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Applications of Microfluidic Devices with Mass Spectrometry Detection in Proteomics

  • Xiuli Mao
  • Iulia M. LazarEmail author
Chapter

Abstract

Mass spectrometry (MS) was first used as a detection tool for microfluidic devices in the late nineties (Figeys et al., Anal Chem 69:3153–3160, 1997; Ramsey and Ramsey, Anal Chem 69:1174–1178, 1997; Xue et al., Anal Chem 69:426–430, 1997), and since then, significant efforts have been invested in the further development of efficient microfluidic-MS interfaces and the exploration of microfluidic-MS applicability in biomolecular analysis. Microfluidic devices can be coupled to MS through both electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) interfaces. Both conventional, such as capillary electrophoresis (CE)/high performance liquid chromatography (HPLC) liquid sheath, liquid junction and micro/nano-ESI interfaces, as well as novel interfaces based on unique features enabled by microfabrication, have been developed. Current protein identification protocols proceed through a series of steps that are generally time-consuming and labor-intensive. The development of microfluidic devices with MS detection has facilitated protein analysis by minimizing sample consumption and enabling high-throughput, automatic sample manipulations. In this chapter, the applicability of microfluidic chips with MS detection in proteomics research is reviewed. Applications that focus on protein analysis, including sample pretreatment, proteolytic digestion and separation are described. Recent progress on cell culture and lysis, protein quantitation, and analysis of protein posttranslational modifications is discussed.

Keywords

Microfluidic device Mass spectrometry Proteomics Sample preparation 

Abbreviations

2D

two dimensional

BSA

bovine serum albumin

CD

compact disc

CE

capillary electrophoresis

CEC

capillary electrochromatography

CGE

capillary gel electrophoresis

Cu(II)-IMAC

copper(II)-immobilized metal affinity chromatography

EOF

electroosmotic flow

ESI

electrospray ionization

EWOD

electro-wetting-on-dielectric

HPLC

high performance liquid chromatography

IEF

isoelectric focusing

IMAC

ion immobilized affinity chromatography

iTRAQ

isobaric tags for relative and absolute quantitation

MALDI

matrix-assisted laser desorption ionization

MEKC

micellar electrokinetic chromatography

MS

mass spectrometry

PMMA

poly(methyl methacrylate)

RP

reversed phase

SCX

strong cation exchange

SPE

solid phase extraction

TOFMS

time of flight mass spectrometry

Notes

Acknowledgment

This work was supported by NCI/NIH grant 1R21CA126669-01A1.

References

  1. Abu-Farha, M., Elisma, F., Zhou, H.J., Tian, R.J., Zhou, H., Asmer, M.S., and Figeys, D. (2009). Proteomics: From technology developments to biological applications. Anal Chem 81, 4585–4599.CrossRefGoogle Scholar
  2. Armani, M., Rodriguez-Canales, J., Gillespie, J., Tangrea, M., Erickson, H., Emmert-Buck, M.R., Shapiro, B., and Smela, E. (2009). 2D-PCR: A method of mapping DNA in tissue sections. LOC 9, 3526–3534.Google Scholar
  3. Armenta, J.M., Dawoud, A.A., and Lazar, I.M. (2009). Microfluidic chips for protein differential expression profiling. Electrophoresis 30, 1145–1156.CrossRefGoogle Scholar
  4. Balagadde, F.K., You, L.C., Hansen, C.L., Arnold, F.H., and Quake, S.R. (2005). Long-term monitoring of bacteria undergoing programmed population control in a microchemostat. Science 309, 137–140.CrossRefGoogle Scholar
  5. Bedair, M., and Oleschuk, R.D. (2006). Lectin affinity chromatography using porous polymer monolith assisted nanoelectrospray MS/MS. Analyst 131, 1316–1321.CrossRefGoogle Scholar
  6. Belder, D. (2005). Microfluidics with droplets. Ang Chem Int Edn 44, 3521–3522.CrossRefGoogle Scholar
  7. Bindila, L., Froesch, M., Lion, N., Vukeli, Z., Rossier, J.S., Girault, H.H., Peter-Katalini, J., and Zamfir, A.D. (2004). A thin chip microsprayer system coupled to Fourier transform ion cyclotron resonance mass spectrometry for glycopeptide screening. Rapid Commun Mass Spectrom 18, 2913–2920.CrossRefGoogle Scholar
  8. Brambilla, F., Resta, D., Isak, I., Zanotti, M., and Arnoldi, A. (2009). A label-free internal standard method for the differential analysis of bioactive lupin proteins using nano HPLC-Chip coupled with ion trap mass spectrometry. Proteomics 9, 272–286.CrossRefGoogle Scholar
  9. Callipo, L., Foglia, P., Gubbiotti, R., Samperi, R., and Lagana, A. (2009). HPLC-CHIP coupled to a triple quadrupole mass spectrometer for carbonic anhydrase II quantification in human serum. Anal Bioanal Chem 394, 811–820.CrossRefGoogle Scholar
  10. Chen, W.Z., Shen, J., Yin, X.F., and Yu, Y.N. (2007). Optimization of microfabricated nanoliter-scale solid-phase extraction device for detection of gel-separated proteins in low abundance by matrix-assisted laser desorption/ionization mass spectrometry. Rapid Commun Mass Spectrom 21, 35–43.CrossRefGoogle Scholar
  11. Chu, C.S., Ninonuevo, M.R., Clowers, B.H., Perkins, P.D., An, H.J., Yin, H.F., Killeen, K., Miyamoto, S., Grimm, R., and Lebrilla, C.B. (2009). Profile of native N-linked glycan structures from human serum using high performance liquid chromatography on a microfluidic chip and time-of-flight mass spectrometry. Proteomics 9, 1939–1951.CrossRefGoogle Scholar
  12. Chung, W.J., Kim, M.S., Cho, S., Park, S.S., Kim, J.H., Kim, Y.K., Kim, B.G., and Lee, Y.S. (2005). Microaffinity purification of proteins based on photolytic elution: Toward an efficient microbead affinity chromatography on a chip. Electrophoresis 26, 694–702.CrossRefGoogle Scholar
  13. Dahlin, A.P., Bergstrom, S.K., Andren, P.E., Markides, K.E., and Bergquist, J. (2005). Poly(dimethylsiloxane)-based microchip for two-dimensional solid-phase extraction-capillary electrophoresis with an integrated electrospray emitter tip. Anal Chem 77, 5356–5363.CrossRefGoogle Scholar
  14. Das, C., Zhang, J., Denslow, N.D., and Fan, Z.H. (2007). Integration of isoelectric focusing with multi-channel gel electrophoresis by using microfluidic pseudo-valves. LOC 7, 1806–1812.Google Scholar
  15. Dawoud, A.A., Sarvalyal, H.A., and Lazar, I.M. (2007). Microfluidic platform with mass spectrometry detection for the analysis of phosphoproteins. Electrophoresis 28, 4645–4660.CrossRefGoogle Scholar
  16. Devoe, D.L., and Lee, C.S. (2006). Microfluidic technologies for MALDI-MS in proteomics. Electrophoresis 27, 3559–3568.CrossRefGoogle Scholar
  17. Dolnik, V., and Liu, S. (2005). Applications of capillary electrophoresis on microchip. J Sep Sci 28, 1994–2009.CrossRefGoogle Scholar
  18. Ekstrom, S., Wallman, L., Hok, D., Marko-Varga, G., and Laurell, T. (2006). Miniaturized solid-phase extraction and sample preparation for MALDI MS using a microfabricated integrated selective enrichment target. J Proteome Res 5, 1071–1081.CrossRefGoogle Scholar
  19. El-Ali, J., Gaudet, S., Günther, A., Sorger, P.K., and Jensen, K.F. (2005). Cell stimulus and lysis in a microfluidic device with segmented gas–liquid flow. Anal Chem 77, 3629–3636.CrossRefGoogle Scholar
  20. Ethier, M., Hou, W.M., Duewel, H.S., and Figeys, D. (2006). The proteomic reactor: A microfluidic device for processing minute amounts of protein prior to mass spectrometry analysis. J Proteome Res 5, 2754–2759.CrossRefGoogle Scholar
  21. Fair, R.B. (2007). Digital microfluidics: Is a true lab-on-a-chip possible? Microfluidics Nanofluidics 3, 245–281.CrossRefGoogle Scholar
  22. Fan, H.Z., and Chen, G. (2007). Fiber-packed channel bioreactor for microfluidic protein digestion. Proteomics 7, 3445–3449.CrossRefGoogle Scholar
  23. Figeys, D., and Aebersold, R. (1998). Nanoflow solvent gradient delivery from a microfabricated device for protein identifications by electrospray ionization mass spectrometry. Anal Chem 70, 3721–3727.CrossRefGoogle Scholar
  24. Figeys, D., Gygi, S.P., McKinnon, G., and Aebersold, R. (1998). An integrated microfluidics tandem mass spectrometry system for automated protein analysis. Anal Chem 70, 3728–3734.CrossRefGoogle Scholar
  25. Figeys, D., Ning, Y.B., and Aebersold, R. (1997). A microfabricated device for rapid protein identification by microelectrospray ion trap mass spectrometry. Anal Chem 69, 3153–3160.CrossRefGoogle Scholar
  26. Fonslow, B.R., and Yates, J.R., III (2009). Capillary electrophoresis applied to proteomic analysis. J Sep Sci 32, 1175–1188.CrossRefGoogle Scholar
  27. Foret, F., and Kusy, P. (2006). Microdevices in Mass Spectrometry. Paper presented at: 17th International Mass Spectrometry Conference (Prague, Czech Republic).Google Scholar
  28. Fortier, M.H., Bonneil, E., Goodley, P., and Thibault, P. (2005). Integrated microfluidic device for mass spectrometry-based proteomics and its application to biomarker discovery programs. Anal Chem 77, 1631–1640.CrossRefGoogle Scholar
  29. Ghitun, M., Bonneil, E., Fortier, M.H., Yin, H.F., Killeen, K., and Thibault, P. (2006). Integrated microfluidic devices with enhanced separation performance: Application to phosphoproteome analyses of differentiated cell model systems. J Sep Sci 29, 1539–1549.CrossRefGoogle Scholar
  30. Griebel, A., Rund, S., Schonfeld, F., Dorner, W., Konrad, R., and Hardt, S. (2004). Integrated polymer chip for two-dimensional capillary gel electrophoresis. LOC 4, 18–23.Google Scholar
  31. Gustafsson, M., Hirschberg, D., Palmberg, C., Jornvall, H., and Bergman, T. (2004). Integrated sample preparation and MALDI mass spectrometry on a microfluidic compact disk. Anal Chem 76, 345–350.CrossRefGoogle Scholar
  32. Hardouin, J., Duchateau, M., Joubert-Caron, R., and Caron, M. (2006). Usefulness of an integrated microfluidic device (HPLC-Chip-MS) to enhance confidence in protein identification by proteomics. Rapid Commun Mass Spectrom 20, 3236–3244.CrossRefGoogle Scholar
  33. Herr, A.E., Molho, J.I., Drouvalakis, K.A., Mikkelsen, J.C., Utz, P.J., Santiago, J.G., and Kenny, T.W. (2003). On-chip coupling of isoelectric focusing and free solution electrophoresis for multidimensional separations. Anal Chem 75, 1180–1187.CrossRefGoogle Scholar
  34. Huo, Y., and Kok, W.T. (2008). Recent applications in CEC. Electrophoresis 29, 80–93.CrossRefGoogle Scholar
  35. Ibanez, A.J., Muck, A., and Svatos, A. (2007). Metal-chelating plastic MALDI (pMALDI) chips for the enhancement of phosphorylated-peptide/protein signals. J Proteome Res 6, 3842–3848.CrossRefGoogle Scholar
  36. Inoue, A., Han, A., Makino, K., Hosokawa, K., and Maeda, M. (2009). SNP genotyping of unpurified PCR products by sandwich-type affinity electrophoresis on a microchip with programmed autonomous solution filling. LOC 9, 3297–3302.Google Scholar
  37. Jankovicova, B., Rosnerova, S., Slovakova, M., Zverinova, Z., Hubalek, M., Hernychova, L., Rehulka, P., Viovy, J.L., and Bilkova, Z. (2008). Epitope Mapping of Allergen Ovalbumin Using Biofunctionalized Magnetic Beads Packed in Microfluidic Channels: The First Step Towards Epitope-Based Vaccines. Paper presented at: 22nd International Symposium on Microscale Bioseparations and Methods for Systems Biology (Berlin, Germany).Google Scholar
  38. Jebrail, M.J., and Wheeler, A.R. (2009). Digital microfluidic method for protein extraction by precipitation. Anal Chem 81, 330–335.CrossRefGoogle Scholar
  39. Jensen, K., and Lee, A. (2004). The science & applications of droplets in microfluidic devices. LOC 4, 31 N–32 N.Google Scholar
  40. Jiang, Y., and Lee, C.S. (2001). On-Line Coupling of Micro-enzyme Reactor with Micro-membrane Chromatography for Protein Digestion, Peptide Separation, and Protein Identification Using Electrospray Ionization Mass Spectrometry. Paper presented at: 14th International Symposium on Microscale Separations and Analysis (Boston, MA).Google Scholar
  41. Kim, J., Johnson, M., Hill, P., and Gale, B.K. (2009). Microfluidic sample preparation: Cell lysis and nucleic acid purification. Integr Biol 1, 574–586.CrossRefGoogle Scholar
  42. Koster, S., and Verpoorte, E. (2007). A decade of microfluidic analysis coupled with electrospray mass spectrometry: An overview. LOC 7, 1394–1412.Google Scholar
  43. Krenkova, J., Lacher, N.A., and Svec, F. (2009). Highly efficient enzyme reactors containing trypsin and endoproteinase LysC immobilized on porous polymer monolith coupled to MS suitable for analysis of antibodies. Anal Chem 81, 2004–2012.CrossRefGoogle Scholar
  44. Kutter, J.P., Jacobson, S.C., and Ramsey, J.M. (1999). Solid Phase Extraction on Microfluidic Devices. Paper presented at: 21st International Symposium on Capillary Chromatography and Electrophoresis (Park City, UT).Google Scholar
  45. Lazar, I.M. (2007). Microfluidic Devices with Mass Spectrometry Detection. In Handbook of Capillary and Microchip Electrophoresis and Associated Microtechniques, 3rd Edition, J.P. Landers, ed. (CRC Press, New York, NY), pp 1459–1506 13th Dec 2007.Google Scholar
  46. Lazar, I.M. (2009). Recent advances in capillary and microfluidic platforms with MS detection for the analysis of phosphoproteins. Electrophoresis 30, 262–275.CrossRefGoogle Scholar
  47. Lazar, I.M., Grym, J., and Foret, F. (2006a). Microfabricated devices: A new sample introduction approach to mass spectrometry. Mass Spectrom Rev 25, 573–594.CrossRefGoogle Scholar
  48. Lazar, I.M., and Karger, B.L. (2003a). Microchip Integrated Separation Systems for Proteomic Applications. 51th Conference on Mass Spectrometry and Allied Topics (Montreal, QC).Google Scholar
  49. Lazar, I.M., and Karger, B.L. (2002). Multiple open-channel electroosmotic pumping system for microfluidic sample handling. Anal Chem 74, 6259–6268.Google Scholar
  50. Lazar, I.M., Li, L.J., Yang, Y., and Karger, B.L. (2003b). Microfluidic device for capillary electrochromatography-mass spectrometry. Electrophoresis 24, 3655–3662.CrossRefGoogle Scholar
  51. Lazar, I.M., Ramsey, R.S., and Ramsey, J.M. (2001). On-chip proteolytic digestion and analysis using “wrong-way-round” electrospray time-of-flight mass spectrometry. Anal Chem 73, 1733–1739.CrossRefGoogle Scholar
  52. Lazar, I.M., Trisiripisal, P., and Sarvaiya, H.A. (2006b). Microfluidic liquid chromatography system for proteomic applications and biomarker screening. Anal Chem 78, 5513–5524.CrossRefGoogle Scholar
  53. Le Nel, A., Krenkova, J., Kleparnik, K., Smadja, C., Taverna, M., Viovy, J.L., and Foret, F. (2008). On-chip tryptic digest with direct coupling to ESI-MS using magnetic particles. Electrophoresis 29, 4944–4947.CrossRefGoogle Scholar
  54. Lee, E.Z., Huh, Y.S., Jun, Y.-S., Won, H.J., Hong, Y.K., Park, T.J., Lee, S.Y., and Hong, W.H. (2008a). Removal of bovine serum albumin using solid-phase extraction with in-situ polymerized stationary phase in a microfluidic device. J Chromatogr, A 1187, 11–17.CrossRefGoogle Scholar
  55. Lee, J., Musyimi, H.K., Soper, S.A., and Murray, K.K. (2008b). Development of an automated digestion and droplet deposition microfluidic chip for MALDI-TOF MS. J Am Soc Mass Spectrom 19, 964–972.CrossRefGoogle Scholar
  56. Levkin, P.A., Eeltink, S., Stratton, T.R., Brennen, R., Robotti, K., Yin, H., Killeen, K., Svec, F., and Frechet, J.M.J. (2007). Monolithic Porous Polymer Stationary Phases in Polyimide Chips for the Fast High-Performance Liquid Chromatography Separation of Proteins and Peptides. Paper presented at: 31st International Symposium on Capillary Chromatography (Albuquerque, NM).Google Scholar
  57. Li, J.J., LeRiche, T., Tremblay, T.L., Wang, C., Bonneil, E., Harrison, D.J., and Thibault, P. (2002). Application of microfluidic devices to proteomics research – identification of trace-level protein digests and affinity capture of target peptides. Mol Cell Proteomic 1, 157–168.CrossRefGoogle Scholar
  58. Li, Y., Buch, J.S., Rosenberger, F., DeVoe, D.L., and Lee, C.S. (2004). Integration of isoelectric focusing with parallel sodium dodecyl sulfate gel electrophoresis for multidimensional protein separations in a plastic microfluidic network. Anal Chem 76, 742–748.CrossRefGoogle Scholar
  59. Liu, J., Chen, C.-F., Tsao, C.-W., Chang, C.-C., Chu, C.-C., and De Voe, D.L. (2009a). Polymer microchips integrating solid-phase extraction and high-performance liquid chromatography using reversed-phase polymethacrylate monoliths. Anal Chem 81, 2545–2554.CrossRefGoogle Scholar
  60. Liu, J.K., Yang, S., Lee, C.S., and Devoe, D.L. (2008). Polyacrylamide gel plugs enabling 2-D microfluidic protein separations via isoelectric focusing and multiplexed sodium dodecyl sulfate gel electrophoresis. Electrophoresis 29, 2241–2250.CrossRefGoogle Scholar
  61. Liu, T., Wang, S., and Chen, G. (2009b). Immobilization of trypsin on silica-coated fiberglass core in microchip for highly efficient proteolysis. Talanta 77, 1767–1773.CrossRefGoogle Scholar
  62. Liu, Y., Lu, H.J., Zhong, W., Song, P.Y., Kong, J.L., Yang, P.Y., Girault, H.H., and Liu, B.H. (2006). Multi layer-assembled microchip for enzyme immobilization as reactor toward low-level protein identification. Anal Chem 78, 801–808.CrossRefGoogle Scholar
  63. Mao, X.L., Chu, I.K., and Lin, B.C. (2006). A sheath-flow nanoelectrospray interface of microchip electrophoresis MS for glycoprotein and glycopeptide analysis. Electrophoresis 27, 5059–5067.CrossRefGoogle Scholar
  64. Meyvantsson, I., and Beebe, D.J. (2008). Cell culture models in microfluidic systems. Annu Rev Anal Chem 1, 423–449.CrossRefGoogle Scholar
  65. Mogensen, K.B., Klank, H., and Kutter, J.P. (2004). Recent developments in detection for microfluidic systems. Electrophoresis 25, 3498–3512.CrossRefGoogle Scholar
  66. Mohammed, S., Kraiczek, K., Pinkse, M.W. H., Lemeer, S., Benschop, J.J., and Heck, A.J. R. (2008). Chip-based enrichment and NanoLC-MS/MS analysis of phosphopeptides from whole lysates. J Proteome Res 7, 1565–1571.CrossRefGoogle Scholar
  67. Moon, H., Wheeler, A.R., Garrell, R.L., Loo, J.A., and Kim, C.J. (2006). An integrated digital microfluidic chip for multiplexed proteomic sample preparation and analysis by MALDI-MS. LOC 6, 1213–1219.Google Scholar
  68. Nedelkov, D., and Nelson, R.W. (2006). New and Emerging Proteomic Techniques (Totowa, NJ, Humana Press).Google Scholar
  69. Oleschuk, R.D., Shultz-Lockyear, L.L., Ning, Y.B., and Harrison, D.J. (2000). Trapping of bead-based reagents within microfluidic systems: On-chip solid-phase extraction and electrochromatography. Anal Chem 72, 585–590.CrossRefGoogle Scholar
  70. Osiri, J.K., Shadpour, H., Park, S., Snowden, B.C., Chen, Z.Y., and Soper, S.A. (2008). Generating high peak capacity 2-D maps of complex proteomes using PMMA microchip electrophoresis. Electrophoresis 29, 4984–4992.CrossRefGoogle Scholar
  71. Peterson, D.S., Rohr, T., Svec, F., and Frechet, J.M.J. (2003). Dual-function microanalytical device by in situ photolithographic grafting of porous polymer monolith: Integrating solid-phase extraction and enzymatic digestion for peptide mass mapping. Anal Chem 75, 5328–5335.CrossRefGoogle Scholar
  72. Prudent, M., Rossier, J.S., Lion, N., and Girault, H.H. (2008). Microfabricated dual sprayer for on-line mass tagging of phosphopeptides. Anal Chem 80, 2531–2538.CrossRefGoogle Scholar
  73. Qiao, L., Roussel, C., Wan, J.J., Yang, P.Y., Girault, H.H., and Liu, B.H. (2007). Specific on-plate enrichment of phosphorylated peptides for direct MALDI-TOF MS analysis. J Proteome Res 6, 4763–4769.CrossRefGoogle Scholar
  74. Qu, H.Y., Wang, H.T., Huang, Y., Zhong, W., Lu, H.J., Kong, J.L., Yang, P.Y., and Liu, B.H. (2004). Stable microstructured network for protein patterning on a plastic microfluidic channel: Strategy and characterization of on-chip enzyme microreactors. Anal Chem 76, 6426–6433.CrossRefGoogle Scholar
  75. Ramsey, J.D., and Collins, G.E. (2005). Integrated microfluidic device for solid-phase extraction coupled to micellar electrokinetic chromatography separation. Anal Chem 77, 6664–6670.CrossRefGoogle Scholar
  76. Ramsey, J.D., Jacobson, S.C., Culbertson, C.T., and Ramsey, J.M. (2003). High-efficiency, two-dimensional separations of protein digests on microfluidic devices. Anal Chem 75, 3758–3764.CrossRefGoogle Scholar
  77. Ramsey, R.S., and Ramsey, J.M. (1997). Generating electrospray from microchip devices using electroosmotic pumping. Anal Chem 69, 1174–1178.CrossRefGoogle Scholar
  78. Shi, Y. (2006). DNA sequencing and multiplex STR analysis on plastic microfluidic devices. Electrophoresis 27, 3703–3711.CrossRefGoogle Scholar
  79. Slentz, B.E., Penner, N.A., and Regnier, F.E. (2003). Protein proteolysis and the multi-dimensional electrochromatographic separation of histidine-containing peptide fragments on a chip. J Chromatogr A 984, 97–107.CrossRefGoogle Scholar
  80. Slovakova, M., Minc, N., Bilkova, Z., Smadja, C., Faigle, W., Futterer, C., Taverna, M., and Viovy, J.L. (2005). Use of self assembled magnetic beads for on-chip protein digestion. LOC 5, 935–942.Google Scholar
  81. Sommer, G.J., and Hatch, A.V. (2009). IEF in microfluidic devices. Electrophoresis 30, 742–757.CrossRefGoogle Scholar
  82. Srbek, J., Eickhoff, J., Effelsberg, U., Kraiczek, K., van de Goor, T., and Coufal, P. (2007). Chip-based nano-LC-MS/MS identification of proteins in complex biological samples using a novel polymer microfluidic device. J Sep Sci 30, 2046–2052.CrossRefGoogle Scholar
  83. Sung, W.C., Makamba, H., and Chen, S.H. (2005). Chip-based microfluidic devices coupled with electrospray ionization-mass spectrometry. Electrophoresis 26, 1783–1791.CrossRefGoogle Scholar
  84. Teh, S.Y., Lin, R., Hung, L.H., and Lee, A.P. (2008). Droplet microfluidics. LOC 8, 198–220.Google Scholar
  85. Tia, S., and Herr, A.E. (2009). On-chip technologies for multidimensional separations. LOC 9, 2524–2536.Google Scholar
  86. Uchiyama, K., Nakajima, H., and Hobo, T. (2004). Detection method for microchip separations. Anal Bioanal Chem 379, 375–382.CrossRefGoogle Scholar
  87. Vasilescu, J., Zweitzig, D.R., Denis, N.J., Smith, J.C., Ethier, M., Haines, D.S., and Figeys, D. (2007). The proteomic reactor facilitates the analysis of affinity-purified proteins by mass spectrometry: Application for identifying ubiquitinated proteins in human cells. J Proteome Res 6, 298–305.CrossRefGoogle Scholar
  88. Verpoorte, E. (2003). Beads and chips: New recipes for analysis. LOC 3, 60 N–68 N.Google Scholar
  89. Vollmer, M., Horth, P., Rozing, G., Coute, Y., Grimm, R., Hochstrasser, D., and Sanchez, J.C. (2006). Multi-dimensional HPLUMS of the nucleolar proteome using HPLC-chip/MS. J Sep Sci 29, 499–509.CrossRefGoogle Scholar
  90. Wang, C., Oleschuk, R., Ouchen, F., Li, J.J., Thibault, P., and Harrison, D.J. (2000). Integration of immobilized trypsin bead beds for protein digestion within a microfluidic chip incorporating capillary electrophoresis separations and an electrospray mass spectrometry interface. Rapid Commun Mass Spectrom 14, 1377–1383.CrossRefGoogle Scholar
  91. Wang, Y.C., Choi, M.N., and Han, J.Y. (2004). Two-dimensional protein separation with advanced sample and buffer isolation using microfluidic valves. Anal Chem 76, 4426–4431.CrossRefGoogle Scholar
  92. West, J., Becker, M., Tombrink, S., and Manz, A. (2008). Micro total analysis systems: Latest achievements. Anal Chem 80, 4403–4419.CrossRefGoogle Scholar
  93. Wheeler, A.R., Moon, H., Bird, C.A., Loo, R.R. O., Kim, C.J., Loo, J.A., and Garrell, R.L. (2005). Digital microfluidics with in-line sample purification for proteomics analyses with MALDI-MS. Anal Chem 77, 534–540.CrossRefGoogle Scholar
  94. Wheeler, A.R., Moon, H., Kim, C.J., Loo, J.A., and Garrell, R.L. (2004). Electrowetting-based microfluidics for analysis of peptides and proteins by matrix-assisted laser desorption/ionization mass spectrometry. Anal Chem 76, 4833–4838.CrossRefGoogle Scholar
  95. Wu, H.L., Zhai, J.J., Tian, Y.P., Lu, H.J., Wang, X.Y., Jia, W.T., Liu, B.H., Yang, P.Y., Xu, Y.M., and Wang, H.H. (2004). Microfluidic enzymatic-reactors for peptide mapping: Strategy, characterization, and performance. LOC 4, 588–597.Google Scholar
  96. Xie, J., Miao, Y.N., Shih, J., He, Q., Liu, J., Tai, Y.C., and Lee, T.D. (2004a). An electrochemical pumping system for on-chip gradient generation. Anal Chem 76, 3756–3763.CrossRefGoogle Scholar
  97. Xie, J., Miao, Y.N., Shih, J., Tai, Y.C., and Lee, T.D. (2005). Microfluidic platform for liquid chromatography-tandem mass spectrometry analyses of complex peptide mixtures. Anal Chem 77, 6947–6953.CrossRefGoogle Scholar
  98. Xie, J., Shih, J., He, Q., Pang, C.L., Tai, Y.C., Miao, Y., Lee, T.D., and Ieee (2004b). An Integrated LC-ESI Chip with Electrochemical-Based Gradient Generation. Paper presented at: 17th IEEE International Conference on Micro Electro Mechanical Systems (Maastricht, The Netherlands).Google Scholar
  99. Xu, A.H., Sluszny, C., and Yeung, E.S. (2004). Prototype for Integrated Two-Dimensional Gel Electrophoresis for Protein Separation. Paper presented at: 25th International Symposium on Chromatography (Paris, France).Google Scholar
  100. Xu, X.J., Wang, X.Y., Liu, Y., Liu, B.H., Wu, H.L., and Yang, P.Y. (2008). Trypsin entrapped in poly(diallyldimethylammonium chloride) silica sol-gel microreactor coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 22, 1257–1264.CrossRefGoogle Scholar
  101. Xue, Q.F., Foret, F., Dunayevskiy, Y.M., Zavracky, P.M., McGruer, N.E., and Karger, B.L. (1997). Multichannel microchip electrospray mass spectrometry. Anal Chem 69, 426–430.CrossRefGoogle Scholar
  102. Yang, S., Liu, J., Lee, C.S., and DeVoe, D.L. (2009a). Microfluidic 2-D PAGE using multifunctional in situ polyacrylamide gels and discontinuous buffers. LOC 9, 592–599.Google Scholar
  103. Yang, S., Liu, J.K., Lee, C.S., and Devoe, D.L. (2009b). Microfluidic 2-D PAGE using multifunctional in situ polyacrylamide gels and discontinuous buffers. LOC 9, 592–599.Google Scholar
  104. Yang, Y.N., Li, C., Lee, K.H., and Craighead, H.G. (2005). Coupling on-chip solid-phase extraction to electrospray mass spectrometry through an integrated electrospray tip. Electrophoresis 26, 3622–3630.CrossRefGoogle Scholar
  105. Yin, N.F., Killeen, K., Brennen, R., Sobek, D., Werlich, M., and van de Goor, T.V. (2005). Microfluidic chip for peptide analysis with an integrated HPLC column, sample enrichment column, and nanoelectrospray tip. Anal Chem 77, 527–533.CrossRefGoogle Scholar
  106. Yu, C., Davey, M.H., Svec, F., and Frechet, J.M.J. (2001). Monolithic porous polymer for on-chip solid-phase extraction and preconcentration prepared by photoinitiated in situ polymerization within a microfluidic device. Anal Chem 73, 5088–5096.CrossRefGoogle Scholar
  107. Yu, C., Xu, M.C., Svec, F., and Frechet, J.M. J. (2002). Preparation of monolithic polymers with controlled porous properties for microfluidic chip applications using photoinitiated free-radical polymerization. J Polymer Sci Polymer Chem 40, 755–769.Google Scholar
  108. Zamfir, A., Vakhrushev, S., Sterling, A., Niebel, H.J., Allen, M., and Peter-Katalinic, J. (2004). Fully automated chip-based mass spectrometry for complex carbohydrate system analysis. Anal Chem 76, 2046–2054.CrossRefGoogle Scholar
  109. Zamfir, A.D. (2007). Recent advances in sheathless interfacing of capillary electrophoresis and electrospray ionization mass spectrometry. J Chromatogr A 1159, 2–13.CrossRefGoogle Scholar
  110. Zamfir, A.D., Lion, N., Vukelic, Z., Bindila, L., Rossier, J., Girault, H.H., and Peter-Katalinic, J. (2005). Thin chip microsprayer system coupled to quadrupole time-of-flight mass spectrometer for glycoconjugate analysis. LOC 5, 298–307.Google Scholar
  111. Zhang, S., and Chelius, D. (2004). Characterization of protein glycosylation using chip-based infusion nanoelectrospray linear ion trap tandem mass spectrometry. J Biomol Tech 15, 120–133.Google Scholar
  112. Zhang, S., and Williamson Brian, L. (2005). Characterization of protein glycosylation using chip-based nanoelectrospray with precursor ion scanning quadrupole linear ion trap mass spectrometry. J Biomol Tech 16, 209–219.Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Virginia Bioinformatics InstituteBlacksburgUSA
  2. 2.Department of Biological SciencesVirginia Polytechnic Institute and State UniversityBlacksburgUSA

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