–593. doi: 10.1002/jms.1585 CrossRefGoogle Scholar
  283. 283.
    Chao TC, Hansmeier N (2013) Microfluidic devices for high-throughput proteome analyses. Proteomics 13(3–4):467–479. doi: 10.1002/pmic.201200411 CrossRefGoogle Scholar
  284. 284.
    Vollmer M, Hörth P, Rozing G, Couté Y, Grimm R, Hochstrasser D, Sanchez J-C (2006) Multi-dimensional HPLC/MS of the nucleolar proteome using HPLC-chip/MS. J Sep Sci 29(4):499–509. doi: 10.1002/jssc.200500334 CrossRefGoogle Scholar
  285. 285.
    Lee J, Soper SA, Murray KK (2009) Microfluidics with MALDI analysis for proteomics—a review. Anal Chim Acta 649(2):180–190. doi: 10.1016/j.aca.2009.07.037 CrossRefGoogle Scholar
  286. 286.
    Lee J, Soper SA, Murray KK (2011) A solid-phase bioreactor with continuous sample deposition for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 25(6):693–699. doi: 10.1002/rcm.4921 CrossRefGoogle Scholar
  287. 287.
    Rubakhin SS, Romanova EV, Nemes P, Sweedler JV (2011) Profiling metabolites and peptides in single cells. Nat Methods 8(4 Suppl):S20–S29. doi: 10.1038/nmeth.1549 CrossRefGoogle Scholar
  288. 288.
    Kraly JR, Holcomb RE, Guan Q, Henry CS (2009) Review: microfluidic applications in metabolomics and metabolic profiling. Anal Chim Acta 653(1):23–35. doi: 10.1016/j.aca.2009.08.037 CrossRefGoogle Scholar
  289. 289.
    Lin L, Lin JM (2015) Development of cell metabolite analysis on microfluidic platform. J Pharm Anal 5(6):337–347. doi: 10.1016/j.jpha.2015.09.003 CrossRefGoogle Scholar
  290. 290.
    He X, Chen Q, Zhang Y, Lin JM (2014) Recent advances in microchip-mass spectrometry for biological analysis. TrAC Trends Anal Chem 53:84–97. doi: 10.1016/j.trac.2013.09.013 CrossRefGoogle Scholar
  291. 291.
    Liu W, Wang N, Lin X, Ma Y, Lin JM (2014) Interfacing microsampling droplets and mass spectrometry by paper spray ionization for online chemical monitoring of cell culture. Anal Chem 86(14):7128–7134. doi: 10.1021/ac501678q CrossRefGoogle Scholar
  292. 292.
    Mao S, Gao D, Liu W, Wei H, Lin JM (2012) Imitation of drug metabolism in human liver and cytotoxicity assay using a microfluidic device coupled to mass spectrometric detection. Lab Chip 12(1):219–226. doi: 10.1039/c1lc20678h CrossRefGoogle Scholar
  293. 293.
    Chen Q, Wu J, Zhang Y, Lin JM (2012) Qualitative and quantitative analysis of tumor cell metabolism via stable isotope labeling assisted microfluidic chip electrospray ionization mass spectrometry. Anal Chem 84(3):1695–1701. doi: 10.1021/ac300003k CrossRefGoogle Scholar
  294. 294.
    Zhuang Q, Wang S, Zhang J, He Z, Li H, Ma Y, Lin JM (2015) Nephrocyte-neurocyte interaction and cellular metabolic analysis on membrane-integrated microfluidic device. Sci China Chem 59(2):243–250. doi: 10.1007/s11426-015-5453-3 CrossRefGoogle Scholar
  295. 295.
    Wang BL, Ghaderi A, Zhou H, Agresti J, Weitz DA, Fink GR, Stephanopoulos G (2014) Microfluidic high-throughput culturing of single cells for selection based on extracellular metabolite production or consumption. Nat Biotechnol 32(5):473–478. doi: 10.1038/nbt.2857 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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