During the last two decades, the manufacturing techniques of microfluidics-based devices have been phenomenally advanced, offering unlimited potential for bio-medical technologies. However, the direct applications of these technologies toward diagnostics and therapeutics are still far from maturity. The present challenges lay at the interfaces between the engineering systems and the biocomplex systems. A precisely designed engineering system with narrow dynamic range is hard to seamlessly integrate with the adaptive biological system in order to achieve the design goals. These differences remain as the roadblock between two fundamentally non-compatible systems. This paper will not extensively review the existing microfluidic sensors and actuators; rather, we will discuss the sources of the gaps for integration. We will also introduce system interface technologies for bridging the differences to lead toward paradigm shifts in diagnostics and therapeutics.
References
[1]
Ho, C.M. Micro-Nano Technology Systems for Biomedical Applications: Microfluids, Optics & Surface Chemistry; Oxford University Press Inc.: New York, NY, USA, 2010.
[2]
Ottino, J.M. Complex systems. AIChE J. 2004, 49, 292–299, doi:10.1002/aic.690490202.
[3]
Parrish, J.K.; Edelstein-Keshet, L. Complexity, pattern, and evolutionary trade-offs in animal aggregation. Science 1999, 284, 99–101, doi:10.1126/science.284.5411.99.
[4]
Weng, G.; Bhalla, U.S.; Iyengar, R. Complexity in biological signaling systems. Science 1999, 284, 92–96, doi:10.1126/science.284.5411.92.
[5]
Misteli, T. The concept of self-organization in cellular architecture. J. Cell Biol. 2001, 155, 181–186, doi:10.1083/jcb.200108110.
[6]
Loscalzo, J. Systems biology and personalized medicine a network approach to human disease. Proc. Am. Thorac. Soc. 2011, 8, 196–198, doi:10.1513/pats.201006-041MS.
[7]
Loscalzo, J.; Barabasi, A.L. Systems biology and the future of medicine. WIREs Syst. Biol. Med. 2011, 3, 619–627, doi:10.1002/wsbm.144.
[8]
Manz, A.; Graber, N.; Widmer, H. Miniaturized total chemical analysis systems: A novel concept for chemical sensing. Sens. Actuator. B Chem. 1990, 1, 244–248, doi:10.1016/0925-4005(90)80209-I.
[9]
Liu, J.; Tai, Y.C.; Pong, K.C.; Ho, C.M. Micromachined Channel/Pressure Sensor Systems for Micro Flow Studies. In Proceedings of the 7th International Conference on Solid-State Sensors and Actuators (Transducers '93), Yokohama, Japan, 7–10 June 1993; pp. 995–997.
[10]
Brenner, S.; Johnson, M.; Bridgham, J.; Golda, G.; Lloyd, D.H.; Johnson, D.; Luo, S.; McCurdy, S.; Foy, M.; Ewan, M. Gene expression analysis by massively parallel signature sequencing (mpss) on microbead arrays. Nat. Biotechnol. 2000, 18, 630–634.
[11]
Grody, W.W.; Nakamura, R.M.; Kiechle, F.L. Molecular Diagnostics: Techniques and Applications for the Clinical Laboratory; Academic Press: London, UK, 2010.
[12]
Pushkarev, D.; Neff, N.F.; Quake, S.R. Single-molecule sequencing of an individual human genome. Nat. Biotechnol. 2009, 27, 847–850, doi:10.1038/nbt.1561.
[13]
Patani, G.A.; LaVoie, E.J. Bioisosterism: A rational approach in drug design. Chem. Rev. 1996, 96, 3147–3176, doi:10.1021/cr950066q.
[14]
Nolan, G.P. What’s wrong with drug screening today. Nat. Chem. Biol. 2007, 3, 187–191, doi:10.1038/nchembio0407-187.
[15]
Barabási, A.L. Network medicine—From obesity to the “diseasome”. NEJM 2007, 357, 404–407, doi:10.1056/NEJMe078114.
[16]
Barabási, A.L.; Gulbahce, N.; Loscalzo, J. Network medicine: A network-based approach to human disease. Nat. Rev. Genet. 2011, 12, 56–68, doi:10.1038/nrg2918.
[17]
Pawson, T.; Linding, R. Network medicine. FEBS Lett. 2008, 582, 1266–1270, doi:10.1016/j.febslet.2008.02.011.
[18]
Del Sol, A.; Balling, R.; Hood, L.; Galas, D. Diseases as network perturbations. Curr. Opin. Biotechnol. 2010, 21, 566–571, doi:10.1016/j.copbio.2010.07.010.
[19]
Hood, L.; Heath, J.R.; Phelps, M.E.; Lin, B. Systems biology and new technologies enable predictive and preventative medicine. Science 2004, 306, 640–643, doi:10.1126/science.1104635.
[20]
Weston, A.D.; Hood, L. Systems biology, proteomics, and the future of health care: Toward predictive, preventative, and personalized medicine. J. Proteome Res. 2004, 3, 179–196, doi:10.1021/pr0499693.
[21]
Ho, D.; Ho, C.M. System control-mediated drug delivery towards complex systems via nanodiamond carriers. IJSNM 2010, 1, 69–81.
Wong, P.K.; Yu, F.; Shahangian, A.; Cheng, G.; Sun, R.; Ho, C.M. Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm. Proc. Natl. Acad. Sci. USA 2008, 105, 5105–5110.
[24]
Ding, X.; Sanchez, D.J.; Shahangian, A.; Al-Shyoukh, I.; Cheng, G.; Ho, C.M. Cascade search for hsv-1 combinatorial drugs with high antiviral efficacy and low toxicity. Int. J. Nanomedicine 2012, 7, 2281–2292.
[25]
Tsutsui, H.; Valamehr, B.; Hindoyan, A.; Qiao, R.; Ding, X.; Guo, S.; Witte, O.N.; Liu, X.; Ho, C.M.; Wu, H. An optimized small molecule inhibitor cocktail supports long-term maintenance of human embryonic stem cells. Nat. Commun. 2011, 2, doi:10.1038/ncomms1165.
[26]
Whitesides, G.M. The origins and the future of microfluidics. Nature 2006, 442, 368–373, doi:10.1038/nature05058.
[27]
Squires, T.M.; Quake, S.R. Microfluidics: Fluid physics at the nanoliter scale. Rev. Mod. Phys. 2005, 77, 977–1026, doi:10.1103/RevModPhys.77.977.
[28]
Beebe, D.J.; Mensing, G.A.; Walker, G.M. Physics and applications of microfluidics in biology. Annu. Rev. Biomed. Eng. 2002, 4, 261–286, doi:10.1146/annurev.bioeng.4.112601.125916.
Yeo, L.Y.; Chang, H.C.; Chan, P.P.Y.; Friend, J.R. Microfluidic devices for bioapplications. Small 2011, 7, 12–48, doi:10.1002/smll.201000946.
[31]
Ho, C.M. Fluidics—The Link between Micro and Nano Sciences and Technologies. In Proceedings of the 14th IEEE International Conference on Micro Electro Mechanical Systems, (MEMS 2001), Interlaken, Switzerland, 21–25 January 2001; pp. 375–384.
[32]
Ho, C.M.; Tai, Y.C. Micro-electro-mechanical-systems (MEMS) and fluid flows. Annu. Rev. Fluid Mech. 1998, 30, 579–612, doi:10.1146/annurev.fluid.30.1.579.
[33]
Haeberle, S.; Roth, G.; von Stetten, F.; Zengerle, R. Microfluidic lab-on-a-chip platforms: Requirements, characteristics and applications. Chem. Soc. Rev. 2010, 39, 1153–1182.
[34]
Stone, H.A.; Stroock, A.D.; Ajdari, A. Engineering flows in small devices. Annu. Rev. Fluid Mech. 2004, 36, 381–411, doi:10.1146/annurev.fluid.36.050802.122124.
[35]
Oh, K.W.; Ahn, C.H. A review of microvalves. J. Micromech. Microeng. 2006, 16, R13–R39, doi:10.1088/0960-1317/16/5/R01.
[36]
Kovacs, G.T.A. Micromachined Transducers Sourcebook; WCB/McGraw-Hill: New York, NY, USA, 1998.
[37]
Duffy, D.C.; McDonald, J.C.; Schueller, O.J.A.; Whitesides, G.M. Rapid prototyping of microfluidic systems in poly (dimethylsiloxane). Anal. Chem. 1998, 70, 4974–4984, doi:10.1021/ac980656z.
[38]
Laser, D.; Santiago, J. A review of micropumps. J. Micromech. Microeng. 2004, 14, R35–R64, doi:10.1088/0960-1317/14/6/R01.
[39]
Fox, M.; Esveld, D.; Valero, A.; Luttge, R.; Mastwijk, H.; Bartels, P.; van den Berg, A.; Boom, R. Electroporation of cells in microfluidic devices: A review. Anal. Bioanal. Chem. 2006, 385, 474–485, doi:10.1007/s00216-006-0327-3.
[40]
Wilson, S.A.; Jourdain, R.P.J.; Zhang, Q.; Dorey, R.A.; Bowen, C.R.; Willander, M.; Wahab, Q.U.; Al-hilli, S.M.; Nur, O.; Quandt, E. New materials for micro-scale sensors and actuators: An engineering review. Mater. Sci. Eng. R Rep. 2007, 56, 1–129.
[41]
Anderson, J.R.; Chiu, D.T.; Wu, H.; Schueller, O.J.A.; Whitesides, G.M. Fabrication of microfluidic systems in poly (dimethylsiloxane). Electrophoresis 2000, 21, 27–40, doi:10.1002/(SICI)1522-2683(20000101)21:1<27::AID-ELPS27>3.0.CO;2-C.
[42]
Nguyen, N.T.; Wu, Z. Micromixers—A review. J. Micromech. Microeng. 2004, 15, R1–R16, doi:10.1088/0960-1317/15/2/R01.
[43]
Kuswandi, B.; Huskens, J.; Verboom, W. Optical sensing systems for microfluidic devices: A review. Anal. Chim. Acta 2007, 601, 141–155, doi:10.1016/j.aca.2007.08.046.
[44]
Melin, J.; Quake, S.R. Microfluidic large-scale integration: The evolution of design rules for biological automation. Annu. Rev. Biophys. Biomol. Struct. 2007, 36, 213–231, doi:10.1146/annurev.biophys.36.040306.132646.
[45]
De Jong, J.; Lammertink, R.; Wessling, M. Membranes and microfluidics: A review. Lab Chip 2006, 6, 1125–1139, doi:10.1039/b603275c.
[46]
Congreve, M.; Murray, C.W.; Blundell, T.L. Keynote review: Structural biology and drug discovery. Drug Discov. Today 2005, 10, 895–907, doi:10.1016/S1359-6446(05)03484-7.
[47]
Debouck, C.; Goodfellow, P.N. DNA microarrays in drug discovery and development. Nat. Genet. 1999, 21, 48–50, doi:10.1038/4475.
[48]
Drews, J. Drug discovery: A historical perspective. Science 2000, 287, 1960–1964, doi:10.1126/science.287.5460.1960.
[49]
Schreiber, S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000, 287, 1964–1969, doi:10.1126/science.287.5460.1964.
[50]
Butcher, E.C.; Berg, E.L.; Kunkel, E.J. Systems biology in drug discovery. Nat. Biotechnol. 2004, 22, 1253–1259, doi:10.1038/nbt1017.
[51]
Wong, T.S.; Brough, B.; Ho, C.M. Creation of functional micro/nano systems through top-down and bottom-up approaches. Mol. Cell. Biomech. (MCB) 2009, 6, 1–55.
Wei, F.; Lillehoj, P.B.; Ho, C.M. DNA diagnostics: Nanotechnology-enhanced electrochemical detection of nucleic acids. Pediat. Res. 2010, 67, 458–468, doi:10.1203/PDR.0b013e3181d361c3.
[54]
Wei, F.; Liao, W.; Xu, Z.; Yang, Y.; Wong, D.T.; Ho, C.M. Bio/abiotic interface constructed from nanoscale DNA dendrimer and conducting polymer for ultrasensitive biomolecular diagnosis. Small 2009, 5, 1784–1790, doi:10.1002/smll.200900369.
[55]
Liu, X.; Tan, W. A fiber-optic evanescent wave DNA biosensor based on novel molecular beacons. Anal. Chem. 1999, 71, 5054–5059, doi:10.1021/ac990561c.
[56]
Sekar, R.B.; Periasamy, A. Fluorescence resonance energy transfer (fret) microscopy imaging of live cell protein localizations. J. Cell Biol. 2003, 160, 629–633, doi:10.1083/jcb.200210140.
[57]
Trelles, O.; Prins, P.; Snir, M.; Jansen, R.C. Big data, but are we ready? Nat. Rev. Genet. 2011, 12, 224–224, doi:10.1038/nrg2857-c1.
Schadt, E.E.; Turner, S.; Kasarskis, A. A window into third-generation sequencing. Hum. Mol. Genet. 2010, 19, R227–R240, doi:10.1093/hmg/ddq416.
[60]
Chen, C.H.; Lu, Y.; Sin, M.L.Y.; Mach, K.E.; Zhang, D.D.; Gau, V.; Liao, J.C.; Wong, P.K. Antimicrobial susceptibility testing using high surface-to-volume ratio microchannels. Anal. Chem. 2010, 82, 1012–1019.
[61]
Szita, N.; Polizzi, K.; Jaccard, N.; Baganz, F. Microfluidic approaches for systems and synthetic biology. Curr. Opin. Biotechnology 2010, 21, 517–523.
[62]
Lander, E.S.; Linton, L.M.; Birren, B.; Nusbaum, C.; Zody, M.C.; Baldwin, J.; Devon, K.; Dewar, K.; Doyle, M.; FitzHugh, W. Initial sequencing and analysis of the human genome. Nature 2001, 409, 860–921, doi:10.1038/35057062.
[63]
Collins, F.S.; McKusick, V.A. Implications of the human genome project for medical science. JAMA 2001, 285, 540–544, doi:10.1001/jama.285.5.540.
[64]
Bras, J.; Guerreiro, R.; Hardy, J. Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. Nat. Rev. Neurosci. 2012, 13, 453–464, doi:10.1038/nrn3271.
[65]
Cirulli, E.T.; Goldstein, D.B. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat. Rev. Genet. 2010, 11, 415–425, doi:10.1038/nrg2779.
Mardis, E.R. A decade’s perspective on DNA sequencing technology. Nature 2011, 470, 198–203, doi:10.1038/nature09796.
[68]
Branton, D.; Deamer, D.W.; Marziali, A.; Bayley, H.; Benner, S.A.; Butler, T.; Di Ventra, M.; Garaj, S.; Hibbs, A.; Huang, X. The potential and challenges of nanopore sequencing. Nat. Biotechnol. 2008, 26, 1146–1153.
[69]
Carlson, B. SNPs—A Shortcut to Personalized Medicine. Available online: http://www.genengnews.com/gen-articles/snps-a-shortcut-to-personalized-medicine/2507/ (accessed on 10 December 2012).
[70]
Syvanen, A. Accessing genetic variation: Genotyping single nucleotide polymorphisms. Nature Rev. Genet. 2001, 2, 930–942, doi:10.1038/35103535.
[71]
Sochol, R.; Mahajerin, A.; Casavant, B.; Singh, P.; Dueck, M.; Lee, L.; Lin, L. Bead-Immobilized Molecular Beacons for High Throughput Snp Genotyping via a Microfluidic System. In Proceedings of IEEE 22nd International Conference on Micro Electro Mechanical Systems (MEMS 2009), Sorrento, Italy, 25–29 January 2009; pp. 304–307.
[72]
Cheng, I.F.; Senapati, S.; Cheng, X.; Basuray, S.; Chang, H.C. A rapid field-use assay for mismatch number and location of hybridized dnas. Lab Chip 2010, 10, 828–831, doi:10.1039/b925854j.
[73]
Altshuler, D.M.; Lander, E.S.; Ambrogio, L.; Bloom, T.; Cibulskis, K.; Fennell, T.J.; Gabriel, S.B.; Jaffe, D.B.; Shefler, E.; Sougnez, C.L. A map of human genome variation from population scale sequencing. Nature 2010, 467, 1061–1073, doi:10.1038/nature09534.
[74]
Wheeler, D.A.; Srinivasan, M.; Egholm, M.; Shen, Y.; Chen, L.; McGuire, A.; He, W.; Chen, Y.J.; Makhijani, V.; Roth, G.T. The complete genome of an individual by massively parallel DNA sequencing. Nature 2008, 452, 872–876, doi:10.1038/nature06884.
[75]
Mill, J.; Tang, T.; Kaminsky, Z.; Khare, T.; Yazdanpanah, S.; Bouchard, L.; Jia, P.; Assadzadeh, A.; Flanagan, J.; Schumacher, A. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am. J. Hum. Genet. 2008, 82, 696–711, doi:10.1016/j.ajhg.2008.01.008.
[76]
Esteller, M.; Herman, J.G. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J. Pathol. 2001, 196, 1–7, doi:10.1002/path.1024.
[77]
Wang, C.; Hsu, K.; Chou, C.; Lee, G. Enzyme Digestion-Based Microfluidic System for DNA Methylation Assay. In Proceedings of IEEE 25th International Conference on Micro Electro Mechanical Systems (MEMS 2012), Paris, France, 29 January–2 February 2012; pp. 985–988.
[78]
Cerf, A.; Cipriany, B.R.; Beni？tez, J.J.; Craighead, H.G. Single DNA molecule patterning for high-throughput epigenetic mapping. Anal. Chem. 2011, 83, 8073–8077, doi:10.1021/ac202506j.
[79]
Beane, J.; Vick, J.; Schembri, F.; Anderlind, C.; Gower, A.; Campbell, J.; Luo, L.; Zhang, X.H.; Xiao, J.; Alekseyev, Y.O. Characterizing the impact of smoking and lung cancer on the airway transcriptome using RNA-seq. Cancer Prev. Res. 2011, 4, 803–817, doi:10.1158/1940-6207.CAPR-11-0212.
[80]
Yeoh, E.J.; Ross, M.E.; Shurtleff, S.A.; Williams, W.K.; Patel, D.; Mahfouz, R.; Behm, F.G.; Raimondi, S.C.; Relling, M.V.; Patel, A. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002, 1, 133–144, doi:10.1016/S1535-6108(02)00032-6.
[81]
Van’t Veer, L.J.; Dai, H.; van de Vijver, M.J.; He, Y.D.; Hart, A.A.M.; Mao, M.; Peterse, H.L.; van der Kooy, K.; Marton, M.J.; Witteveen, A.T. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415, 530–536.
[82]
Moore, D.F.; Li, H.; Jeffries, N.; Wright, V.; Cooper, R.A., Jr.; Elkahloun, A.; Gelderman, M.P.; Zudaire, E.; Blevins, G.; Yu, H. Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke. Circulation 2005, 111, 212–221, doi:10.1161/01.CIR.0000152105.79665.C6.
[83]
Wang, Z.; Gerstein, M.; Snyder, M. RNA-seq: A revolutionary tool for transcriptomics. Nature Rev. Genet. 2009, 10, 57–63, doi:10.1038/nrg2484.
[84]
Marioni, J.C.; Mason, C.E.; Mane, S.M.; Stephens, M.; Gilad, Y. RNA-seq: An assessment of technical reproducibility and comparison with gene expression arrays. Genome Res. 2008, 18, 1509–1517, doi:10.1101/gr.079558.108.
[85]
Sachidanandam, R.; Weissman, D.; Schmidt, S.C.; Kakol, J.M.; Stein, L.D.; Marth, G.; Sherry, S.; Mullikin, J.C.; Mortimore, B.J.; Willey, D.L. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001, 409, 928–933.
[86]
Jimenez-Sanchez, G.; Childs, B.; Valle, D. Human disease genes. Nature 2001, 409, 853–855, doi:10.1038/35057050.
[87]
Hirschhorn, J.N.; Daly, M.J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 2005, 6, 95–108, doi:10.1038/nrg1521.
[88]
Goh, K.I.; Cusick, M.E.; Valle, D.; Childs, B.; Vidal, M.; Barabási, A.L. The human disease network. Proc. Natl. Acad. Sci. USA 2007, 104, 8685–8690.
[89]
Liu, P.; Mathies, R.A. Integrated microfluidic systems for high-performance genetic analysis. Trends Biotech. 2009, 27, 572–581, doi:10.1016/j.tibtech.2009.07.002.
[90]
Collins, F.; Galas, D. A New Five-Year Plan for the US Human Genome Project. Available online: http://ww.esp.org/misc/genome/goals.pdf (accessed on 10 December 2012).
[91]
Bentley, D.R. The human genome project—An overview. Med. Res. Rev. 2000, 20, 189–196, doi:10.1002/(SICI)1098-1128(200005)20:3<189::AID-MED2>3.0.CO;2-#.
[92]
Shendure, J.; Ji, H. Next-generation DNA sequencing. Nat. Biotechnol. 2008, 26, 1135–1145, doi:10.1038/nbt1486.
[93]
Eid, J.; Fehr, A.; Gray, J.; Luong, K.; Lyle, J.; Otto, G.; Peluso, P.; Rank, D.; Baybayan, P.; Bettman, B. Real-time DNA sequencing from single polymerase molecules. Science 2009, 323, 133–138.
[94]
Schneider, G.F.; Dekker, C. DNA sequencing with nanopores. Nat. Biotechnol. 2012, 30, 326–328, doi:10.1038/nbt.2181.
[95]
Venkatesan, B.M.; Bashir, R. Nanopore sensors for nucleic acid analysis. Nat. Nanotechnol. 2011, 6, 615–624.
[96]
Church, G.; Deamer, D.W.; Branton, D.; Baldarelli, R.; Kasianowicz, J. Characterization of Individual Polymer Molecules Based on Monomer-Interface Interactions. U.S. Patent 5,795,782, August 1998.
[97]
Dekker, C. Solid-state nanopores. Nat. Nanotechnol. 2007, 2, 209–215, doi:10.1038/nnano.2007.27.
[98]
Rhee, M.; Burns, M.A. Nanopore sequencing technology: Research trends and applications. Trends Biotech. 2006, 24, 580–586, doi:10.1016/j.tibtech.2006.10.005.
[99]
Levene, M.J.; Korlach, J.; Turner, S.W.; Foquet, M.; Craighead, H.G.; Webb, W.W. Zero-mode waveguides for single-molecule analysis at high concentrations. Science 2003, 299, 682–686, doi:10.1126/science.1079700.
[100]
Flusberg, B.A.; Webster, D.R.; Lee, J.H.; Travers, K.J.; Olivares, E.C.; Clark, T.A.; Korlach, J.; Turner, S.W. Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat. Methods 2010, 7, 461–465, doi:10.1038/nmeth.1459.
Ingolia, N.T.; Ghaemmaghami, S.; Newman, J.R.S.; Weissman, J.S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 2009, 324, 218–223, doi:10.1126/science.1168978.
[103]
Heller, M.J. DNA microarray technology: Devices, systems, and applications. Annu. Rev. Biomed. Eng. 2002, 4, 129–153, doi:10.1146/annurev.bioeng.4.020702.153438.
[104]
Wang, L.; Li, P.C.H. Microfluidic DNA microarray analysis: A review. Anal. Chim. Acta 2011, 687, 12–27, doi:10.1016/j.aca.2010.11.056.
Martins, S.; Prazeres, D.; Fonseca, L.; Monteiro, G. Application of central composite design for DNA hybridization onto magnetic microparticles. Anal. Biochem. 2009, 391, 17–23, doi:10.1016/j.ab.2009.05.006.
[107]
Gabig-Ciminska, M.; Holmgren, A.; Andresen, H.; Bundvig Barken, K.; Wümpelmann, M.; Albers, J.; Hintsche, R.; Breitenstein, A.; Neubauer, P.; Los, M. Electric chips for rapid detection and quantification of nucleic acids. Biosens. Bioelectron. 2004, 19, 537–546, doi:10.1016/S0956-5663(03)00273-2.
[108]
Chang, H.C. Nanobead electrokinetics: The enabling microfluidic platform for rapid multi-target pathogen detection. AICHE J. 2007, 53, 2486–2492, doi:10.1002/aic.11286.
[109]
Anderson, N.L.; Anderson, N.G. The human plasma proteome history, character, and diagnostic prospects. Mol. Cell. Proteomics 2002, 1, 845–867, doi:10.1074/mcp.R200007-MCP200.
[110]
Gygi, S.P.; Rochon, Y.; Franza, B.R.; Aebersold, R. Correlation between protein and mrna abundance in yeast. Mol. Cell. Biol. 1999, 19, 1720–1730.
[111]
Jiang, Y.; Wang, P.C.; Locascio, L.E.; Lee, C.S. Integrated plastic microfluidic devices with ESI-MS for drug screening and residue analysis. Anal. Chem. 2001, 73, 2048–2053, doi:10.1021/ac001474j.
[112]
Wheeler, A.R.; Moon, H.; Bird, C.A.; Loo, R.R.O.; Kim, C.J.; Loo, J.A.; Garrell, R.L. Digital microfluidics with in-line sample purification for proteomics analyses with MALDI-MS. Anal. Chem. 2005, 77, 534–540.
[113]
Wheeler, A.R.; Moon, H.; Kim, C.J.; Loo, J.A.; Garrell, R.L. Electrowetting-based microfluidics for analysis of peptides and proteins by matrix-assisted laser desorption/ionization mass spectrometry. Anal. Chem. 2004, 76, 4833–4838.
Lee, J.; Soper, S.A.; Murray, K.K. Microfluidic chips for mass spectrometry-based proteomics. J. Mass Spectrom. 2009, 44, 579–593.
[116]
Biemann, K. Mass spectrometry of peptides and proteins. Annu. Rev. Biochem. 1992, 61, 977–1010, doi:10.1146/annurev.bi.61.070192.004553.
[117]
Zhu, H.; Snyder, M. Protein chip technology. Curr. Opin. Chem. Biol. 2003, 7, 55–63, doi:10.1016/S1367-5931(02)00005-4.
[118]
Phizicky, E.; Bastiaens, P.I.H.; Zhu, H.; Snyder, M.; Fields, S. Protein analysis on a proteomic scale. Nature 2003, 422, 208–215.
[119]
He, M.; Stoevesandt, O.; Taussig, M.J. In situ synthesis of protein arrays. Curr. Opin. Biotechnol. 2008, 19, 4–9.
[120]
Gerber, D.; Maerkl, S.J.; Quake, S.R. An in vitro microfluidic approach to generating protein-interaction networks. Nat. Methods 2008, 6, 71–74, doi:10.1038/nmeth.1289.
[121]
Maerkl, S.J.; Quake, S.R. Experimental determination of the evolvability of a transcription factor. Proc. Natl. Acad. Sci. USA 2009, 106, 18650–18655, doi:10.1073/pnas.0907688106.
[122]
Hartmann, M.; Roeraade, J.; Stoll, D.; Templin, M.F.; Joos, T.O. Protein microarrays for diagnostic assays. Anal. Bioanal. Chem. 2009, 393, 1407–1416, doi:10.1007/s00216-008-2379-z.
[123]
Maerkl, S.J. Next generation microfluidic platforms for high-throughput protein biochemistry. Curr. Opin. Biotechnol. 2011, 22, 59–65, doi:10.1016/j.copbio.2010.08.010.
[124]
Spratlin, J.L.; Serkova, N.J.; Eckhardt, S.G. Clinical applications of metabolomics in oncology: A review. Clin. Cancer Res. 2009, 15, 431–440, doi:10.1158/1078-0432.CCR-08-1059.
[125]
Sreekumar, A.; Poisson, L.M.; Rajendiran, T.M.; Khan, A.P.; Cao, Q.; Yu, J.; Laxman, B.; Mehra, R.; Lonigro, R.J.; Li, Y. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009, 457, 910–914.
[126]
Rubakhin, S.S.; Romanova, E.V.; Nemes, P.; Sweedler, J.V. Profiling metabolites and peptides in single cells. Nat. Methods 2011, 8, S20–S29, doi:10.1038/nmeth.1549.
Perez, O.D.; Nolan, G.P. Phospho-proteomic immune analysis by flow cytometry: From mechanism to translational medicine at the single-cell level. Immunol. Rev. 2006, 210, 208–228, doi:10.1111/j.0105-2896.2006.00364.x.
[139]
Krutzik, P.O.; Trejo, A.; Schulz, K.R.; Nolan, G.P. Phospho flow cytometry methods for the analysis of kinase signaling in cell lines and primary human blood samples. Methods Mol. Biol. 2011, 699, 179–202.
[140]
Perez, O.D. Using phosphoflow？ to study signaling events of subpopulations resistant to current therapies. Targeted Therapies 2011, 95–112, doi:10.1007/978-1-60761-478-4_5.
[141]
Krutzik, P.O.; Irish, J.M.; Nolan, G.P.; Perez, O.D. Analysis of protein phosphorylation and cellular signaling events by flow cytometry: Techniques and clinical applications. Clin. Immunol. 2004, 110, 206–221, doi:10.1016/j.clim.2003.11.009.
[142]
De Rosa, S.C.; Herzenberg, L.A.; Roederer, M. 11-color, 13-parameter flow cytometry: Identification of human naive T cells by phenotype, function, and T-cell receptor diversity. Nat. Med. 2001, 7, 245–248, doi:10.1038/84701.
Galligan, C.L.; Siebert, J.C.; Siminovitch, K.A.; Keystone, E.C.; Bykerk, V.; Perez, O.D.; Fish, E.N. Multiparameter phospho-flow analysis of lymphocytes in early rheumatoid arthritis: Implications for diagnosis and monitoring drug therapy. PloS ONE 2009, 4, doi:10.1371/journal.pone.0006703.
