Analytical and Bioanalytical Chemistry

, Volume 405, Issue 17, pp 5743–5758 | Cite as

Quantitative microfluidic biomolecular analysis for systems biology and medicine

Review

Abstract

In the postgenome era, biology and medicine are rapidly evolving towards quantitative and systems studies of complex biological systems. Emerging breakthroughs in microfluidic technologies and innovative applications are transforming systems biology by offering new capabilities to address the challenges in many areas, such as single-cell genomics, gene regulation networks, and pathology. In this review, we focus on recent progress in microfluidic technology from the perspective of its applications to promoting quantitative and systems biomolecular analysis in biology and medicine.

Keywords

Microfluidics Quantitative analysis Systems biology Medicine Single cell Genomics Proteomics 

References

  1. 1.
    Bruggeman FJ, Westerhoff HV (2007) The nature of systems biology. Trends Microbiol 15(1):45–50CrossRefGoogle Scholar
  2. 2.
    Sauer U, Heinemann M, Zamboni N (2007) Genetics. Getting closer to the whole picture. Science 316(5824):550–551CrossRefGoogle Scholar
  3. 3.
    Oates AC, Gorfinkiel N, Gonzalez-Gaitan M, Heisenberg CP (2009) Quantitative approaches in developmental biology. Nat Rev Genet 10(8):517–530CrossRefGoogle Scholar
  4. 4.
    Spencer SL, Gerety RA, Pienta KJ, Forrest S (2006) Modeling somatic evolution in tumorigenesis. PLoS Comput Biol 2(8):e108CrossRefGoogle Scholar
  5. 5.
    Newman JRS, Ghaemmaghami S, Ihmels J, Breslow DK, Noble M, DeRisi JL, Weissman JS (2006) Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441(7095):840–846CrossRefGoogle Scholar
  6. 6.
    Taniguchi Y, Choi PJ, Li GW, Chen H, Babu M, Hearn J, Emili A, Xie XS (2010) Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329(5991):533–538CrossRefGoogle Scholar
  7. 7.
    Manz A, Graber N, Widmer HM (1990) Miniaturized total chemical analysis systems - a novel concept for chemical sensing. Sens Actuators B Chem 1(1–6):244–248CrossRefGoogle Scholar
  8. 8.
    Harrison DJ, Fluri K, Seiler K, Fan ZH, Effenhauser CS, Manz A (1993) Micromachining a miniaturized capillary electrophoresis-based chemical analysis system on a chip. Science 261(5123):895–897CrossRefGoogle Scholar
  9. 9.
    Arora A, Simone G, Salieb-Beugelaar GB, Kim JT, Manz A (2010) Latest developments in micro total analysis systems. Anal Chem 82(12):4830–4847CrossRefGoogle Scholar
  10. 10.
    Unger MA, Chou HP, Thorsen T, Scherer A, Quake SR (2000) Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288(5463):113–116CrossRefGoogle Scholar
  11. 11.
    Thorsen T, Maerkl SJ, Quake SR (2002) Microfluidic large-scale integration. Science 298(5593):580–584CrossRefGoogle Scholar
  12. 12.
    Grover WH, Skelley AM, Liu CN, Lagally ET, Mathies RA (2003) Monolithic membrane valves and diaphragm pumps for practical large-scale integration into glass microfluidic devices. Sens Actuators B Chem 89(3):315–323CrossRefGoogle Scholar
  13. 13.
    Jensen EC, Zeng Y, Kim J, Mathies RA (2010) Microvalve enabled digital microfluidic systems for high-performance biochemical and genetic analysis. J Lab Autom 15(6):455–463CrossRefGoogle Scholar
  14. 14.
    Liu WM, Li L, Wang JC, Tu Q, Ren L, Wang YL, Wang JY (2012) Dynamic trapping and high-throughput patterning of cells using pneumatic microstructures in an integrated microfluidic device. Lab Chip 12(9):1702–1709CrossRefGoogle Scholar
  15. 15.
    Eyer K, Kuhn P, Hanke C, Dittrich PS (2012) A microchamber array for single cell isolation and analysis of intracellular biomolecules. Lab Chip 12(4):765–772CrossRefGoogle Scholar
  16. 16.
    Shemesh J, Nir A, Bransky A, Levenberg S (2011) Coalescence-assisted generation of single nanoliter droplets with predefined composition. Lab Chip 11(19):3225–3230CrossRefGoogle Scholar
  17. 17.
    Kim J, Kang M, Jensen EC, Mathies RA (2012) Lifting gate polydimethylsiloxane microvalves and pumps for microfluidic control. Anal Chem 84(4):2067–2071CrossRefGoogle Scholar
  18. 18.
    Chen CY, Chen CH, Tu TY, Lin CM, Wo AM (2011) Electrical isolation and characteristics of permanent magnet-actuated valves for PDMS microfluidics. Lab Chip 11(4):733–737CrossRefGoogle Scholar
  19. 19.
    Bhagat AAS, Hou HW, Li LD, Lim CT, Han JY (2011) Pinched flow coupled shear-modulated inertial microfluidics for high-throughput rare blood cell separation. Lab Chip 11(11):1870–1878CrossRefGoogle Scholar
  20. 20.
    Hou HW, Bhagat AAS, Chong AGL, Mao P, Tan KSW, Han JY, Lim CT (2010) Deformability based cell margination—a simple microfluidic design for malaria-infected erythrocyte separation. Lab Chip 10(19):2605–2613CrossRefGoogle Scholar
  21. 21.
    Jones PV, Staton SJR, Hayes MA (2011) Blood cell capture in a sawtooth dielectrophoretic microchannel. Anal Bioanal Chem 401(7):2103–2111CrossRefGoogle Scholar
  22. 22.
    Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239CrossRefGoogle Scholar
  23. 23.
    Gleghorn JP, Pratt ED, Denning D, Liu H, Bander NH, Tagawa ST, Nanus DM, Giannakakou PA, Kirby BJ (2010) Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. Lab Chip 10(1):27–29CrossRefGoogle Scholar
  24. 24.
    Wang ZK, Chin SY, Chin CD, Sarik J, Harper M, Justman J, Sia SK (2010) Microfluidic CD4+ T-cell counting device using chemiluminescence-based detection. Anal Chem 82(1):36–40CrossRefGoogle Scholar
  25. 25.
    Mittal S, Wong IY, Deen WM, Toner M (2012) Antibody-functionalized fluid-permeable surfaces for rolling cell capture at high flow rates. Biophys J 102(4):721–730CrossRefGoogle Scholar
  26. 26.
    Chen GD, Fachin F, Fernandez-Suarez M, Wardle BL, Toner M (2011) Nanoporous elements in microfluidics for multiscale manipulation of bioparticles. Small 7(8):1061–1067CrossRefGoogle Scholar
  27. 27.
    Lien KY, Chuang YH, Hung LY, Hsu KF, Lai WW, Ho CL, Chou CY, Lee GB (2010) Rapid isolation and detection of cancer cells by utilizing integrated microfluidic systems. Lab Chip 10(21):2875–2886CrossRefGoogle Scholar
  28. 28.
    Shah AM, Yu M, Nakamura Z, Ciciliano J, Ulman M, Kotz K, Stott SL, Maheswaran S, Haber DA, Toner M (2012) Biopolymer system for cell recovery from microfluidic cell capture devices. Anal Chem 84(8):3682–3688CrossRefGoogle Scholar
  29. 29.
    Hatch A, Hansmann G, Murthy SK (2011) Engineered alginate hydrogels for effective microfluidic capture and release of endothelial progenitor cells from whole blood. Langmuir 27(7):4257–4264CrossRefGoogle Scholar
  30. 30.
    He M, Novak J, Julian BA, Herr AE (2011) Membrane-assisted online renaturation for automated microfluidic lectin blotting. J Am Chem Soc 133(49):19610–19613CrossRefGoogle Scholar
  31. 31.
    Tia SQ, He M, Kim D, Herr AE (2011) Multianalyte on-chip native Western blotting. Anal Chem 83(9):3581–3588CrossRefGoogle Scholar
  32. 32.
    He M, Zeng Y, Sun X, Harrison DJ (2008) Confinement effects on the morphology of photopatterned porous polymer monoliths for capillary and microchip electrophoresis of proteins. Electrophoresis 29(14):2980–2986Google Scholar
  33. 33.
    He M, Zeng Y, Jemere AB, Harrison DJ (2012) Tunable thick polymer coatings for on-chip electrophoretic protein and peptide separation. J Chromatogr A 1241:112–116CrossRefGoogle Scholar
  34. 34.
    He M, Herr AE (2010) Polyacrylamide gel photopatterning enables automated protein immunoblotting in a two-dimensional microdevice. J Am Chem Soc 132(8):2512–2513CrossRefGoogle Scholar
  35. 35.
    Zeng Y, He M, Harrison DJ (2008) Microfluidic self-patterning of large-scale crystalline nanoarrays for high-throughput continuous DNA fractionation. Angew Chem Int Ed 47(34):6388–6391CrossRefGoogle Scholar
  36. 36.
    Zeng Y, Harrison DJ (2007) Self-assembled colloidal arrays as three-dimensional nanofluidic sieves for separation of biomolecules on microchips. Anal Chem 79(6):2289–2295CrossRefGoogle Scholar
  37. 37.
    Saliba AE, Saias L, Psychari E, Minc N, Simon D, Bidard FC, Mathiot C, Pierga JY, Fraisier V, Salamero J, Saada V, Farace F, Vielh P, Malaquin L, Viovy JL (2010) Microfluidic sorting and multimodal typing of cancer cells in self-assembled magnetic arrays. Proc Natl Acad Sci USA 107(33):14524–14529CrossRefGoogle Scholar
  38. 38.
    Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28(6):595–599CrossRefGoogle Scholar
  39. 39.
    Rondelez Y, Tresset G, Tabata KV, Arata H, Fujita H, Takeuchi S, Noji H (2005) Microfabricated arrays of femtoliter chambers allow single molecule enzymology. Nat Biotechnol 23(3):361–365CrossRefGoogle Scholar
  40. 40.
    Ma C, Fan R, Ahmad H, Shi QH, 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):738–743CrossRefGoogle Scholar
  41. 41.
    White AK, VanInsberghe M, Petriv OI, Hamidi M, Sikorski D, Marra MA, Piret J, Aparicio S, Hansen CL (2011) High-throughput microfluidic single-cell RT-qPCR. Proc Natl Acad Sci USA 108(34):13999–14004CrossRefGoogle Scholar
  42. 42.
    Fan HC, Wang JB, Potanina A, Quake SR (2011) Whole-genome molecular haplotyping of single cells. Nat Biotechnol 29(1):51–57CrossRefGoogle Scholar
  43. 43.
    Kim S, Streets AM, Lin RR, Quake SR, Weiss S, Majumdar DS (2011) High-throughput single-molecule optofluidic analysis. Nat Methods 8(3):242–245CrossRefGoogle Scholar
  44. 44.
    Powell AA, Talasaz AH, Zhang HY, Coram MA, Reddy A, Deng G, Telli ML, Advani RH, Carlson RW, Mollick JA, Sheth S, Kurian AW, Ford JM, Stockdale FE, Quake SR, Pease RF, Mindrinos MN, Bhanot G, Dairkee SH, Davis RW, Jeffrey SS (2012) Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One 7(5):e33788CrossRefGoogle Scholar
  45. 45.
    Wang YL, Shah P, Phillips C, Sims CE, Allbritton NL (2012) Trapping cells on a stretchable microwell array for single-cell analysis. Anal Bioanal Chem 402(3):1065–1072CrossRefGoogle Scholar
  46. 46.
    Heyries KA, Tropini C, VanInsberghe M, Doolin C, Petriv OI, Singhal A, Leung K, Hughesman CB, Hansen CL (2011) Megapixel digital PCR. Nat Methods 8(8):649–664CrossRefGoogle Scholar
  47. 47.
    Ota S, Kitagawa H, Takeuchi S (2012) Generation of femtoliter reactor arrays within a microfluidic channel for biochemical analysis. Anal Chem 84(15):6346–6350CrossRefGoogle Scholar
  48. 48.
    Zhang H, Nie S, Etson CM, Wang RM, Walt DR (2012) Oil-sealed femtoliter fiber-optic arrays for single molecule analysis. Lab Chip 12(12):2229–2239CrossRefGoogle Scholar
  49. 49.
    Men YF, Fu YS, Chen ZT, Sims PA, Greenleaf WJ, Huang YY (2012) Digital polymerase chain reaction in an array of femtoliter polydimethylsiloxane microreactors. Anal Chem 84(10):4262–4266CrossRefGoogle Scholar
  50. 50.
    Sims PA, Greenleaf WJ, Duan HF, Xie S (2011) Fluorogenic DNA sequencing in PDMS microreactors. Nat Methods 8(7):575–584CrossRefGoogle Scholar
  51. 51.
    Teh SY, Lin R, Hung LH, Lee AP (2008) Droplet microfluidics. Lab Chip 8(2):198–220CrossRefGoogle Scholar
  52. 52.
    Niu X, Demello AJ (2012) Building droplet-based microfluidic systems for biological analysis. Biochem Soc Trans 40(4):615–623CrossRefGoogle Scholar
  53. 53.
    Guo MT, Rotem A, Heyman JA, Weitz DA (2012) Droplet microfluidics for high-throughput biological assays. Lab Chip 12(12):2146–2155CrossRefGoogle Scholar
  54. 54.
    Vogelstein B, Kinzler KW (1999) Digital PCR. Proc Natl Acad Sci USA 96(16):9236–9241CrossRefGoogle Scholar
  55. 55.
    Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B (2003) Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci USA 100(15):8817–8822CrossRefGoogle Scholar
  56. 56.
    Zeng Y, Novak R, Shuga J, Smith MT, Mathies RA (2010) High-performance single cell genetic analysis using microfluidic emulsion generator arrays. Anal Chem 82(8):3183–3190CrossRefGoogle Scholar
  57. 57.
    Zeng Y, Shin M, Wang T (2013) Programmable active droplet generation enabled by integrated pneumatic micropumps. Lab Chip 13(2):267–273CrossRefGoogle Scholar
  58. 58.
    Abbyad P, Dangla R, Alexandrou A, Baroud CN (2011) Rails and anchors: guiding and trapping droplet microreactors in two dimensions. Lab Chip 11(5):813–821CrossRefGoogle Scholar
  59. 59.
    Abate AR, Hung T, Mary P, Agresti JJ, Weitz DA (2010) High-throughput injection with microfluidics using picoinjectors. Proc Natl Acad Sci USA 107(45):19163–19166CrossRefGoogle Scholar
  60. 60.
    Simon MG, Lin R, Fisher JS, Lee AP (2012) A Laplace pressure based microfluidic trap for passive droplet trapping and controlled release. Biomicrofluidics 6(1):014110CrossRefGoogle Scholar
  61. 61.
    Ahn B, Lee K, Lee H, Panchapakesan R, Oh KW (2011) Parallel synchronization of two trains of droplets using a railroad-like channel network. Lab Chip 11(23):3956–3962CrossRefGoogle Scholar
  62. 62.
    Mazutis L, Griffiths AD (2012) Selective droplet coalescence using microfluidic systems. Lab Chip 12(10):1800–1806CrossRefGoogle Scholar
  63. 63.
    Franke T, Braunmuller S, Schmid L, Wixforth A, Weitz DA (2010) Surface acoustic wave actuated cell sorting (SAWACS). Lab Chip 10(6):789–794CrossRefGoogle Scholar
  64. 64.
    Niu XZ, Gielen F, Edel JB, deMello AJ (2011) A microdroplet dilutor for high-throughput screening. Nat Chem 3(6):437–442CrossRefGoogle Scholar
  65. 65.
    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):2156–2166CrossRefGoogle Scholar
  66. 66.
    El Debs B, Utharala R, Balyasnikova IV, Griffiths AD, Merten CA (2012) Functional single-cell hybridoma screening using droplet-based microfluidics. Proc Natl Acad Sci USA 109(29):11570–11575CrossRefGoogle Scholar
  67. 67.
    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 Ed 50(2):390–395CrossRefGoogle Scholar
  68. 68.
    Derda R, Tang SKY, Whitesides GM (2010) Uniform amplification of phage with different growth characteristics in individual compartments consisting of monodisperse droplets. Angew Chem Int Ed 49(31):5301–5304CrossRefGoogle Scholar
  69. 69.
    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 (vol 170, pg 4004, 2010). Proc Natl Acad Sci USA 107(14):6550–6550CrossRefGoogle Scholar
  70. 70.
    Fallah-Araghi A, Baret JC, Ryckelynck M, Griffiths AD (2012) A completely in vitro ultrahigh-throughput droplet-based microfluidic screening system for protein engineering and directed evolution. Lab Chip 12(5):882–891CrossRefGoogle Scholar
  71. 71.
    Wheeler AR (2008) Putting electrowetting to work. Science 322(5901):539–540CrossRefGoogle Scholar
  72. 72.
    Lee J, Moon H, Fowler J, Schoellhammer T, Kim CJ (2002) Electrowetting and electrowetting-on-dielectric for microscale liquid handling. Sens Actuators A Phys 95(2–3):259–268CrossRefGoogle Scholar
  73. 73.
    Pollack MG, Fair RB, Shenderov AD (2000) Electrowetting-based actuation of liquid droplets for microfluidic applications. Appl Phys Lett 77(11):1725–1726CrossRefGoogle Scholar
  74. 74.
    Cho SK, Moon HJ, Kim CJ (2003) Creating, transporting, cutting, and merging liquid droplets by electrowetting-based actuation for digital microfluidic circuits. J Microelectromech Syst 12(1):70–80CrossRefGoogle Scholar
  75. 75.
    Choi K, Ng AH, Fobel R, Wheeler AR (2012) Digital microfluidics. Annu Rev Anal Chem 5:413–440CrossRefGoogle Scholar
  76. 76.
    Malic L, Brassard D, Veres T, Tabrizian M (2010) Integration and detection of biochemical assays in digital microfluidic LOC devices. Lab Chip 10(4):418–431CrossRefGoogle Scholar
  77. 77.
    Jebrail MJ, Bartsch MS, Patel KD (2012) Digital microfluidics: a versatile tool for applications in chemistry, biology and medicine. Lab Chip 12(14):2452–2463CrossRefGoogle Scholar
  78. 78.
    Jones RB, Gordus A, Krall JA, MacBeath G (2006) A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439(7073):168–174CrossRefGoogle Scholar
  79. 79.
    Maerkl SJ, Quake SR (2007) A systems approach to measuring the binding energy landscapes of transcription factors. Science 315(5809):233–237CrossRefGoogle Scholar
  80. 80.
    Fordyce PM, Pincus D, Kimmig P, Nelson CS, El-Samad H, Walter P, DeRisi JL (2012) Basic leucine zipper transcription factor Hac1 binds DNA in two distinct modes as revealed by microfluidic analyses. Proc Natl Acad Sci USA 109(45):E3084–E3093CrossRefGoogle Scholar
  81. 81.
    Fordyce PM, Gerber D, Tran D, Zheng J, Li H, DeRisi JL, Quake SR (2010) De novo identification and biophysical characterization of transcription-factor binding sites with microfluidic affinity analysis. Nat Biotechnol 28(9):970–975CrossRefGoogle Scholar
  82. 82.
    Geertz M, Shore D, Maerkl SJ (2012) Massively parallel measurements of molecular interaction kinetics on a microfluidic platform. Proc Natl Acad Sci USA 109(41):16540–16545CrossRefGoogle Scholar
  83. 83.
    Rockel S, Geertz M, Hens K, Deplancke B, Maerkl SJ (2013) iSLIM: a comprehensive approach to mapping and characterizing gene regulatory networks. Nucleic Acids Res 41(4):e52CrossRefGoogle Scholar
  84. 84.
    Gerber D, Maerkl SJ, Quake SR (2009) An in vitro microfluidic approach to generating protein-interaction networks. Nat Methods 6(1):71–74CrossRefGoogle Scholar
  85. 85.
    Meier M, Sit RV, Quake SR (2013) Proteome-wide protein interaction measurements of bacterial proteins of unknown function. Proc Natl Acad Sci USA 110(2):477–482CrossRefGoogle Scholar
  86. 86.
    Meier M, Sit R, Pan W, Quake SR (2012) High-performance binary protein interaction screening in a microfluidic format. Anal Chem 84(21):9572–9578Google Scholar
  87. 87.
    Martin L, Meier M, Lyons SM, Sit RV, Marzluff WF, Quake SR, Chang HY (2012) Systematic reconstruction of RNA functional motifs with high-throughput microfluidics. Nat Methods 9(12):1192–1194CrossRefGoogle Scholar
  88. 88.
    Einav S, Gerber D, Bryson PD, Sklan EH, Elazar M, Maerkl SJ, Glenn JS, Quake SR (2008) Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 26(9):1019–1027CrossRefGoogle Scholar
  89. 89.
    Chou CK, Jing N, Yamaguchi H, Tsou PH, Lee HH, Chen CT, Wang YN, Hong S, Su C, Kameoka J, Hung MC (2010) High speed digital protein interaction analysis using microfluidic single molecule detection system. Lab Chip 10(14):1793–1798CrossRefGoogle Scholar
  90. 90.
    Choi JW, Kang DK, Park H, deMello AJ, Chang SI (2012) High-throughput analysis of protein-protein interactions in picoliter-volume droplets using fluorescence polarization. Anal Chem 84(8):3849–3854CrossRefGoogle Scholar
  91. 91.
    Lombardi D, Dittrich PS (2011) Droplet microfluidics with magnetic beads: a new tool to investigate drug-protein interactions. Anal Bioanal Chem 399(1):347–352CrossRefGoogle Scholar
  92. 92.
    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):1645–1648CrossRefGoogle Scholar
  93. 93.
    Williams LD, Ghosh T, Mastrangelo CH (2010) Low noise detection of biomolecular interactions with signal-locking surface plasmon resonance. Anal Chem 82(14):6025–6031CrossRefGoogle Scholar
  94. 94.
    Amarie D, Alileche A, Dragnea B, Glazier JA (2010) Microfluidic devices integrating microcavity surface-plasmon-resonance sensors: glucose oxidase binding-activity detection. Anal Chem 82(1):343–352CrossRefGoogle Scholar
  95. 95.
    Ouellet E, Lausted C, Lin T, Yang CW, Hood L, Lagally ET (2010) Parallel microfluidic surface plasmon resonance imaging arrays. Lab Chip 10(5):581–588CrossRefGoogle Scholar
  96. 96.
    Lee SH, Lindquist NC, Wittenberg NJ, Jordan LR, Oh SH (2012) Real-time full-spectral imaging and affinity measurements from 50 microfluidic channels using nanohole surface plasmon resonance. Lab Chip 12(20):3882–3890CrossRefGoogle Scholar
  97. 97.
    Soon WW, Hariharan M, Snyder MP (2013) High-throughput sequencing for biology and medicine. Mol Syst Biol 9:640CrossRefGoogle Scholar
  98. 98.
    Liu P, Mathies RA (2009) Integrated microfluidic systems for high-performance genetic analysis. Trends Biotechnol 27(10):572–581CrossRefGoogle Scholar
  99. 99.
    Tang F, Lao K, Surani MA (2011) Development and applications of single-cell transcriptome analysis. Nat Methods 8(4 Suppl):S6–S11Google Scholar
  100. 100.
    Kalisky T, Quake SR (2011) Single-cell genomics. Nat Methods 8(4):311–314CrossRefGoogle Scholar
  101. 101.
    Shuga J, Zeng Y, Novak R, Mathies RA, Hainaut P, Smith MT (2010) Selected technologies for measuring acquired genetic damage in humans. Environ Mol Mutagen 51(8–9):851–870CrossRefGoogle Scholar
  102. 102.
    Roy S, Soh JH, Gao Z (2011) A microfluidic-assisted microarray for ultrasensitive detection of miRNA under an optical microscope. Lab Chip 11(11):1886–1894CrossRefGoogle Scholar
  103. 103.
    Chapin SC, Appleyard DC, Pregibon DC, Doyle PS (2011) Rapid microRNA profiling on encoded gel microparticles. Angew Chem Int Ed 50(10):2289–2293Google Scholar
  104. 104.
    Sundberg SO, Wittwer CT, Gao C, Gale BK (2010) Spinning disk platform for microfluidic digital polymerase chain reaction. Anal Chem 82(4):1546–1550CrossRefGoogle Scholar
  105. 105.
    Shen F, Davydova EK, Du W, Kreutz JE, Piepenburg O, Ismagilov RF (2011) Digital isothermal quantification of nucleic acids via simultaneous chemical initiation of recombinase polymerase amplification reactions on SlipChip. Anal Chem 83(9):3533–3540CrossRefGoogle Scholar
  106. 106.
    Shen F, Sun B, Kreutz JE, Davydova EK, Du WB, Reddy PL, Joseph LJ, Ismagilov RF (2011) Multiplexed quantification of nucleic acids with large dynamic range using multivolume digital RT-PCR on a rotational SlipChip tested with HIV and hepatitis C viral load. J Am Chem Soc 133(44):17705–17712CrossRefGoogle Scholar
  107. 107.
    Kreutz JE, Munson T, Huynh T, Shen F, Du W, Ismagilov RF (2011) Theoretical design and analysis of multivolume digital assays with wide dynamic range validated experimentally with microfluidic digital PCR. Anal Chem 83(21):8158–8168CrossRefGoogle Scholar
  108. 108.
    Pinheiro LB, Coleman VA, Hindson CM, Herrmann J, Hindson BJ, Bhat S, Emslie KR (2012) Evaluation of a droplet digital polymerase chain reaction format for DNA copy number quantification. Anal Chem 84(2):1003–1011CrossRefGoogle Scholar
  109. 109.
    Sanders R, Huggett JF, Bushell CA, Cowen S, Scott DJ, Foy CA (2011) Evaluation of digital PCR for absolute DNA quantification. Anal Chem 83(17):6474–6484CrossRefGoogle Scholar
  110. 110.
    Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, Kitano TK, Hodel MR, Petersen JF, Wyatt PW, Steenblock ER, Shah PH, Bousse LJ, Troup CB, Mellen JC, Wittmann DK, Erndt NG, Cauley TH, Koehler RT, So AP, Dube S, Rose KA, Montesclaros L, Wang S, Stumbo DP, Hodges SP, Romine S, Milanovich FP, White HE, Regan JF, Karlin-Neumann GA, Hindson CM, Saxonov S, Colston BW (2011) High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 83(22):8604–8610CrossRefGoogle Scholar
  111. 111.
    Whale AS, Huggett JF, Cowen S, Speirs V, Shaw J, Ellison S, Foy CA, Scott DJ (2012) Comparison of microfluidic digital PCR and conventional quantitative PCR for measuring copy number variation. Nucleic Acids Res 40(11):e82CrossRefGoogle Scholar
  112. 112.
    Zhang HF, Jenkins G, Zou Y, Zhu Z, Yang CJ (2012) Massively parallel single-molecule and single-cell emulsion reverse transcription polymerase chain reaction using agarose droplet microfluidics. Anal Chem 84(8):3599–3606CrossRefGoogle Scholar
  113. 113.
    Wang JB, Fan HC, Behr B, Quake SR (2012) Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell 150(2):402–412CrossRefGoogle Scholar
  114. 114.
    Dalerba P, Kalisky T, Sahoo D, Rajendran PS, Rothenberg ME, Leyrat AA, Sim S, Okamoto J, Johnston DM, Qian D, Zabala M, Bueno J, Neff NF, Wang J, Shelton AA, Visser B, Hisamori S, Shimono Y, van de Wetering M, Clevers H, Clarke MF, Quake SR (2011) Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol 29(12):1120–1127CrossRefGoogle Scholar
  115. 115.
    Chao TC, Hansmeier N (2012) Microfluidic devices for high-throughput proteome analyses. Proteomics 13(3–4):467–479Google Scholar
  116. 116.
    Chun HG, Chung TD, Ramsey JM (2010) High yield sample preconcentration using a highly ion-conductive charge-selective polymer. Anal Chem 82(14):6287–6292CrossRefGoogle Scholar
  117. 117.
    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):10368–10371CrossRefGoogle Scholar
  118. 118.
    Polat AN, Kraiczek K, Heck AJ, Raijmakers R, Mohammed S (2012) Fully automated isotopic dimethyl labeling and phosphopeptide enrichment using a microfluidic HPLC phosphochip. Anal Bioanal Chem 404(8):2507–2512CrossRefGoogle Scholar
  119. 119.
    Tian RJ, Hoa XYD, Lambert JP, Pezacki JP, Veres T, Figeys D (2011) Development of a multiplexed microfluidic proteomic reactor and its application for studying protein-protein interactions. Anal Chem 83(11):4095–4102CrossRefGoogle Scholar
  120. 120.
    Zhou H, Hou WM, Lambert JP, Figeys D (2010) New ammunition for the proteomic reactor: strong anion exchange beads and multiple enzymes enhance protein identification and sequence coverage. Anal Bioanal Chem 397(8):3421–3430CrossRefGoogle Scholar
  121. 121.
    Lin SL, Bai HY, Lin TY, Fuh MR (2012) Microfluidic chip-based liquid chromatography coupled to mass spectrometry for determination of small molecules in bioanalytical applications. Electrophoresis 33(4):635–643CrossRefGoogle Scholar
  122. 122.
    Sommer GJ, Mai J, Singh AK, Hatch AV (2011) Microscale isoelectric fractionation using photopolymerized membranes. Anal Chem 83(8):3120–3125CrossRefGoogle Scholar
  123. 123.
    Chambers AG, Mellors JS, Henley WH, Ramsey JM (2011) Monolithic integration of two-dimensional liquid chromatography–capillary electrophoresis and electrospray ionization on a microfluidic device. Anal Chem 83(3):842–849CrossRefGoogle Scholar
  124. 124.
    Mao P, Gomez-Sjoberg R, Wang D (2012) Multinozzle emitter array chips for small-volume proteomics. Anal Chem 85(2):816–819CrossRefGoogle Scholar
  125. 125.
    Hughes AJ, Lin RK, Peehl DM, Herr AE (2012) Microfluidic integration for automated targeted proteomic assays. Proc Natl Acad Sci USA 109(16):5972–5977CrossRefGoogle Scholar
  126. 126.
    Karns K, Herr AE (2011) Human tear protein analysis enabled by an alkaline microfluidic homogeneous immunoassay. Anal Chem 83(21):8115–8122CrossRefGoogle Scholar
  127. 127.
    Luk VN, Fiddes LK, Luk VM, Kumacheva E, Wheeler AR (2012) Digital microfluidic hydrogel microreactors for proteomics. Proteomics 12(9):1310–1318CrossRefGoogle Scholar
  128. 128.
    Yang H, Mudrik JM, Jebrail MJ, Wheeler AR (2011) A digital microfluidic method for in situ formation of porous polymer monoliths with application to solid-phase extraction. Anal Chem 83(10):3824–3830CrossRefGoogle Scholar
  129. 129.
    Miller EM, Ng AH, Uddayasankar U, Wheeler AR (2011) A digital microfluidic approach to heterogeneous immunoassays. Anal Bioanal Chem 399(1):337–345CrossRefGoogle Scholar
  130. 130.
    Aijian AP, Chatterjee D, Garrell RL (2012) Fluorinated liquid-enabled protein handling and surfactant-aided crystallization for fully in situ digital microfluidic MALDI-MS analysis. Lab Chip 12(14):2552–2559CrossRefGoogle Scholar
  131. 131.
    Shih SC, Yang H, Jebrail MJ, Fobel R, McIntosh N, Al-Dirbashi OY, Chakraborty P, Wheeler AR (2012) Dried blood spot analysis by digital microfluidics coupled to nanoelectrospray ionization mass spectrometry. Anal Chem 84(8):3731–3738CrossRefGoogle Scholar
  132. 132.
    Chatterjee D, Ytterberg AJ, Son SU, Loo JA, Garrell RL (2010) Integration of protein processing steps on a droplet microfluidics platform for MALDI-MS analysis. Anal Chem 82(5):2095–2101CrossRefGoogle Scholar
  133. 133.
    Kan CW, Rivnak AJ, Campbell TG, Piech T, Rissin DM, Mosl M, Peterca A, Niederberger HP, Minnehan KA, Patel PP, Ferrell EP, Meyer RE, Chang L, Wilson DH, Fournier DR, Duffy DC (2012) Isolation and detection of single molecules on paramagnetic beads using sequential fluid flows in microfabricated polymer array assemblies. Lab Chip 12(5):977–985CrossRefGoogle Scholar
  134. 134.
    Sun J, Masterman-Smith MD, Graham NA, Jiao J, Mottahedeh J, Laks DR, Ohashi M, DeJesus J, Kamei K, Lee KB, Wang H, Yu ZTF, Lu YT, Hou SA, Li KY, Liu M, Zhang NG, Wang ST, 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):6128–6138CrossRefGoogle Scholar
  135. 135.
    Kim MS, Kwon S, Kim T, Lee ES, Park JK (2011) Quantitative proteomic profiling of breast cancers using a multiplexed microfluidic platform for immunohistochemistry and immunocytochemistry. Biomaterials 32(5):1396–1403CrossRefGoogle Scholar
  136. 136.
    Kotz KT, Xiao W, Miller-Graziano C, Qian WJ, Russom A, Warner EA, Moldawer LL, De A, Bankey PE, Petritis BO, Camp DG, Rosenbach AE, Goverman J, Fagan SP, Brownstein BH, Irimia D, Xu WH, Wilhelmy J, Mindrinos MN, Smith RD, Davis RW, Tompkins RG, Toner M, Injury IHR (2010) Clinical microfluidics for neutrophil genomics and proteomics. Nat Med 1(9):1042–1142CrossRefGoogle Scholar
  137. 137.
    Muzzey D, van Oudenaarden A (2009) Quantitative time-lapse fluorescence microscopy in single cells. Annu Rev Cell Dev Biol 25:301–327CrossRefGoogle Scholar
  138. 138.
    Stott SL, Lee RJ, Nagrath S, Yu M, Miyamoto DT, Ulkus L, Inserra EJ, Ulman M, Springer S, Nakamura Z, Moore AL, Tsukrov DI, Kempner ME, Dahl DM, Wu CL, Iafrate AJ, Smith MR, Tompkins RG, Sequist LV, Toner M, Haber DA, Maheswaran S (2010) Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2(25):25ra23CrossRefGoogle Scholar
  139. 139.
    Stott SL, Hsu CH, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, Rothenberg SM, Shah AM, Smas ME, Korir GK, Floyd FP, 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 USA 107(43):18392–18397CrossRefGoogle Scholar
  140. 140.
    Yu M, Ting DT, Stott SL, Wittner BS, Ozsolak F, Paul S, Ciciliano JC, Smas ME, Winokur D, Gilman AJ, Ulman MJ, Xega K, Contino G, Alagesan B, Brannigan BW, Milos PM, Ryan DP, Sequist LV, Bardeesy N, Ramaswamy S, Toner M, Maheswaran S, Haber DA (2012) RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 487(7408):510–513CrossRefGoogle Scholar
  141. 141.
    Kirby BJ, Jodari M, Loftus MS, Gakhar G, Pratt ED, Chanel-Vos C, Gleghorn JP, Santana SM, Liu H, Smith JP, Navarro VN, Tagawa ST, Bander NH, Nanus DM, Giannakakou P (2012) Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device. PLoS One 7(4):1–10CrossRefGoogle Scholar
  142. 142.
    Chen GD, Fachin F, Colombini E, Wardle BL, Toner M (2012) Nanoporous micro-element arrays for particle interception in microfluidic cell separation. Lab Chip 12(17):3159–3167CrossRefGoogle Scholar
  143. 143.
    Dharmasiri U, Njoroge SK, Witek MA, Adebiyi MG, Kamande JW, Hupert ML, Barany F, Soper SA (2011) High-throughput selection, enumeration, electrokinetic manipulation, and molecular profiling of low-abundance circulating tumor cells using a microfluidic system. Anal Chem 83(6):2301–2309CrossRefGoogle Scholar
  144. 144.
    Issadore D, Chung J, Shao HL, Liong M, Ghazani AA, Castro CM, Weissleder R, Lee H (2012) Ultrasensitive clinical enumeration of rare cells ex vivo using a μ-Hall detector. Sci Transl Med 4(141):141ra92CrossRefGoogle Scholar
  145. 145.
    Xu T, Lu B, Tai YC, Goldkorn A (2010) A cancer detection platform which measures telomerase activity from live circulating tumor cells captured on a microfilter. Cancer Res 70(16):6420–6426CrossRefGoogle Scholar
  146. 146.
    Chin CD, Laksanasopin T, Cheung YK, Steinmiller D, Linder V, Parsa H, Wang J, Moore H, Rouse R, Umviligihozo G, Karita E, Mwambarangwe L, Braunstein SL, van de Wijgert J, Sahabo R, Justman JE, El-Sadr W, Sia SK (2011) Microfluidics-based diagnostics of infectious diseases in the developing world. Nat Med 17(8):1015–1019CrossRefGoogle Scholar
  147. 147.
    Chin CD, Linder V, Sia SK (2012) Commercialization of microfluidic point-of-care diagnostic devices. Lab Chip 12(12):2118–2134CrossRefGoogle Scholar
  148. 148.
    Tsui NB, Kadir RA, Chan KC, Chi C, Mellars G, Tuddenham EG, Leung TY, Lau TK, Chiu RW, Lo YM (2011) Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood 117(13):3684–3691CrossRefGoogle Scholar
  149. 149.
    Azuara D, Ginesta MM, Gausachs M, Rodriguez-Moranta F, Fabregat J, Busquets J, Pelaez N, Boadas J, Galter S, Moreno V, Costa J, de Oca J, Capella G (2012) Nanofluidic digital PCR for KRAS mutation detection and quantification in gastrointestinal cancer. Clin Chem 58(9):1332–1341CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Chemistry and Ralph N Adams Institute of Bioanalytical ChemistryUniversity of KansasLawrenceUSA
  2. 2.Bioengineering Graduate ProgramUniversity of KansasLawrenceUSA

Personalised recommendations