Analytical microdevices for mass spectrometry

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Analytical microdevices for mass spectrometryRichard D. Oleschuk, D. Jed Harrison*Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada

The seemingly unlikely marriage between largemass spectrometers and small microchips isactually a good one. Micro£uidic devices havebeen coupled to mass spectrometers using electro-spray ionization interfaces. Different interfacedesigns and various integrated protein preparationand preconcentration procedures are reviewed. Thepotential role of chip-mass spectrometry in proteo-mics and drug discovery is also discussed. z2000Elsevier Science B.V. All rights reserved.

Keywords: Micro£uidics; Mass spectrometry; Electrosprayionization; Proteomics; Micro total analysis systems;Chip-mass spectrometry

1. Introduction

Since the concept of micro total analysis systems(W-TAS) was ¢rst envisioned, micro£uidic devicescapable of conducting chemical analyses, reactionsand assays on a single microchip have been devel-oped [ 1^3 ]. Although the evolution of micro£uidicdevices has been quite rapid, laser-induced £uores-cence (LIF) has been relied upon almost exclu-sively as the method of detection because of itssimplicity and sensitivity. However, LIF is not anideal detection scheme, because it requires the ana-lyte of interest to be £uorescent. Since most com-pounds are not natural £uorophores, a derivatiza-tion step is often required to make them amenableto this type of detection.

Currently, mass spectrometry (MS) is beinginvestigated as an alternative method of detectionfor micro£uidic devices. However, when thinkingof MS, an image of a large bulky piece of instrumen-tation comes to mind. The seemingly unlikely mar-riage between MS and microchips is actually a goodone [ 4 ]. Microchips should provide an excellent

means of performing sample preparation for massspectrometers. Sample preparation protocols suchas solid phase extraction (SPE), tryptic digestion,preconcentration and separation methods can beconveniently performed on a microchip, makingsample preparation for the mass spectrometerfaster and more ef¢cient. The mass spectrometerand the microchip are well-matched, due to thesimilarity in £ow rates generated by the microchipwith those required for electrospray ionization MS(ESI-MS), despite the mismatch in physical dimen-sions illustrated in Fig. 1.

ESI has become one of the most versatile ioniza-tion methods for MS [ 5 ]. Liquid, under the in£uenceof a high electric ¢eld, is sprayed into a mass spec-trometer where the mass to charge ratio of the ana-lyte is determined. The relatively soft ionizationtechnique can be utilized to measure a largerange of molecules (several hundred to severalthousand molecular weight ) including proteinsand peptides, yielding both molecular weight andstructural information. Unlike £uorescence, ESI-MSrequires that the sample can be ionized in the gasphase, making it a more universal method of detec-tion.

Although several applications have been devel-oped for micro£uidic devices, with the most signi¢-cant to date being genetic analysis [ 6 ], the emerg-ing ¢eld of proteomics may prove to be the nextmajor application area with high commercialpotential. Proteomics is concerned with both devel-oping a comprehensive description of proteinsencoded by an organism's genome, and under-standing the in£uence of disease, stress and druginteractions on protein expression [ 7 ]. Researchersin the ¢eld of proteomics have recognized the needfor a larger scale, high throughput method for pro-tein analysis and identi¢cation in order to contrib-ute to the current evolution in drug discovery. Atpresent, proteomics researchers utilize a variety ofgel-based methods for protein analysis [ 8 ].Recently, the analysis of proteins has been revolu-tionized by the development of new mass spectro-metric techniques [ 9 ]. Nevertheless, the ¢eld ofproteomics will demand a staggering number of

0165-9936/00/$ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved.PII: S 0 1 6 5 - 9 9 3 6 ( 0 0 ) 0 0 0 1 3 - 3

*Corresponding author. Tel.: +1 (780) 492-3254;Fax: +1 (780) 492-8231

trends in analytical chemistry, vol. 19, no. 6, 2000 379

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protein analyses to be performed, and currentmethods of sample preparation for ESI-MS areunlikely to keep pace with the demand. Chip de-vices are capable of rapidly handling extremelysmall volumes of multiple samples [ 4 ] and intro-ducing them to the mass spectrometer, thus poten-tially solving the demands of proteomics for highthroughput. The groups of Barry Karger [ 10 ] andRuedi Aebersold [ 11 ] were the ¢rst to realize theadvantages of microchips for protein sample prep-aration for ESI-MS, and have played a prominentrole in the initial demonstration of the promise ofchip-MS for protein analysis.

Sample preparation such as enzyme digestion ofproteins, separation of sample from other compo-nents such as salts and detergents during isolationand extraction, and separation of proteins or theirdigests by electrokinetic or chromatographic meth-ods have all been demonstrated on-chip in someform [ 1^3 ]. The coupling of such sample process-ing with the additional separation and identi¢cationpower of tandem MS (MS /MS) may reduce or elim-inate the need for the slow, two-dimensional (2D)gel electrophoresis step commonly used now.Analyses that were previously too slow or costlyto be performed conveniently with MS may soonbe performed routinely utilizing chip-MS.

2. Device development /performance

In the early stages of developing a hyphenatedtechnique, the initial research focuses on couplingthe two methods. However, the ultimate bene¢ts ofthis technology will come as sample handling toolsand are integrated within the microchips. Thisreview will focus ¢rst on interface research andthen on sample handling.

In the last 2 years, several groups have proposeddifferent chip-MS couplings based primarily on twodifferent interface designs. These methods can becharacterized as interfaces that `spray' directly froman exposed channel at the side of a chip, and thosethat use a capillary attached to the microchip as theelectrospray emitter. Several designs are illustratedschematically in Fig. 2. While many of the earlypapers did not demonstrate separations within the

Fig. 1. Photograph of the chip-MS con¢guration used in ourlaboratory, showing the chip support / manipulator, electri-cal connections, chip with attached capillary and the sam-pling ori¢ce of the Sciex 150ex mass spectrometer.

Fig. 2. Schematic diagram of different electrospray interfacesthat have been developed for chip-ESI-MS: (A) sprayingdirectly from an exposed channel at the edge of a chip; (B)liquid junction capillary interface; (C) gold-coated capillaryinterface; and (D) coaxial sheath £ow con¢guration. HVdenotes points to which the electrospray voltage is applied.

380 trends in analytical chemistry, vol. 19, no. 6, 2000

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chips, it seems clear that this has been a primarygoal of most groups. The interface has proven tobe a key factor in achieving on-chip separations.

2.1. Electrospray directly from the chip

Karger's and J.M. Ramsey's groups ¢rst examinedsimply spraying the £uid out the side of a microchipfrom an exposed channel [ 10,12 ]. The design isattractive because it does not require any complexmachining, since the outlet can be formed simplyby dicing the chip. This interface was used to gen-erate mass spectra from continuously £owing sam-ples, but the performance highlighted problemswith the chip-ESI interface design. The £at-facefrom which the infused sample was sprayed led tothe formation of large liquid droplets (volume s 12nl ) at the surface of the chip, as illustrated in Fig. 3.Such large droplets at the exit ori¢ce cause exces-

sive band broadening and sample dilution, pre-cluding the use of this interface for on-chip separa-tions [ 13 ]. Attempts to minimize droplet size haveincluded coating [ 12 ] and derivatizing [ 10 ] the exitori¢ce with a hydrophobic reagent or pneumati-cally assisting the droplet formation [ 14 ]. Pneu-matically assisting the spray, using the device inFig. 4, enabled the interface to be used with anon-chip electrophoretic separation of a peptidemixture, producing 70 000 theoretical plates / m.However, the pneumatically assisted interface stilldid not produce ef¢ciencies as high as those con-structed with an attached capillary.

2.2. Electrospray from an attached capillary sprayer

The second category of interfaces for microchip-MS involves using a capillary coupled to a chip asthe electrospray emitter, as ¢rst introduced by Fig-eys et al. [ 11 ]. This coupling is similar to those usedfor capillary electrophoresis [ 15 ] and offers severaladvantages over spraying directly from the chip, theprimary one being that good electrospray condi-tions are more readily achieved (see Fig. 2). Theelectrospray nozzle can be made with a sharp,tapered capillary end (10 Wm diameter ), fromwhich the liquid sprays to produce small, well-de¢ned droplets. The production of smaller drop-lets enhances both the sensitivity and resolution ofthe electrospray process. Another advantage of themethod is that it allows the electrospray voltage to

Fig. 3. Photomicrographs of ( top) a water droplet (volumeW12 nl) forced through a channel opening at the side of amicrochip and ( bottom) the Taylor cone and electrospraygenerated from the same opening when a 3 kV potential isapplied between the microchip and the target electrode. Theformation of large droplets at the electrospray ori¢ce, such asthose shown here, causes excessive band-broadening andsample dilution. Reprinted with permission from [ 12 ]. z1997 American Chemical Society.

Fig. 4. A microdevice designed by Zhang et al. to spray directlyfrom the chip. An internal pneumatic nebulizer was incorpo-rated in the design to minimize droplet formation at the elec-trospray ori¢ce. This device is the ¢rst to demonstrate an on-chip separation with mass spectrometric detection whilespraying directly from the edge of a chip. Reprinted withpermission from [ 14 ]. z 1999 American Chemical Society.


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be controlled at the point where the liquid is emit-ted, using either a liquid junction or a direct elec-trical connection through a gold-coated capillary. Itis also helpful that the electrospray capillary can beremoved and replaced, preserving the expensivemicro£uidic device [ 13 ], since clogging is a signi¢-cant problem when using capillaries with taperedends.

Figeys et al. [ 16 ] demonstrated that the chip canbe used to deliver not only simple samples, but alsoto effuse complex samples such as tryptic digests.The combined chip-MS con¢guration provided suf-¢cient resolution that the observed tryptic frag-ments could be used to search a protein databaseidentifying the native protein. However, at thatstage, no separation was performed on the chip,instead the resolving power of the mass spectrom-eter was relied upon. The capillary interface hasgenerated 5 fmol /Wl and 160 amol /Wl [ 16 ] concen-tration detection limits on an infused tryptic digestsample, obtained with MS and MS /MS modes ofoperation, respectively. Recently, Ramsey and co-workers [ 17 ] have obtained mass spectra on sub-attomole amounts of protein utilizing the fastacquisition rates of a time-of-£ight mass analyzerwith effusion from a capillary /chip interface.

Our laboratory has recently shown [ 18 ] that deadvolume is critical to the performance of the capillarysprayer design if separation is to be performed on-chip. Two methods of coupling, illustrated in Fig. 5,were employed and compared in terms of deadvolume and ef¢ciency using LIF. One coupling pos-sessed 0.7 nl of dead volume while the other cou-pling had no dead volume associated with it. Strik-ingly, the 0.7 nl dead volume lowered the platenumber after the coupling to 16^25% of the pre-dicted values. However, the low dead volume cou-pling produced 98% of the predicted plate num-bers. The low dead volume connection preservesthe separation that occurs on the chip prior to theconnection, by preventing the band broadeningassociated with the capillary /chip junction.

2.3. Incorporating separation with chip-ESI-MS

The question arises as to why a separation isneeded at all, when an MS has the ability to resolveseveral analytes simultaneously? Even though theMS has the ability to analyze and resolve severalcomponents simultaneously, interferents withincomplex samples can cause electrospray signalsuppression or background chemical noise. Sepa-

ration provides an ef¢cient means of removingmass spectral interferences, allowing the analysisof discrete sample peaks. In the earliest report dem-onstrating separations, shown in Fig. 6, Figeys et al.[ 19 ] used the chip to feed an attached separationcapillary and performed a solvent gradient-medi-ated frontal analysis. The key role of the chip inthat application was the facile generation of a sol-vent gradient with electrokinetic pumping.

Whether it will be preferable to use chips to sup-ply an external separation capillary or to performthe separation within the device has not beenclearly established at present. We believe that ifhigh separation speed is needed, and on-chip sam-ple processing takes place, then performing theseparation on-chip will prove preferable. The ¢rston-chip separations coupled with MS detectionwere performed by Li et al. [ 13 ]. They utilized thecoupling method described in [ 13 ] in different

Fig. 5. Two methods of constructing a capillary /device inter-face with minimal dead volume: (A) shows a coupling with afrusto-conical hole showing minimal but signi¢cant dead vol-ume (0.7 nl ); while (B) shows a capillary ¢tted into a £at-bottomed hole eliminating the dead volume associated withthe previous connection. Small dead volumes were found toseriously degrade the performance of on-chip separations.Reprinted with permission from [ 18 ]. z 1999 AmericanChemical Society.


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Fig. 6. Analysis of a band of yeast proteins separated by 1D gel electrophoresis from a yeast total cell lysate and digested with trypsin.The frontal analysis was carried out by supplying a solvent gradient, generated by a microchip device, to a C18 extraction cartridge inan attached capillary followed by MS analysis. The separation /detection scheme provided both sample clean-up prior to analysisand excellent resolution. Reprinted with permission from [ 19 ]. z 1998 American Chemical Society.

Fig. 7. The analysis of a tryptic digest of a lectin from Pisum sativum using a capillary sheath £ow ESI interface. These were the ¢rstresults demonstrating on-chip separation coupled with mass spectrometric detection when using a capillary coupling. Reprintedwith permission from [ 13 ]. z 1998 American Chemical Society.


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manners with different coatings and sheath £ows.Chip-MS and MS /MS analysis of a peptide mixtureutilizing this design have provided separation ef¢-ciencies as high as 300 000 plates / m. A representa-tive result is shown in Fig. 7. Resolution in an anal-ysis of a tryptic digest, using only 150 fmol ofprotein, was suf¢cient to allow the protein to beidenti¢ed when comparing tryptic fragments to aprotein database. The analysis allowed the peptidesequence to be identi¢ed with a 45 amol /Wl con-centration detection limit using chip-MS /MS.

Another design developed by Karger's group uti-lized wet etching [ 14 ] to create a sleeve in the chipthat a capillary was inserted into, establishing thechip /capillary connection. They then evaluatedand compared both pneumatically assisted electro-spray directly from a chip and the capillary-coupledelectrospray. They found that capillary couplingperformed substantially better, yielding 300 000plates / m compared to 70 000 plates / m with thepneumatically assisted device. In addition to sepa-rating a simple peptide mixture as shown in Fig. 8,the separation of a cytochrome c tryptic digest wasalso performed with the capillary device. However,

the design still yielded dead volume at the capil-lary /chip junction that can potentially degradethe separation performance of the system.

Research into the proper design for interfacing tomass spectrometers is still required to enable thismethod to be conducted on a routine basis andmanufactured at a low cost. Although a capillaryattached to a chip has proven to be suitable forhigh-resolution separations, it still requires substan-tial machining to fabricate and prepare the device.A more attractive alternative would be to fabricatethe electrospray tip /nozzle within the structure ofthe microchip using the remarkable capabilities ofmodern micromachining [ 20 ]. Methods to fabricateelectrospray tips as part of a chip should eventuallyprovide robust devices for electrospray chip-MS.Two studies in particular have illustrated the poten-tial for forming sophisticated electrospray nozzles /tips in silicon [ 21,22 ]. However, the conductivity ofsilicon [ 23 ] and fragility of the devices in siliconhave so far precluded their signi¢cant use in electri-cally driven systems that utilize high voltages.Efforts are underway to fabricate these same struc-tures within plastic [ 24 ], as shown in Fig. 9.

Fig. 8. Chip-ESI-MS separation and analysis of a mixture of angiotensin peptides using a liquid junction capillary interface. Theinstrumental setup used in this investigation allowed both MS and UV /Vis absorption data to be gathered simultaneously. Reprintedwith permission from [ 14 ]. z 1999 American Chemical Society.


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3. Multiplexing

Multiplexing is another aspect of chip-MS cou-pling that has remained mostly unexplored. Theability to handle multiple samples ( multiplexing)using microchip devices, either simultaneously orsequentially, is one of the most signi¢cant advan-tages offered by micro£uidic networks. The ¢rstexample of multiplexing combined with chip-MSinvolved spraying directly from the edge of thechip, utilizing six independent devices on onewafer with six separate spray ori¢ces [ 10 ]. Thedevices were changed by translating the wafer ona stage so that a particular device was aimed at theelectrospray interface. This is the most rudimentaryway of conducting multiplexing, requiring multipleindividual electrospray outlets. The position of thespray ori¢ce /needle is critical to performance ofthe spray source, making it dif¢cult to optimize mul-tiple outlets. Instead, a design that has all ef£uent£owing through a common electrospray tip may bepreferred. Aebersold and co-workers have shownan example of automating the continuous £owanalysis of three [ 11 ] and nine [ 16 ] samples on asingle chip using a single electrospray outlet, as

shown in Fig. 10. Voltages applied to each samplereservoir sequentially caused each protein sampleto £ow into and through the effusion channel andout through a single electrospray needle. While thethree-sample design suffered from cross contami-nation of samples, caused by £ow leakage [ 25,26 ]and siphoning effects, the nine-sample con¢gura-

Fig. 9. An image of a Parylene substrate microchip with an overhanging microcapillary 2.5 mm in length. The polymer chip has beensuccessfully interfaced with a mass spectrometer. The design incorporated a 5 WmU10 Wm spray ori¢ce and built-in microparticle¢lters to help prevent particulate matter from clogging the nozzle. Reprinted with permission from the Proceedings of the 12thInternational Conference on Micro Electromechanical Systems 1999, p. 523. z 1999 IEEE.

Fig. 10. Schematic diagram of an integrated nine-positionmicrofabricated device coupled to a mass spectrometeradapted from that shown in [ 16 ]. Sample £ow was con-trolled using a number of high-voltage relays. The device uti-lized a single capillary from which all samples were sprayedand was designed to minimize sample carry-over. Reprintedwith permission from [ 16 ].z 1998 American Chemical Soci-ety.


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tion produced much lower sample cross contami-nation. Careful consideration of leakage effectswhen designing the chips and the use of pushback voltages to control £ow [ 27^29 ] should helpto reduce cross contamination, unless it arises fromadsorption in the electrospray needle.

While most of the chip-MS couplings have usedESI as the method of ionization, Little et al. [ 30 ]have developed a method utilizing matrix-assistedlaser desorption ionization (MALDI) with a chip.Microfabrication was employed to fabricate a 100element array of micro-wells to contain samples foreventual MALDI-MS analysis. DNA samples wereadministered with a piezoelectric pipette, theneach well was subjected to MALDI to yield 100mass spectra from a sample device less than 1 in2.This combination demonstrates another possibleapplication of microfabrication for rapid sampleintroduction to mass spectrometers.

4. Integration of sample preparation

One of the most important advantages of W-TAStechnologies is the ability to integrate multiple func-tions onto a single planar device. Micro£uidic sys-tems have been developed that perform chemicalreactions, enzyme assays, DNA ampli¢cation, sep-aration and detection on a single microchip. Forchip-MS, the primary application of micro£uidicswill be sample preparation. Sample preparationcan encompass a number of speci¢c processesoccurring in stepwise fashion, including reactionsand separations. However, sample preparation ona microchip for delivery to a mass spectrometer ispresently in its infancy. The ¢rst use of a microchipto perform sample handling prior to the mass spec-trometer was presented by Xue et al. [ 31 ]. Thepaper demonstrated a tryptic proteolysis of a pep-tide on-chip, followed by effusion into a MS.Although the proteolysis reaction was carried outon a relatively large scale within the solution reser-voirs of the chip, the paper pointed out the valuemicro£uidics has for handling, manipulating andintroducing samples to the mass spectrometer.

One of the dif¢culties in coupling a chip with amass spectrometer is the strain the chip puts on thedetection limits of the mass spectrometer. The smalldimensions of the microchip result in minuteamounts of sample, yet mass spectrometers arenot as sensitive as LIF [ 32 ] (LIF can provide singlemolecule detection). Fortunately, sample precon-

centration methods can be built into the microchipto enhance the sample prior to analysis. To date,preconcentration on-chip has been performed bysample stacking (SS) [ 33 ], isotachophoresis ( ITP)[ 14 ] and electrokinetic concentration [ 34 ].

Sample stacking uses differences in the relativeconductivity of the separation buffer compared tothe sample buffer [ 35 ]. This type of preconcentra-tion is relatively simple, but requires prior informa-tion about the sample and the size of sample thatcan be loaded and stacked is limited by the volumeinside the chip. In micro£uidic devices, Ramsey andco-workers [ 33 ] were the ¢rst to utilize SS, provid-ing a concentration enhancement W14. Morerecently, Li et al. [ 36 ] have used SS in combinationwith chip-MS to provide a concentration enhance-ment of 3^50-fold when compared to using a nor-mal double `T' injection of a few hundred pl [ 29 ].This preconcentration allowed the analysis of sub-nanomolar concentrations of peptide mixtures. Theconcentration enhancement could be improvedfurther using a chip speci¢cally designed for SS.In ITP, the sample is separated in zones based onelectrophoretic mobility, and sandwiched betweenleading and terminating electrolytes. Zhang et al.have utilized ITP [ 14 ] to achieve an order of mag-nitude increase in sensitivity and resolution whenanalyzing a 1035 M peptide mixture. However, afully integrated micro£uidic device able to controlsample loading, ITP and subsequent mobilizationhas yet to be demonstrated.

SPE is an ideal method of preconcentration formicro£uidic devices. Unlike SS and ITP, SPE doesnot require precise control of buffer conditions.Instead, it relies on an interaction between the sam-ple and the stationary phase. SPE can be tailor-made for a speci¢c analyte, so that only the targetanalyte is retained and the other interferences arewashed away. With SS and ITP, sample loading islimited to the volume of the separation channel orcapillary. SPE, however, enables a large volume ofsolution ( in excess of severalWl ) to be concentratedand then eluted in a narrow band. SPE has beenutilized in conjunction with chip-MS, but only inan off-chip manner, possibly due to the dif¢cultyof packing portions of a complex micro£uidicmanifold with beads or other chromatographicmaterial. Figeys et al. [ 19 ] have shown that a chipcombined with an SPE cartridge in an attachedcapillary can be used to analyze low concentrationsof peptide mixtures and proteolytic digest prod-ucts. Utilizing the chip to provide differential elec-


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troosmotic pumping of aqueous and organicphases, a solvent gradient could be generated andsupplied to a reverse phase cartridge to perform afrontal analysis. An outstanding detection limit of0.1 nM was obtained and the system could beused for the identi¢cation of proteins separatedfrom 1D and 2D gel electrophoresis. Thibeaultand co-workers have directly compared SS on-chip with SPE using an on-line C18 membrane[ 36 ]. SS was found to provide higher peptide recov-eries than SPE, but SPE provided a convenientmeans of injecting several Wl of sample.

In addition to preconcentration, sample clean-upis a major concern for ESI-MS. In particular, sampleconstituents such as low molecular weight saltspresent limitations for analyzing proteins and pep-tides. Smith and co-workers [ 37,38 ] have utilizedan on-chip dialysis unit to clean up samples prior toMS analysis. They showed improvements in themass spectrum of a protein mixture by removingsalts within the sample prior to MS analysis. Bothhigh and low molecular weight cut off ¢lters weredemonstrated to provide dual micro-dialysis,removing both high and low molecular weightinterferences. Figeys et al. have also shown [ 19 ]that an off-chip SPE cartridge attached to the chipeliminated interferences within a protein digest,allowing a frontal analysis to be performed moreeasily.

Recently, we have demonstrated [ 39 ] bead-based electrochromatography and SPE on-chip.The utilization of bead-based reagents will expandthe current micro£uidic tools available to includeenzyme-linked assays, SPE and electrochromatog-raphy on-chip. These designs should prove usefulin creating integrated sample preparation devicesfor MS.

5. Future prospects

The overall aim of micro£uidics is to miniaturizethose components that bene¢t from being miniatur-ized. The shrinking of the mass spectrometer,although attractive from a size point of view, doeslittle to enhance the sensitivity or speed of the anal-ysis. Conversely, miniaturization of the samplepreparation protocols onto a microchip offers sev-eral advantages, such as reduced sample require-ments, faster analysis times, increased automationand less exposure to lab contaminants. The advan-

tages of using micro£uidics as a sample introduc-tion method for MS have become clear to a numberof research groups, as evidenced by a dramaticincrease in the number of on-chip-MS papers pre-sented at the June, 1999 American Society for MassSpectrometry Conference (ASMS) [ 40 ].

To date, most research has focused on the devel-opment of an ef¢cient way of plumbing the chip tothe mass spectrometer. However, now that ef¢cientcoupling between a chip and a mass spectrometerhas been accomplished, more focus will shift toperforming multiple sample handling steps on amicro£uidic device. The on going development ofmicro£uidic devices has enabled a number of sam-ple preparation steps to be carried out on a micro-chip. Continued research in the area will furtherexpand the micro£uidic toolbox to include mostcommon sample preparation protocols. Integrationof all aspects of protein sample handling within amicro£uidic device is clearly the goal of manyresearch groups. Several groups are developingMS-interfaced devices in materials other than glass[ 24,37,38,41 ], in order to reduce unit costs. Whileattractive, issues associated with chemical noiseand solvent compatibility arising from the devicematerials will also require examination [ 41,42 ].Integration of sample handling on glass or plasticdevices will enable faster, more reproducible andmore highly automated sample preparation forintroduction into the mass spectrometer, providinga powerful tool for the burgeoning ¢eld of proteo-mics.

Recently, the ¢rst commercial micro£uidic instru-ment was marketed by Hewlett Packard (AgilentCorp. ) [ 43 ]. While genetic analysis is a clear com-mercial opportunity for micro£uidics, the develop-ing trend in proteomics research signals anothersigni¢cant opportunity. Besides sample prepara-tion for the MS, there is perhaps another signi¢cantapplication of chip-MS still waiting to be realizedarising from the use of combinatorial methods indrug discovery. The pharmaceutical industry hasdeveloped combinatorial chemistry and solidphase synthesis to rapidly generate and screenlibraries of compounds for possible drug candi-dates. However, once the primary screening stepidenti¢es leads, there are a large number of com-pounds that require identi¢cation and further test-ing, causing an analysis `bottle neck'. Multiplexedchip-MS may be the answer to this potential tidalwave of analyses of drug candidates.


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Acknowledgements

We would like to acknowledge MDS Sciex for¢nancial assistance and the Natural Sciences andEngineering Research Council of Canada for both¢nancial support and for a post doctoral fellowshipawarded to R.D. Oleschuk.

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D. Jed Harrison is a Professor of Chemistry at the University ofAlberta in Edmonton, AB T6G 2G2, Canada. He received a B.Sc.from Simon Fraser University in 1980 and a Ph.D. in Chemistryfrom Massachusetts Institute of Technology 1984, when he joinedthe Faculty at Alberta. He shares the 1996 Merck Prize inAnalytical Chemistry with Andreas Manz, for his contributions toelectrokinetic micro£uidics. His research interests are in developingbiochemical and biological analysis with microfabricated systems.

Richard Oleschuk is currently a Natural Sciences and EngineeringResearch Council of Canada Post Doctoral Fellow at the Universityof Alberta, where he is working on microfabricated SPE, electro-chromatography and chip-MS devices. He earned his Ph.D. at theUniversity of Manitoba in 1997, researching polymer-basedextraction methods for metal complexes and polymeric membranesample preparation for the MS of proteins and peptides. Richard willbe joining the faculty of the Department of Chemistry at QueensUniversity, Kingston, ON, Canada, in the summer of 2000.


Analytical microdevices for mass spectrometry

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