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Quantitative microfluidic biomolecular analysis for systems biology and medicine

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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.

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References

  1. Bruggeman FJ, Westerhoff HV (2007) The nature of systems biology. Trends Microbiol 15(1):45–50

    Article  CAS  Google Scholar 

  2. Sauer U, Heinemann M, Zamboni N (2007) Genetics. Getting closer to the whole picture. Science 316(5824):550–551

    Article  CAS  Google Scholar 

  3. Oates AC, Gorfinkiel N, Gonzalez-Gaitan M, Heisenberg CP (2009) Quantitative approaches in developmental biology. Nat Rev Genet 10(8):517–530

    Article  CAS  Google Scholar 

  4. Spencer SL, Gerety RA, Pienta KJ, Forrest S (2006) Modeling somatic evolution in tumorigenesis. PLoS Comput Biol 2(8):e108

    Article  CAS  Google Scholar 

  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):840–846

    Article  CAS  Google Scholar 

  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):533–538

    Article  CAS  Google Scholar 

  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):244–248

    Article  CAS  Google Scholar 

  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):895–897

    Article  CAS  Google Scholar 

  9. Arora A, Simone G, Salieb-Beugelaar GB, Kim JT, Manz A (2010) Latest developments in micro total analysis systems. Anal Chem 82(12):4830–4847

    Article  CAS  Google Scholar 

  10. Unger MA, Chou HP, Thorsen T, Scherer A, Quake SR (2000) Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288(5463):113–116

    Article  CAS  Google Scholar 

  11. Thorsen T, Maerkl SJ, Quake SR (2002) Microfluidic large-scale integration. Science 298(5593):580–584

    Article  CAS  Google Scholar 

  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):315–323

    Article  CAS  Google Scholar 

  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):455–463

    Article  CAS  Google Scholar 

  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):1702–1709

    Article  CAS  Google Scholar 

  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):765–772

    Article  CAS  Google Scholar 

  16. Shemesh J, Nir A, Bransky A, Levenberg S (2011) Coalescence-assisted generation of single nanoliter droplets with predefined composition. Lab Chip 11(19):3225–3230

    Article  CAS  Google Scholar 

  17. Kim J, Kang M, Jensen EC, Mathies RA (2012) Lifting gate polydimethylsiloxane microvalves and pumps for microfluidic control. Anal Chem 84(4):2067–2071

    Article  CAS  Google Scholar 

  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):733–737

    Article  CAS  Google Scholar 

  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):1870–1878

    Article  CAS  Google Scholar 

  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):2605–2613

    Article  CAS  Google Scholar 

  21. Jones PV, Staton SJR, Hayes MA (2011) Blood cell capture in a sawtooth dielectrophoretic microchannel. Anal Bioanal Chem 401(7):2103–2111

    Article  CAS  Google Scholar 

  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):1235–1239

    Article  CAS  Google Scholar 

  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):27–29

    Article  CAS  Google Scholar 

  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):36–40

    Article  CAS  Google Scholar 

  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):721–730

    Article  CAS  Google Scholar 

  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):1061–1067

    Article  CAS  Google Scholar 

  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):2875–2886

    Article  CAS  Google Scholar 

  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):3682–3688

    Article  CAS  Google Scholar 

  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):4257–4264

    Article  CAS  Google Scholar 

  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):19610–19613

    Article  CAS  Google Scholar 

  31. Tia SQ, He M, Kim D, Herr AE (2011) Multianalyte on-chip native Western blotting. Anal Chem 83(9):3581–3588

    Article  CAS  Google Scholar 

  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):2980–2986

    CAS  Google Scholar 

  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 1241:112–116

    Article  CAS  Google Scholar 

  34. He M, Herr AE (2010) Polyacrylamide gel photopatterning enables automated protein immunoblotting in a two-dimensional microdevice. J Am Chem Soc 132(8):2512–2513

    Article  CAS  Google Scholar 

  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):6388–6391

    Article  CAS  Google Scholar 

  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):2289–2295

    Article  CAS  Google Scholar 

  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):14524–14529

    Article  CAS  Google Scholar 

  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):595–599

    Article  CAS  Google Scholar 

  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):361–365

    Article  CAS  Google Scholar 

  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):738–743

    Article  CAS  Google Scholar 

  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):13999–14004

    Article  CAS  Google Scholar 

  42. Fan HC, Wang JB, Potanina A, Quake SR (2011) Whole-genome molecular haplotyping of single cells. Nat Biotechnol 29(1):51–57

    Article  CAS  Google Scholar 

  43. Kim S, Streets AM, Lin RR, Quake SR, Weiss S, Majumdar DS (2011) High-throughput single-molecule optofluidic analysis. Nat Methods 8(3):242–245

    Article  CAS  Google Scholar 

  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):e33788

    Article  CAS  Google Scholar 

  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):1065–1072

    Article  CAS  Google Scholar 

  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):649–664

    Article  CAS  Google Scholar 

  47. Ota S, Kitagawa H, Takeuchi S (2012) Generation of femtoliter reactor arrays within a microfluidic channel for biochemical analysis. Anal Chem 84(15):6346–6350

    Article  CAS  Google Scholar 

  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):2229–2239

    Article  CAS  Google Scholar 

  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):4262–4266

    Article  CAS  Google Scholar 

  50. Sims PA, Greenleaf WJ, Duan HF, Xie S (2011) Fluorogenic DNA sequencing in PDMS microreactors. Nat Methods 8(7):575–584

    Article  CAS  Google Scholar 

  51. Teh SY, Lin R, Hung LH, Lee AP (2008) Droplet microfluidics. Lab Chip 8(2):198–220

    Article  CAS  Google Scholar 

  52. Niu X, Demello AJ (2012) Building droplet-based microfluidic systems for biological analysis. Biochem Soc Trans 40(4):615–623

    Article  CAS  Google Scholar 

  53. Guo MT, Rotem A, Heyman JA, Weitz DA (2012) Droplet microfluidics for high-throughput biological assays. Lab Chip 12(12):2146–2155

    Article  CAS  Google Scholar 

  54. Vogelstein B, Kinzler KW (1999) Digital PCR. Proc Natl Acad Sci USA 96(16):9236–9241

    Article  CAS  Google Scholar 

  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):8817–8822

    Article  CAS  Google Scholar 

  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):3183–3190

    Article  CAS  Google Scholar 

  57. Zeng Y, Shin M, Wang T (2013) Programmable active droplet generation enabled by integrated pneumatic micropumps. Lab Chip 13(2):267–273

    Article  CAS  Google Scholar 

  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):813–821

    Article  CAS  Google Scholar 

  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):19163–19166

    Article  CAS  Google Scholar 

  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):014110

    Article  Google Scholar 

  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):3956–3962

    Article  CAS  Google Scholar 

  62. Mazutis L, Griffiths AD (2012) Selective droplet coalescence using microfluidic systems. Lab Chip 12(10):1800–1806

    Article  CAS  Google Scholar 

  63. Franke T, Braunmuller S, Schmid L, Wixforth A, Weitz DA (2010) Surface acoustic wave actuated cell sorting (SAWACS). Lab Chip 10(6):789–794

    Article  CAS  Google Scholar 

  64. Niu XZ, Gielen F, Edel JB, deMello AJ (2011) A microdroplet dilutor for high-throughput screening. Nat Chem 3(6):437–442

    Article  CAS  Google Scholar 

  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):2156–2166

    Article  CAS  Google Scholar 

  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):11570–11575

    Article  CAS  Google Scholar 

  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):390–395

    Article  CAS  Google Scholar 

  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):5301–5304

    Article  CAS  Google Scholar 

  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):6550–6550

    Article  CAS  Google Scholar 

  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):882–891

    Article  CAS  Google Scholar 

  71. Wheeler AR (2008) Putting electrowetting to work. Science 322(5901):539–540

    Article  CAS  Google Scholar 

  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):259–268

    Article  CAS  Google Scholar 

  73. Pollack MG, Fair RB, Shenderov AD (2000) Electrowetting-based actuation of liquid droplets for microfluidic applications. Appl Phys Lett 77(11):1725–1726

    Article  CAS  Google Scholar 

  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):70–80

    Article  Google Scholar 

  75. Choi K, Ng AH, Fobel R, Wheeler AR (2012) Digital microfluidics. Annu Rev Anal Chem 5:413–440

    Article  CAS  Google Scholar 

  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):418–431

    Article  CAS  Google Scholar 

  77. Jebrail MJ, Bartsch MS, Patel KD (2012) Digital microfluidics: a versatile tool for applications in chemistry, biology and medicine. Lab Chip 12(14):2452–2463

    Article  CAS  Google Scholar 

  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):168–174

    Article  CAS  Google Scholar 

  79. Maerkl SJ, Quake SR (2007) A systems approach to measuring the binding energy landscapes of transcription factors. Science 315(5809):233–237

    Article  CAS  Google Scholar 

  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–E3093

    Article  CAS  Google Scholar 

  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):970–975

    Article  CAS  Google Scholar 

  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):16540–16545

    Article  CAS  Google Scholar 

  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):e52

    Article  CAS  Google Scholar 

  84. Gerber D, Maerkl SJ, Quake SR (2009) An in vitro microfluidic approach to generating protein-interaction networks. Nat Methods 6(1):71–74

    Article  CAS  Google Scholar 

  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):477–482

    Article  CAS  Google Scholar 

  86. Meier M, Sit R, Pan W, Quake SR (2012) High-performance binary protein interaction screening in a microfluidic format. Anal Chem 84(21):9572–9578

    CAS  Google Scholar 

  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):1192–1194

    Article  CAS  Google Scholar 

  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):1019–1027

    Article  CAS  Google Scholar 

  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):1793–1798

    Article  CAS  Google Scholar 

  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):3849–3854

    Article  CAS  Google Scholar 

  91. Lombardi D, Dittrich PS (2011) Droplet microfluidics with magnetic beads: a new tool to investigate drug-protein interactions. Anal Bioanal Chem 399(1):347–352

    Article  CAS  Google Scholar 

  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):1645–1648

    Article  CAS  Google Scholar 

  93. Williams LD, Ghosh T, Mastrangelo CH (2010) Low noise detection of biomolecular interactions with signal-locking surface plasmon resonance. Anal Chem 82(14):6025–6031

    Article  CAS  Google Scholar 

  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):343–352

    Article  CAS  Google Scholar 

  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):581–588

    Article  CAS  Google Scholar 

  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):3882–3890

    Article  CAS  Google Scholar 

  97. Soon WW, Hariharan M, Snyder MP (2013) High-throughput sequencing for biology and medicine. Mol Syst Biol 9:640

    Article  Google Scholar 

  98. Liu P, Mathies RA (2009) Integrated microfluidic systems for high-performance genetic analysis. Trends Biotechnol 27(10):572–581

    Article  CAS  Google Scholar 

  99. Tang F, Lao K, Surani MA (2011) Development and applications of single-cell transcriptome analysis. Nat Methods 8(4 Suppl):S6–S11

    CAS  Google Scholar 

  100. Kalisky T, Quake SR (2011) Single-cell genomics. Nat Methods 8(4):311–314

    Article  CAS  Google Scholar 

  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):851–870

    Article  CAS  Google Scholar 

  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):1886–1894

    Article  CAS  Google Scholar 

  103. Chapin SC, Appleyard DC, Pregibon DC, Doyle PS (2011) Rapid microRNA profiling on encoded gel microparticles. Angew Chem Int Ed 50(10):2289–2293

    CAS  Google Scholar 

  104. Sundberg SO, Wittwer CT, Gao C, Gale BK (2010) Spinning disk platform for microfluidic digital polymerase chain reaction. Anal Chem 82(4):1546–1550

    Article  CAS  Google Scholar 

  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):3533–3540

    Article  CAS  Google Scholar 

  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):17705–17712

    Article  CAS  Google Scholar 

  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):8158–8168

    Article  CAS  Google Scholar 

  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):1003–1011

    Article  CAS  Google Scholar 

  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):6474–6484

    Article  CAS  Google Scholar 

  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):8604–8610

    Article  CAS  Google Scholar 

  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):e82

    Article  CAS  Google Scholar 

  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):3599–3606

    Article  CAS  Google Scholar 

  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):402–412

    Article  CAS  Google Scholar 

  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):1120–1127

    Article  CAS  Google Scholar 

  115. Chao TC, Hansmeier N (2012) Microfluidic devices for high-throughput proteome analyses. Proteomics 13(3–4):467–479

    Google Scholar 

  116. Chun HG, Chung TD, Ramsey JM (2010) High yield sample preconcentration using a highly ion-conductive charge-selective polymer. Anal Chem 82(14):6287–6292

    Article  CAS  Google Scholar 

  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):10368–10371

    Article  CAS  Google Scholar 

  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):2507–2512

    Article  CAS  Google Scholar 

  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):4095–4102

    Article  CAS  Google Scholar 

  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):3421–3430

    Article  CAS  Google Scholar 

  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):635–643

    Article  CAS  Google Scholar 

  122. Sommer GJ, Mai J, Singh AK, Hatch AV (2011) Microscale isoelectric fractionation using photopolymerized membranes. Anal Chem 83(8):3120–3125

    Article  CAS  Google Scholar 

  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):842–849

    Article  CAS  Google Scholar 

  124. Mao P, Gomez-Sjoberg R, Wang D (2012) Multinozzle emitter array chips for small-volume proteomics. Anal Chem 85(2):816–819

    Article  CAS  Google Scholar 

  125. Hughes AJ, Lin RK, Peehl DM, Herr AE (2012) Microfluidic integration for automated targeted proteomic assays. Proc Natl Acad Sci USA 109(16):5972–5977

    Article  CAS  Google Scholar 

  126. Karns K, Herr AE (2011) Human tear protein analysis enabled by an alkaline microfluidic homogeneous immunoassay. Anal Chem 83(21):8115–8122

    Article  CAS  Google Scholar 

  127. Luk VN, Fiddes LK, Luk VM, Kumacheva E, Wheeler AR (2012) Digital microfluidic hydrogel microreactors for proteomics. Proteomics 12(9):1310–1318

    Article  CAS  Google Scholar 

  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):3824–3830

    Article  CAS  Google Scholar 

  129. Miller EM, Ng AH, Uddayasankar U, Wheeler AR (2011) A digital microfluidic approach to heterogeneous immunoassays. Anal Bioanal Chem 399(1):337–345

    Article  CAS  Google Scholar 

  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):2552–2559

    Article  CAS  Google Scholar 

  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):3731–3738

    Article  CAS  Google Scholar 

  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):2095–2101

    Article  CAS  Google Scholar 

  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):977–985

    Article  CAS  Google Scholar 

  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):6128–6138

    Article  CAS  Google Scholar 

  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):1396–1403

    Article  CAS  Google Scholar 

  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):1042–1142

    Article  CAS  Google Scholar 

  137. Muzzey D, van Oudenaarden A (2009) Quantitative time-lapse fluorescence microscopy in single cells. Annu Rev Cell Dev Biol 25:301–327

    Article  CAS  Google Scholar 

  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):25ra23

    Article  CAS  Google Scholar 

  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):18392–18397

    Article  CAS  Google Scholar 

  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):510–513

    Article  CAS  Google Scholar 

  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):1–10

    Article  CAS  Google Scholar 

  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):3159–3167

    Article  CAS  Google Scholar 

  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):2301–2309

    Article  CAS  Google Scholar 

  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):141ra92

    Article  CAS  Google Scholar 

  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):6420–6426

    Article  CAS  Google Scholar 

  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):1015–1019

    Article  CAS  Google Scholar 

  147. Chin CD, Linder V, Sia SK (2012) Commercialization of microfluidic point-of-care diagnostic devices. Lab Chip 12(12):2118–2134

    Article  CAS  Google Scholar 

  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):3684–3691

    Article  CAS  Google Scholar 

  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):1332–1341

    Article  CAS  Google Scholar 

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Acknowledgments

The work was supported by the new faculty start-up funds from the University of Kansas.

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Correspondence to Yong Zeng.

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Zeng, Y., Wang, T. Quantitative microfluidic biomolecular analysis for systems biology and medicine. Anal Bioanal Chem 405, 5743–5758 (2013). https://doi.org/10.1007/s00216-013-6930-1

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  • DOI: https://doi.org/10.1007/s00216-013-6930-1

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