Coupling Microfluidics with Mass Spectrometry

Combining numerous steps (reaction or sample preparation) into one miniature device provides immediate benefits for studying chemical reactions. Products of such reactions can promptly be detected by MS while reducing the time lag between the reaction and the detection. The typical flow rates in microfluidic chips are measured in microliters down to nanohters per minute thus, the microfluidic chips are compatible with some of the atmospheric pressure ion sources. 

Miniaturized ESI interfaces (nanospray electrospray ionization, nanoESI) match the dimensions of microfluidic chips. On-line couphng of microchips with ESI can be accomplished using different interface geometries blunt end, comer outlet, external capillary, external emitter, or monolithic emitter [27], some of which resemble the nanoESI emitters used in CE-MS (see also Chapter 6). In fact, on-chip capillary channels are often used as CE or LC separation columns, and directly linked with the nanoESI emitters. Atmospheric pressure chemical ionization (APCI) and photoionization (APPI) have also been subject to miniaturization but they have not attracted as much attention when it comes to hyphenation with microchips [28]. This situation may change when the novel nanoAPCI interfaces [29] are perfected, providing the way to transmit and ionize non-polar analytes at low flow rates. 

In one approach, the microchip interface was constmcted from modified 1/16-inch high-performance liquid chromatography (HPLC) fittings [30]. It incorporates a freestanding liquid junction formed via continuous delivery of a flow of suitable solvent which carries the separation effluent through a pneumatically assisted electrospray needle located in front of the MS orifice. In some cases, stmctural features of microchips can be utilized as parts of the ion source (e.g., ESI emitter). Thus, the resulting coupled microchip-MS systems are more compact, and the delay time between the on-chip incubation and MS detection can be decreased. For example, a capillary nanoESI emitter was successfully incorporated into a microchip CE channel for on-line CE-MS analysis [31]. Such microchip-MS systems do not require the use of external pumps because analytes can be driven toward the ion source (ESI or nanoESI) by means of electroosmosis and electrophoresis [32]. 

Setting up microchip-MS systems also incurs certain technical difficulties which need to be overcome. The ion source emitter needs to be aligned with the MS orifice to prevent substantial losses of analytes/ions. The small size of microchannels and emitters leads to clogging by sample residues. While the clogging issue can be solved when implementing folded polyimide tape emitters [33], such emitters may not be compatible with many types of microchips. Microchips are often fabricated in clean rooms but in MS laboratories they are exposed to a dusty environment, which - in some cases - can affect their performance. To minimize this effect, a microchip-MS interface has been developed 

Electrophoretic and chromatographic separations conducted on microchips are often fast therefore, they do not lower the temporal resolution of the whole analytical process as much as most conventional hyphenated systems (see Chapter 6). Although microscale separations are not always expected to present as good resolution as the conventional ones, they can often contribute to the selectivity of the analytical process. For example, MS cannot directly be used to distinguish ions of optical isomers. Chiral separations can be carried 

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Interfaces Between Microfluidics and Mass Spectrometry, Fig. 4 Digital microfluidics - nanoelectrospray interface, (a) Image showing the dried blood spot (DBS) and droplets sitting on actuation electrodes. The device couples directly with the nanospray (capillary) emitter, (b) Side-view schematic of the DMF device. The application... 

Baker CA, Roper MG (2012) Online coupling of digital microfluidic devices with mass spectrometry detection using an eductor with electrospray ionization. Anal Chem 84 2955-2960... 

Jin, D.-Q., Zhu, Y, Fang, Q. (2014) Swan Probe A Nanoliter-scale and High-throughput Sampling Interface for Coupling Electrospray Ionization Mass Spectrometry with Microfluidic Droplet Array and Multiwell Plate. Anal. Chem. 86 10796-10803. 

Baker, C.A., Roper, M.G. (2012) Online Coupling of Digital Microfluidic Devices with Mass Spectrometry Detection Using an Eductor with Electrospray Ionization. Anal. Chem. 84 2955-2960. 

Some reviews [5-7] have appeared on NCE-electrospray ionization-mass spectrometry (NCE-ESI-MS) discussing various factors responsible for detection. Recently, Zamfir [8] reviewed sheathless interfacing in NCE-ESI-MS in which the authors discussed several issues related to sheathless interfaces. Feustel et al. [9] attempted to couple mass spectrometry with microfluidic devices in 1994. Other developments in mass spectroscopy have been made by different workers. McGruer and Karger [10] successfully interfaced a microchip with an electrospray mass spectrometer and achieved detection limits lower than 6x 10-8 mole for myoglobin. Ramsey and Ramsey [11] developed electrospray from small channels etched on glass planar substrates and tested its successful application in an ion trap mass spectrometer for tetrabutylammonium iodide as model compound. Desai et al. [12] reported an electrospray microdevice with an integrated particle filter on silicon nitride. 

In this book we endeavor to cover most of the topics highlighted in the introduction, and to present (i) technological developments achieved for the coupling of microfluidic systems to MS, both for the ESI and MALDI ionization techniques, (ii) relevant applications of microfluidics-to-MS couplings and (iii) research aiming at miniaturizing the mass spectrometer itself. We hope thereby to give a complete and comprehensive view to the reader of the miniaturization and mass spectrometry field with this collection of chapters. 

Mass spectrometry (MS) is one of the most powerful detection techniques used in liquid-phase analyses,1 mainly due to the ease of interfacing with separation techniques such as capillary electrophoresis (CE)2,3 and high-performance liquid chromatography (HPLC).4 Due to its sensitivity and applicability to a wide variety of chemical and biochemical species, MS is also used for the analysis of (bio)chemical molecules processed in microfluidics devices.5,6 Electrospray ionization (ESI)7 10 is often used to transfer samples from microfluidics chips to a mass spectrometer, involving analyte ionization directly from solutions and operating at flow rates typically used in microfluidics devices.11 Due to its effectiveness, the use of chip-MS coupling has rapidly spread in many research areas with bioanalytical applications,12 such as the... 

Microfluidic chips and Compact disks have also been successfully coupled with MALDI-TOF mass spectrometry . 

Sung, W.C., Makamba, H., and Chen, S.H., Chip-based microfluidic devices coupled with electrospray ionization-mass spectrometry. Electrophoresis, 26,1783-1791, 2005. 

Figure 7,3 Coupling chip-based free-flow electrophoresis nanoESI-MS. (a) Layout of a microfluidic free-flow electrophoresis-MS chip (I = left), (b) The analysis principle. The separated analytes are directed towards the mass spectrometric outlet by alteration of the buffer s hydrodynamic flow. Arrows indicate relative flow rates and the rectangle ( ) labels the area visualized by fluorescence imaging [46]. Reproduced from Benz, C., Boomhoff, M., Appun, j., Schneider, C., Beider, D. (2015) Chip-based Tree-Flow Electrophoresis with Integrated Nanospray Mass-Spectrometry. Angew. Chem. Int. Ed. 54 2766-2770 with permission from lohn Wiley and Sons...

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