Microdevices in mass spectrometry

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F. Foret and P. Kusý, Eur. J. Mass Spectrom. 13, 41–44 (2007)


Microdevices in mass spectrometry F. Foret and P. Kusý Institute of Analytical Chemistry, Veveří 97, 60200 Brno, Czech Republic

Miniaturization of laboratory instrumentation is becoming critical in achieving the speed and throughput required by the current revolutionary progress in biology. This mini review critically summarizes the present status of microfluidic devices designed for use in mass spectrometry. Keywords: microfluidics, mass spectrometry coupling

Miniaturization, microfluidics and nanotechnologies represent an important direction in the development of ­analytical instrumentation. Current technologies allow fabrication of microsystems, which can integrate a number of unit operations in a way similar to the microelectronic circuits. As well as manipulation with extremely small sample volumes (down to the sub-cellular level), microchemical reactors and separations come immediately to mind. Many of the ideas leading to such developments can be traced back to the lecture by Richard P. Feynman in 19591 and, although the first microfluidic experiments were carried out over ­thirty years ago, the practical applications have emerged in conjunction with current progress, particularly in biology and medicine. Many processes proceed faster on the microscale and, also, often quite differently than in the macro-world. While nanotechnology is a very broad discipline influencing very diverse areas of science and technology (for example, from clean fuel production, through smart drug delivery to the paint and detergent industries), the development of micro­ fluidic devices is more focused. Nanotechnology is, ­typically, dealing with objects on the scale of 100 nm or smaller. Some processes commonly used in mass spectrometry prior to the current nanotechnology boom (for example, laser desorption, matrix-assisted laser desorption/ionization, surface modifications or solid phase extraction) qualify as nano­ technology. Future applications will certainly benefit from the current nanotechnology research, especially in respect of surface modifications and in combination with microfluidics for sample handling. The first examples of the development of the micro­ fabricated instrumentation can be traced back to the mid ­seventies when the reports of the famous gas chromatograph

doi: 10.1255/ejms.834

on a silicone chip were published;2 however, the major trend of miniaturization and integration of analytical processes and instrumentation has only been witnessed in the past decade. It can be anticipated that microfluidics (Lab-on-a-chip)3 will play an important role in the new instrumentation for high ­sensitivity/high throughput analyses. The main advantages of the technology include speed of analysis, minimum consumption of the reagents and samples, integration of functional elements and the possibility of creating massively parallel systems for high throughput. Typical examples of the applications of miniaturization and microfluidics in analytical instrumentation include systems for microcolumn chromatography and electrophoresis, sample processing units, for example, for preconcentration and desalting, or chemical microreactors. The current applications are aimed mainly at the analysis of deoxyribonucleic acid (DNA), proteins and peptides or drug screening. In an increasing number of cases, mass ­ spectrometry ­coupling is required and this trend will keep growing, especially with the evolution of proteomics.4 Indeed, the first commercial microfabricated systems for ­electrospray mass spectrometry coupling are already available from ­several vendors. From the perspective of a separation scientist, the leak-free, zero dead volume junctions represent one of the most important features of micro­fabricated devices. Additionally, when a structure ­performance is optimized, the available replication ­technologies can easily mass produce systems with identical performance. Fabrication tech­nology includes the processes used commonly in electronics, for example, photo­lithography and wet chemical etching or ­reactive ion etching in glass or ­silicon. Structures as small as 60 nm can currently be ­fabricated in microelectronics; however, two orders of magnitude larger structures are more common in microfluidics. Precision injec-

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tion molding can be used for replication in plastic materials. The easy replication of many identical structures opens up new possibilities for the construction of very high throughput analytical systems which are difficult or impossible to achieve with standard technologies. An example of such technology advancement is the recent development of the high throughput DNA analysis system based on parallel pyrosequencing of DNA fragments prepared simultaneously in several hundreds of thousands of microwells.5 The evolution of microfluidic systems for mass spectro­ metry coupling can be traced in a number of recent review articles.4,6–11 The first microfluidic devices for electro­spray ionization mass spectrometry (ESI/MS) coupling were reported by Karger et al.12,13 This concept of spraying directly from the surface of a chip was later expanded by Schultz and Corso14 to a microfabricated emitter which was developed into a commercial product.15 Currently, there are several directions in the development of the microfluidics for ESI-MS applications and further applications will depend on the advances in pumping systems, design of the electrospray emitters and integration of additional unit operations, such as sample preconcentration, chemical reactors or separations. Apart from the use of syringe pumps, electro-osmotic flow, generated with the help of additional electrodes integrated along the fluid path, was an obvious choice for the sample delivery.16,17 In the more recent work, both the theoretical and practical considerations of the electro-osmotic pumping systems for the use in ESIMS systems have been ­described.18 So far, the most widely used system is based on the array of nanosprayers fabricated, for example, by deep reactive ion etching in silicon.14,19 This concept, ­pioneered by Schultz and Corso,14 has recently been commercialized and fully-automated nanoelectrospray ­systems ­utilizing a micro­fabricated array of electrospray tips for infusion and liquid chromatography/mass spectrometry analyses are now available for a number of mass spectrometers.20–23 The microdevices prepared from plastic materials, including polyimide24 or polypropylene,25 were also demonstrated. A recent review on microchip devices coupled with mass spectrometry has been reported.26 The development of microfabricated systems with ­integrated separation columns is a logical extension of the miniaturization technology, eliminating some of the problems of standard approaches with the added benefit of significant space saving.27–33 In this case, the microfluidic unit serves as a miniaturized interface between the sample and the mass spectrometer. The concept has been extensively tested, particularly in conjunction with capillary electrophoresis (CE) separations and attempts to integrate additional functions, for example, on-line reactors with immobilized trypsin, have also been ­described.34,35 Given the small ­dimensions, the performance of the ­electrophoresisbased systems can be very fast with good resolution and ­ reproducibility comparable to standard ­ capillary ­electrophoresis systems. In many of the ­ early ­ designs of the CE/MS microdevices, the ESI coupling was performed using either a fused silica capillary electro­spray tip or an

Microdevices in Mass Spectrometry

external interface connected to the micro­device using a low dead volume connection. The use of the flat opening of the chip as the ESI exit port, described in the early infusion studies, turned out to be unsuitable for coupling with separations due to the very large dead volume associated with the droplet formed around the surface of the exit port. Although some encouraging results were achieved with an integrated nebulizer dispersing this droplet with ­ external aerodynamic focusing nebulizer36 or with monolithic ­material polymerized in the exit port37 preventing the formation of the droplet altogether, more work will be needed before these approaches will be ­commercially viable. Some of the latest attempts on ESI ionization nozzle fab­rication include the use of poly(dimethylsiloxane) (PDMS),38,39 SU-8 ­photoresist40–42 or using plasma or laser ­ablation for ­creation of the required structures in plastic materials such as polyimide.43–45 The first microfluidics ­ system integrating the ­ sample loading loop, chromatographic separation ­column and the electrospray exit port46 is now ­commercially ­available.47 Direct coupling of microfluidics to matrix-assisted ­laser desorption/ionization (MALDI) MS is not a mainstream ­ application at present. Although experiments with liquid matrices for on-line coupling to separations have been ­described,48 MALDI is generally practiced in an off-line ­arrangement.11,49 Quasi on-line operation utilized streaking of the effluent from the microcolumn separations on a moving surface, for example, rotating wheel50 or a polymeric film.51 A rotating ball interface was also demonstrated for on-line coupling with a polymer-based ­electrophoresis chip.52 The development of the microfluidic devices for and use of nanotechnologies in mass spectrometry coupling is still in its infancy. Multiplexed, high throughput operation is one of the strengths often mentioned when describing micro­ fluidic ­systems. The potential, especially on the technology side, has been clearly demonstrated; however, the future success will ­depend on the technological robustness as well as sufficiently low cost in daily operation to convince both the instrument manufacturers and practical users to adopt this technology in practice. Acknowledgement Supported by the Grant Agency of the Czech Republic (203/06/1685), the Ministry of Education, Youth and Sports (LC06023) of the Czech Republic and the Grant Agency of the Czech Academy of Sciences KAN400310651. References 1. 2.

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F. Foret and P. Kusý, Eur. J. Mass Spectrom. 13, 41–44 (2007)


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31��������������������������������������������������������������� . B. Zhang, H. Liu, B.L. Karger and F. Foret, “Microfabricated ����������������� devices for capillary electrophoresis-electrospray mass spectrometry��� ”, Anal. Chem. ����� 71, 3258 (1999). doi: 10.1021/ ac990090u 32������������������������������������������������������������� . B. Zhang, F. Foret and B.L. Karger, ����������������������� “A microdevice with integrated liquid junction for facile peptide and protein analysis by capillary electrophoresis/electrospray mass spectrometry��� ”, Anal. Chem. 72, 1015 (2000). doi: 10.1021/ac991150z 33������������������������������������������������������� . B. Zhang, F. Foret and B.L. Karger, “High-throughput ����������������� ­microfabricated CE/ESI-MS: automated sampling from a microwell plate��� ”, Anal. Chem. 73, 2675 (2001). doi: 10.1021/ ac001432v 34���������������������������������������������������������� . S. Ekstrom, P. Onnerfjord, J. Nilsson, M. Bengtsson, T. Laurell and G. Marko-Varga, “Integrated ���������������������������� microanalytical technology enabling rapid and automated protein identification��� ”, Anal. Chem. 72, 286 (2000). doi: 10.1021/ac990731l 35����������������������������������������������������������� . Y. Liu, H. Lu, W. Zhong, P. Song, J. Kong, P. Yang, H.H. Girault and B. Liu, ������������������������������������ “Multilayer-assembled microchip for enzyme immobilization as reactor toward low-level protein identification��� ”, Anal. Chem. ������ 78, 801 (2006). doi: 10.1021/ ac051463w 36. J. Grym, M. Otevrel and F. Foret, “Aerodynamic mass spectrometry interfacing of microdevices without electrospray tips”, Lab. Chip, in press (2006). doi: 10.1039/b605599k 37. M.F. Bedair and R.D. Oleschuk, “Fabrication of porous polymer monoliths in polymeric microfluidic chips as an ­electrospray emitter for direct coupling to mass spectrometry”, Anal. Chem. 78, 1130 (2006). doi: 10.1021/ac0514570 38. A.P. Dahlin, S.K. Bergstrom, P.E. Andren, K.E. Markides and J. Bergquist, “Poly(dimethylsiloxane)-based microchip for two-dimensional solid-phase extraction-capillary electrophoresis with an integrated electrospray emitter tip”, Anal. Chem. 77, 5356 (2005). doi: 10.1021/ac050495g 39. G. Liljegren, A. Dahlin, C. Zettersten, J. Bergquist and L. Nyholm, “On-line coupling of a microelectrode ­ array equipped poly(dimethylsiloxane) microchip with an ­integrated graphite electrospray emitter for electrospray ionisation mass spectrometry”, Lab. Chip 5, 1008 (2005). doi: 10.1039/b506289f 40��������������������������������������������������������� . K. Huikko, P. Ostman, K. Grigoras, S. Tuomikoski, V.M. Tiainen, A. Soininen, K. Puolanne, A. Manz, S. Franssila, R. Kostiainen and T. Kotiaho, “Poly(dimethylsiloxane) ������������������������ electrospray devices fabricated with diamond-like carbonpoly(dimethylsiloxane) coated SU-8 masters��� ”, Lab. Chip 3, 67 (2003)������� . doi: 10.1039/b300345k 41. J. Carlier, S. Arscott, V. Thomy, J.C. Camart, C. Cren-Olive and S. Le Gac, “Integrated microfabricated systems including a purification module and an on-chip nano electrospray ionization interface for biological analysis”, J. Chromatogr. 1071, 213 (2005). doi:10.1016/j.chroma.2004.12.037 42. S. Le Gac, C. Rolando and S. Arscott, “An open design ­microfabricated nib-like nanoelectrospray emitter tip on a

Microdevices in Mass Spectrometry

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Received: 28 November 2006 Revised: 22 January 2007 Accepted: 22 January 2007 Publication: 15 February 2007