Advertisement

Droplet-Based Microfluidic Technology for Cell Analysis

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

Abstract

The mainstream of microfluidic chip research has transformed from the platform construction and method development to a wide range of applications. As a typical multiphase micro-functional unit, the droplet can be used as an independent microreactor with a volume ranging from pL to nL and formation rate up to thousands of droplets per second. It has the advantages of restricted diffusion, accelerated mixing, high heat transfer, effective mass transfer and so on. Droplet-based microfluidic technology has been emerged as a powerful tool to carry out high throughput screening and droplet manipulation research. Thus cell analysis, especially single cell analysis, and cell manipulation in droplets are easy and effective to be implemented with the assistance of a series of analytical methods. In this Chapter, we have briefly introduced an overview of droplet generation and corresponding principle by microfluidic chip. Besides, some usual methods coupled with droplet analysis have also been presented such as fluorescence analysis, mass spectrometry, capillary electrophoresis and others. Then we have mainly discussed the progress of droplets in cell analysis of recent decades. Finally, a summary and possible predication of droplet-based microfluidic chip are made at the end of this chapter.

Keywords

Microfluidics Droplet Single cell analysis Cell manipulation 

References

  1. 1.
    Woodruff K, Maerkl SJ (2016) A high-throughput microfluidic platform for mammalian cell transfection and culturing. Sci Rep 6:23937. doi: 10.1038/srep23937 CrossRefGoogle Scholar
  2. 2.
    Vidi PA, Maleki T, Ochoa M, Wang L, Clark SM, Leary JF, Lelievre SA (2014) Disease-on-a-chip: mimicry of tumor growth in mammary ducts. Lab Chip 14(1):172–177. doi: 10.1039/c3lc50819f CrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    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
  5. 5.
    Bergstrom G, Nilsson K, Mandenius CF, Robinson ND (2014) Macroporous microcarriers for introducing cells into a microfluidic chip. Lab Chip 14(18):3502–3504. doi: 10.1039/c4lc00693c CrossRefGoogle Scholar
  6. 6.
    Deng Y, Zhang Y, Sun S, Wang Z, Wang M, Yu B, Czajkowsky DM, Liu B, Li Y, Wei W, Shi Q (2014) An integrated microfluidic chip system for single-cell secretion profiling of rare circulating tumor cells. Sci Rep 4:7499. doi: 10.1038/srep07499 CrossRefGoogle Scholar
  7. 7.
    Shapiro OH, Kramarsky-Winter E, Gavish AR, Stocker R, Vardi A (2016) A coral-on-a-chip microfluidic platform enabling live-imaging microscopy of reef-building corals. Nat Commun 7:10860. doi: 10.1038/ncomms10860 CrossRefGoogle Scholar
  8. 8.
    Whitesides GM (2006) The origins and the future of microfluidics. Nature 442(7101):368–373. doi: 10.1038/nature05058 CrossRefGoogle Scholar
  9. 9.
    Niu XZ, Zhang B, Marszalek RT, Ces O, Edel JB, Klug DR, deMello AJ (2009) Droplet-based compartmentalization of chemically separated components in two-dimensional separations. Chem Commun 41:6159–6161. doi: 10.1039/b918100h CrossRefGoogle Scholar
  10. 10.
    Niu X, deMello AJ (2012) Building droplet-based microfluidic systems for biological analysis. Biochem Soc Trans 40(4):615–623. doi: 10.1042/BST20120005 CrossRefGoogle Scholar
  11. 11.
    Song H, Chen DL, Ismagilov RF (2006) Reactions in droplets in microfluidic channels. Angew Chem Int Edit 45(44):7336–7356. doi: 10.1002/anie.200601554 CrossRefGoogle Scholar
  12. 12.
    Kintses B, van Vliet LD, Devenish SR, Hollfelder F (2010) Microfluidic droplets: new integrated workflows for biological experiments. Curr Opin Chem Biol 14(5):548–555. doi: 10.1016/j.cbpa.2010.08.013 CrossRefGoogle Scholar
  13. 13.
    Boybay MS, Jiao A, Glawdel T, Ren CL (2013) Microwave sensing and heating of individual droplets in microfluidic devices. Lab Chip 13(19):3840–3846. doi: 10.1039/c3lc50418b CrossRefGoogle Scholar
  14. 14.
    Srisa-Art M, Bonzani IC, Williams A, Stevens MM, deMello AJ, Edel JB (2009) Identification of rare progenitor cells from human periosteal tissue using droplet microfluidics. Analyst 134(11):2239–2245. doi: 10.1039/b910472k CrossRefGoogle Scholar
  15. 15.
    Wang T, Zhu H, Zhuo J, Zhu Z, Papakonstantinou P, Lubarsky G, Lin J, Li M (2013) Biosensor based on ultrasmall MoS2 nanoparticles for electrochemical detection of H2O2 released by cells at the nanomolar level. Anal Chem 85(21):10289–10295. doi: 10.1021/ac402114c CrossRefGoogle Scholar
  16. 16.
    Schaerli Y, Hollfelder F (2009) The potential of microfluidic water-in-oil droplets in experimental biology. Mol BioSyst 5(12):1392–1404. doi: 10.1039/b907578j CrossRefGoogle Scholar
  17. 17.
    Baroud CN, de Saint Vincent MR, Delville JP (2007) An optical toolbox for total control of droplet microfluidics. Lab Chip 7(8):1029–1033. doi: 10.1039/b702472j CrossRefGoogle Scholar
  18. 18.
    Schmid L, Weitz DA, Franke T (2014) Sorting drops and cells with acoustics: acoustic microfluidic fluorescence-activated cell sorter. Lab Chip 14(19):3710–3718. doi: 10.1039/c4lc00588k CrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    Hatch AC, Fisher JS, Tovar AR, Hsieh AT, Lin R, Pentoney SL, Yang DL, Lee AP (2011) 1-Million droplet array with wide-field fluorescence imaging for digital PCR. Lab Chip 11(22):3838–3845. doi: 10.1039/c1lc20561g CrossRefGoogle Scholar
  21. 21.
    Sabhachandani P, Motwani V, Cohen N, Sarkar S, Torchilin V, Konry T (2016) Generation and functional assessment of 3D multicellular spheroids in droplet based microfluidics platform. Lab Chip 16(3):497–505. doi: 10.1039/c5lc01139f CrossRefGoogle Scholar
  22. 22.
    Brouzes E, Medkova M, Savenelli N, Marran D, Twardowski M, Hutchison JB, Rothberg JM, Link DR, Perrimon N, Samuels ML (2009) Droplet microfluidic technology for single-cell high-throughput screening. Proc Natl Acad Sci U S A 106(34):14195–14200. doi: 10.1073/pnas.0903542106 CrossRefGoogle Scholar
  23. 23.
    Theberge AB, Courtois F, Schaerli Y, Fischlechner M, Abell C, Hollfelder F, Huck WT (2010) Microdroplets in microfluidics: an evolving platform for discoveries in chemistry and biology. Angew Chem Int Edit 49(34):5846–5868. doi: 10.1002/anie.200906653 CrossRefGoogle Scholar
  24. 24.
    Nossal GJ, Lederberg J (1958) Antibody production by single cells. Nature 181(4620):1419–1420CrossRefGoogle Scholar
  25. 25.
    Baroud CN, Gallaire F, Dangla R (2010) Dynamics of microfluidic droplets. Lab Chip 10(16):2032. doi: 10.1039/c001191f CrossRefGoogle Scholar
  26. 26.
    Shen F, Li Y, Liu Z-M, Cao R-T, Wang G-R (2015) Advances in micro-droplets coalescence using microfluidics. Chin J Anal Chem 43(12):1942–1954. doi: 10.1016/s1872-2040(15)60886-6 CrossRefGoogle Scholar
  27. 27.
    Yang C-G, Xu Z-R, Wang J-H (2010) Manipulation of droplets in microfluidic systems. TrAC Trends Anal Chem 29(2):141–157. doi: 10.1016/j.trac.2009.11.002 CrossRefGoogle Scholar
  28. 28.
    Niu X, Gulati S, Edel JB, deMello AJ (2008) Pillar-induced droplet merging in microfluidic circuits. Lab Chip 8(11):1837–1841. doi: 10.1039/b813325e CrossRefGoogle Scholar
  29. 29.
    Bayley H, Cronin B, Heron A, Holden MA, Hwang WL, Syeda R, Thompson J, Wallace M (2008) Droplet interface bilayers. Mol BioSyst 4(12):1191–1208. doi: 10.1039/b808893d CrossRefGoogle Scholar
  30. 30.
    Wu J, Wen W, Sheng P (2012) Smart electroresponsive droplets in microfluidics. Soft Matter 8(46):11589. doi: 10.1039/c2sm26286j CrossRefGoogle Scholar
  31. 31.
    Movahednejad E, Ommi F, Hosseinalipour SM (2010) Prediction of droplet size and velocity distribution in droplet formation region of liquid spray. Entropy 12(6):1484–1498. doi: 10.3390/e12061484 CrossRefGoogle Scholar
  32. 32.
    Gu H, Duits MH, Mugele F (2011) Droplets formation and merging in two-phase flow microfluidics. Int J Mol Sci 12(4):2572–2597. doi: 10.3390/ijms12042572 CrossRefGoogle Scholar
  33. 33.
    Zhao C-X, Middelberg APJ (2011) Two-phase microfluidic flows. Chem Eng Sci 66(7):1394–1411. doi: 10.1016/j.ces.2010.08.038 CrossRefGoogle Scholar
  34. 34.
    Cao J, Köhler JM (2015) Droplet-based microfluidics for microtoxicological studies. Eng Life Sci 15(3):306–317. doi: 10.1002/elsc.201400074 CrossRefGoogle Scholar
  35. 35.
    Zec H, Shin DJ, Wang TH (2014) Novel droplet platforms for the detection of disease biomarkers. Expert Rev Mol Diag 14(7):787–801. doi: 10.1586/14737159.2014.945437 CrossRefGoogle Scholar
  36. 36.
    Fleury J-B, Schiller UD, Thutupalli S, Gompper G, Seemann R (2014) Mode coupling of phonons in a dense one-dimensional microfluidic crystal. New J Phys 16(6):063029. doi: 10.1088/1367-2630/16/6/063029 CrossRefGoogle Scholar
  37. 37.
    Thorsen T, Roberts RW, Arnold FH, Quake SR (2001) Dynamic pattern formation in a vesicle-generating microfluidic device. Phys Rev Lett 86(18):4163–4166. doi: 10.1103/PhysRevLett.86.4163 CrossRefGoogle Scholar
  38. 38.
    Basova EY, Foret F (2015) Droplet microfluidics in (bio)chemical analysis. Analyst 140(1):22–38. doi: 10.1039/c4an01209g CrossRefGoogle Scholar
  39. 39.
    Okushima S, Nisisako T, Torii T, Higuchi T (2004) Controlled production of monodisperse double emulsions by two-step droplet breakup in microfluidic devices. Langmuir 20(23):9905–9908. doi: 10.1021/la0480336 CrossRefGoogle Scholar
  40. 40.
    Collins DJ, Neild A, deMello A, Liu AQ, Ai Y (2015) The Poisson distribution and beyond: methods for microfluidic droplet production and single cell encapsulation. Lab Chip 15(17):3439–3459. doi: 10.1039/c5lc00614g CrossRefGoogle Scholar
  41. 41.
    Park SY, Wu TH, Chen Y, Teitell MA, Chiou PY (2011) High-speed droplet generation on demand driven by pulse laser-induced cavitation. Lab Chip 11(6):1010–1012. doi: 10.1039/c0lc00555j CrossRefGoogle Scholar
  42. 42.
    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
  43. 43.
    Tan YC, Lee AP (2005) Microfluidic separation of satellite droplets as the basis of a monodispersed micron and submicron emulsification system. Lab Chip 5(10):1178–1183. doi: 10.1039/b504497a CrossRefGoogle Scholar
  44. 44.
    Song H, Tice JD, Ismagilov RF (2003) A microfluidic system for controlling reaction networks in time. Angew Chem Int Edit 115(7):792–796. doi: 10.1002/anie.200390203 CrossRefGoogle Scholar
  45. 45.
    Adamson DN, Mustafi D, Zhang JX, Zheng B, Ismagilov RF (2006) Production of arrays of chemically distinct nanolitre plugs via repeated splitting in microfluidic devices. Lab Chip 6(9):1178–1186. doi: 10.1039/b604993a CrossRefGoogle Scholar
  46. 46.
    Xiao Z, Niu M, Zhang B (2012) Droplet microfluidics based microseparation systems. J Sep Sci 35(10–11):1284–1293. doi: 10.1002/jssc.201200115 CrossRefGoogle Scholar
  47. 47.
    Collins DJ, Alan T, Helmerson K, Neild A (2013) Surface acoustic waves for on-demand production of picoliter droplets and particle encapsulation. Lab Chip 13(16):3225–3231. doi: 10.1039/c3lc50372k CrossRefGoogle Scholar
  48. 48.
    He M, Kuo JS, Chiu DT (2005) Electro-generation of single femtoliter- and picoliter-volume aqueous droplets in microfluidic systems. Appl Phys Lett 87(3):031916. doi: 10.1063/1.1997280 CrossRefGoogle Scholar
  49. 49.
    Huebner A, Srisa-Art M, Holt D, Abell C, Hollfelder F, deMello AJ, Edel JB (2007) Quantitative detection of protein expression in single cells using droplet microfluidics. Chem Commun 12:1218–1220. doi: 10.1039/b618570c CrossRefGoogle Scholar
  50. 50.
    Kapanidis AN, Strick T (2009) Biology, one molecule at a time. Trends Biochem Sci 34(5):234–243. doi: 10.1016/j.tibs.2009.01.008 CrossRefGoogle Scholar
  51. 51.
    Casadevall iSX, Niu X, Leeper K, Cho S, Chang SI, Edel JB, deMello AJ (2011) Fluorescence detection methods for microfluidic droplet platforms. JoVE-J Vis Exp 58. doi: 10.3791/3437
  52. 52.
    Chen CH, Sarkar A, Song YA, Miller MA, Kim SJ, Griffith LG, Lauffenburger DA, Han J (2011) Enhancing protease activity assay in droplet-based microfluidics using a biomolecule concentrator. J Am Chem Soc 133(27):10368–10371. doi: 10.1021/ja2036628 CrossRefGoogle Scholar
  53. 53.
    Harris TD, Buzby PR, Babcock H, Beer E, Bowers J, Braslavsky I, Causey M, Colonell J, Dimeo J, Efcavitch JW, Giladi E, Gill J, Healy J, Jarosz M, Lapen D, Moulton K, Quake SR, Steinmann K, Thayer E, Tyurina A, Ward R, Weiss H, Xie Z (2008) Single-molecule DNA sequencing of a viral genome. Science 320(5872):106–109. doi: 10.1126/science.1150427 CrossRefGoogle Scholar
  54. 54.
    Trivedi V, Doshi A, Kurup GK, Ereifej E, Vandevord PJ, Basu AS (2010) A modular approach for the generation, storage, mixing, and detection of droplet libraries for high throughput screening. Lab Chip 10(18):2433–2442. doi: 10.1039/c004768f CrossRefGoogle Scholar
  55. 55.
    Gu SQ, Zhang YX, Zhu Y, Du WB, Yao B, Fang Q (2011) Multifunctional picoliter droplet manipulation platform and its application in single cell analysis. Anal Chem 83(19):7570–7576. doi: 10.1021/ac201678g CrossRefGoogle Scholar
  56. 56.
    Huebner A, Bratton D, Whyte G, Yang M, Demello AJ, Abell C, Hollfelder F (2009) Static microdroplet arrays: a microfluidic device for droplet trapping, incubation and release for enzymatic and cell-based assays. Lab Chip 9(5):692–698. doi: 10.1039/b813709a CrossRefGoogle Scholar
  57. 57.
    Shi W, Qin J, Ye N, Lin B (2008) Droplet-based microfluidic system for individual Caenorhabditis elegans assay. Lab Chip 8(9):1432–1435. doi: 10.1039/b808753a CrossRefGoogle Scholar
  58. 58.
    Fidalgo LM, Whyte G, Bratton D, Kaminski CF, Abell C, Huck WT (2008) From microdroplets to microfluidics: selective emulsion separation in microfluidic devices. Angew Chem Int Edit 47(11):2042–2045. doi: 10.1002/anie.200704903 CrossRefGoogle Scholar
  59. 59.
    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
  60. 60.
    Chen CH, Miller MA, Sarkar A, Beste MT, Isaacson KB, Lauffenburger DA, Griffith LG, Han J (2013) Multiplexed protease activity assay for low-volume clinical samples using droplet-based microfluidics and its application to endometriosis. J Am Chem Soc 135(5):1645–1648. doi: 10.1021/ja307866z CrossRefGoogle Scholar
  61. 61.
    Khorshidi MA, Rajeswari PK, Wahlby C, Joensson HN, Andersson Svahn H (2014) Automated analysis of dynamic behavior of single cells in picoliter droplets. Lab Chip 14(5):931–937. doi: 10.1039/c3lc51136g CrossRefGoogle Scholar
  62. 62.
    Chokkalingam V, Tel J, Wimmers F, Liu X, Semenov S, Thiele J, Figdor CG, Huck WT (2013) Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics. Lab Chip 13(24):4740–4744. doi: 10.1039/c3lc50945a CrossRefGoogle Scholar
  63. 63.
    Courtois F, Olguin LF, Whyte G et al (2009) Controlling the retention of small molecules in emulsion microdroplets for use in cell-based assays. Anal Chem 81(8):3008–3016. doi: 10.1021/ac802658n CrossRefGoogle Scholar
  64. 64.
    Farkas DL, Nicolau DV, Leif RC, Song YS, Won YJ, Lee S-H, Kim DY (2014) Fluorescence lifetime imaging of lipids during 3T3-L1 cell differentiation. Langmuir 8947:89471W. doi: 10.1117/12.2036160 Google Scholar
  65. 65.
    Casadevall iSX, Srisaart M, Demello AJ, Edel JB (2010) Mapping of Fluidic Mixing in Microdroplets with 1 μs Time Resolution Using Fluorescence Lifetime Imaging. Anal Chem 82(9):3950–3956. doi: 10.1021/ac100055g CrossRefGoogle Scholar
  66. 66.
    Mazutis L, Araghi AF, Miller OJ, Baret JC, Frenz L, Janoshazi A, Taly V, Miller BJ, Hutchison JB, Link D, Griffiths AD, Ryckelynck M (2009) Droplet-based microfluidic systems for high-throughput single DNA molecule isothermal amplification and analysis. Anal Chem 81(12):4813CrossRefGoogle Scholar
  67. 67.
    Agresti JJ, Antipov E, Abate AR, Ahn K, Rowat AC, Baret JC, Marquez M, Klibanov AM, Griffiths AD, Weitz DA (2010) Ultrahigh-throughput screening in drop-based microfluidics for directed evolution. Proc Natl Acad Sci U S A 107(9):4004–4009. doi: 10.1073/pnas.0910781107 CrossRefGoogle Scholar
  68. 68.
    Fidalgo LM, Whyte G, Ruotolo BT, Benesch JL, Stengel F, Abell C, Robinson CV, Huck WT (2009) Coupling microdroplet microreactors with mass spectrometry: reading the contents of single droplets online. Angew Chem Int Edit 48(20):3665–3668. doi: 10.1002/anie.200806103 CrossRefGoogle Scholar
  69. 69.
    Wang XL, Zhu Y, Fang Q (2014) Coupling liquid chromatography/mass spectrometry detection with microfluidic droplet array for label-free enzyme inhibition assay. Analyst 139(1):191–197. doi: 10.1039/c3an01917a CrossRefGoogle Scholar
  70. 70.
    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
  71. 71.
    Sun S, Slaney TR, Kennedy RT (2012) Label free screening of enzyme inhibitors at femtomole scale using segmented flow electrospray ionization mass spectrometry. Anal Chem 84(13):5794–5800. doi: 10.1021/ac3011389 CrossRefGoogle Scholar
  72. 72.
    Kuster SK, Pabst M, Jefimovs K, Zenobi R, Dittrich PS (2014) High-resolution droplet-based fractionation of nano-LC separations onto microarrays for MALDI-MS analysis. Anal Chem 86(10):4848–4855. doi: 10.1021/ac4041982 CrossRefGoogle Scholar
  73. 73.
    Luo C, Ma Y, Li H, Chen F, Uchiyama K, Lin JM (2013) Generation of picoliter droplets of liquid for electrospray ionization with piezoelectric inkjet. J Mass Spectrom 48(3):321–328. doi: 10.1002/jms.3159 CrossRefGoogle Scholar
  74. 74.
    Gasilova N, Yu Q, Qiao L, Girault HH (2014) On-chip spyhole mass spectrometry for droplet-based microfluidics. Angew Chem Int Edit 53(17):4408–4412. doi: 10.1002/anie.201310795 CrossRefGoogle Scholar
  75. 75.
    Chen F, Lin L, Zhang J, He Z, Uchiyama K, Lin JM (2016) Single-cell analysis using drop-on-demand inkjet printing and probe electrospray ionization mass spectrometry. Anal Chem 88(8):4354–4360. doi: 10.1021/acs.analchem.5b04749 CrossRefGoogle Scholar
  76. 76.
    Liu W, Lin JM (2016) Online monitoring of lactate efflux by multi-channel microfluidic chip-mass spectrometry for rapid drug evaluation. ACS Sens 1:344–347. doi: 10.1021/acssensors.5b00221 CrossRefGoogle Scholar
  77. 77.
    Kelly RT, Page JS, Marginean I, Tang K, Smith RD (2009) Dilution-free analysis from picoliter droplets by nano-electrospray ionization mass spectrometry. Angew Chem Int Edit 48(37):6832–6835. doi: 10.1002/anie.200902501 CrossRefGoogle Scholar
  78. 78.
    Smith CA, Li X, Mize TH, Sharpe TD, Graziani EI, Abell C, Huck WT (2013) Sensitive, high throughput detection of proteins in individual, surfactant-stabilized picoliter droplets using nanoelectrospray ionization mass spectrometry. Anal Chem 85(8):3812–3816. doi: 10.1021/ac400453t CrossRefGoogle Scholar
  79. 79.
    Su Y, Zhu Y, Fang Q (2013) A multifunctional microfluidic droplet-array chip for analysis by electrospray ionization mass spectrometry. Lab Chip 13(10):1876–1882. doi: 10.1039/c3lc00063j CrossRefGoogle Scholar
  80. 80.
    Kuster SK, Fagerer SR, Verboket PE, Eyer K, Jefimovs K, Zenobi R, Dittrich PS (2013) Interfacing droplet microfluidics with matrix-assisted laser desorption/ionization mass spectrometry: label-free content analysis of single droplets. Anal Chem 85(3):1285–1289. doi: 10.1021/ac3033189 CrossRefGoogle Scholar
  81. 81.
    Verboket PE, Borovinskaya O, Meyer N, Gunther D, Dittrich PS (2014) A new microfluidics-based droplet dispenser for ICPMS. Anal Chem 86(12):6012–6018. doi: 10.1021/ac501149a CrossRefGoogle Scholar
  82. 82.
    Lee JK, Jansson ET, Nam HG, Zare RN (2016) High-resolution live-cell imaging and analysis by laser desorption/ionization droplet delivery mass spectrometry. Anal Chem 88(10):5453–5461. doi: 10.1021/acs.analchem.6b00881 CrossRefGoogle Scholar
  83. 83.
    Zhang XC, Wei ZW, Gong XY, Si XY, Zhao YY, Yang CD, Zhang SC, Zhang XR (2016) Integrated droplet-based microextraction with ESI-MS for removal of matrix interference in single-cell analysis. Sci Rep 6:24730. doi: 10.1038/srep24730 CrossRefGoogle Scholar
  84. 84.
    Zhu Y, Fang Q (2013) Analytical detection techniques for droplet microfluidics—a review. Anal Chim Acta 787:24–35. doi: 10.1016/j.aca.2013.04.064 CrossRefGoogle Scholar
  85. 85.
    Moiseeva EV, Fletcher AA, Harnett CK (2011) Thin-film electrode based droplet detection for microfluidic systems. Sens Actuat B-Ch 155(1):408–414. doi: 10.1016/j.snb.2010.11.028 CrossRefGoogle Scholar
  86. 86.
    Cahill BP, Land R, Nacke T, Min M, Beckmann D (2011) Contactless sensing of the conductivity of aqueous droplets in segmented flow. Sens Actuat B-Ch 159(1):286–293. doi: 10.1016/j.snb.2011.07.006 CrossRefGoogle Scholar
  87. 87.
    Luo C, Yang X, Fu Q, Sun M, Ouyang Q, Chen Y, Ji H (2006) Picoliter-volume aqueous droplets in oil: electrochemical detection and yeast cell electroporation. Electrophoresis 27(10):1977–1983. doi: 10.1002/elps.200500665 CrossRefGoogle Scholar
  88. 88.
    Liu S, Gu Y, Le Roux RB, Matthews SM, Bratton D, Yunus K, Fisher AC, Huck WT (2008) The electrochemical detection of droplets in microfluidic devices. Lab Chip 8(11):1937–1942. doi: 10.1039/b809744e CrossRefGoogle Scholar
  89. 89.
    Elbuken C, Glawdel T, Chan D, Ren CL (2011) Detection of microdroplet size and speed using capacitive sensors. Sens Actuat A-Ph 171(2):55–62. doi: 10.1016/j.sna.2011.07.007 CrossRefGoogle Scholar
  90. 90.
    Edgar JS, Pabbati CP, Lorenz RM et al (2006) Capillary electrophoresis separation in the presence of an immiscible boundary for droplet analysis. Anal Chem 78(19):6948. doi: 10.1021/ac0613131 CrossRefGoogle Scholar
  91. 91.
    Wang M, Roman GT, Perry ML et al (2009) Microfluidic chip for high efficiency electrophoretic analysis of segmented flow from a microdialysis probe and in vivo chemical monitoring. Anal Chem 81(21):9072. doi: 10.1021/ac901731v CrossRefGoogle Scholar
  92. 92.
    Cecchini MP, Hong J, Lim C, Choo J, Albrecht T, Demello AJ, Edel JB (2011) Ultrafast surface enhanced resonance Raman scattering detection in droplet-based microfluidic systems. Anal Chem 83(8):3076–3081. doi: 10.1021/ac103329b CrossRefGoogle Scholar
  93. 93.
    Shen H, Fang Q, Fang ZL (2006) A microfluidic chip based sequential injection system with trapped droplet liquid-liquid extraction and chemiluminescence detection. Lab Chip 6(10):1387–1389. doi: 10.1039/b605332g CrossRefGoogle Scholar
  94. 94.
    Buettner F, Natarajan KN, Casale FP, Proserpio V, Scialdone A, Theis FJ, Teichmann SA, Marioni JC, Stegle O (2015) Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells. Nat Biotechnol 33(2):155–160. doi: 10.1038/nbt.3102 CrossRefGoogle Scholar
  95. 95.
    Schubert C (2011) Single-cell analysis: The deepest differences. Nature 480(7375):133. doi: 10.1038/480133a CrossRefGoogle Scholar
  96. 96.
    Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134(5):703–707. doi: 10.1016/j.cell.2008.08.021 CrossRefGoogle Scholar
  97. 97.
    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
  98. 98.
    Spiller DG, Wood CD, Rand DA, White MR (2010) Measurement of single-cell dynamics. Nature 465(7299):736–745. doi: 10.1038/nature09232 CrossRefGoogle Scholar
  99. 99.
    Kang A, Park J, Ju J, Jeong GS, Lee SH (2014) Cell encapsulation via microtechnologies. Biomaterials 35(9):2651–2663. doi: 10.1016/j.biomaterials.2013.12.073 CrossRefGoogle Scholar
  100. 100.
    Li JL, Day D, Gu M (2010) Design of a compact microfludic device for controllable cell distribution. Lab Chip 10(22):3054–3057. doi: 10.1039/c0lc00090f CrossRefGoogle Scholar
  101. 101.
    Moon D, Im DJ, Lee S, Kang IS (2014) A novel approach for drop-on-demand and particle encapsulation based on liquid bridge breakup. Exp Therm Fluid Sci 53:251–258. doi: 10.1016/j.expthermflusci.2013.12.016 CrossRefGoogle Scholar
  102. 102.
    Kemna EW, Schoeman RM, Wolbers F, Vermes I, Weitz DA, van den Berg A (2012) High-yield cell ordering and deterministic cell-in-droplet encapsulation using Dean flow in a curved microchannel. Lab Chip 12(16):2881–2887. doi: 10.1039/c2lc00013j CrossRefGoogle Scholar
  103. 103.
    Hong J, deMello AJ, Jayasinghe SN (2010) Bio-electrospraying and droplet-based microfluidics: control of cell numbers within living residues. Biomed Mater 5(2):21001. doi: 10.1088/1748-6041/5/2/021001 CrossRefGoogle Scholar
  104. 104.
    Collins DJ, Alan T, Neild A (2014) The particle valve: on-demand particle trapping, filtering, and release from a microfabricated polydimethylsiloxane membrane using surface acoustic waves. Appl Phys Lett 105(3):033509. doi: 10.1063/1.4891424 CrossRefGoogle Scholar
  105. 105.
    Amini H, Lee W, Di Carlo D (2014) Inertial microfluidic physics. Lab Chip 14(15):2739–2761. doi: 10.1039/c4lc00128a CrossRefGoogle Scholar
  106. 106.
    Lagus TP, Edd JF (2013) A review of the theory, methods and recent applications of high-throughput single-cell droplet microfluidics. J Phys D Appl Phys 46(11):114005. doi: 10.1088/0022-3727/46/11/114005 CrossRefGoogle Scholar
  107. 107.
    Morimoto Y, Tan WH, Tsuda Y, Takeuchi S (2009) Monodisperse semi-permeable microcapsules for continuous observation of cells. Lab Chip 9(15):2217–2223. doi: 10.1039/b900035f CrossRefGoogle Scholar
  108. 108.
    Edd JF, Di CD, Humphry KJ et al (2008) Controlled encapsulation of single-cells into monodisperse picolitre drops. Lab Chip 8(8):1262. doi: 10.1039/B805456H CrossRefGoogle Scholar
  109. 109.
    Brouzes E, Kruse T, Kimmerling R, Strey HH (2015) Rapid and continuous magnetic separation in droplet microfluidic devices. Lab Chip 15(3):908–919. doi: 10.1039/c4lc01327a CrossRefGoogle Scholar
  110. 110.
    Morimoto Y, Tan WH, Takeuchi S (2009) Three-dimensional axisymmetric flow-focusing device using stereolithography. Biomed Microdevic 11(2):369–377. doi: 10.1007/s10544-008-9243-y CrossRefGoogle Scholar
  111. 111.
    Verbruggen B, Tóth T, Cornaglia M, Puers R, Gijs MAM, Lammertyn J (2014) Separation of magnetic microparticles in segmented flow using asymmetric splitting regimes. Microfluid Nanofluid 18(1):91–102. doi: 10.1007/s10404-014-1409-8 CrossRefGoogle Scholar
  112. 112.
    He M, Edgar JS, Jeffries GDM et al (2009) Selective encapsulation of single cells and subcellular organelles into picoliter- and femtoliter-volume droplets. Anal Chem 77(6):1539. doi: 10.1021/ac0480850 CrossRefGoogle Scholar
  113. 113.
    Schoendube J, Wright D, Zengerle R, Koltay P (2015) Single-cell printing based on impedance detection. Biomicrofluidics 9(1):014117. doi: 10.1063/1.4907896 CrossRefGoogle Scholar
  114. 114.
    Um E, Rha E, Choi SL, Lee SG, Park JK (2012) Mesh-integrated microdroplet array for simultaneous merging and storage of single-cell droplets. Lab Chip 12(9):1594. doi: 10.1039/C2LC21266H CrossRefGoogle Scholar
  115. 115.
    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
  116. 116.
    Jing T, Ramji R, Warkiani ME, Han J, Lim CT, Chen CH (2015) Jetting microfluidics with size-sorting capability for single-cell protease detection. Biosens Bioelectron 66:19–23. doi: 10.1016/j.bios.2014.11.001 CrossRefGoogle Scholar
  117. 117.
    Nam J, Lim H, Kim C, Yoon Kang J, Shin S (2012) Density-dependent separation of encapsulated cells in a microfluidic channel by using a standing surface acoustic wave. Biomicrofluidics 6(2):24120–2412010. doi: 10.1063/1.4718719 CrossRefGoogle Scholar
  118. 118.
    Chen A, Byvank T, Chang WJ, Bharde A, Vieira G, Miller BL, Chalmers JJ, Bashir R, Sooryakumar R (2013) On-chip magnetic separation and encapsulation of cells in droplets. Lab Chip 13(6):1172–1181. doi: 10.1039/c2lc41201b CrossRefGoogle Scholar
  119. 119.
    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
  120. 120.
    Tan Y-C, Ho YL, Lee AP (2007) Microfluidic sorting of droplets by size. Microfluid Nanofluid 4(4):343–348. doi: 10.1007/s10404-007-0184-1 CrossRefGoogle Scholar
  121. 121.
    Joensson HN, Uhlen M, Svahn HA (2011) Droplet size based separation by deterministic lateral displacement-separating droplets by cell–induced shrinking. Lab Chip 11(7):1305–1310. doi: 10.1039/c0lc00688b CrossRefGoogle Scholar
  122. 122.
    Chabert M, Viovy JL (2008) Microfluidic high-throughput encapsulation and hydrodynamic self-sorting of single cells. Proc Natl Acad Sci U S A 105(9):3191–3196. doi: 10.1073/pnas.0708321105 CrossRefGoogle Scholar
  123. 123.
    Landenberger B, Hofemann H, Wadle S, Rohrbach A (2012) Microfluidic sorting of arbitrary cells with dynamic optical tweezers. Lab Chip 12(17):3177–3183. doi: 10.1039/c2lc21099a CrossRefGoogle Scholar
  124. 124.
    Shim JU, Ranasinghe RT, Smith CA et al (2013) Ultrarapid generation of femtoliter microfluidic droplets for single-molecule-counting immunoassays. ACS Nano 7(7):5955–5964. doi: 10.1021/nn401661d CrossRefGoogle Scholar
  125. 125.
    Levison HF, Morbidelli A (2003) The formation of the Kuiper belt by the outward transport of bodies during Neptune’s migration. Nature 426(6965):419–421. doi: 10.1038/nature02120 CrossRefGoogle Scholar
  126. 126.
    Chen Y, Wu TH, Kung YC, Teitell MA, Chiou PY (2013) 3D pulsed laser-triggered high-speed microfluidic fluorescence-activated cell sorter. Analyst 138(24):7308–7315. doi: 10.1039/c3an01266b CrossRefGoogle Scholar
  127. 127.
    Huang LR, Edward CC, Robert HA, James CS (2004) Continuous particle separation through deterministic lateral displacement. Science 14(304):987–990. doi: 10.1126/science.1094567 CrossRefGoogle Scholar
  128. 128.
    Wu L, Chen P, Dong Y, Feng X, Liu BF (2013) Encapsulation of single cells on a microfluidic device integrating droplet generation with fluorescence-activated droplet sorting. Biomed Microdevic 15(3):553–560. doi: 10.1007/s10544-013-9754-z CrossRefGoogle Scholar
  129. 129.
    Joensson HN, Samuels ML, Brouzes ER et al (2009) Detection and analysis of low-abundance cell-surface biomarkers using enzymatic amplification in microfluidic droplets. Angew Chem Int Edit 48(14):2518–2521. doi: 10.1002/anie.200804326 CrossRefGoogle Scholar
  130. 130.
    Link DR, Grasland-Mongrain E, Duri A, Sarrazin F, Cheng Z, Cristobal G, Marquez M, Weitz DA (2006) Electric control of droplets in microfluidic devices. Angew Chem Int Edit 45(16):2556–2560. doi: 10.1002/anie.200503540 CrossRefGoogle Scholar
  131. 131.
    Franke T, Braunmuller S, Schmid L, Wixforth A, Weitz DA (2010) Surface acoustic wave actuated cell sorting (SAWACS). Lab Chip 10(6):789–794. doi: 10.1039/b915522h CrossRefGoogle Scholar
  132. 132.
    Eastburn DJ, Sciambi A, Abate AR (2014) Identification and genetic analysis of cancer cells with PCR-activated cell sorting. Nucleic Acids Res 42(16):e128. doi: 10.1093/nar/gku606 CrossRefGoogle Scholar
  133. 133.
    Kemna EW, Segerink LI, Wolbers F et al (2013) Label-free, high-throughput, electrical detection of cells in droplets. Analyst 138(16):4585–4592. doi: 10.1039/C3AN00569K CrossRefGoogle Scholar
  134. 134.
    Yu D, Gustafson WC, Han C, Lafaye C, Noirclerc-Savoye M, Ge WP, Thayer DA, Huang H, Kornberg TB, Royant A, Jan LY, Jan YN, Weiss WA, Shu X (2014) An improved monomeric infrared fluorescent protein for neuronal and tumour brain imaging. Nat Commun 5:3626. doi: 10.1038/ncomms4626 Google Scholar
  135. 135.
    Cesinaro AM, Natoli C, Grassadonia A, Tinari N, Iacobelli S, Trentini GP (2002) Expression of the 90 K tumor-associated protein in benign and malignant melanocytic lesions. J Invest Dermatol NLM 119(1):187–190. doi: 10.1046/j.1523-1747.2002.17642.x CrossRefGoogle Scholar
  136. 136.
    Ramdzan YM, Polling S, Chia CP, Ng IH, Ormsby AR, Croft NP, Purcell AW, Bogoyevitch MA, Ng DC, Gleeson PA, Hatters DM (2012) Tracking protein aggregation and mislocalization in cells with flow cytometry. Nat Methods 9(5):467–470. doi: 10.1038/nmeth.1930 CrossRefGoogle Scholar
  137. 137.
    Franci C, Takkunen M, Dave N, Alameda F, Gomez S, Rodriguez R, Escriva M, Montserrat-Sentis B, Baro T, Garrido M, Bonilla F, Virtanen I, Garcia de Herreros A (2006) Expression of Snail protein in tumor-stroma interface. Oncogene 25(37):5134–5144. doi: 10.1038/sj.onc.1209519 Google Scholar
  138. 138.
    Guo MT, Rotem A, Heyman JA, Weitz DA (2012) Droplet microfluidics for high-throughput biological assays. Lab Chip 12(12):2146–2155. doi: 10.1039/c2lc21147e CrossRefGoogle Scholar
  139. 139.
    Kang D-K, Monsur Ali M, Zhang K, Pone EJ, Zhao W (2014) Droplet microfluidics for single-molecule and single-cell analysis in cancer research, diagnosis and therapy. TrAC-Trend Anal Chem 58:145–153. doi: 10.1016/j.trac.2014.03.006 CrossRefGoogle Scholar
  140. 140.
    Hummer D, Kurth F, Naredi-Rainer N, Dittrich PS (2016) Single cells in confined volumes: microchambers and microdroplets. Lab Chip 16(3):447–458. doi: 10.1039/c5lc01314c CrossRefGoogle Scholar
  141. 141.
    Konry T, Smolina I, Yarmush JM, Irimia D, Yarmush ML (2011) Ultrasensitive detection of low-abundance surface-marker protein using isothermal rolling circle amplification in a microfluidic nanoliter platform. Small 7(3):395–400. doi: 10.1002/smll.201001620 CrossRefGoogle Scholar
  142. 142.
    Easley CJ, Rocheleau JV, Head WS, Piston DW (2009) Quantitative measurement of zinc secretion from pancreatic islets with high temporal resolution using droplet-based microfluidics. Anal Chem 81(21):9086–9095. doi: 10.1021/ac9017692 CrossRefGoogle Scholar
  143. 143.
    Joensson HN, Samuels ML, Brouzes ER, Medkova M, Uhlen M, Link DR, Andersson-Svahn H (2009) Detection and analysis of low-abundance cell-surface biomarkers using enzymatic amplification in microfluidic droplets. Angew Chem Int Edit 48(14):2518–2521. doi: 10.1002/anie.200804326 CrossRefGoogle Scholar
  144. 144.
    Konry T, Golberg A, Yarmush M (2013) Live single cell functional phenotyping in droplet nano-liter reactors. Sci Rep 3:3179. doi: 10.1038/srep03179 CrossRefGoogle Scholar
  145. 145.
    Konry T, Dominguez-Villar M, Baecher-Allan C, Hafler DA, Yarmush ML (2011) Droplet-based microfluidic platforms for single T cell secretion analysis of IL-10 cytokine. Biosens Bioelectron 26(5):2707–2710. doi: 10.1016/j.bios.2010.09.006 CrossRefGoogle Scholar
  146. 146.
    Wu N, Zhu Y, Brown S, Oakeshott J, Peat TS, Surjadi R, Easton C, Leech PW, Sexton BA (2009) A PMMA microfluidic droplet platform for in vitro protein expression using crude E. coli S30 extract. Lab Chip 9(23):3391–3398. doi: 10.1039/b911581a CrossRefGoogle Scholar
  147. 147.
    Novak R, Zeng Y, Shuga J, Venugopalan G, Fletcher DA, Smith MT, Mathies RA (2011) Single-cell multiplex gene detection and sequencing with microfluidically generated agarose emulsions. Angew Chem Int Edit 50(2):390–395. doi: 10.1002/anie.201006089 CrossRefGoogle Scholar
  148. 148.
    Eastburn DJ, Sciambi A, Abate AR (2013) Ultrahigh-throughput mammalian single-cell reverse-transcriptase polymerase chain reaction in microfluidic drops. Anal Chem 85(16):8016–8021. doi: 10.1021/ac402057q CrossRefGoogle Scholar
  149. 149.
    Hatch AC, Ray T, Lintecum K, Youngbull C (2014) Continuous flow real-time PCR device using multi-channel fluorescence excitation and detection. Lab Chip 14(3):562–568. doi: 10.1039/c3lc51236c CrossRefGoogle Scholar
  150. 150.
    Zhang Y, Ozdemir P (2009) Microfluidic DNA amplification—a review. Anal Chim Acta 638(2):115–125. doi: 10.1016/j.aca.2009.02.038 CrossRefGoogle Scholar
  151. 151.
    Zhang Y, Jiang HR (2016) A review on continuous-flow microfluidic PCR in droplets: advances, challenges and future. Anal Chim Acta 914:7–16. doi: 10.1016/j.aca.2016.02.006 CrossRefGoogle Scholar
  152. 152.
    Curcio M, Roeraade J (2003) Continuous segmented-flow polymerase chain reaction for high-throughput miniaturized DNA amplification. Anal Chem 75(1):1–7. doi: 10.1021/ac0204146 CrossRefGoogle Scholar
  153. 153.
    Zhong Q, Bhattacharya S, Kotsopoulos S, Olson J, Taly V, Griffiths AD, Link DR, Larson JW (2011) Multiplex digital PCR: breaking the one target per color barrier of quantitative PCR. Lab Chip 11(13):2167–2174. doi: 10.1039/c1lc20126c CrossRefGoogle Scholar
  154. 154.
    Wang P, Jing F, Li G, Wu Z, Cheng Z, Zhang J, Zhang H, Jia C, Jin Q, Mao H, Zhao J (2015) Absolute quantification of lung cancer related microRNA by droplet digital PCR. Biosens Bioelectron 74:836–842. doi: 10.1016/j.bios.2015.07.048 CrossRefGoogle Scholar
  155. 155.
    Leman M, Abouakil F, Griffiths AD, Tabeling P (2015) Droplet-based microfluidics at the femtolitre scale. Lab Chip 15(3):753–765. doi: 10.1039/c4lc01122h CrossRefGoogle Scholar
  156. 156.
    Pekin D, Skhiri Y, Baret JC, Le Corre D, Mazutis L, Salem CB, Millot F, El Harrak A, Hutchison JB, Larson JW, Link DR, Laurent-Puig P, Griffiths AD, Taly V (2011) Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. Lab Chip 11(13):2156–2166. doi: 10.1039/c1lc20128j CrossRefGoogle Scholar
  157. 157.
    Hartung R, Brosing A, Sczcepankiewicz G, Liebert U, Hafner N, Durst M, Felbel J, Lassner D, Kohler JM (2009) Application of an asymmetric helical tube reactor for fast identification of gene transcripts of pathogenic viruses by micro flow-through PCR. Biomed Microdevic 11(3):685–692. doi: 10.1007/s10544-008-9280-6 CrossRefGoogle Scholar
  158. 158.
    Mohr S, Zhang YH, Macaskill A, Day PJR, Barber RW, Goddard NJ, Emerson DR, Fielden PR (2007) Numerical and experimental study of a droplet-based PCR chip. Microfluid Nanofluid 3(5):611–621. doi: 10.1007/s10404-007-0153-8 CrossRefGoogle Scholar
  159. 159.
    Leng X, Zhang W, Wang C, Cui L, Yang CJ (2010) Agarose droplet microfluidics for highly parallel and efficient single molecule emulsion PCR. Lab Chip 10(21):2841–2843. doi: 10.1039/c0lc00145g CrossRefGoogle Scholar
  160. 160.
    Kim H, Dixit S, Green CJ et al (2009) Nanodroplet real-time PCR system with laser assisted heating. Opt Express 17(1):218–227. doi: 10.1364/OE.17.000218 CrossRefGoogle Scholar
  161. 161.
    Yun H, Kim K, Lee WG (2013) Cell manipulation in microfluidics. Biofabrication 5(2):022001. doi: 10.1088/1758-5082/5/2/022001 CrossRefGoogle Scholar
  162. 162.
    Ding Y, Qiu F, Casadevall iSX, Chiu F, Nelson B, deMello A (2016) Microfluidic-based droplet and cell manipulations using artificial bacterial flagella. Micromachines 7(2):25. doi: 10.3390/mi7020025 CrossRefGoogle Scholar
  163. 163.
    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
  164. 164.
    Koehler KR, Mikosz AM, Molosh AI, Patel D, Hashino E (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500(7461):217–221. doi: 10.1038/nature12298 CrossRefGoogle Scholar
  165. 165.
    Headen DM, Aubry G, Lu H, Garcia AJ (2014) Microfluidic-based generation of size-controlled, biofunctionalized synthetic polymer microgels for cell encapsulation. Adv Mater 26(19):3003–3008. doi: 10.1002/adma.201304880 CrossRefGoogle Scholar
  166. 166.
    Liu K, Deng Y, Zhang N, Li S, Ding H, Guo F, Liu W, Guo S, Zhao X-Z (2012) Generation of disk-like hydrogel beads for cell encapsulation and manipulation using a droplet-based microfluidic device. Microfluid Nanofluid 13(5):761–767. doi: 10.1007/s10404-012-0998-3 CrossRefGoogle Scholar
  167. 167.
    Seiffert S (2011) Functional microgels tailored by droplet-based microfluidics. Macromol Rapid Commun 32(20):1600–1609. doi: 10.1002/marc.201100342 CrossRefGoogle Scholar
  168. 168.
    Sakakihara S, Araki S, Iino R, Noji H (2010) A single-molecule enzymatic assay in a directly accessible femtoliter droplet array. Lab Chip 10(24):3355–3362. doi: 10.1039/c0lc00062k CrossRefGoogle Scholar
  169. 169.
    Tumarkin E, Kumacheva E (2009) Microfluidic generation of microgels from synthetic and natural polymers. Chem Soc Rev 38(8):2161–2168. doi: 10.1039/b809915b CrossRefGoogle Scholar
  170. 170.
    Siltanen C, Yaghoobi M, Haque A, You J, Lowen J, Soleimani M, Revzin A (2016) Microfluidic fabrication of bioactive microgels for rapid formation and enhanced differentiation of stem cell spheroids. Acta Biomater 34:125–132. doi: 10.1016/j.actbio.2016.01.012 CrossRefGoogle Scholar
  171. 171.
    Kumachev A, Greener J, Tumarkin E, Eiser E, Zandstra PW, Kumacheva E (2011) High-throughput generation of hydrogel microbeads with varying elasticity for cell encapsulation. Biomaterials 32(6):1477–1483. doi: 10.1016/j.biomaterials.2010.10.033 CrossRefGoogle Scholar
  172. 172.
    Du GS, Pan JZ, Zhao SP, Zhu Y, den Toonder JM, Fang Q (2013) Cell-based drug combination screening with a microfluidic droplet array system. Anal Chem 85(14):6740–6747. doi: 10.1021/ac400688f CrossRefGoogle Scholar
  173. 173.
    Yu JQ, Huang W, Chin LK, Lei L, Lin ZP, Ser W, Chen H, Ayi TC, Yap PH, Chen CH, Liu AQ (2014) Droplet optofluidic imaging for lambda-bacteriophage detection via co-culture with host cell Escherichia coli. Lab Chip 14(18):3519–3524. doi: 10.1039/c4lc00042k CrossRefGoogle Scholar
  174. 174.
    Zhang J, Chen F, He Z, Ma Y, Uchiyama K, Lin JM (2016) A novel approach for precisely controlled multiple cell patterning in microfluidic chips by inkjet printing and the detection of drug metabolism and diffusion. Analyst 141(10):2940–2947. doi: 10.1039/c6an00395h CrossRefGoogle Scholar
  175. 175.
    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 3(6):653–662. doi: 10.1039/c1ib00002k CrossRefGoogle Scholar
  176. 176.
    Liu Z, Shum HC (2013) Fabrication of uniform multi-compartment particles using microfludic electrospray technology for cell co-culture studies. Biomicrofluidics 7(4):44117. doi: 10.1063/1.4817769 CrossRefGoogle Scholar
  177. 177.
    Peng Lee C, Hsin Chen Y, Hang Wei Z (2013) Fabrication of hexagonally packed cell culture substrates using droplet formation in a T-shaped microfluidic junction. Biomicrofluidics 7(1):14101. doi: 10.1063/1.4774315 CrossRefGoogle Scholar
  178. 178.
    Chen H, Sun J, Wolvetang E, Cooper-White J (2015) High-throughput, deterministic single cell trapping and long-term clonal cell culture in microfluidic devices. Lab Chip 15(4):1072–1083. doi: 10.1039/c4lc01176g CrossRefGoogle Scholar
  179. 179.
    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

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

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

Personalised recommendations