CRITICAL REVIEW www.rsc.org/loc | Lab on a Chip Proteome-on-a-chip: Mirage, or on the horizon?

Proteomics has emerged as the next great scientific challenge in the post-genome era. But even the most basic form of proteomics, proteome profiling, i.e., identifying all of the proteins expressed in a given sample, has proven to be a demanding task. The proteome presents unique analytical challenges, including significant molecular diversity, an extremely wide concentration range, and a tendency to adsorb to solid surfaces. Microfluidics has been touted as being a useful tool for developing new methods to solve complex analytical challenges, and, as such, seems a natural fit for application to proteome profiling. In this review, we summarize the recent progress in the field of microfluidics in four key areas related to this application: chemical processing, sample preconcentration and cleanup, chemical separations, and interfaces with mass spectrometry. We identify the bright spots and challenges for the marriage of microfluidics and proteomics, and speculate on the outlook for progress.

[1]  Jun Wang,et al.  Protein and small molecule microarrays: powerful tools for high-throughput proteomics. , 2006, Molecular bioSystems.

[2]  C. Kim,et al.  An integrated digital microfluidic chip for multiplexed proteomic sample preparation and analysis by MALDI-MS. , 2006, Lab on a chip.

[3]  D. Knapp,et al.  Plastic microchip liquid chromatography-matrix-assisted laser desorption/ionization mass spectrometry using monolithic columns. , 2006, Journal of chromatography. A.

[4]  Michael G. Roper,et al.  Protein digestion and phosphopeptide enrichment on a glass microchip. , 2006, Analytica chimica acta.

[5]  Haojie Lu,et al.  Zeolite nanoparticle modified microchip reactor for efficient protein digestion. , 2006, Lab on a chip.

[6]  Georges L Gauthier,et al.  Miniaturization: Chip-based liquid chromatography and proteomics. , 2006, Drug discovery today. Technologies.

[7]  Rajiv Bharadwaj,et al.  On-chip millionfold sample stacking using transient isotachophoresis. , 2006, Analytical chemistry.

[8]  Baohong Liu,et al.  Multilayer-assembled microchip for enzyme immobilization as reactor toward low-level protein identification. , 2006, Analytical chemistry.

[9]  Kermit K. Murray,et al.  Direct coupling of polymer‐based microchip electrophoresis to online MALDI‐MS using a rotating ball inlet , 2005, Electrophoresis.

[10]  Yu-Chong Tai,et al.  Microfluidic platform for liquid chromatography-tandem mass spectrometry analyses of complex peptide mixtures. , 2005, Analytical chemistry.

[11]  D. DeVoe,et al.  Electrospray interfacing of polymer microfluidics to MALDI‐MS , 2005, Electrophoresis.

[12]  T. Kole,et al.  Disposable hydrophobic surface on MALDI targets for enhancing MS and MS/MS data of peptides. , 2005, Analytical chemistry.

[13]  Greg E Collins,et al.  Integrated microfluidic device for solid-phase extraction coupled to micellar electrokinetic chromatography separation. , 2005, Analytical chemistry.

[14]  Jean-Louis Viovy,et al.  Use of self assembled magnetic beads for on-chip protein digestion. , 2005, Lab on a chip.

[15]  Jun Kameoka,et al.  A polymeric microchip with integrated tips and in situ polymerized monolith for electrospray mass spectrometry. , 2005, Lab on a chip.

[16]  K. Markides,et al.  Poly(dimethylsiloxane)-based microchip for two-dimensional solid-phase extraction-capillary electrophoresis with an integrated electrospray emitter tip. , 2005, Analytical chemistry.

[17]  T. Shepodd,et al.  Microchip HPLC of peptides and proteins. , 2005, Analytical chemistry.

[18]  Robert S Foote,et al.  Stacking due to ionic transport number mismatch during sample sweeping on microchips. , 2005, Lab on a chip.

[19]  A. van den Berg,et al.  A MALDI-chip integrated system with a monitoring window. , 2005, Lab on a chip.

[20]  Pierre Thibault,et al.  Integrated microfluidic device for mass spectrometry-based proteomics and its application to biomarker discovery programs. , 2005, Analytical chemistry.

[21]  Leif Nyholm,et al.  Capillary electrophoresis coupled to mass spectrometry from a polymer modified poly(dimethylsiloxane) microchip with an integrated graphite electrospray tip. , 2005, The Analyst.

[22]  H. Yin,et al.  Microfluidic chip for peptide analysis with an integrated HPLC column, sample enrichment column, and nanoelectrospray tip. , 2005, Analytical chemistry.

[23]  C. Kim,et al.  Digital microfluidics with in-line sample purification for proteomics analyses with MALDI-MS. , 2005, Analytical chemistry.

[24]  Robert S Foote,et al.  Preconcentration of proteins on microfluidic devices using porous silica membranes. , 2005, Analytical chemistry.

[25]  Bingcheng Lin,et al.  Integrated lectin affinity microfluidic chip for glycoform separation. , 2004, Analytical chemistry.

[26]  K. Elenitoba-Johnson,et al.  Proteomics in pathology research , 2004, Laboratory Investigation.

[27]  C. Cren-olivé,et al.  Monoliths for microfluidic devices in proteomics. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[28]  Simon Song,et al.  Electrophoretic concentration of proteins at laser-patterned nanoporous membranes in microchips. , 2004, Analytical chemistry.

[29]  Monica Veszelei,et al.  Poly(dimethylsiloxane) microchip: microchannel with integrated open electrospray tip. , 2004, Lab on a chip.

[30]  D. DeVoe,et al.  Efficient electrospray ionization from polymer microchannels using integrated hydrophobic membranes. , 2004, Lab on a chip.

[31]  Aaron R Wheeler,et al.  Electrowetting-based microfluidics for analysis of peptides and proteins by matrix-assisted laser desorption/ionization mass spectrometry. , 2004, Analytical chemistry.

[32]  Yu-Chong Tai,et al.  An electrochemical pumping system for on-chip gradient generation. , 2004, Analytical chemistry.

[33]  Jongyoon Han,et al.  Two-dimensional protein separation with advanced sample and buffer isolation using microfluidic valves. , 2004, Analytical chemistry.

[34]  J. Roeraade,et al.  Simple fabrication of a structured matrix-assisted laser desorption/ionization target coating for increased sensitivity in mass spectrometric analysis of membrane proteins. , 2004, Rapid communications in mass spectrometry : RCM.

[35]  A. Neyer,et al.  A new on-chip ESI nozzle for coupling of MS with microfluidic devices. , 2004, Lab on a chip.

[36]  Linda Sage,et al.  Product Review: Protein biochips go high tech , 2004 .

[37]  Linda C. Sage Protein biochips go high tech. , 2004, Analytical chemistry.

[38]  D. J. Harrison,et al.  A glassy carbon microfluidic device for electrospray mass spectrometry. , 2004, Analytical chemistry.

[39]  Frédéric Reymond,et al.  Why the move to microfluidics for protein analysis? , 2004, Current opinion in biotechnology.

[40]  Steffen Hardt,et al.  Integrated polymer chip for two-dimensional capillary gel electrophoresis. , 2004, Lab on a chip.

[41]  H. Löwe,et al.  Chemistry in microstructured reactors. , 2004, Angewandte Chemie.

[42]  M. Gustafsson,et al.  Integrated sample preparation and MALDI mass spectrometry on a microfluidic compact disk. , 2004, Analytical chemistry.

[43]  Yan Li,et al.  Integration of isoelectric focusing with parallel sodium dodecyl sulfate gel electrophoresis for multidimensional protein separations in a plastic microfludic network , 2004 .

[44]  Andras Kalman,et al.  Biosensor-based determination of riboflavin in milk samples. , 2004, Analytical chemistry.

[45]  Loïc Dayon,et al.  Microfluidic systems in proteomics , 2003, Electrophoresis.

[46]  Rajiv Bharadwaj,et al.  Thousandfold signal increase using field‐amplified sample stacking for on‐chip electrophoresis , 2003, Electrophoresis.

[47]  Niels Lion,et al.  On-chip protein sample desalting and preparation for direct coupling with electrospray ionization mass spectrometry. , 2003, Journal of chromatography. A.

[48]  J Michael Ramsey,et al.  High-efficiency, two-dimensional separations of protein digests on microfluidic devices. , 2003, Analytical chemistry.

[49]  Andrew Emili,et al.  Going global: protein expression profiling using shotgun mass spectrometry. , 2003, Current opinion in molecular therapeutics.

[50]  Amy E Herr,et al.  On-chip coupling of isoelectric focusing and free solution electrophoresis for multidimensional separations. , 2003, Analytical chemistry.

[51]  Cheng S. Lee,et al.  Membrane-based nanoscale proteolytic reactor enabling protein digestion, peptide separation, and protein identification using mass spectrometry. , 2003, Analytical chemistry.

[52]  F. Regnier,et al.  Protein proteolysis and the multi-dimensional electrochromatographic separation of histidine-containing peptide fragments on a chip. , 2003, Journal of chromatography. A.

[53]  Masaru Kato,et al.  Creation of an on-chip enzyme reactor by encapsulating trypsin in sol-gel on a plastic microchip. , 2003, Analytical chemistry.

[54]  Ying Zhang,et al.  Integration of nanocapillary arrays into microfluidic devices for use as analyte concentrators. , 2003, The Analyst.

[55]  James P Landers,et al.  A microchip-based proteolytic digestion system driven by electroosmotic pumping. , 2003, Lab on a chip.

[56]  Qifeng Xue,et al.  Sample pre-concentration by isotachophoresis in microfluidic devices. , 2002, Journal of chromatography. A.

[57]  Jun Kameoka,et al.  An electrospray ionization source for integration with microfluidics. , 2002, Analytical chemistry.

[58]  J. Rossier,et al.  Integration of a membrane‐based desalting step in a microfabricated disposable polymer injector for mass spectrometric protein analysis , 2002, Electrophoresis.

[59]  A. van den Berg,et al.  Integrated microfluidic system enabling (bio)chemical reactions with on-line MALDI-TOF mass spectrometry. , 2002, Analytical chemistry.

[60]  Frantisek Svec,et al.  Enzymatic microreactor-on-a-chip: protein mapping using trypsin immobilized on porous polymer monoliths molded in channels of microfluidic devices. , 2002, Analytical chemistry.

[61]  G. Whitesides,et al.  A prototype two-dimensional capillary electrophoresis system fabricated in poly(dimethylsiloxane). , 2002, Analytical chemistry.

[62]  F. Regnier,et al.  Capillary electrochromatography of peptides on microfabricated poly(dimethylsiloxane) chips modified by cerium(IV)-catalyzed polymerization. , 2002, Journal of chromatography. A.

[63]  D. Jed Harrison,et al.  Application of Microfluidic Devices to Proteomics Research , 2002, Molecular & Cellular Proteomics.

[64]  T. Shepodd,et al.  Electrochromatography in microchips: reversed-phase separation of peptides and amino acids using photopatterned rigid polymer monoliths. , 2002, Analytical chemistry.

[65]  F. Švec,et al.  Monolithic porous polymer for on-chip solid-phase extraction and preconcentration prepared by photoinitiated in situ polymerization within a microfluidic device. , 2001, Analytical chemistry.

[66]  Gwo-Bin Lee,et al.  A disposable poly(methylmethacrylate)‐based microfluidic module for protein identification by nanoelectrospray ionization‐tandem mass spectrometry , 2001, Electrophoresis.

[67]  L. Locascio,et al.  Integrated microfluidic system enabling protein digestion, peptide separation, and protein identification. , 2001, Analytical chemistry.

[68]  B. Karger,et al.  High-throughput microfabricated CE/ESI-MS: automated sampling from a microwell plate. , 2001, Analytical chemistry.

[69]  N Gottschlich,et al.  Two-dimensional electrochromatography/capillary electrophoresis on a microchip. , 2001, Analytical chemistry.

[70]  J. Yates,et al.  Large-scale analysis of the yeast proteome by multidimensional protein identification technology , 2001, Nature Biotechnology.

[71]  S. Fields Proteomics in Genomeland , 2001, Science.

[72]  T Laurell,et al.  Signal amplification using "spot-on-a-chip" technology for the identification of proteins via MALDI-TOF MS. , 2001, Analytical chemistry.

[73]  D. J. Harrison,et al.  Chip-based capillary electrophoresis/mass spectrometry determination of carnitines in human urine. , 2001, Analytical chemistry.

[74]  D. Figeys,et al.  Proteomics on a chip: Promising developments , 2001, Electrophoresis.

[75]  J. Ramsey,et al.  A microfabricated fluidic device for performing two-dimensional liquid-phase separations. , 2000, Analytical chemistry.

[76]  Corso,et al.  A fully integrated monolithic microchip electrospray device for mass spectrometry , 2000, Analytical chemistry.

[77]  N Gottschlich,et al.  Integrated microchip-device for the digestion, separation and postcolumn labeling of proteins and peptides. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[78]  K. Gevaert,et al.  Protein identification methods in proteomics , 2000, Electrophoresis.

[79]  R. Oleschuk,et al.  Trapping of bead-based reagents within microfluidic systems: on-chip solid-phase extraction and electrochromatography , 2000, Analytical chemistry.

[80]  Y. Tai,et al.  A micromachined chip-based electrospray source for mass spectrometry. , 2000, Analytical chemistry.

[81]  D. Figeys,et al.  An enhanced microfluidic chip coupled to an electrospray Qstar mass spectrometer for protein identification , 2000, Electrophoresis.

[82]  H. Jörnvall,et al.  Proteomics in Functional Genomics , 2000, EXS.

[83]  D. N. Perkins,et al.  Probability‐based protein identification by searching sequence databases using mass spectrometry data , 1999, Electrophoresis.

[84]  R. Aebersold,et al.  Microfabricated polymer devices for automated sample delivery of peptides for analysis by electrospray ionization tandem mass spectrometry. , 1999, Analytical chemistry.

[85]  J. Ramsey,et al.  Subattomole-Sensitivity Microchip Nanoelectrospray Source with Time-of-Flight Mass Spectrometry Detection. , 1999, Analytical chemistry.

[86]  R. Cotter,et al.  MALDI on a Chip: Analysis of Arrays of Low-Femtomole to Subfemtomole Quantities of Synthetic Oligonucleotides and DNA Diagnostic Products Dispensed by a Piezoelectric Pipet , 1997 .

[87]  J. Ramsey,et al.  Generating electrospray from microchip devices using electroosmotic pumping. , 1997, Analytical chemistry.

[88]  P. Zavracky,et al.  Multichannel microchip electrospray mass spectrometry. , 1997, Analytical chemistry.

[89]  D. Hochstrasser,et al.  Progress with proteome projects: why all proteins expressed by a genome should be identified and how to do it. , 1996, Biotechnology & genetic engineering reviews.

[90]  P. Brown,et al.  A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. , 1996, Genome research.

[91]  J. Yates,et al.  An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database , 1994, Journal of the American Society for Mass Spectrometry.

[92]  D. J. Harrison,et al.  Capillary electrophoresis and sample injection systems integrated on a planar glass chip , 1992 .

[93]  D. J. Harrison,et al.  Planar chips technology for miniaturization and integration of separation techniques into monitoring systems. Capillary electrophoresis on a chip , 1992 .

[94]  Barry L. Karger,et al.  Analytical and micropreparative ultrahigh resolution of oligonucleotides by polyacrylamide gel high-performance capillary electrophoresis , 1990 .

[95]  D. Mccormick Sequence the Human Genome , 1986, Bio/Technology.