Microfluidics and Nanofluidics

, Volume 16, Issue 5, pp 941–963

Microfluidic platforms for discovery and detection of molecular biomarkers

  • Lien-Yu Hung
  • Hui-Wen Wu
  • Kuangwen Hsieh
  • Gwo-Bin Lee
Research Paper

Abstract

Microfluidics has emerged as a promising platform for discovery and detection of molecular biomarkers recently. With this approach, the discovery of these biomarkers could be more efficient in time and consumes less samples and reagents. Furthermore, the entire discovery process could be automated since all the functional microfluidic devices such as micropumps and microvalves could be integrated on a single chip. Similarly, the detection of the discovered molecular biomarkers is also promising. Detection of nucleic acid biomarkers, protein biomarkers, and metabolite biomarkers has been demonstrated on microfluidic platforms recently. When compared with their large-scale counterparts, the miniature system can perform the detection of these biomarkers within less analysis time while a multiplexed detection scheme could be easily achieved. Furthermore, the entire detection process could be automated on the single chip as well. This review paper is therefore to review the recent development of microfluidic devices and systems for the discovery and detection of the molecular biomarker. Techniques for biomarker discovery, verification, and detection that have been adapted into microfluidics were first reviewed, and their advantages were highlighted. The new approach of biomarker screening based on in vitro-generated affinity reagents such as nucleic acid aptamers and peptide affinity reagents was then reviewed. Finally, in the biomarker detection section, this review placed a special emphasis on commercialized microfluidic-based diagnostics for molecular biomarkers.

Keywords

Microfluidics Molecular biomarker Discovery of biomarkers Detection of biomarkers 

References

  1. Aebersold R, Mann M (2003) Mass spectrometry-based proteomics. Nature 422(6928):198–207Google Scholar
  2. Ahn JY, Jo M, Dua P, Lee DK, Kim S (2011) A sol-gel-based microfluidics system enhances the efficiency of RNA aptamer selection. Oligonucleotides 21(2):93–100Google Scholar
  3. Alley WR, Madera M, Mechref Y, Novotny MV (2010) Chip-based reversed-phase liquid chromatography-mass spectrometry of permethylated N-linked glycans: a potential methodology for cancer-biomarker discovery. Anal Chem 82(12):5095–5106Google Scholar
  4. Alom J, Galard R, Catalan R, Castellanos JM, Schwartz S, Tolosa E (1990) Cerebrospinal fluid neuropeptide y in Alzheimer’s disease. Eur Neurol 30(4):207–210Google Scholar
  5. Armenta JM, Dawoud AA, Lazar IM (2009) Microfluidic chips for protein differential expression profiling. Electrophoresis 30(7):1145–1156Google Scholar
  6. Atkinson AJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, Oates JA, Peck CC, Schooley RT, Spilker BA, Woodcock J, Zeger SL, Grp BDW (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95Google Scholar
  7. Barroso I, Luan J, Middelberg RPS, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O’Rahilly S, Wareham NJ (2003) Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 1(1):41–55Google Scholar
  8. Beebe DJ, Mensing GA, Walker GM (2002) Physics and applications of microfluidics in biology. Annu Rev Biomed Eng 4:261–286Google Scholar
  9. Belgrader P, Tanner SC, Regan JF, Koehler R, Hindson BJ, Brown AS (2013) Droplet digital PCR measurement of HER2 copy number alteration in formalin-fixed paraffin-embedded breast carcinoma tissue. Clin Chem 59(6):991–994Google Scholar
  10. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG (1998) Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 95(20):11891–11896Google Scholar
  11. Bell D, Berchuck A, Birrer M, Chien J, Cramer DW, Dao F, Dhir R, DiSaia P, Gabra H, Glenn P, Godwin AK, Gross J, Hartmann L, Huang M, Huntsman DG, Iacocca M, Imielinski M, Kalloger S, Karlan BY, Levine DA, Mills GB, Morrison C, Mutch D, Olvera N, Orsulic S, Park K, Petrelli N, Rabeno B, Rader JS, Sikic BI, Smith-McCune K, Sood AK, Bowtell D, Penny R, Testa JR, Chang K, Dinh HH, Drummond JA, Fowler G, Gunaratne P, Hawes AC, Kovar CL, Lewis LR, Morgan MB, Newsham IF, Santibanez J, Reid JG, Trevino LR, Wu YQ, Wang M, Muzny DM, Wheeler DA, Gibbs RA, Getz G, Lawrence MS, Cibulskis K, Sivachenko AY, Sougnez C, Voet D, Wilkinson J, Bloom T, Ardlie K, Fennell T, Baldwin J, Gabriel S, Lander ES, Ding L, Fulton RS, Koboldt DC, McLellan MD, Wylie T, Walker J, O’Laughlin M, Dooling DJ, Fulton L, Abbott R, Dees ND, Zhang Q, Kandoth C, Wendl M, Schierding W, Shen D, Harris CC, Schmidt H, Kalicki J, Delehaunty KD, Fronick CC, Demeter R, Cook L, Wallis JW, Lin L, Magrini VJ, Hodges JS, Eldred JM, Smith SM, Pohl CS, Vandin F, Raphael BJ, Weinstock GM, Mardis R, Wilson RK, Meyerson M, Winckler W, Verhaak RGW, Carter SL, Mermel CH, Saksena G, Nguyen H, Onofrio RC, Hubbard D, Gupta S, Crenshaw A, Ramos AH, Chin L, Protopopov A, Zhang J, Kim TM, Perna I, Xiao Y, Zhang H, Ren G, Sathiamoorthy N, Park RW, Lee E, Park PJ, Kucherlapati R, Absher DM, Waite L, Sherlock G, Brooks JD, Li JZ, Xu J, Myers RM, Laird PW, Cope L, Herman JG, Shen H, Weisenberger DJ, Noushmehr H, Pan F, Triche T Jr, Berman BP, Van den Berg DJ, Buckley J, Baylin SB, Spellman PT, Purdom E, Neuvial P, Bengtsson H, Jakkula LR, Durinck S, Han J, Dorton S, Marr H, Choi YG, Wang V, Wang NJ, Ngai J, Conboy JG, Parvin B, Feiler HS, Speed TP, Gray JW, Socci ND, Liang Y, Taylor BS, Schultz N, Borsu L, Lash AE, Brennan C, Viale A, Sander C, Ladanyi M, Hoadley KA, Meng S, Du Y, Shi Y, Li L, Turman YJ, Zang D, Helms EB, Balu S, Zhou X, Wu J, Topal MD, Hayes DN, Perou CM, Zhang J, Wu CJ, Shukla S, Sivachenko A, Jing R, Liu Y, Noble M, Carter H, Kim D, Karchin R, Korkola JE, Heiser LM, Cho RJ, Hu Z, Cerami E, Olshen A, Reva B, Antipin Y, Shen R, Mankoo P, Sheridan R, Ciriello G, Chang WK, Bernanke JA, Haussler D, Benz CC, Stuart JM, Benz SC, Sanborn JZ, Vaske CJ, Zhu J, Szeto C, Scott GK, Yau C, Wilkerson MD, Zhang N, Akbani R, Baggerly KA, Yung WK, Weinstein JN, Shelton T, Grimm D, Hatfield M, Morris S, Yena P, Rhodes P, Sherman M, Paulauskis J, Millis S, Kahn A, Greene JM, Sfeir R, Jensen MA, Chen J, Whitmore J, Alonso S, Jordan J, Chu A, Zhang J, Barker A, Compton C, Eley G, Ferguson M, Fielding P, Gerhard DS, Myles R, Schaefer C, Shaw KRM, Vaught J, Vockley JB, Good PJ, Guyer MS, Ozenberger B, Peterson J, Thomson E (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):609–615Google Scholar
  12. Berezovski MV, Lechmann M, Musheev MU, Mak TW, Krylov SN (2008) Aptamer-facilitated biomarker discovery (AptaBiD). J Am Chem Soc 130(28):9137–9143Google Scholar
  13. Bllaci L, Kjellstrom S, Eliasson L, Friend JR, Yeo LY, Nilsson S (2013) Fast surface acoustic wave-matrix-assisted laser desorption ionization mass spectrometry of cell response from islets of Langerhans. Anal Chem 85(5):2623–2629Google Scholar
  14. Boja ES, Rodriguez H (2012) Mass spectrometry-based targeted quantitative proteomics: achieving sensitive and reproducible detection of proteins. Proteomics 12(8):1093–1110Google Scholar
  15. Cambien F, Tiret L (2007) Genetics of cardiovascular diseases—from single mutations to the whole genome. Circulation 116(15):1714–1724Google Scholar
  16. Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, Dekernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, Macfarlane MT, Southwick PC (1994) Comparison of digital rectal examination and serum prostate-specific antigen in the early detection of prostate-cancer—results of a multicenter clinical-trial of 6,630 men. J Urol 151(5):1283–1290Google Scholar
  17. Caudle WM, Bammler TK, Lin Y, Pan S, Zhang J (2010) Using ‘omics’ to define pathogenesis and biomarkers of Parkinson’s disease. Expert Rev Neurother 10(6):925–942Google Scholar
  18. Chaiet L, Wolf FJ (1964) The properties of streptavidin, a biotin-binding protein produced by streptomycetes. Arch Biochem Biophys 106:1–5Google Scholar
  19. Chang CM, Chang WH, Wang CH, Wang JH, Mai JD, Lee GB (2013) Nucleic acid amplification using microfluidic systems. Lab Chip 13(7):1225–1242Google Scholar
  20. Chen YH, Lin HI, Huang CJ, Shiesh SC, Lee GB (2012) An automatic microfluidic system that continuously performs the systematic evolution of ligands by exponential enrichment. Microfluid Nanofluid 13(6):929–939Google Scholar
  21. Cho M, Xiao Y, Nie J, Stewart R, Csordas AT, Oh SS, Thomson JA, Soh HT (2010) Quantitative selection of DNA aptamers through microfluidic selection and high-throughput sequencing. Proc Natl Acad Sci USA 107(35):15373–15378Google Scholar
  22. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ, Natl High Blood Pressure Educ P (2003) Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42(6):1206–1252Google Scholar
  23. Choi S, Goryll M, Sin LYM, Wong PK, Chae J (2011) Microfluidic-based biosensors toward point-of-care detection of nucleic acids and proteins. Microfluid Nanofluid 10(2):231–247Google Scholar
  24. Churchill E, Budas G, Vallcntin A, Koyanag T, Mochly-Rosen D (2008) PKC isozymes in chronic cardiac disease: possible therapeutic targets? Annu Rev Pharmacol 48:569–599Google Scholar
  25. Clackson T, Hoogenboom HR, Griffiths AD, Winter G (1991) Making antibody fragments using phage display libraries. Nature 352(6336):624–628Google Scholar
  26. Cung K, Slater RL, Cui Y, Manivannan S, Jones SE, Ahmad H, Nelson CM, Naik RR, McAlpine MC (2012) Rapid, multiplexed microfluidic phage display. Lab Chip 12(24):5281Google Scholar
  27. de Wit M, Fijneman RJA, Verheul HMW, Meijer GA, Jimenez CR (2013) Proteomics in colorectal cancer translational research: biomarker discovery for clinical applications. Clin Biochem 46(6):466–479Google Scholar
  28. Decressac M, Wright B, Tyers P, Gaillard A, Barker RA (2010) Neuropeptide y modifies the disease course in the R6/2 transgenic model of Huntington’s disease. Exp Neurol 226(1):24–32Google Scholar
  29. Doerr A (2013) Mass spectrometry-based targeted proteomics. Nat Methods 10(1):23MathSciNetGoogle Scholar
  30. 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):11570–11575Google Scholar
  31. Fan R, Vermesh O, Srivastava A, Yen BKH, Qin LD, Ahmad H, Kwong GA, Liu CC, Gould J, Hood L, Heath JR (2008) Integrated barcode chips for rapid, multiplexed analysis of proteins in microliter quantities of blood. Nat Biotechnol 26(12):1373–1378Google Scholar
  32. Fang XH, Tan WH (2010) Aptamers generated from cell-SELEX for molecular medicine: a chemical biology approach. Acc Chem Res 43(1):48–57Google Scholar
  33. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol Mech Dis 6:479–507Google Scholar
  34. Fiehn O (2002) Metabolomics - the link between genotypes and phenotypes. Plant Mol Biol 48(1–2):155–171Google Scholar
  35. Fiehn O, Kopka J, Dormann P, Altmann T, Trethewey RN, Willmitzer L (2000) Metabolite profiling for plant functional genomics. Nat Biotechnol 18(11):1157–1161Google Scholar
  36. Fortier MH, Bonneil E, Goodley P, Thibault P (2005) Integrated microfluidic device for mass spectrometry-based proteomics and its application to biomarker discovery programs. Anal Chem 77(6):1631–1640Google Scholar
  37. Garcia CD, Henry CS (2004) Enhanced determination of glucose by microchip electrophoresis with pulsed amperometric detection. Anal Chim Acta 508(1):1–9Google Scholar
  38. Garcia-Perez I, Vallejo M, Garcia A, Legido-Quigley C, Barbas C (2008) Metabolic fingerprinting with capillary electrophoresis. J Chromatogr A 1204(2):130–139Google Scholar
  39. Gaster RS, Xu L, Han SJ, Wilson RJ, Hall DA, Osterfeld SJ, Yu H, Wang SX (2011) Quantification of protein interactions and solution transport using high-density GMR sensor arrays. Nat Nanotechnol 6(5):314–320Google Scholar
  40. Ges IA, Baudenbacher F (2010) Enzyme-coated microelectrodes to monitor Lactate production in a nanoliter microfluidic cell culture device. Biosens Bioelectron 26(2):828–833Google Scholar
  41. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM (2003) Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52(2):568–572Google Scholar
  42. Gortzak-Uzan L, Ignatchenko A, Evangelou AI, Agochiya M, Brown KA, Onge PS, Kireeva I, Schmitt-Ulms G, Brown TJ, Murphy J, Rosen B, Shaw P, Jurisica I, Kislinger T (2008) A proteome resource of ovarian cancer ascites: integrated proteomic and bioinformatic analyses to identify putative biomarkers. J Proteome Res 7(1):339–351Google Scholar
  43. Hamilton RG, MacGlashan DW, Saini SS (2010) IgE antibody-specific activity in human allergic disease. Immunol Res 47(1–3):273–284Google Scholar
  44. Hanash SM, Baik CS, Kallioniemi O (2011) Emerging molecular biomarkers-blood-based strategies to detect and monitor cancer. Nat Rev Clin Oncol 8(3):142–150Google Scholar
  45. Hardouin J, Joubert-Caron R, Caron M (2007) HPLC-chip-mass spectrometry for protein signature identifications. J Sep Sci 30(10):1482–1487Google Scholar
  46. Hardy J, Selkoe DJ (2002) Medicine—the amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356Google Scholar
  47. Herr AE, Hatch AV, Throckmorton DJ, Tran HM, Brennan JS, Giannobile WV, Singh AK (2007) Microfluidic immunoassays as rapid saliva-based clinical diagnostics. Proc Natl Acad Sci USA 104(13):5268–5273Google Scholar
  48. Hirschfield GM, Pepys MB (2003) C-reactive protein and cardiovascular disease: new insights from an old molecule. QJM-Int J Med 96(11):793–807Google Scholar
  49. Ho MM, Ng AV, Lam S, Hung JY (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67(10):4827–4833Google Scholar
  50. Hu Y, Gopal A, Lin K, Peng Y, Tasciotti E, Zhang XJ, Ferrari M (2011) Microfluidic enrichment of small proteins from complex biological mixture on nanoporous silica chip. Biomicrofluidics 5(1):013410Google Scholar
  51. Huang CJ, Lin HI, Shiesh SC, Lee GB (2010) Integrated microfluidic system for rapid screening of crp aptamers utilizing systematic evolution of ligands by exponential enrichment (SELEX). Biosens Bioelectron 25(7):1761–1766Google Scholar
  52. Huang CJ, Lin HI, Shiesh SC, Lee GB (2012) An integrated microfluidic system for rapid screening of alpha-fetoprotein-specific aptamers. Biosens Bioelectron 35(1):50–55Google Scholar
  53. Hughes AJ, Lin RKC, Peehl DM, Herr AE (2012) Microfluidic integration for automated targeted proteomic assays. Proc Natl Acad Sci USA 109(16):5972–5977Google Scholar
  54. Idle JR, Gonzalez FJ (2007) Metabolomics. Cell Metab 6(5):348–351Google Scholar
  55. Irgon J, Huang CC, Zhang Y, Talantov D, Bhanot G, Szalma S (2010) Robust multi-tissue gene panel for cancer detection. BMC Cancer 10:319Google Scholar
  56. Jakupciak JP, Wang W, Markowitz ME, Ally D, Coble M, Srivastava S, Maitra A, Barker PE, Sidransky D, O’Connell CD (2005) Mitochondrial DNA as a cancer biomarker. J Mol Diagn 7(2):258–267Google Scholar
  57. Jiang H, Weng XA, Li DQ (2011) Microfluidic whole-blood immunoassays. Microfluid Nanofluid 10(5):941–964Google Scholar
  58. Jimeno A, Hidalgo M (2006) Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer. Mol Cancer Ther 5(4):787–796Google Scholar
  59. Keller A, Leidinger P, Bauer A, ElSharawy A, Haas J, Backes C, Wendschlag A, Giese N, Tjaden C, Ott K, Werner J, Hackert T, Ruprecht K, Huwer H, Huebers J, Jacobs G, Rosenstiel P, Dommisch H, Schaefer A, Muller-Quernheim J, Wullich B, Keck B, Graf N, Reichrath J, Vogel B, Nebel A, Jager SU, Staehler P, Amarantos I, Boisguerin V, Staehler C, Beier M, Scheffler M, Buchler MW, Wischhusen J, Haeusler SFM, Dietl J, Hofmann S, Lenhof HP, Schreiber S, Katus HA, Rottbauer W, Meder B, Hoheisel JD, Franke A, Meese E (2011) Toward the blood-borne miRNome of human diseases. Nat Methods 8(10):841–843Google Scholar
  60. Kew M (1974) Alpha-fetoprotein in primary liver cancer and other diseases. Gut 15(10):814–821Google Scholar
  61. Kijanka G, Murphy D (2009) Protein arrays as tools for serum autoantibody marker discovery in cancer. J Proteomics 72(6):936–944Google Scholar
  62. Konopatskaya O, Poole AW (2010) Protein kinase Calpha: disease regulator and therapeutic target. Trends Pharmacol Sci 31(1):8–14Google Scholar
  63. Kotz KT, Xiao W, Miller-Graziano C, Qian W-J, Russom A, Warner EA, Moldawer LL, De A, Bankey PE, Petritis BO, Camp DG II, Rosenbach AE, Goverman J, Fagan SP, Brownstein BH, Irimia D, Xu W, Wilhelmy J, Mindrinos MN, Smith RD, Davis RW, Tompkins RG, Toner M, Inflammation Host Response (2010) Clinical microfluidics for neutrophil genomics and proteomics. Nat Med 16(9):1042–1047Google Scholar
  64. Kraly JR, Holcomb RE, Guan Q, Henry CS (2009) Review: microfluidic applications in metabolomics and metabolic profiling. Anal Chim Acta 653(1):23–35Google Scholar
  65. Lagalla G, Millevolte M, Capecci M, Provinciali L, Ceravolo MG (2006) Botulinum toxin type a for drooling in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord 21(5):704–707Google Scholar
  66. Lazar IM, Trisiripisal P, Sarvaiya HA (2006) Microfluidic liquid chromatography system for proteomic applications and biomarker screening. Anal Chem 78(15):5513–5524Google Scholar
  67. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854Google Scholar
  68. Li JJ, LeRiche T, Tremblay TL, Wang C, Bonneil E, Harrison DJ, Thibault P (2002) Application of microfluidic devices to proteomics research—identification of trace-level protein digests and affinity capture of target peptides. Mol Cell Proteomics 1(2):157–168Google Scholar
  69. Lim LS, Hu M, Huang MC, Cheong WC, Gan ATL, Looi XL, Leong SM, Koay ESC, Li MH (2012) Microsieve lab-chip device for rapid enumeration and fluorescence in situ hybridization of circulating tumor cells. Lab Chip 12(21):4388–4396Google Scholar
  70. Lin CC, Wang JH, Wu HW, Lee GB (2010) Microfluidic immunoassays. J Lab Autom 15(3):253–274MathSciNetGoogle Scholar
  71. Lindon JC, Holmes E, Bollard ME, Stanley EG, Nicholson JK (2004) Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers 9(1):1–31Google Scholar
  72. Liu Y, Adams JD, Turner K, Cochran FV, Gambhir SS, Soh HT (2009) Controlling the selection stringency of phage display using a microfluidic device. Lab Chip 9(8):1033–1036Google Scholar
  73. Loos RJF, Bouchard C (2008) Fto: the first gene contributing to common forms of human obesity. Obes Rev 9(3):246–250Google Scholar
  74. Lou X, Qian J, Xiao Y, Viel L, Gerdon AE, Lagally ET, Atzberger P, Tarasow TM, Heeger AJ, Soh HT (2009) Micromagnetic selection of aptamers in microfluidic channels. Proc Natl Acad Sci USA 106(9):2989–2994Google Scholar
  75. Malo N, Hanley JA, Cerquozzi S, Pelletier J, Nadon R (2006) Statistical practice in high-throughput screening data analysis. Nat Biotechnol 24(2):167–175Google Scholar
  76. Mandecki W, Chen YCJ, Grihalde N (1995) A mathematical-model for biopanning (affinity selection) using peptide libraries on filamentous phage. J Theor Biol 176(4):523–530Google Scholar
  77. Mascini M, Palchetti I, Tombelli S (2012) Nucleic acid and peptide aptamers: fundamentals and bioanalytical aspects. Angew Chem Int Ed 51(6):1316–1332Google Scholar
  78. Meagher RJ, Hatch AV, Renzi RF, Singh AK (2008) An integrated microfluidic platform for sensitive and rapid detection of biological toxins. Lab Chip 8(12):2046–2053Google Scholar
  79. Mendonsa SD, Bowser MT (2004) In vitro selection of high-affinity DNA ligands for human IgE using capillary electrophoresis. Anal Chem 76(18):5387–5392Google Scholar
  80. Mendonsa SD, Bowser MT (2005) In vitro selection of aptamers with affinity for neuropeptide y using capillary electrophoresis. J Am Chem Soc 127(26):9382–9383Google Scholar
  81. Merriman TR, Dalbeth N (2011) The genetic basis of hyperuricaemia and gout. Joint Bone Spine 78(1):35–40Google Scholar
  82. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105(30):10513–10518Google Scholar
  83. Mohammed MI, Desmulliez MPY (2011) Lab-on-a-chip based immunosensor principles and technologies for the detection of cardiac biomarkers: a review. Lab Chip 11(4):569–595Google Scholar
  84. Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L, Stoeppler H, Simko J, Hilton JF, Carroll P, Blelloch R (2011) Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Res 71(2):550–560Google Scholar
  85. Mori Y, Olaru AV, Cheng YL, Agarwal R, Yang J, Luvsanjav D, Yu WN, Selaru FM, Hutfless S, Lazarev M, Kwon JH, Brant SR, Marohn MR, Hutcheon DF, Duncan MD, Goel A, Meltzer SJ (2011) Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning. Endocr Relat Cancer 18(4):465–478Google Scholar
  86. Mosing RK, Bowser MT (2007) Microfluidic selection and applications of aptamers. J Sep Sci 30(10):1420–1426Google Scholar
  87. Mosing RK, Mendonsa SD, Bowser MT (2005) Capillary electrophoresis-SELEX selection of aptamers with affinity for HIV-1 reverse transcriptase. Anal Chem 77(19):6107–6112Google Scholar
  88. Murphy BM, He X, Dandy D, Henry CS (2008) Competitive immunoassays for simultaneous detection of metabolites and proteins using micromosaic patterning. Anal Chem 80(2):444–450Google Scholar
  89. Nibbe RK, Koyutuerk M, Chance MR (2010) An integrative -omics approach to identify functional sub-networks in human colorectal cancer. PLoS Comput Biol 6(1):e1000639Google Scholar
  90. Njoroge SK, Chen HW, Witek MA, Soper SA (2011) Integrated microfluidic systems for DNA analysis. Top Curr Chem 304:203–260Google Scholar
  91. Oblak TD, Meyer JA, Spence DM (2009) A microfluidic technique for monitoring bloodstream analytes indicative of C-peptide resistance in type 2 diabetes. Analyst 134(1):188–193Google Scholar
  92. Ouattara DA, Prot J-M, Bunescu A, Dumas M-E, Elena-Herrmann B, Leclerc E, Brochot C (2012) Metabolomics-on-a-chip and metabolic flux analysis for label-free modeling of the internal metabolism of HepG2/C3a cells. Mol BioSyst 8(7):1908–1920Google Scholar
  93. Park SM, Ahn JY, Jo M, Lee DK, Lis JT, Craighead HG, Kim S (2009) Selection and elution of aptamers using nanoporous sol-gel arrays with integrated microheaters. Lab Chip 9(9):1206–1212Google Scholar
  94. Patel R, Tsan A, Tam R, Desai R, Schoenbrunner N, Myers TW, Bauer K, Smith E, Raja R (2012) Mutation scanning using MUT-MAP, a high-throughput, microfluidic chip-based, multi-analyte panel. PLoS ONE 7(12):e51153Google Scholar
  95. Pedraza V, Gomez-Capilla JA, Escaramis G, Gomez C, Torne P, Rivera JM, Gil A, Araque P, Olea N, Estivill X, Esther Farez-Vidal M (2010) Gene expression signatures in breast cancer distinguish phenotype characteristics, histologic subtypes, and tumor invasiveness. Cancer 116(2):486–496Google Scholar
  96. Pekin D, Skhiri Y, Baret J-C, Le Corre D, Mazutis L, Ben Salem C, 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):2156–2166Google Scholar
  97. Pepe MS, Etzioni R, Feng ZD, Potter JD, Thompson ML, Thornquist M, Winget M, Yasui Y (2001) Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 93(14):1054–1061Google Scholar
  98. Pernagallo S, Ventimiglia G, Cavalluzzo C, Alessi E, Ilyine H, Bradley M, Diaz-Mochon JJ (2012) Novel biochip platform for nucleic acid analysis. Sensors 12(6):8100–8111Google Scholar
  99. Pertega-Gomes N, Vizcaino JR, Gouveia C, Jeronimo C, Henrique RM, Lopes C, Baltazar F (2013) Monocarboxylate transporter 2 (MCT2) as putative biomarker in prostate cancer. Prostate 73(7):763–769Google Scholar
  100. Petricoin EF, Ardekani AM, Hitt BA (2004) Use of proteomic patterns in serum to identify ovarian cancer. Lancet 364(9434):582Google Scholar
  101. Phillips KA, Van Bebber S, Issa AM (2006) Diagnostics and biomarker development: priming the pipeline. Nat Rev Drug Discov 5(6):463–469Google Scholar
  102. Pritchard CC, Cheng HH, Tewari M (2012) MicroRNA profiling: approaches and considerations. Nat Rev Genet 13(5):358–369Google Scholar
  103. Prot JM, Leclerc E (2012) The current status of alternatives to animal testing and predictive toxicology methods using liver microfluidic biochips. Ann Biomed Eng 40(6):1228–1243Google Scholar
  104. Qian JR, Lou XH, Zhang YT, Xiao Y, Soh HT (2009) Generation of highly specific aptamers via micromagnetic selection. Anal Chem 81(13):5490–5495Google Scholar
  105. Rahimov F, King OD, Leung DG, Bibat GM, Emerson CP, Kunkel LM, Wagner KR (2012) Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers. Proc Natl Acad Sci USA 109(40):16234–16239Google Scholar
  106. Ramachandran N, Srivastava S, LaBaer J (2008) Applications of protein microarrays for biomarker discovery. Proteomics Clin App 2(10–11):1444–1459Google Scholar
  107. Ramadan Q, Jafarpoorchekab H, Huang C, Silacci P, Carrara S, Koklue G, Ghaye J, Ramsden J, Ruffert C, Vergeres G, Gijs MAM (2013) Nutrichip: nutrition analysis meets microfluidics. Lab Chip 13(2):196–203Google Scholar
  108. Rapi S, Bazzini C, Tozzetti C, Sbolci V, Modesti PA (2009) Point-of-care testing of cholesterol and triglycerides for epidemiologic studies; evaluation of the multicare-in system. Transl Res 153(2):71–76Google Scholar
  109. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ (2004) ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. New Engl J Med 351(9):893–901Google Scholar
  110. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T (2007) Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 13(11):1359–1362Google Scholar
  111. Reginato AM, Mount DB, Yang I, Choi HK (2012) The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 8(10):610–621Google Scholar
  112. Ridker PM, Stampfer MJ, Rifai N (2001) Novel risk factors for systemic atherosclerosis—a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. J Am Med Assoc (JAMA) 285(19):2481–2485Google Scholar
  113. Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24(8):971–983Google Scholar
  114. 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):595–599Google Scholar
  115. Rizzi F, Belloni L, Crafa P, Lazzaretti M, Remondini D, Ferretti S, Cortellini P, Corti A, Bettuzzi S (2008) A novel gene signature for molecular diagnosis of human prostate cancer by RT-qPCR. PLoS ONE 3(10):e3617Google Scholar
  116. Rocheleau JV, Walker GM, Head WS, McGuinness OP, Piston DW (2004) Microfluidic glucose stimulation reveals limited coordination of intracellular Ca2+ activity oscillations in pancreatic islets. Proc Natl Acad Sci USA 101(35):12899–12903Google Scholar
  117. Rodriguez S, Al-Ghamdi OA, Burrows K, Guthrie PAI, Lane JA, Davis M, Marsden G, Alharbi KK, Cox A, Hamdy FC, Neal DE, Donovan JL, Day INM (2013) Very low PSA concentrations and deletions of the KLK3 gene. Clin Chem 59(1):234–244Google Scholar
  118. Rusling JF, Kumar CV, Gutkind JS, Patel V (2010) Measurement of biomarker proteins for point-of-care early detection and monitoring of cancer. Analyst 135(10):2496–2511Google Scholar
  119. Sadygov RG, Cociorva D, Yates JR (2004) Large-scale database searching using tandem mass spectra: looking up the answer in the back of the book. Nat Methods 1(3):195–202Google Scholar
  120. Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363(9423):1783–1793Google Scholar
  121. Savoia C, Schiffrin EL (2007) Reduction of C-reactive protein and the use of anti-hypertensives. Vasc Health Risk Manage 3(6):975–983Google Scholar
  122. Schena M, Shalon D, Davis RW, Brown PO (1995) Quantitative monitoring of gene-expression patterns with a complementary-DNA microarray. Science 270(5235):467–470Google Scholar
  123. Schmitz U, Versmold A, Kaufmann P, Frank HG (2000) Phage display: a molecular tool for the generation of antibodies—a review. Placenta 21:S106–S112Google Scholar
  124. Sefah K, Shangguan D, Xiong XL, O’Donoghue MB, Tan WH (2010) Development of DNA aptamers using cell-SELEX. Nat Protoc 5(6):1169–1185Google Scholar
  125. Shephard M, Peake M, Corso O, Shephard A, Mazzachi B, Spaeth B, Barbara J, Mathew T (2010) Assessment of the Nova StatSensor whole blood point-of-care creatinine analyzer for the measurement of kidney function in screening for chronic kidney disease. Clin Chem Lab Med 48(8):1113–1119Google Scholar
  126. Shintu L, Baudoin R, Navratil V, Prot JM, Pontoizeau C, Defernez M, Blaise BJ, Domange C, Pery AR, Toulhoat P, Legallais C, Brochot C, Leclerc E, Dumas ME (2012) Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs. Anal Chem 84(4):1840–1848Google Scholar
  127. Sidhu SS, Fairbrother WJ, Deshayes K (2003) Exploring protein–protein interactions with phage display. ChemBioChem 4(1):14–25Google Scholar
  128. Sieben VJ, Marun CSD, Pilarski PM, Kaigala GV, Pilarski LM, Backhouse CJ (2007) FISH and chips: chromosomal analysis on microfluidic platforms. IET Nanobiotechnol 1(3):27–35Google Scholar
  129. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, Mcguire WL (1987) Human-breast cancer—correlation of relapse and survival with amplification of the HER-2 neu oncogene. Science 235(4785):177–182Google Scholar
  130. Smith GP (1985) Filamentous fusion phage—novel expression vectors that display cloned antigens on the virion surface. Science 228(4705):1315–1317Google Scholar
  131. Snouber LC, Bunescu A, Naudot M, Legallais C, Brochot C, Dumas ME, Elena-Herrmann B, Leclerc E (2013) Metabolomics-on-a-chip of hepatotoxicity induced by anticancer drug flutamide and its active metabolite hydroxyflutamide using HepG2/C3a microfluidic biochips. Toxicol Sci 132(1):8–20Google Scholar
  132. Spurgeon SL, Jones RC, Ramakrishnan R (2008) High throughput gene expression measurement with real time PCR in a microfluidic dynamic array. PLoS ONE 3(2):e1662Google Scholar
  133. Srikumar N, Brown NJ, Hopkins PN, Jeunemaitre X, Hunt SC, Vaughan DE, Williams GH (2002) PAI-1 in human hypertension: relation to hypertensive groups. Am J Hypertens 15(8):683–690Google Scholar
  134. Stern E, Vacic A, Rajan NK, Criscione JM, Park J, Ilic BR, Mooney DJ, Reed MA, Fahmy TM (2010) Label-free biomarker detection from whole blood. Nat Nanotechnol 5(2):138–142Google Scholar
  135. Stoltenburg R, Reinemann C, Strehlitz B (2007) SELEX-A (r)evolutionary method to generate high-affinity nucleic acid ligands. Biomol Eng 24(4):381–403Google Scholar
  136. Strimbu K, Tavel JA (2010) What are biomarkers? Curr Opin HIV AIDS 5(6):463–466Google Scholar
  137. Suzuki H, Matsugi Y (2005) Integrated microfluidic system for the simultaneous determination of ammonia, creatinine, and urea. Sensor Actuat B-Chem 108(1–2):700–707Google Scholar
  138. Tai CH, Ho CL, Chen YL, Chen WL, Lee GB (2013) A novel integrated microfluidic platform to perform fluorescence in situ hybridization for chromosomal analysis. Microfluid Nanofluid. doi:10.1007/s10404-10013-11190-10400 Google Scholar
  139. Tang SSK, Gui GPH (2012) Biomarkers in the diagnosis of primary and recurrent breast cancer. Biomark Med 6(5):567–585MathSciNetGoogle Scholar
  140. Tang J, Xie J, Shao N, Yan Y (2006) The DNA aptamers that specifically recognize ricin toxin are selected by two in vitro selection methods. Electrophoresis 27(7):1303–1311Google Scholar
  141. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci USA 106(38):16157–16162Google Scholar
  142. Thongboonkerd V, Songtawee N, Sritippayawan S (2007) Urinary proteome profiling using microfluidic technology on a chip. J Proteome Res 6(5):2011–2018Google Scholar
  143. Todd JA, Bell JI, McDevitt HO (1987) HLA-DQ-beta gene contributes to susceptibility and resistance to insulin-dependent diabetes-mellitus. Nature 329(6140):599–604Google Scholar
  144. Tok J, Lai J, Leung T, Li SFY (2010) Selection of aptamers for signal transduction proteins by capillary electrophoresis. Electrophoresis 31(12):2055–2062Google Scholar
  145. Toriello NM, Liu CN, Mathies RA (2006) Multichannel reverse transcription-polymerase chain reaction microdevice for rapid gene expression and biomarker analysis. Anal Chem 78(23):7997–8003Google Scholar
  146. Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment—RNA ligands to bacteriophage T4 DNA-polymerase. Science 249(4968):505–510Google Scholar
  147. Ulrich H, Trujillo CA, Nery AA, Alves JM, Majumder P, Resende RR, Martins AH (2006) DNA and RNA aptamers: from tools for basic research towards therapeutic applications. Comb Chem High Throughput Screen 9(8):619–632Google Scholar
  148. Vafiadis P, Ounissi-Benkalha H, Palumbo M, Grabs R, Rousseau M, Goodyer CG, Polychronakos C (2001) Class iii alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocr Metab 86(8):3705–3710Google Scholar
  149. Valleron W, Laprevotte E, Gautier EF, Quelen C, Demur C, Delabesse E, Agirre X, Prosper F, Kiss T, Brousset P (2012a) Specific small nucleolar RNA expression profiles in acute leukemia. Leukemia 26(9):2052–2060Google Scholar
  150. Valleron W, Ysebaert L, Berquet L, Fataccioli V, Quelen C, Martin A, Parrens M, Lamant L, de Leval L, Gisselbrecht C, Gaulard P, Brousset P (2012b) Small nucleolar RNA expression profiling identifies potential prognostic markers in peripheral T-cell lymphoma. Blood 120(19):3997–4005Google Scholar
  151. van de Vijver MJ, He YD, van ‘t Veer LJ, Dai H, Hart AAM, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009Google Scholar
  152. Van Roon-Mom WMC, Reid SJ, Faull RLM, Snell RG (2005) TATA-binding protein in neurodegenerative disease. Neuroscience 133(4):863–872Google Scholar
  153. Vansteenkiste J, Dooms C, Mascaux C, Nackaerts K (2012) Screening and early detection of lung cancer. Ann Oncol 23:320–327Google Scholar
  154. VerBerkmoes NC, Bundy JL, Hauser L, Asano KG, Razumovskaya J, Larimer F, Hettich RL, Stephenson JL (2002) Integrating “top-down” and “bottom-up” mass spectrometric approaches for proteomic analysis of shewanella oneidensis. J Proteome Res 1(3):239–252Google Scholar
  155. Villanueva J, Philip J, Entenberg D, Chaparro CA, Tanwar MK, Holland EC, Tempst P (2004) Serum peptide profiling by magnetic particle-assisted, automated sample processing and MALDI-TOF mass spectrometry. Anal Chem 76(6):1560–1570Google Scholar
  156. Vodnik M, Zager U, Strukelj B, Lunder M (2011) Phage display: selecting straws instead of a needle from a haystack. Molecules 16(1):790–817Google Scholar
  157. Wallman L, Ekstrom S, Magnusson M, Bolmsjo G, Olsson M, Nilsson J, Marko-Varga G, Laurell T (2006) Robotic implementation of a microchip-based protein clean-up and enrichment system for MALDI-TOF MS readout. Meas Sci Technol 17(12):3147–3153Google Scholar
  158. Walter K, Holcomb T, Januario T, Du P, Evangelista M, Kartha N, Iniguez L, Soriano R, Huw L, Stern H, Modrusan Z, Seshagiri S, Hampton GM, Amler LC, Bourgon R, Yauch RL, Shames DS (2012) DNA methylation profiling defines clinically relevant biological subsets of non-small cell lung cancer. Clin Cancer Res 18(8):2360–2373Google Scholar
  159. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Selhub J, Robins SJ, Benjamin EJ, D’Agostino RB, Vasan RS (2006) Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 355(25):2631–2639Google Scholar
  160. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10(1):57–63Google Scholar
  161. Wang J, Liu Y, Teesalu T, Sugahara KN, Kotamrajua VR, Adams JD, Ferguson BS, Gong Q, Oh SS, Csordas AT, Cho M, Ruoslahti E, Xiao Y, Soh HT (2011) Selection of phage-displayed peptides on live adherent cells in microfluidic channels. Proc Natl Acad Sci USA 108(17):6909–6914Google Scholar
  162. Wang XZ, Takebayashi SI, Bernardin E, Gilbert DM, Chella R, Guan JJ (2012) Microfluidic extraction and stretching of chromosomal DNA from single cell nuclei for DNA fluorescence in situ hybridization. Biomed Microdevices 14(3):443–451Google Scholar
  163. Wang CH, Lai HC, Liou TML, Hsu KFH, Chou CYC, Lee GB (2013) A DNA methylation assay for detection of ovarian cancer cells using a HpaII/MspI digestion-based PCR assay in an integrated microfluidic system. Microfluid Nanofluid 15(5):575–585Google Scholar
  164. Waring SC, Rosenberg RN (2008) Genome-wide association studies in Alzheimer disease. Arch Neurol 65(3):329–334Google Scholar
  165. Washburn AL, Gunn LC, Bailey RC (2009) Label-free quantitation of a cancer biomarker in complex media using silicon photonic microring resonators. Anal Chem 81(22):9499–9506Google Scholar
  166. Washburn AL, Luchansky MS, Bowman AL, Bailey RC (2010) Quantitative, label-free detection of five protein biomarkers using multiplexed arrays of silicon photonic microring resonators. Anal Chem 82(1):69–72Google Scholar
  167. Weng CH, Hsieh IS, Hung LY, Lin HI, Shiesh SC, Chen YL, Lee GB (2013) An automatic microfluidic system for rapid screening of cancer stem-like cell-specific aptamers. Microfluid Nanofluid 14(3–4):753–765Google Scholar
  168. Whiteaker JR, Lin C, Kennedy J, Hou L, Trute M, Sokal I, Yan P, Schoenherr RM, Zhao L, Voytovich UJ, Kelly-Spratt KS, Krasnoselsky A, Gafken PR, Hogan JM, Jones LA, Wang P, Amon L, Chodosh LA, Nelson PS, McIntosh MW, Kemp CJ, Paulovich AG (2011) A targeted proteomics-based pipeline for verification of biomarkers in plasma. Nat Biotechnol 29(7):625–634Google Scholar
  169. Wilm M, Mann M (1996) Analytical properties of the nanoelectrospray ion source. Anal Chem 68(1):1–8Google Scholar
  170. Winter G, Griffiths AD, Hawkins RE, Hoogenboom HR (1994) Making antibodies by phage display technology. Annu Rev Immunol 12:433–455Google Scholar
  171. Wu AHB, Smith A, Christenson RH, Murakami MM, Apple FS (2004) Evaluation of a point-of-care assay for cardiac markers for patients suspected of acute myocardial infarction. Clin Chim Acta 346(2):211–219Google Scholar
  172. Wu RG, Yeung WSB, Fung YS (2011) 2-D t-ITP/CZE determination of clinical urinary proteins using a microfluidic-chip capillary electrophoresis device. Electrophoresis 32(23):3406–3414Google Scholar
  173. Xie J, Miao YN, Shih J, Tai YC, Lee TD (2005) Microfluidic platform for liquid chromatography-tandem mass spectrometry analyses of complex peptide mixtures. Anal Chem 77(21):6947–6953Google Scholar
  174. Yang Y, Iyer LK, Adelstein SJ, Kassis AI (2008) Integrative genomic data mining for discovery of potential blood-borne biomarkers for early diagnosis of cancer. PLoS ONE 3(11):e3661Google Scholar
  175. Yu LM, Yu S, Mui EYY, McKelvie JC, Pham TPT, Yap YW, Wong WQ, Wu JW, Deng WQ, Orner BP (2009) Phage display screening against a set of targets to establish peptide-based sugar mimetics and molecular docking to predict binding site. Bioorg Med Chem 17(13):4825–4832Google Scholar
  176. Yu D-C, Li Q-G, Ding X-W, Ding Y-T (2011a) Circulating microRNAs: potential biomarkers for cancer. Int J Mol Sci 12(3):2055–2063Google Scholar
  177. Yu M, Wang QS, Patterson JE, Woolley AT (2011b) Multilayer polymer microchip capillary array electrophoresis devices with integrated on-chip labeling for high-throughput protein analysis. Anal Chem 83(9):3541–3547Google Scholar
  178. Zhou XC, Mao JH, Ai JM, Deng YP, Roth MR, Pound C, Henegar J, Welti R, Bigler SA (2012) Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics. PLoS ONE 7(11):e3661Google Scholar
  179. Ziober BL, Mauk MG, Falls EM, Chen Z, Ziober AF, Bau HH (2008) Lab-on-a-chip for oral cancer screening and diagnosis. Head Neck-J Sci Spec 30(1):111–121Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lien-Yu Hung
    • 1
  • Hui-Wen Wu
    • 1
  • Kuangwen Hsieh
    • 1
  • Gwo-Bin Lee
    • 1
  1. 1.Department of Power Mechanical EngineeringNational Tsing Hua UniversityHsinchuTaiwan

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