Microfluidic Tools for DNA Analysis



This chapter introduces the use of microfluidic tools for DNA analysis. It will cover both qualitative analysis and quantitative analysis. A microfluidic device typically implies multicomponent integration. Most reviews in scientific journals discuss microfluidics by a sequential introduction for each component. In order to present the great power of microfluidics as emerging tools for DNA research, we organized each section according to the primary function that can be achieved by a kind of microfluidic device, and emphasize the primary innovation leading to the unique function for each specific device. As microfluidic tools showed many distinct advantages over existing approaches and thus hold dramatic commercial potential, we will also discuss the problems during the commercialization process of microfluidic devices. DNA analysis we discussed herein includes amplification, detection, sequencing, counting, sizing, and weighing, and our perspective covers a wide range of related fields including chemistry, molecular biology, physics, and micro/nano-fabrication technologies, which reveals that DNA analysis on microfluidic devices is a highly interdisciplinary subject and will have lasting impact among biologists, chemists, physicians, and engineers.


Microfluidic chip DNA Miniaturization Amplification Solid phase Sample-in–answer-out Droplet Structural variation Cantilever Qualitative analysis Quantitative analysis 


  1. 1.
    Manz A, Graber N, Widmer HM (1990) Miniaturized total chemical-analysis systems – a novel concept for chemical sensing. Sens Actuator B Chem 1(1–6):244–248. doi: 10.1016/0925-4005(90)80209-I CrossRefGoogle Scholar
  2. 2.
    Beebe DJ, Mensing GA, Walker GM (2002) Physics and applications of microfluidics in biology. Annu Rev Biomed Eng 4:261–286. doi: 10.1146/annurev.bioeng.4.112601.125916 CrossRefGoogle Scholar
  3. 3.
    Oda RP, Strausbauch MA, Huhmer AFR, Borson N, Jurrens SR, Craighead J, Wettstein PJ, Eckloff B, Kline B, Landers JP (1998) Infrared-mediated thermocycling for ultrafast polymerase chain reaction amplification of DNA. Anal Chem 70(20):4361–4368. doi: 10.1021/ac980452i CrossRefGoogle Scholar
  4. 4.
    Huhmer AFR, Landers JP (2000) Noncontact infrared-mediated thermocycling for effective polymerase chain reaction amplification of DNA in nanoliter volumes. Anal Chem 72(21):5507–5512. doi: 10.1021/ac23j CrossRefGoogle Scholar
  5. 5.
    Roper MG, Easley CJ, Legendre LA, Humphrey JAC, Landers JP (2007) Infrared temperature control system for a completely noncontact polymerase chain reaction in microfluidic chips. Anal Chem 79(4):1294–1300. doi: 10.1021/ac0613277 CrossRefGoogle Scholar
  6. 6.
    Yu YJ, Li BW, Baker CA, Zhang XY, Roper MG (2012) Quantitative polymerase chain reaction using infrared heating on a microfluidic chip. Anal Chem 84(6):2825–2829. doi: 10.1021/ac203307h CrossRefGoogle Scholar
  7. 7.
    Kim H, Vishniakou S, Faris GW (2009) Petri dish PCR: laser-heated reactions in nanoliter droplet arrays. Lab Chip 9(9):1230–1235. doi: 10.1039/b817288a CrossRefGoogle Scholar
  8. 8.
    Kopp MU, Mello AJ, Manz A (1998) Chemical amplification: continuous-flow PCR on a chip. Science 280(5366):1046–1048. doi: 10.1126/science.280.5366.1046 CrossRefGoogle Scholar
  9. 9.
    Chen L, West J, Auroux PA, Manz A, Day PJR (2007) Ultrasensitive PCR and real-time detection from human genomic samples using a bidirectional flow microreactor. Anal Chem 79(23):9185–9190. doi: 10.1021/ac701668k CrossRefGoogle Scholar
  10. 10.
    Sun Y, Nguyen NT, Kwok YC (2008) High-throughput polymerase chain reaction in parallel circular loops using magnetic actuation. Anal Chem 80(15):6127–6130. doi: 10.1021/ac800787g CrossRefGoogle Scholar
  11. 11.
    Wu W, Kieu The Loan T, Lee NY (2012) Flow-through PCR on a 3D qiandu-shaped polydimethylsiloxane (PDMS) microdevice employing a single heater: toward microscale multiplex PCR. Analyst 137(9):2069–2076. doi: 10.1039/c2an35077g CrossRefGoogle Scholar
  12. 12.
    Liu C, Mauk MG, Hart R, Qiu X, Bau HH (2011) A self-heating cartridge for molecular diagnostics. Lab Chip 11(16):2686–2692. doi: 10.1039/C1LC20345B CrossRefGoogle Scholar
  13. 13.
    LaBarre P, Hawkins KR, Gerlach J, Wilmoth J, Beddoe A, Singleton J, Boyle D, Weigl B (2011) A simple, inexpensive device for nucleic acid amplification without electricity-toward instrument-free molecular diagnostics in Low-resource settings. PLoS One 6(5):e19738. doi: 10.1371/journal.pone.0019738 CrossRefGoogle Scholar
  14. 14.
    Hatano B, Maki T, Obara T, Fukumoto H, Hagisawa K, Matsushita Y, Okutani A, Bazartseren B, Inoue S, Sata T, Katano H (2010) LAMP using a disposable pocket warmer for anthrax detection, a highly mobile and reliable method for anti-bioterrorism. Jpn J Infect Dis 63(1):36–40Google Scholar
  15. 15.
    Wang JB, Zhou Y, Qiu HW, Huang H, Sun CH, Xi JZ, Huang YY (2009) A chip-to-chip nanoliter microfluidic dispenser. Lab Chip 9(13):1831–1835. doi: 10.1039/B901635j CrossRefGoogle Scholar
  16. 16.
    Zhang Y, Zhu Y, Yao B, Fang Q (2011) Nanolitre droplet array for real time reverse transcription polymerase chain reaction. Lab Chip 11(8):1545–1549. doi: 10.1039/c0lc00502a CrossRefGoogle Scholar
  17. 17.
    Baret J-C (2012) Surfactants in droplet-based microfluidics. Lab Chip 12(3):422–433. doi: 10.1039/c1lc20582j CrossRefGoogle Scholar
  18. 18.
    Kalinina O, Lebedeva I, Brown J, Silver J (1997) Nanoliter scale PCR with TaqMan detection. Nucleic Acids Res 25(10):1999–2004. doi: 10.1093/nar/25.10.1999 CrossRefGoogle Scholar
  19. 19.
    Nakano M, Komatsu J, Matsuura S, Takashima K, Katsura S, Mizuno A (2003) Single-molecule PCR using water-in-oil emulsion. J Biotechnol 102(2):117–124. doi: 10.1016/S0168-1656(03)3-3 CrossRefGoogle Scholar
  20. 20.
    Chabert M, Dorfman KD, de Cremoux P, Roeraade J, Viovy J-L (2006) Automated microdroplet platform for sample manipulation and polymerase chain reaction. Anal Chem 78(22):7722–7728. doi: 10.1021/ac061205e CrossRefGoogle Scholar
  21. 21.
    Garstecki P, Fuerstman MJ, Stone HA, Whitesides GM (2006) Formation of droplets and bubbles in a microfluidic T-junction – scaling and mechanism of break-up. Lab Chip 6(3):437–446. doi: 10.1039/b510841a CrossRefGoogle Scholar
  22. 22.
    Anna SL, Bontoux N, Stone HA (2003) Formation of dispersions using “flow focusing” in microchannels. Appl Phys Lett 82(3):364–366. doi: 10.1063/1.1537519 CrossRefGoogle Scholar
  23. 23.
    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
  24. 24.
    Kumaresan P, Yang CJ, Cronier SA, Blazej RG, Mathies RA (2008) High-throughput single copy DNA amplification and cell analysis in engineered nanoliter droplets. Anal Chem 80(10):3522–3529. doi: 10.1021/ac800327d CrossRefGoogle Scholar
  25. 25.
    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 U S A 100(15):8817–8822. doi: 10.1073/pnas.1133470100 CrossRefGoogle Scholar
  26. 26.
    Zhang H, 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. doi: 10.1021/ac2033084 CrossRefGoogle Scholar
  27. 27.
    Zhang WY, Zhang W, Liu Z, Li C, Zhu Z, Yang CJ (2011) Highly parallel single-molecule amplification approach based on agarose droplet polymerase chain reaction for efficient and cost-effective aptamer selection. Anal Chem 84(1):350–355. doi: 10.1021/ac2026942 CrossRefGoogle Scholar
  28. 28.
    Adessi C, Matton G, Ayala G, Turcatti G, Mermod JJ, Mayer P, Kawashima E (2000) Solid phase DNA amplification: characterisation of primer attachment and amplification mechanisms. Nucleic Acids Res 28(20):e87. doi: 10.1093/nar/28.20.e87 CrossRefGoogle Scholar
  29. 29.
    Drobyshev AL, Nasedkina TV, Zakharova NV (2009) The role of DNA diffusion in solid phase polymerase chain reaction with gel-immobilized primers in planar and capillary microarray format. Biomicrofluidics 3(4):044112. doi: 10.1063/1.3271461 CrossRefGoogle Scholar
  30. 30.
    Sun Y, Dhumpa R, Bang DD, Hogberg J, Handberg K, Wolff A (2011) A lab-on-a-chip device for rapid identification of avian influenza viral RNA by solid-phase PCR. Lab Chip 11(8):1457–1463. doi: 10.1039/c0lc00528b CrossRefGoogle Scholar
  31. 31.
    Huber M, Losert D, Hiller R, Harwanegg C, Mueller MW, Schmidt WM (2001) Detection of single base alterations in genomic DNA by solid phase polymerase chain reaction on oligonucleotide microarrays. Anal Biochem 299(1):24–30. doi: 10.1006/abio.2001.5355 CrossRefGoogle Scholar
  32. 32.
    Mercier JF, Slater GW, Mayer P (2003) Solid phase DNA amplification: a simple Monte Carlo lattice model. Biophys J 85(4):2075–2086. doi: 10.1016/S-3495(03)74636-0 CrossRefGoogle Scholar
  33. 33.
    Mercier JF, Slater GW (2005) Solid phase DNA amplification: a Brownian dynamics study of crowding effects. Biophys J 89(1):32–42. doi: 10.1529/biophysj.104.051904 CrossRefGoogle Scholar
  34. 34.
    Westin L, Xu X, Miller C, Wang L, Edman CF, Nerenberg M (2000) Anchored multiplex amplification on a microelectronic chip array. Nat Biotechnol 18(2):199–204. doi: 10.1038/72658 CrossRefGoogle Scholar
  35. 35.
    Sosnowski RG, Tu E, Butler WF, O’Connell JP, Heller MJ (1997) Rapid determination of single base mismatch mutations in DNA hybrids by direct electric field control. Proc Natl Acad Sci U S A 94(4):1119–1123. doi: 10.1073/pnas.94.4.1119 CrossRefGoogle Scholar
  36. 36.
    Lizardi PM, Huang XH, Zhu ZR, Bray-Ward P, Thomas DC, Ward DC (1998) Mutation detection and single-molecule counting using isothermal rolling-circle amplification. Nat Genet 19(3):225–232. doi: 10.1038/898 CrossRefGoogle Scholar
  37. 37.
    Sato K, Tachihara A, Renberg B, Mawatari K, Tanaka Y, Jarvius J, Nilsson M, Kitamori T (2010) Microbead-based rolling circle amplification in a microchip for sensitive DNA detection. Lab Chip 10(10):1262–1266. doi: 10.1039/b927460j CrossRefGoogle Scholar
  38. 38.
    Burns MA, Johnson BN, Brahmasandra SN, Handique K, Webster JR, Krishnan M, Sammarco TS, Man PM, Jones D, Heldsinger D, Mastrangelo CH, Burke DT (1998) An integrated nanoliter DNA analysis device. Science 282(5388):484–487. doi: 10.1126/science.282.5388.484 CrossRefGoogle Scholar
  39. 39.
    Walker GT, Fraiser MS, Schram JL, Little MC, Nadeau JG, Malinowski DP (1992) Strand displacement amplification—an isothermal, in vitro DNA amplification technique. Nucleic Acids Res 20(7):1691–1696. doi: 10.1093/nar/20.7.1691 CrossRefGoogle Scholar
  40. 40.
    Fang X, Chen H, Xu L, Jiang X, Wu W, Kong J (2012) A portable and integrated nucleic acid amplification microfluidic chip for identifying bacteria. Lab Chip 12:1495–1499. doi: 10.1039/C2LC40055C CrossRefGoogle Scholar
  41. 41.
    Wolfe KA, Breadmore MC, Ferrance JP, Power ME, Conroy JF, Norris PM, Landers JP (2002) Toward a microchip-based solid-phase extraction method for isolation of nucleic acids. Electrophoresis 23(5):727–733. doi:10.1002/1522-2683(200203)23:5<727::aid-elps727>;2-oCrossRefGoogle Scholar
  42. 42.
    Breadmore MC, Wolfe KA, Arcibal IG, Leung WK, Dickson D, Giordano BC, Power ME, Ferrance JP, Feldman SH, Norris PM, Landers JP (2003) Microchip-based purification of DNA from biological samples. Anal Chem 75(8):1880–1886. doi: 10.1021/ac0204855 CrossRefGoogle Scholar
  43. 43.
    Easley CJ, Karlinsey JM, Bienvenue JM, Legendre LA, Roper MG, Feldman SH, Hughes MA, Hewlett EL, Merkel TJ, Ferrance JP, Landers JP (2006) A fully integrated microfluidic genetic analysis system with sample-in-answer-out capability. Proc Natl Acad Sci U S A 103(51):19272–19277. doi: 10.1073/pnas.0604663103 CrossRefGoogle Scholar
  44. 44.
    Cady NC, Stelick S, Kunnavakkam MV, Batt CA (2005) Real-time PCR detection of Listeria monocytogenes using an integrated microfluidics platform. Sens Actuator B Chem 107(1):332–341. doi: 10.1016/j.snb.2004.10.022 CrossRefGoogle Scholar
  45. 45.
    Cady NC, Stelick S, Batt CA (2003) Nucleic acid purification using microfabricated silicon structures. Biosens Bioelectron 19(1):59–66. doi: 10.1016/s0956-5663(03)00123-4 CrossRefGoogle Scholar
  46. 46.
    Reedy CR, Price CW, Sniegowski J, Ferrance JP, Begley M, Landers JP (2011) Solid phase extraction of DNA from biological samples in a post-based, high surface area poly(methyl methacrylate) (PMMA) microdevice. Lab Chip 11(9):1603–1611. doi: 10.1039/c0lc00597e CrossRefGoogle Scholar
  47. 47.
    Wu QQ, Jin W, Zhou C, Han SH, Yang WX, Zhu QY, Jin QH, Mu Y (2011) Integrated glass microdevice for nucleic acid purification, loop-mediated isothermal amplification, and online detection. Anal Chem 83(9):3336–3342. doi: 10.1021/ac103129e CrossRefGoogle Scholar
  48. 48.
    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. doi: 10.1126/science.288.5463.113 CrossRefGoogle Scholar
  49. 49.
    Wang CH, Lien KY, Wu JJ, Lee GB (2011) A magnetic bead-based assay for the rapid detection of methicillin-resistant Staphylococcus aureus by using a microfluidic system with integrated loop-mediated isothermal amplification. Lab Chip 11(8):1521–1531. doi: 10.1039/c0lc00430h CrossRefGoogle Scholar
  50. 50.
    Liu C, Geva E, Mauk M, Qiu X, Abrams WR, Malamud D, Curtis K, Owen SM, Bau HH (2011) An isothermal amplification reactor with an integrated isolation membrane for point-of-care detection of infectious diseases. Analyst 136(10):2069–2076. doi: 10.1039/c1an7a CrossRefGoogle Scholar
  51. 51.
    Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA, Berka J, Braverman MS, Chen Y-J, Chen Z, Dewell SB, Du L, Fierro JM, Gomes XV, Godwin BC, He W, Helgesen S, Ho CH, Irzyk GP, Jando SC, Alenquer MLI, Jarvie TP, Jirage KB, Kim J-B, Knight JR, Lanza JR, Leamon JH, Lefkowitz SM, Lei M, Li J, Lohman KL, Lu H, Makhijani VB, McDade KE, McKenna MP, Myers EW, Nickerson E, Nobile JR, Plant R, Puc BP, Ronan MT, Roth GT, Sarkis GJ, Simons JF, Simpson JW, Srinivasan M, Tartaro KR, Tomasz A, Vogt KA, Volkmer GA, Wang SH, Wang Y, Weiner MP, Yu P, Begley RF, Rothberg JM (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437(7057):376–380. doi: 10.1038/nature03959 Google Scholar
  52. 52.
    Sims PA, Greenleaf WJ, Duan HF, Xie S (2011) Fluorogenic DNA sequencing in PDMS microreactors. Nat Methods 8(7):U575–U584. doi: 10.1038/nmeth.1629 CrossRefGoogle Scholar
  53. 53.
    Eid J, Fehr A, Gray J, Luong K, Lyle J, Otto G, Peluso P, Rank D, Baybayan P, Bettman B, Bibillo A, Bjornson K, Chaudhuri B, Christians F, Cicero R, Clark S, Dalal R, Dewinter A, Dixon J, Foquet M, Gaertner A, Hardenbol P, Heiner C, Hester K, Holden D, Kearns G, Kong XX, Kuse R, Lacroix Y, Lin S, Lundquist P, Ma CC, Marks P, Maxham M, Murphy D, Park I, Pham T, Phillips M, Roy J, Sebra R, Shen G, Sorenson J, Tomaney A, Travers K, Trulson M, Vieceli J, Wegener J, Wu D, Yang A, Zaccarin D, Zhao P, Zhong F, Korlach J, Turner S (2009) Real-time DNA sequencing from single polymerase molecules. Science 323(5910):133–138. doi: 10.1126/science.1162986 CrossRefGoogle Scholar
  54. 54.
    Zhu P, Craighead HG (2012) Zero-mode waveguides for single-molecule analysis. Ann Rev Biophys 41:269–293. doi: 10.1146/annurev-biophys-050511-102338 CrossRefGoogle Scholar
  55. 55.
    Baner J, Nilsson M, Mendel-Hartvig M, Landegren U (1998) Signal amplification of padlock probes by rolling circle replication. Nucleic Acids Res 26(22):5073–5078. doi: 10.1093/nar/26.22.5073 CrossRefGoogle Scholar
  56. 56.
    Notomi T, Okayama H, Masubuchi H, Yonekawa T, Watanabe K, Amino N, Hase T (2000) Loop-mediated isothermal amplification of DNA. Nucleic Acids Res 28(12):e63. doi: 10.1093/nar/28.12.e63 CrossRefGoogle Scholar
  57. 57.
    Mitani Y, Lezhava A, Kawai Y, Kikuchi T, Oguchi-Katayama A, Kogo Y, Itoh M, Miyagi T, Takakura H, Hoshi K, Kato C, Arakawa T, Shibata K, Fukui K, Masui R, Kuramitsu S, Kiyotani K, Chalk A, Tsunekawa K, Murakami M, Kamataki T, Oka T, Shimada H, Cizdziel PE, Hayashizaki Y (2007) Rapid SNP diagnostics using asymmetric isothermal amplification and a new mismatch-suppression technology. Nat Methods 4(3):257–262. doi: 10.1038/nmeth1007 CrossRefGoogle Scholar
  58. 58.
    Vincent M, Xu Y, Kong HM (2004) Helicase-dependent isothermal DNA amplification. EMBO Rep 5(8):795–800. doi: 10.1038/sj.embor.7400200 CrossRefGoogle Scholar
  59. 59.
    Piepenburg O, Williams CH, Stemple DL, Armes NA (2006) DNA detection using recombination proteins. PLoS Biol 4(7):1115–1121. doi: 10.1371/journal.pbio.0040204 CrossRefGoogle Scholar
  60. 60.
    Ramalingam N, San TC, Kai TJ, Mak MYM, Gong H-Q (2009) Microfluidic devices harboring unsealed reactors for real-time isothermal helicase-dependent amplification. Microfluid Nanofluid 7(3):325–336. doi: 10.1007/s10404-008-0378-1 CrossRefGoogle Scholar
  61. 61.
    Kawai Y, Kimura Y, Lezhava A, Kanamori H, Usui K, Hanami T, Soma T, MorlighemJ-E, Saga S, Ishizu Y, Aoki S, Endo R, Oguchi-Katayama A, Kogo Y, Mitani Y, Ishidao T, Kawakami C, Kurata H, Furuya Y, Saito T, Okazaki N, Chikahira M, Hayashi E, S-i T, Toguchi T, Saito Y, Ban T, Izumi S, Uryu H, Kudo K, Sakai-Tagawa Y, Kawaoka Y, Hirai A, Hayashizaki Y, Ishikawa T (2012) One-step detection of the 2009 pandemic influenza a(H1N1) virus by the RT-SmartAmp assay and its clinical validation. PLoS One 7(1):e30236. doi: 10.1371/journal.pone.0030236 CrossRefGoogle Scholar
  62. 62.
    Enomoto Y, Yoshikawa T, Ihira M, Akimoto S, Miyake F, Usui C, Suga S, Suzuki K, Kawana T, Nishiyama Y, Asano Y (2005) Rapid diagnosis of herpes simplex virus infection by a loop-mediated isothermal amplification method. J Clin Microbiol 43(2):951–955. doi: 10.1128/jcm.43.2.951-955.2005 CrossRefGoogle Scholar
  63. 63.
    Ihira M, Akimoto S, Miyake F, Fujita A, Sugata K, Suga S, Ohashi M, Nishimura N, Ozaki T, Asano Y, Yoshikawa T (2007) Direct detection of human herpesvirus 6 DNA in serum by the loop-mediated isothermal amplification method. J Clin Virol 39(1):22–26. doi: 10.1016/j.jcv.2007.02.001 CrossRefGoogle Scholar
  64. 64.
    Fang XE, Liu YY, Kong JL, Jiang XY (2010) Loop-mediated isothermal amplification integrated on microfluidic chips for point-of-care quantitative detection of pathogens. Anal Chem 82(7):3002–3006. doi: 10.1021/ac152 CrossRefGoogle Scholar
  65. 65.
    Liu CC, Mauk MG, Bau HH (2011) A disposable, integrated loop-mediated isothermal amplification cassette with thermally actuated valves. Microfluid Nanofluid 11(2):209–220. doi: 10.1007/s10404-011-0788-3 CrossRefGoogle Scholar
  66. 66.
    Martinez AW, Phillips ST, Whitesides GM, Carrilho E (2010) Diagnostics for the developing world: microfluidic paper-based analytical devices. Anal Chem 82(1):3–10. doi: 10.1021/ac9013989 CrossRefGoogle Scholar
  67. 67.
    Nie Z, Nijhuis CA, Gong J, Chen X, Kumachev A, Martinez AW, Narovlyansky M, Whitesides GM (2010) Electrochemical sensing in paper-based microfluidic devices. Lab Chip 10(4):477–483. doi: 10.1039/b917150a CrossRefGoogle Scholar
  68. 68.
    Nie Z, Deiss F, Liu X, Akbulut O, Whitesides GM (2010) Integration of paper-based microfluidic devices with commercial electrochemical readers. Lab Chip 10(22):3163–3169. doi: 10.1039/c0lc00237b CrossRefGoogle Scholar
  69. 69.
    Dossi N, Toniolo R, Pizzariello A, Carrilho E, Piccin E, Battiston S, Bontempelli G (2012) An electrochemical gas sensor based on paper supported room temperature ionic liquids. Lab Chip 12(1):153–158. doi: 10.1039/c1lc20663j CrossRefGoogle Scholar
  70. 70.
    Govindarajan AV, Ramachandran S, Vigil GD, Yager P, Boehringer KF (2012) A low cost point-of-care viscous sample preparation device for molecular diagnosis in the developing world; an example of microfluidic origami. Lab Chip 12(1):174–181. doi: 10.1039/c1lc20622b CrossRefGoogle Scholar
  71. 71.
    Rohrman B, Richards-Kortum R (2012) A paper and plastic device for performing recombinase polymerase amplification of HIV DNA. Lab Chip. doi: 10.1039/C2LC40423K
  72. 72.
    Shen F, Du W, Kreutz JE, Fok A, Ismagilov RF (2010) Digital PCR on a SlipChip. Lab Chip 10(20):2666–2672. doi: 10.1039/c004521g CrossRefGoogle Scholar
  73. 73.
    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):U649–U664. doi: 10.1038/nmeth.1640 CrossRefGoogle Scholar
  74. 74.
    Gansen A, Herrick A, Dimov IK, Lee L, Chiu DT (2012) Digital LAMP in a sample self-digitization (SD) chip. Lab Chip 12:2247–2254. doi: 10.1039/C2LC21247A CrossRefGoogle Scholar
  75. 75.
    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. doi: 10.1021/ac201658s CrossRefGoogle Scholar
  76. 76.
    Kim SH, Iwai S, Araki S, Sakakihara S, Iino R, Noji H (2012) Large-scale femtoliter droplet array for digital counting of single biomolecules. Lab Chip. doi: 10.1039/c2lc40632b
  77. 77.
    Men Y, Fu Y, Chen Z, Sims PA, Greenleaf WJ, Huang Y (2012) Digital polymerase chain reaction in an array of femtoliter polydimethylsiloxane microreactors. Anal Chem 84(10):4262–4266. doi: 10.1021/ac300761n CrossRefGoogle Scholar
  78. 78.
    Ottesen EA, Hong JW, Quake SR, Leadbetter JR (2006) Microfluidic digital PCR enables multigene analysis of individual environmental bacteria. Science 314(5804):1464–1467. doi: 10.1126/science.1131370 CrossRefGoogle Scholar
  79. 79.
    Cohen DE, Schneider T, Wang M, Chiu DT (2010) Self-digitization of sample volumes. Anal Chem 82(13):5707–5717. doi: 10.1021/ac100713u CrossRefGoogle Scholar
  80. 80.
    Zhu QY, Gao YB, Yu BW, Ren H, Qiu L, Han SH, Jin W, Jin QH, Mu Y (2012) Self-priming compartmentalization digital LAMP for point of care. Lab Chip. doi: 10.1039/C2LC40774D
  81. 81.
    Du W, Li L, Nichols KP, Ismagilov RF (2009) SlipChip. Lab Chip 9(16):2286–2292. doi: 10.1039/b908978k CrossRefGoogle Scholar
  82. 82.
    Hosokawa K, Sato K, Ichikawa N, Maeda M (2004) Power-free poly(dimethylsiloxane) microfluidic devices for gold nanoparticle-based DNA analysis. Lab Chip 4(3):181–185. doi: 10.1039/b403930k CrossRefGoogle Scholar
  83. 83.
    Shen F, Davydova EK, Du WB, 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. doi: 10.1021/ac200247e CrossRefGoogle Scholar
  84. 84.
    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 SL, 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. doi: 10.1021/Ac202028g CrossRefGoogle Scholar
  85. 85.
    Feuk L, Carson AR, Scherer SW (2006) Structural variation in the human genome. Nat Rev Genet 7(2):85–97. doi: 10.1038/nrg1767 CrossRefGoogle Scholar
  86. 86.
    Lupski JR (2007) Structural variation in the human genome. N Engl J Med 356(11):1169–1171. doi: 10.1056/NEJMcibr067658 CrossRefGoogle Scholar
  87. 87.
    Stankiewicz P, Lupski JR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61:437–455. doi: 10.1146/annurev-med-100708-204735 CrossRefGoogle Scholar
  88. 88.
    Scherer SW, Lee C, Birney E, Altshuler DM, Eichler EE, Carter NP, Hurles ME, Feuk L (2007) Challenges and standards in integrating surveys of structural variation. Nat Genet 39:S7–S15. doi: 10.1038/ng2093 CrossRefGoogle Scholar
  89. 89.
    Baker M (2012) Structural variation: the genome’s hidden architecture. Nat Methods 9(2):133–137. doi: 10.1038/nmeth.1858 CrossRefGoogle Scholar
  90. 90.
    Cao H, Tegenfeldt JO, Austin RH, Chou SY (2002) Gradient nanostructures for interfacing microfluidics and nanofluidics. Appl Phys Lett 81(16):3058–3060. doi: 10.1063/1.1515115 CrossRefGoogle Scholar
  91. 91.
    Das SK, Austin MD, Akana MC, Deshpande P, Cao H, Xiao M (2010) Single molecule linear analysis of DNA in nano-channel labeled with sequence specific fluorescent probes. Nucleic Acids Res 38(18):e177. doi: 10.1093/nar/gkq673 CrossRefGoogle Scholar
  92. 92.
    Baday M, Cravens A, Hastie A, Kim H, Kudeki DE, Kwok P-Y, Xiao M, Selvin PR (2012) Multicolor super-resolution DNA imaging for genetic analysis. Nano Lett 12:3861–3866. doi: 10.1021/nl302069q CrossRefGoogle Scholar
  93. 93.
    Larson JW, Yantz GR, Zhong Q, Charnas R, D’Antoni CM, Gallo MV, Gillis KA, Neely LA, Phillips KM, Wong GG, Gullans SR, Gilmanshin R (2006) Single DNA molecule stretching in sudden mixed shear and elongational microflows. Lab Chip 6(9):1187–1199. doi: 10.1039/b602845d CrossRefGoogle Scholar
  94. 94.
    Chan EY, Goncalves NM, Haeusler RA, Hatch AJ, Larson JW, Maletta AM, Yantz GR, Carstea ED, Fuchs M, Wong GG, Gullans SR, Gilmanshin R (2004) DNA mapping using microfluidic stretching and single-molecule detection of fluorescent site-specific tags. Genome Res 14(6):1137–1146. doi: 10.1101/gr.1635204 CrossRefGoogle Scholar
  95. 95.
    Dimalanta ET, Lim A, Runnheim R, Lamers C, Churas C, Forrest DK, de Pablo JJ, Graham MD, Coppersmith SN, Goldstein S, Schwartz DC (2004) A microfluidic system for large DNA molecule arrays. Anal Chem 76(18):5293–5301. doi: 10.1021/ac0496401 CrossRefGoogle Scholar
  96. 96.
    Teague B, Waterman MS, Goldstein S, Potamousis K, Zhou SG, Reslewic S, Sarkar D, Valouev A, Churas C, Kidd JM, Kohn S, Runnheim R, Lamers C, Forrest D, Newton MA, Eichler EE, Kent-First M, Surti U, Livny M, Schwartz DC (2010) High-resolution human genome structure by single-molecule analysis. Proc Natl Acad Sci U S A 107(24):10848–10853. doi: 10.1073/pnas.0914638107 CrossRefGoogle Scholar
  97. 97.
    Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004) DNA structure. In: Molecular biology of the gene, 5th edn. Benjamin Cummings/Cold Spring Harbor Laboratory Press, San Francisco/Woodbury, pp 98–111Google Scholar
  98. 98.
    Sischka A, Toensing K, Eckel R, Wilking SD, Sewald N, Ros R, Anselmetti D (2005) Molecular mechanisms and kinetics between DNA and DNA binding ligands. Biophys J 88(1):404–411. doi: 10.1529/biophysj.103.036293 CrossRefGoogle Scholar
  99. 99.
    Kim Y, Kim KS, Kounovsky KL, Chang R, Jung GY, dePablo JJ, Jo K, Schwartz DC (2011) Nanochannel confinement: DNA stretch approaching full contour length. Lab Chip 11(10):1721–1729. doi: 10.1039/c0lc00680g CrossRefGoogle Scholar
  100. 100.
    Huh D, Mills KL, Zhu X, Burns MA, Thouless MD, Takayama S (2007) Tuneable elastomeric nanochannels for nanofluidic manipulation. Nat Mater 6(6):424–428. doi: 10.1038/nmat1907 CrossRefGoogle Scholar
  101. 101.
    Burg TP, Godin M, Knudsen SM, Shen W, Carlson G, Foster JS, Babcock K, Manalis SR (2007) Weighing of biomolecules, single cells and single nanoparticles in fluid. Nature 446(7139):1066–1069. doi: 10.1038/nature05741 CrossRefGoogle Scholar
  102. 102.
    Arlett JL, Myers EB, Roukes ML (2011) Comparative advantages of mechanical biosensors. Nat Nanotechnol 6(4):203–215. doi: 10.1038/nnano.2011.44 CrossRefGoogle Scholar
  103. 103.
    Hwang KS, Lee S-M, Kim SK, Lee JH, Kim TS (2009) Micro- and nanocantilever devices and systems for biomolecule detection. Annu Rev Anal Chem 2:77–98. doi: 10.1146/annurev-anchem-060908-155232 CrossRefGoogle Scholar
  104. 104.
    Fritz J, Baller MK, Lang HP, Rothuizen H, Vettiger P, Meyer E, Guntherodt HJ, Gerber C, Gimzewski JK (2000) Translating biomolecular recognition into nanomechanics. Science 288(5464):316–318. doi: 10.1126/science.288.5464.316 CrossRefGoogle Scholar
  105. 105.
    McKendry R, Zhang JY, Arntz Y, Strunz T, Hegner M, Lang HP, Baller MK, Certa U, Meyer E, Guntherodt HJ, Gerber C (2002) Multiple label-free biodetection and quantitative DNA-binding assays on a nanomechanical cantilever array. Proc Natl Acad Sci U S A 99(15):9783–9788. doi: 10.1073/pnas.152330199 CrossRefGoogle Scholar
  106. 106.
    Zhang J, Lang HP, Huber F, Bietsch A, Grange W, Certa U, McKendry R, Guentgerodt HJ, Hegner M, Gerber C (2006) Rapid and label-free nanomechanical detection of biomarker transcripts in human RNA. Nat Nanotechnol 1(3):214–220. doi: 10.1038/nnano.2006.134 CrossRefGoogle Scholar
  107. 107.
    Chin CD, Linder V, Sia SK (2012) Commercialization of microfluidic point-of-care diagnostic devices. Lab Chip 12:2118–2134. doi: 10.1039/c2lc21204h CrossRefGoogle Scholar
  108. 108.
    van Heeren H (2012) Standards for connecting microfluidic devices? Lab Chip 12(6):1022–1025. doi: 10.1039/c2lc20937c CrossRefGoogle Scholar
  109. 109.
    Stavis SM (2012) A glowing future for lab on a chip testing standards. Lab Chip 12(17):3008–3011. doi: 10.1039/c2lc40511c CrossRefGoogle Scholar
  110. 110.
    Whitesides GM (2011) What comes next? Lab Chip 11(2):191–193. doi: 10.1039/c0lc90101f CrossRefGoogle Scholar
  111. 111.
    Gervais L, de Rooij N, Delamarche E (2011) Microfluidic chips for point-of-care immunodiagnostics. Adv Mater 23(24):H151–H176. doi: 10.1002/adma.201100464 CrossRefGoogle Scholar
  112. 112.
    Becker H (2009) It’s the economy. Lab Chip 9(19):2759–2762. doi: 10.1039/b916505n CrossRefGoogle Scholar
  113. 113.
    Perkel JM (2008) Life science technologies: microfluidics—bringing new things to life science. Science 322(5903):975–977. doi: 10.1126/science.322.5903.975 CrossRefGoogle Scholar
  114. 114.
    Mukhopadhyay R (2007) When PDMS isn’t the best. What are its weaknesses, and which other polymers can researchers add to their toolboxes? Anal Chem 79(9):3248–3253. doi: 10.1021/ac071903e CrossRefGoogle Scholar
  115. 115.
    Liu HB, Gong HQ, Ramalingam N, Jiang Y, Dai CC, Hui KM (2007) Micro air bubble formation and its control during polymerase chain reaction (PCR) in polydimethylsiloxane (PDMS) microreactors. J Micromech Microeng 17(10):2055–2064. doi: 10.1088/0960-1317/17/10/018 CrossRefGoogle Scholar
  116. 116.
    Berthier E, Young EWK, Beebe D (2012) Engineers are from PDMS-land, biologists are from polystyrenia. Lab Chip 12(7):1224–1237. doi: 10.1039/c2lc20982a CrossRefGoogle Scholar
  117. 117.
    Park ES, Krajniak J, Lu H (2010) Packaging for Bio-micro-electro-mechanical Systems (BioMEMS) and microfluidic chips. In: Wong CP, Moon K-SJ, Li Y (eds) Nano-bio- electronic, photonic and MEMS packaging. Springer, New York, pp 505–563. doi: 10.1007/978-1-4419-0040-1_15 CrossRefGoogle Scholar
  118. 118.
    Yager P, Edwards T, Fu E, Helton K, Nelson K, Tam MR, Weigl BH (2006) Microfluidic diagnostic technologies for global public health. Nature 442(7101):412–418. doi: 10.1038/nature05064 CrossRefGoogle Scholar
  119. 119.
    Wilson R (2008) The use of gold nanoparticles in diagnostics and detection. Chem Soc Rev 37(9):2028–2045. doi: 10.1039/b712179m CrossRefGoogle Scholar
  120. 120.
    Aveyard J, Mehrabi M, Cossins A, Braven H, Wilson R (2007) One step visual detection of PCR products with gold nanoparticles and a nucleic acid lateral flow (NALF) device. Chem Commun 41:4251–4253. doi: 10.1039/b708859k CrossRefGoogle Scholar
  121. 121.
    Mao X, Ma YQ, Zhang AG, Zhang LR, Zeng LW, Liu GD (2009) Disposable nucleic acid biosensors based on gold nanoparticle probes and lateral flow strip. Anal Chem 81(4):1660–1668. doi: 10.1021/ac8024653 CrossRefGoogle Scholar
  122. 122.
    He YQ, Zhang SQ, Zhang XB, Baloda M, Gurung AS, Xu H, Zhang XJ, Liu GD (2011) Ultrasensitive nucleic acid biosensor based on enzyme-gold nanoparticle dual label and lateral flow strip biosensor. Biosens Bioelectron 26(5):2018–2024. doi: 10.1016/j.bios.2010.08.079 CrossRefGoogle Scholar
  123. 123.
    Soliman H, El-Matbouli M (2010) Loop mediated isothermal amplification combined with nucleic acid lateral flow strip for diagnosis of cyprinid herpes virus-3. Mol Cell Probes 24(1):38–43. doi: 10.1016/j.mcp. 2009.09.002 CrossRefGoogle Scholar
  124. 124.
    Xiang Y, Lu Y (2011) Using personal glucose meters and functional DNA sensors to quantify a variety of analytical targets. Nat Chem 3(9):697–703. doi: 10.1038/nchem.1092 CrossRefGoogle Scholar
  125. 125.
    Yeung SSW, Lee TMH, Hsing IM (2006) Electrochemical real-time polymerase chain reaction. J Am Chem Soc 128(41):13374–13375. doi: 10.1021/ja065733j CrossRefGoogle Scholar
  126. 126.
    Ahmed MU, Saito M, Hossain MM, Rao SR, Furui S, Hino A, Takamura Y, Takagi M, Tamiya E (2009) Electrochemical genosensor for the rapid detection of GMO using loop-mediated isothermal amplification. Analyst 134(5):966–972. doi: 10.1039/b812569d CrossRefGoogle Scholar
  127. 127.
    Hsieh K, Patterson AS, Ferguson BS, Plaxco KW, Soh HT (2012) Rapid, sensitive, and quantitative detection of pathogenic DNA at the point of care through microfluidic electrochemical quantitative loop-mediated isothermal amplification. Angew Chem Int Ed 51:4896–4900. doi: 10.1002/anie.201109115 CrossRefGoogle Scholar
  128. 128.
    Nagatani N, Yamanaka K, Saito M, Koketsu R, Sasaki T, Ikuta K, Miyahara T, Tamiya E (2011) Semi-real time electrochemical monitoring for influenza virus RNA by reverse transcription loop-mediated isothermal amplification using a USB powered portable potentiostat. Analyst 136(24):5143–5150. doi: 10.1039/c1an15638a CrossRefGoogle Scholar
  129. 129.
    Rogers JA, Someya T, Huang YG (2010) Materials and mechanics for stretchable electronics. Science 327(5973):1603–1607. doi: 10.1126/science.1182383 CrossRefGoogle Scholar
  130. 130.
    Wu Z, Cheng S (2012) Microfluidic electronics. Lab Chip 12:2782–2791. doi: 10.1039/C2LC21176A CrossRefGoogle Scholar
  131. 131.
    Kim DH, Lu NS, Ma R, Kim YS, Kim RH, Wang SD, Wu J, Won SM, Tao H, Islam A, Yu KJ, Kim TI, Chowdhury R, Ying M, Xu LZ, Li M, Chung HJ, Keum H, McCormick M, Liu P, Zhang YW, Omenetto FG, Huang YG, Coleman T, Rogers JA (2011) Epidermal electronics. Science 333(6044):838–843. doi: 10.1126/science.1206157 CrossRefGoogle Scholar
  132. 132.
    Kim DH, Ahn JH, Choi WM, Kim HS, Kim TH, Song JZ, Huang YGY, Liu ZJ, Lu C, Rogers JA (2008) Stretchable and foldable silicon integrated circuits. Science 320(5875):507–511. doi: 10.1126/science.1154367 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Biomedical Engineering, College of EngineeringPeking UniversityBeijingChina
  2. 2.National Center for Nanoscience and TechnologyBeijingChina

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