Advances in Microchip Liquid Chromatography - Analytical Chemistry

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Advances in Microchip Liquid Chromatography Xilong Yuan, and Richard David Oleschuk Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b04329 • Publication Date (Web): 07 Nov 2017 Downloaded from http://pubs.acs.org on November 8, 2017

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Analytical Chemistry

Advances in Microchip Liquid Chromatography Xilong Yuan, Richard Oleschuk* 1

Department of Chemistry, Queen’s University, Kingston, ON, K7L 3N6, Canada [email protected]

ACS Paragon Plus Environment


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Abstract Miniaturized analytical platforms have shown significant benefits over conventional scaled systems including reduced sample requirement, reagent consumption and increased analysis speed. Microchip liquid chromatography (chipLC) is seen as the future of liquid chromatography, where novel fabrication designs and strategies, enhanced chromatographic and substrate materials, miniaturized pumping systems, and detection methodologies are all combined. In this way fluid manipulation and detection may be “simplified” to improve ease of operation, increase sensitivity as well as reduce the environmental, and physical footprints towards both modular, portable chipLC instrumentation. This review examines the background and developments in the chipLC area with emphasis on reports that have appeared in the last two years.


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Introduction and Perspective At its most fundamental, liquid chromatography utilizes a column filled with stationary phase materials to either separate/isolate a compound (for purification) or sequentially deliver an analyte to a detector (for analysis). A wide selection of stationary phase materials is available that can provide highly selective separations based upon different chemical properties (i.e. van der Waals, hydrophobic, hydrophilic, hydrodynamic radius (size), electrostatic forces etc.) As a result, it is the most utilized separation method for compounds of moderate to low volatility, and the global market value for liquid chromatography is in excess of 5.1 billion US dollars per year (2015).1 The miniaturization of analytical platforms and the development of micro total analysis systems is driven by the idea of reduced sample requirement, reagent use, and improved analysis speed. In particular miniaturization is being directed at situations where there is a definite sample limitation, where obtaining more sample would be either difficult or impossible. The challenges to miniaturization of liquid chromatography stem from the “plumbing”, where all the fluidic components need to be assembled with ultra-low dead volume fittings because imperfections in connections, packing and injection become exacerbated as column/device dimensions are reduced. Two strategies have emerged for liquid chromatographic miniaturization. The first would be viewed as miniaturization of conventional LC technologies where column, injection volumes and detection volumes are decreased. Significant research and engineering has been invested in this strategy to reduce sample injection volume, flow / gradient delivery, column manufacture, detection volume, etc.2-4 The first commercial capillary LC instrument was introduced in 1998 after which, the market of capillary LC has grown significantly to meet the demands of bioanalysis.5



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Alternatively microchip LC (chipLC) refers to the integration of liquid handling on a planar substrate, “dubbed“ a microchip. The same functionality as the conventional miniaturized LC systems is offered, however the idea is that the microchip is a “modular” device that can simply be “plug and played”. In this way, the more complex instrumental parameters, that those of us who love chromatography like to manipulate/build, are put within a “black box”, with the hope that they can be operated by individuals with less specialized training. Furthermore, once the module has been utilized/spent, the module can be simply discarded and replaced. The advantages of chipLC have prompted the commercialization of various formats of microchip LC columns and interfaces with mass spectrometers in the past decade.6-8 Regardless of which miniaturization strategy is employed, there are fundamental reasons to miniaturize liquid chromatographic methods. Specifically, capillary LC excels in sample limited applications (e.g. “omic” studies). When coupled with a detection method favourable for miniaturization (e.g. fluorescence, electrochemical, mass spectrometry), a significant increase in mass sensitivity can be realized due to reduced sample dilution in small I.D. columns.9-11 For example, under identical chromatographic and injection conditions, a 235-fold increase in mass sensitivity is expected for a reduction of column I.D. from 4.6 mm to 300 µm.11 In addition to chromatographic performance improvements, there is a significant reduction in packing material required for column construction. The quantity of stationary phase material needed to pack a 10 cm long, 300 µm I.D. capillary column is less than 10 mg. All conditions being equal, this equates to a material saving of more than 99 % compared to a conventional 4.6 mm column, a cost saving the column manufacturers have yet to pass along to capillary LC practitioners. Moving forward, the environmental advantages of miniaturized LC are also becoming more apparent, due to significant reductions in solvent use. Although only a blip, we note the acetonitrile shortage of 2009,12 increasingly stringent disposal standards, and more


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significant disposal costs. One need only recount visits to large analytical facilities that employ large numbers of liquid chromatographs operating at mL/min flow rates, to envision how miniaturization could significantly reduce the “footprint” of liquid chromatographic analysis. Merely 200 mL solvent is consumed if a capillary/chip LC column with a flow rate of 400 nL/min is continuously operated for a year. In comparison, a conventional LC operated at 1 mL/min consumes 500 L solvents (24 hours operation per day, 360 days in a year). We have so far identified the positive attributes associated with miniaturizing LC. There are significant reasons why the analytical world has yet to completely switch to either capillary LC or chipLC systems. For the most part only those that absolutely require the increased sensitivity have adopted capillary LC and/or microchip LC. The resistance emanates from the less robust nature of capillary and microchip LC and the stresses the reduced dimensions put on analyte detection. Capillary LC is more susceptible to fluidic clogging,13 and more complex connections among microfluidic pump, sampler, capillary column, detector etc. also present the difficulty of preventing and locating fluid leakage. Solid reviews of the miniaturized liquid chromatographic field have been published in the past

9,14-18

The review by Desmet et al. in

particular has pointed out that microchip LC is the most important trend for LC miniaturization.9 This is not surprising considering the rapid development of micro total analysis systems (µTAS) beginning in the early 1990s.19,20 The reduced amount of analyte/volume utilized for chipLC necessitates significant enhancements in detector configuration, or the use of only the most sensitive detection methodologies. A decrease in channel volume significantly limits the amount of analyte available to detect. For example, 6 x1011 molecules (at 1 µM concentration) are present in 1 mm3 volume. Reducing the dimensions to 1 µm3 houses only 600 molecules at the same concentration.. Microchip LC inherits the advantages of µTAS with the potential to integrate several ACS Paragon Plus Environment


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functional components of the analytical system on a planar substrate. Development of robust, reliable and efficient chipLC relies on the cooperation of chemists, material scientists, mechanical and electrical engineers etc. Since 2010, a few review articles on chipLC were published focusing on different aspects of the development.14-18 Different metrics are used to describe chromatographic performance including sensitivity, resolution, reduced plate height (hmin), number of theoretical plates (N), peak capacity etc. These reviews provide a good introduction to basic chromatographic theory and how it relates to chipLC. The present review highlights important advances in chipLC over the past two years, relating material and fabrication, geometry and fluidic design, stationary phase formats, spectroscopic detection and interfacing with mass spectrometry etc. Figure 1, shows interesting examples of recent microchip developments from both academic researchers and the commercial sector.


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Figure 1 (A) Schematic of a 2D heart-cut microchip LC featuring 1D fluorescence detection and 2D ESI/MS for enantioselective reaction monitoring. Reproduced from Lotter, C.; Poehler, E.; Heiland, J. J.; Mauritz, L.; Belder, D. Lab Chip 2016, 16, 4648-4652 (ref 21), with permission of The Royal Society of Chemistry. (B) Schematic of microchip-based LC-CE-MS system presenting weirs for packing (blue square), valves for injection and venting, chip corner as electrospray emitter. Reprinted from Chambers, A. G.; Mellors, J. S.; Henley, W. H.; Ramsey, J. M. Analytical Chemistry 2011, 83, 842849 (ref 22) Copyright 2015 American Chemical Society. (C) Photograph of a portable microchip LC set-up with a batteryoperated electroosmotic pump, a reversed phase packed column and an electrochemical detector. Reprinted with permission from Ishida, A.; Fujii, M.; Fujimoto, T.; Sasaki, S.; Yanagisawa, I.; Tani, H.; Tokeshi, M., A Portable Liquid Chromatograph with a Battery-operated Compact Electroosmotic Pump and a Microfluidic Chip Device with a Reversed Phase Packed Column. Analytical Sciences: the international journal of the Japan Society for Analytical Chemistry 2015, 31 (11), 11631169 (ref 23). Copyright (2015) Japan Society for Analytical Chemistry. (D) A microfabricated, polyimide-laminated LC-MS device integrating rotary valves, enrichment column and nanoelectrospray tip. Reprinted from Journal of Chromatography A. Vol. 1218, Zhao, C.; Wu, Z.; Xue, G.; Wang, J.; Zhao, Y.; Xu, Z.; Lin, D.; Herbert, G.; Chang, Y.; Cai, K.; Xu, G. Ultra-high capacity liquid chromatography chip/quadrupole time-of-flight mass spectrometry for pharmaceutical analysis, pp. 36693674 (ref 24). Copyright 2011, with permission from Elsevier. (E) A microfabricated, co-fired ceramic-based LC-MS device packed with 1.7 µm particles, integrated plug-and-play connections, column heater and electrospray emitter. Figure of the iKey® from the Waters ionKey/MS® System is used with permission from Waters Corporation, Copyright 2014.



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Materials, Fabrication and Geometries Gritti et al. described that an ideal microchip LC would be able to operate at pressures as high as 10, 000 bar with integrated sample injection and detection26 and be compatible with a wide range of chromatographic mobile phase. However, current chipLC systems are unable to withstand these elevated pressures and conditions. The possibilities and limitations of microchip LC are dictated by both fabrication techniques and the material properties of their components. Material properties to consider for microchip LC construction include mechanical robustness, UV/Vis transparency, non-specific adsorption, biological compatibility, gas permeability etc. For example, organic solvents are typically used to modulate the retention characteristics of analytes percolating through the chromatographic column. However, organic solvents may cause some chip substrate materials to dissolve, swell or crack. Several excellent reviews have summarized the properties of common materials employed in microfluidic device fabrication.27-29 Silicon was the first substrate material used for microchip LC device manufacture because microfluidics researchers utilized fabrication methods honed in the semiconductor industry to create micron sized fluidic channels. However, silicon is not transparent to UV/visible light complicating device manufacture, use and optical detection. As a result, glass-based substrates attracted more attention resulting from low gas permeability, good solvent compatibility and superior optical transparency.30-32 More refined glass variants, such as quartz and fused silica could be utilized for applications where transmission at wavelengths 500 nm) of the UV region, compared with the common one-photon excitation. As a result, label-free fluorescence is possible on glass and polymeric microchips. Unlike conventional configurations for optical detection, optofluidic technologies seek to integrate all the necessary optical units onto the microfluidic device.191,192 In this way microchannels both handle the fluidics, and transmit light to probe the sample.

Electrochemical detection Electrochemical detection monitors the changes in an electrical signal due to ACS Paragon Plus Environment

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electrochemical reactions on an electrode surface. Conductivity, amperometry, and potentiometry are the most common electrochemical detection approaches in microfluidic devices and have been the subject of reviews.193-195 Randviir et al. have also contributed a review about novel electrode materials and their applications in microchip devices.196 Electrochemical detection is considered the most facile and simplest to miniaturize among all the detection techniques in microchip devices. The combination of electrochemistry and microfluidics has produced a resurgence in interest to develop sensitive, selective,

and

portable laboratory assays.197 “Microelectrodes” and “ultramicroelectrodes” provide additional benefits such as rapid response to changes in applied potential, efficient solute mass transport and the possibility to measure electrical currents as low as nanoamperes to picoamperes. Although microelectrodes generate extremely small currents, background current is reduced further, which can improve signal-to-noise ratios and potentially produce better limits of detection.193,198. Many small molecules (e.g. catecholamine neurotransmitters, nitride oxide) can be directly detected with electrochemical signals without a derivatization.193,199 One possible way to increase the sensitivity of microchip-based electrochemical analysis is through the use of an electrode array.200,201 Platinum black particles deposited on the electrode surface increased electrode surface roughness and surface area producing larger signal intensity.202,203 One of the challenges in electrochemical detection is fouling of the electrodes and their reuse. Conventional microfluidic chips with integrated electrodes do not allow the electrodes to be re-polished or regenerated if the electrode is compromised. Erkal et al. reported 3D printed threaded receiving ports with incorporated electrodes connected through commercially available, polymer-based fittings (Figure 9-1). Different electrode materials can be incorporated and polished for reuse after fouling.204 Munshi et al. compared the sensitivity of a conventional thin layer electrode (TLE, Figure 9-2) and a wall-jet electrode (WJE, Figure 9-3) approach



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using 3-D printed devices. A 16 × higher calibration sensitivity was shown using a 500 µm platinum electrode for the wall-jet electrode device, compared to the thin layer electrode design. Alternatively, a limit of detection of 500 nM was obtained for catechol with WJE, compared to 6 µM for the TLE device when using a glassy carbon electrode. A 3-D printed WJE device was used as an inexpensive electrochemical detector for HPLC.205 The number of theoretical plates was comparable to the use of commercially available UV and MS detectors (Figure 9-4) but at a significantly reduced cost/complexity. Conductivity and potentiometry are the alternative methods for electrochemical detection and capacitively coupled contactless conductivity detection (C4D) is considered one of the most promising detection approaches in microfluidic applications. Vázquez et al. reported the simultaneous determination of ionic and electroactive species using contactless conductivity and amperometry on hybrid PDMS/glass microchips.206 Beutner et al. evaluated the complementary detection capability of C4D and MS with a mixture of phenolic compounds.207 C4D was found to exhibit higher sensitivity for m-cresol, in contrast MS showed higher sensitivity for the neurotransmitters, e.g. epinephrine and dopamine. Contactless conductivity detection utilizes electrodes insulated from the electrolytic solution, overcoming the challenges in contact mode such as bubble formation and electrode fouling. However, compared to amperometric and contact conductivity detection, C4D system presents lower sensitivity (typically ~ µmol/L).208,209


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Figure 9 (1) 3D printed device used for electrochemical detection. A–B) 3D renderings of the device in Autodesk software; C–D) printed 0.5 mm-wide channel device in VeroClear material. The Pt-electrode is screwed into the electrode port, showing alignment of both Pt wires with the 0.5 mm channel (panel C). In panel D, the device is shown with the Pt-electrode, electrode leads, and the fittings used to integrate the device with a syringe pump. Reproduced from Erkal, J. L.; Selimovic, A.; Gross, B. C.; Lockwood, S. Y.; Walton, E. L.; McNamara, S.; Martin, 204 R. S.; Spence, D. M. Lab Chip 2014, 14, 2023-2032 (ref ) with permission of The Royal Society of Chemistry. (2) Schematic of the side profile of the TLE depicting the flow profile. (3) Schematic of the WJE device. As depicted, the sample flow hits the electrode normal to the surface and then flows away radially. This flow regime increases mass transfer of the analyte thus increasing the sensitivity. (4) Chromatographs of epinephrine and dopamine separation. (A) Electrochemical detection using the WJE device; (B) UV detection; (C) MS detection. 205 Reproduced from Munshi, A. S.; Martin, R. S. Analyst 2016, 141, 862-869 (ref ) with permission of The Royal Society of Chemistry.

Mass spectrometry Mass spectrometry, although the most costly of the detection methodologies, is more universal, selective and generates much more analytical information. Mass spectrometers require target analytes to be converted to gas phase ions to facilitate detection. Different ion sources may be interfaced with microfluidic chips, e.g. electrospray ionization (ESI), matrix-



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assisted laser desorption/ionization (MALDI), atmospheric pressure chemical ionization (APCI) / photoionization (APPI) etc.210-219 ESI has been the most successful and widely adopted because of high sensitivity, applicability to a wide variety of analytes, and multiple charging phenomenon. In particular, ESI is useful for proteomic and metabolomic analyses when combined with high resolution LC separation.220,221 The utility of miniaturized LC-MS devices has been the focus of commercial vendors who have launched chipLC-MS products (Figure 1D and 1E)7,25 and LC-MS interfacing instrumentation such as the Triversa Nano-MateTM and Picochip.222,223 A large number of publications for chemical and biochemical analysis are now appearing using commercial chipLC-MS devices.224-226 Zhao et al. demonstrated a commercial “ultra-high capacity” small molecule chip, featuring enhanced trapping capability (i.e. larger enrichment column) for the analysis of complex drug mixtures.24 Despite the commercial availability of microchip LC-ESI devices, enhancements are still required to meet the demands for high sensitivity, high capacity, and rapid bioanalysis. Attempts to improve chip-MS coupling have been reported, including electrospraying from the blunt end of a chip corner, attached external emitter, and monolithic emitter.213 Nozzle wetting is a potential problem of blunt end emitters that causes excessive band-broadening and sensitivity loss. To minimize droplet coalescence hydrophobic coating, chemical derivatization and pneumatically assisted spray etc.227 have been reported. In an effort to improve ionization efficiency, Xiong et al. reported a strategy to enhance nanoelectrospray ionization efficiency and inhibit ion expansion using hydrodynamic focusing.228 Belder and co-workers demonstrated monolithically integrated nanospray on the edge of a glass chip combining both pulling and HF etching steps.229,230 The same group recently demonstrated an integrated a glass chipLC-MS system and evaluated the performance of differently shaped monolithic emitters, including pulled, ground end, corner


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end, and a blunt emitter on edge of the chip (Figure 10). Similar performance was observed for each of the emitters at a relatively high flow rate, ≈ 400 nL/min. However at low flow rates (< 50 nLmin−1), the sharper, pulled nanospray emitters were necessary for the generation of a stable electrospray.32 Other coupling approaches have utilized a tapered capillary approach. Dietze et al. integrated a capillary emitter between glass plates using photo-polymerized polyethylene glycol diacrylate to form the channel network and capillary coupling.231 Polymer monolith based electrochromatography was combined with ESI-MS for reaction monitoring.232 Mats et al. demonstrated a facile emitter integration approach using microstructure fibres as both the ESI emitter and the chromatographic retaining frit.121 The microstructure fibre can be customized with predefined boron-doped regions to produce a radial micronozzle array using chemical etching.233 For additional information readers are directed to recent reviews regarding LC-MS coupling methods of LC-MS 211,234 Although the marriage of large mass spectrometers and small microchips has begun to address the challenges in proteomics and metabolomics studies, the further miniaturization and integration of mass spectrometer instrumentation, including ion source, mass analyzer, detector etc. holds significant potential. Miniaturization of mass analyzers, i.e. ion trap, quadrupole, time of flight, and electrostatic / magnetic filters, detectors, and pumps have been recently reviewed.235,236 and point to the development of small footprint portable chipLC-MS systems for field use or even out of this world applications.237,238



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Figure 10 Schematic drawings (top row) and SEM images (bottom row) of different electrospray emitter geometries. The schematic drawings of the chip show the elution channel with integrated particulate column and one embedded platinum electrode. The elution channel is depicted about three times larger than in the actual chip. The SEM image of the pulled emitter shows the emitter in a side view with cover slide removed revealing the tapered channel. The other geometries are shown in frontal views. Reprinted from Lotter, C.; Heiland, J. J.; 32 Thurmann, S.; Mauritz, L.; Belder, D. Anal. Chem. 2016, 88, 2856-2863 (ref ). Copyright 2016 American Chemical Society.

Outlook It has been 10 years since the first chipLC instrumentation was commercialized. However, adoption of chipLC has not been rapid. There is clearly a movement towards lower flow liquid chromatographic systems with reduced solvent/sample consumption and commensurate smaller physical and environmental footprint. These reductions however can be obtained through the use of downsized traditional chromatographic instrumentation (i.e. micro and nanoliquid chromatography). Notwithstanding there is also a clear direction to move liquid chromatography out of the hands of experienced separation scientists and into to those of less trained operators. For this to happen more facile modular systems that operate in a “plug and play” fashion need to be developed. This, combined with the advantages of portable, field deployable instrumentation will continue to fuel miniaturized column, pumping, detection and chipLC development]at least until the Star Trek tricorder becomes a reality, putting many an


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analytical chemist out of business.

Author Information Corresponding Author *E-mail: [email protected]. Tel: +1.613.533.6704.

Notes The authors declare no competing financial interest.

Biographies Xilong Yuan obtained his MSc degree in 2013 from Xi’an Jiaotong University (Xi’an, China) and is currently a Ph.D. candidate in the Department of Chemistry at Queen’s University (Kingston, ON, Canada). Part of his research focused on the development of chromatographic techniques used for drug development from natural products. He is currently engaged in the development of an environmentally friendly liquid chromatography technique, aimed at reducing the footprint of chemical analysis. He is also interested in research in digital microfluidics and stimuli-responsive materials. Richard Oleschuk obtained his Ph.D. from the Department of Chemistry at the University of Manitoba. Following he was a Natural Sciences and Engineering Research Council (NSERC) Postdoctoral Fellow in Dr. Jed Harrison's laboratory at the University of Alberta. He is currently a full professor at the Queen’s University (Kingston, ON, Canada) and teaches courses on instrumental chemical analysis and microfluidics. His research interests lie in the development of materials / methods for improved separation efficiency and electrospray



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ionization, as well as novel techniques for droplet-based microfluidics.


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Advances in Microchip Liquid Chromatography - Analytical Chemistry

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