Article pubs.acs.org/ac
Development and Characterizations of a Miniature Capillary Electrophoresis Mass Spectrometry System Muyi He,†,⊥ Zhenhua Xue,†,⊥ Yinna Zhang,† Zejian Huang,‡ Xiang Fang,‡ Feng Qu,† Zheng Ouyang,§ and Wei Xu*,† †
Department of Biomedical Engineering, Beijing Institute of Technology, Beijing 100081, China National Institute of Metrology, Beijing 100013, China § Biomedical Engineering Department, Purdue University, West Lafayette, Indiana 47907, United States ‡
S Supporting Information *
ABSTRACT: A miniature capillary electrophoresis mass spectrometry (CE/MS) system has been developed in this work. A 100% electrical driven miniaturized CE device was integrated with a miniature MS instrument, which has a discontinuous atmospheric pressure interface (DAPI) for coupling with atmospheric pressure ionization sources. A nanoelectrospray ionization (nano-ESI) source was developed with a sheath liquid interface for coupling the miniature CE and the MS system. A systematic characterization and optimization of the analytical performance have been done. The analysis of isobaric peptides and avoiding charge competition effects in nano-ESI sources have been demonstrated.
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discontinuous atmospheric pressure interface (DAPI)30 has enabled the coupling of atmospheric pressure ionization and ambient ionization techniques with miniature mass spectrometers. Nonvolatile analytes in complex mixtures, especially biological samples could be analyzed directly,31 which would extend the application of miniature MS systems in POCT for biofluid analyses. With the characteristics of low power consumption and small size, CE is a favorable choice in the development of miniature analytical systems for enhanced liquid sample analysis.32,33 However, it remains challenging when coupling a CE device with mass spectrometers, even for lab-scale instruments.34 In this work, a proof-of-concept miniature CE/MS system has been developed for providing an enhanced liquid sample analysis capability. A miniaturized CE device using only two high voltage supplies, a CE separation capillary and a buffer vial was integrated with a miniature mass spectrometer of a DAPIRIT (rectilinear ion trap, RIT) configuration. A modified nanoESI ionization source was utilized to combine the miniature CE device with the miniature MS device. As a demonstration, isobaric ions and ions with charge competitions were separated and analyzed with the miniature CE/MS instrument after performance optimization.
he coupling of chromatography with mass spectrometry systems has been widely used in the analyses of complex mixtures, such as biological samples.1 The separated analytes from gas chromatography (GC),2 liquid chromatography (LC)3 or capillary electrophoresis4,5 are introduced sequentially into a mass spectrometer for MS and/or tandem MS analyses. With high sensitivity and selectivity, GC/MS, LC/MS and CE/MS have demonstrated capabilities for many applications, such as pharmaceutical drug development,6 metabolomics,7,8 proteomics,9,10 etc. Conventionally, these integrated systems are very delicate and of large sizes, which limits their applications outside the laboratories.11 With the demanding needs for in situ chemical analysis in the fields of environmental monitoring, space exploration, homeland security and point-of-care testing (POCT),12 there have been extensive efforts focused on the development of miniature MS systems13 and portable ion-mobility (IM) systems.13−16 Normally working at relatively higher pressure regions, IM systems are small in size, and have been widely applied in many on site applications, especially for the detection of explosives17,18 and drug abuses.19,20 With enhanced chemical analysis capabilities, miniature mass spectrometers equipped with quadrupole ion trap,21 quadrupole mass filter,22 time-of-flight (TOF)23 or Mattauch−Herzog sector24 have been developed. Most of these instruments have the gas samples leaked into the vacuum, ionized through electron impact (EI) ionization and then mass analyzed subsequently by the mass analyzer.25 Portable GC/MS and IM/MS systems have been developed for the analyses of complex samples.26−29 The invention of © XXXX American Chemical Society
Received: October 7, 2014 Accepted: January 18, 2015
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DOI: 10.1021/ac504868w Anal. Chem. XXXX, XXX, XXX−XXX
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INSTRUMENTATION The miniature CE/MS system consists of three major components: a miniature CE (mini-CE) device, a miniature MS (mini-MS) device and an interface to couple these two devices together (Figure 1). A nano-ESI emitter was used as the
pump (Hipace 10, Pfeiffer vacuum Inc., Germany) and a rough pump (KNF PM25210-84.3 Inc., USA) were used in combination to pump the vacuum chamber. As shown in Figure 1a, a rectilinear ion trap (RIT) was used as the mass analyzer.38,39 The RIT has dimensions of 5 × 4 mm (center-toelectrode) in the x−y cross section, and 40 mm in the zdirection. The electronic control system was developed in house, which provided a radio frequency (rf) signal, a dipolar alternative current (AC) or a SWIFT (stored waveform inverse Fourier transform) signal and multiple direct current (DC) signals. Scan function and operation of the mini-MS system was similar to that described in other works.40−42 Integration of the CE/MS System. Coupling of the CE and the MS devices was achieved through a nano-ESI emitter.43 The CE capillary was inserted into the nano-ESI glass capillary (0.8 mm i.d. × 1.5 mm o.d.) with a sheath liquid interface design.44 The HV2 applied in the nano-ESI emitter provides not only a potential reference for the CE separation but also the voltage required for the electrospray ionization. Without the use of a machinery pump, another important role of HV2 is to drive the sheath buffer in the nano-ESI glass capillary to emitter end based on electroosmotic flow to assist the ESI process.33 A micropipette puller (model P-1000, Sutter Instrument Inc., USA) was used to pull the glass capillaries, whose tip diameters could be tuned within a 1−20 μm range. In a typical sheath flow interface, both acidic and basic CE separation buffer could be used, because the ESI spray condition could be controlled by the sheath buffer.43,45 In this simplified CE/MS interface, the flow rates of CE and nano-ESI are equal to each other (details in the Instrument Optimization section), a solution of 20% methyl alcohol, 80% deionized water and 0.1% formic acid (v:v) was used for both CE separation and nano-ESI. This configuration simplifies the structure of the whole instrument. Another reason to choose nano-ESI as the interface is because CE and nano-ESI have similar flow rates, which would be further discussed in later sections. Samples. Vitamin B1, rhodamine B, MRFA, bradykinin, angiotensin II and angiotensin I were purchased from SigmaAldrich (St. Louis, MO, USA). Samples used for nano-ESI were made by diluting rhodamine B, MRFA and angiotensin II into the solution of 20% methyl alcohol, 80% deionized water, 0.1% formic acid (v:v), resulting in concentration of 10, 20 and 500 μg/mL, respectively.
Figure 1. Schematic structure (a) and 3D structure (b) of the mini CE/MS system. EM, electron multiplier.
interface. Conceptually, a liquid sample is introduced into the mini-CE device, with the analytes separated and then sprayed by the nano-ESI emitter for analysis by the mini-MS. Mini-CE Device. To perform the CE, an electric field (voltage per length) along a fused-silica capillary (50 μm i.d. × 360 μm o.d.) was established with two high DC voltages, as shown in Figure 1a. Liquid sample was transfused into the capillary from the solvent vial with a high voltage (∼7 kV) provided by HV1. In lab-scale CE systems, solvent pumps are typically used to load the samples and/or to drive the liquid flow. To minimize the size and power consumption of the CE device for miniature systems, loading and separation of the samples are all driven by electric field in the mini-CE design. Capillary zone electrophoresis was used for the separation of samples in the capillary, and an electroosmotic flow (EOF) was established to push both positive and negative ions forward. A DC field of 7 kV across the capillary was established with the HV1 of 8.5 kV applied at the entrance end the HV2 of about 1.5 kV applied at the exit end of the capillary (in the nano-ESI emitter). The ions were separated in the capillary based on their physical size and their number of charges. Capillaries with different lengths (20−40 cm) have been tested. Ionization of the capillary wall was enhanced by flushing the capillary once using NaOH (0.1 M) for 30 min, then flushing once again using deionized water for 30 min and finally flushing with running buffer solution for 30 min. Mini-MS Device. Separated fractions from CE were sprayed and ionized by the nano-ESI source. To efficiently transfer the ions from ambient environment to the mass analyzer in a vacuum, the discontinuous atmospheric pressure interface (DAPI)35−37 previously developed at Purdue University was applied for the mini-MS design in this work. A turbo molecular
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RESULTS AND DISCUSSIONS With reduced dimensions and simplified structures, the performance of the mini-CE and mini-MS devices might be compromised. The coupling of CE/MS is also sensitive to many parameters of the setup, such as the value of HV2, tip diameter (d) of the nano-ESI emitter, the distance (L) between the nano-ESI tip and the outlet of the CE capillary, sample loading duration, and the length of the CE capillary. Therefore, an optimization process was carried out to enhance the sensitivity and CE separation resolution of the miniature CE/ MS system. Instrument Optimization. Flow Rate. The flow rate of the CE needed to match that of the nano-ESI; otherwise, the separated fractions out of the CE capillary would remix inside the nano-ESI capillary, if the CE flow rate was too high; or the ion current would be compromised if the CE flow rate was too low. In the experiments, the CE flow rate was adjusted by both the capillary length and the voltage applied across the capillary. In this optimization process, the electric field applied in the CE B
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Figure 2. Optimization of the CE/MS interface. (a) Tip diameter optimization of the nano-ESI emitter. Rhodamine B 10 μg/mL, capillary length ∼ 20 cm, voltage density ∼ 175 V/cm. (b) Distance, L optimization. L: Distance between the nano-ESI emitter tip and the CE outlet. MRFA 5 μg/mL, capillary length ∼ 25 cm, voltage density ∼ 175 V/cm.
Figure 3. (a) Sample loading duration optimization. MRFA 5 μg/mL, capillary length ∼ 25 cm, voltage density ∼ 175 V/cm. (b) CE capillary length effects on mixture separation. Mixture of MRFA (10 ug/mL) and angiotensin II (250 μg/mL), voltage density ∼ 175 V/cm.
capillary was set at ∼175 V/cm, and the length of the capillary was ∼20 cm. With these conditions, the flow rate within the CE capillary was about 67 nL/min (see the Supporting Information for details). The flow rate of the nano-ESI spray was then tuned by changing the diameter of the spray tip and spray voltage HV2. As shown in Figure 2a, a nano-ESI emitter of a tip diameter ∼2.57 μm was initially used with HV2 = 1 kV. However, flow rate of the nano-ESI (∼47 nL/min) was smaller than that of the CE. Both tailing (fwhm ∼ 4 min) and dilution effects could be observed in the electropherogram (top panel in Figure 2a), which was recorded by monitor the analyte ion (rhodamine B) current in the MS spectra as a function of time. To increase the flow rate for the nano-ESI, both the tip diameter and HV2 were increased. At the tip size of about 10.75 μm and an HV2 of 1.5 kV, the flow rates of CE and nano-ESI matched each other well
at about 67 nL/min (see the Supporting Information for details). As shown in the bottom panel of Figure 2a, a peak in electropherogram with much stronger intensity and narrower width (fwhm of 0.6 min) was obtained for rhodamine B. The use of emitters with larger tip sizes also avoids peak tailing effects from blocking of the tip. Furthermore, when a 10.75 μm emitter was used, the distance between spray emitter orifice and separation capillary outlet would be significantly smaller than that from a 2.57 μm emitter, and sample diffusion in the emitter could be minimized.43 Liquid Junction at the Tip of the Nano-ESI Emitter. With the CE capillary inserted into the nano-ESI emitter, the liquid junction between the CE capillary outlet and the emitter tip serves as a coupling interface between CE and nano-ESI; however, the analyte eluted out of the CE capillary could also be dilute in this junction. It has been shown that the detection C
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ratio will be smaller for the 40 cm capillary than those of the other two capillaries. Characterization of the Mini-CE Device. To characterize the reproducibility of the CE/MS method, rhodamine B (0.1 mg/mL) and a mixture of bradykinin (2 mg/mL), angiotensin I (4 mg/mL) and angiotensin II (2 mg/mL) were tested (Figure 4). Under optimized conditions, the miniature CE setup gave
sensitivity is highly related with the distance between the separation capillary outlet and spray emitter orifice,43 and this distance has been reduced to 200 μm for improved sensitivity.46 Therefore, the volume of the liquid junction should be minimized to avoid unnecessary dilution and diffusion in the spray emitter. Meanwhile, a gap should also be kept between the end of the CE capillary and the conical tip of the nano-ESI capillary to allow sheath solution flow within the nano-ESI capillary. In the mini CE/MS setup, an L of ∼1 mm was chosen, and the ion signal decrease in Figure 2b shows the dilution effect for MRFA ions with increased L. Longer diffusion distance in the spray emitter would lead to a broader sample plug.43 On the other hand, the dilution of MRFA and a relatively low MS sensitivity (∼5 μg/mL for MRFA, see the Supporting Information for details) would cause narrowing of the MRFA peak (see the Supporting Information for details). As a result, a narrower peak was observed, when L = 1.5 mm. Another possible reason is that when the distance is ∼1 mm, the capillary outlet is close to the spray emitter inner wall, which might distort the sheath flow in the spray emitter and increases the sample diffusion in the emitter. CE Operation Condition Optimization. Sample Loading Duration. In the mini CE/MS system, samples were injected into the CE capillary using a 7 kV potential established with the two DC power supplies. The amount of samples introduced was dependent on the sample loading duration, which has been varied among 10, 15 and 20 s for the testing of MRFA. The chromatography results are shown in Figure 3a. With a longer sample loading duration, 20 s for example, a broader chromatography peak with sever tailing was observed. For 10 and 15 s, chromatography peaks with similar width were obtained. To maximize ion signal intensity, a sample loading duration of 15 s was chosen in later experiments. CE Capillary Length and Separation Voltage Effects. It is known that the length of the fused-silica capillary would affect the separation resolution of CE. However, the use of a longer CE capillary normally requires a higher DC potential applied across the capillary to sustain adequate electric field along the capillary. To minimize dimension of the CE device as well as to maintain an acceptable performance, effects of separation voltage across the CE capillary as well as the length of the capillary were investigated. Higher separation voltage would result in sharper CE peaks; however, it also requires high voltage generation modules with larger dimensions and bigger power consumptions (see the Supporting Information). Nevertheless, without temperature control in the miniaturized CE device, heating effect would be another problem with high separation voltages. As a result, a 7 kV separation voltage was selected. While keeping other operating conditions unchanged (such as HV1 8.5 kV, HV2 1.5 kV and sample loading duration 15 s), CE capillaries with different lengths were tested. A mixture of MRFA and angiotensin II was loaded in CE capillaries with lengths of 20, 30 and 40 cm, respectively. The voltage drop was kept at 7 kV to maximize the usage of the high voltage module. The separation results are shown in Figure 3b. Increased capillary length has been shown to provide better separations. MRFA and angiotensin II could be completely separated with a 40 cm long capillary, at the cost of longer migration time. The improved separation could be due to two reasons: (1) longer separation capillary; (2) the smaller injected sample ratio. Because the total voltage drop across different capillaries was kept the same for sample injection (15 s), the injected sample
Figure 4. Reproducibility of the CE/MS system. Repeated measurement of (a) rhodamine B (0.1 mg/mL); (b) a mixture of three peptides. 1, bradykinin (2 mg/mL); 2, angiotensin I (4 mg/mL); 3, angiotensin II (2 mg/mL).
satisfactory reproducibility, and the RSD of parallel test was less than 1%. For the mixture of three peptides, three peaks could be observed for these three peptides; however, baseline separation was not achieved for bradykinin and angiotensin I. Besides peak tailing effects from the high sample concentrations, the miniaturization and simplification of the CE system result in a performance sacrifice. Limit of detection (LOD) of the CE/MS system is on the level of μg/mL (1 μg/ mL for rhodamine B and 5 μg/mL for MRFA), and details could be found in the Supporting Information. Analysis of Isobaric Ions. Typically, trade-offs are made for the miniaturization of an analytical instrument. For instance, the mass resolution and/or sensitivity of a miniature MS device could be worse than a lab-scale instrument.47 A similar situation could apply for a CE miniaturization process. Due to the use of air as buffer gas, fabrication (or assemble) imprecision of the ion trap, the instability of control electronics, the mass resolution of the miniature MS used in this work is at a fwhm of ∼1.1 Da for m/z 524.5 Da, in comparison with a unit or better resolution for lab-scale instruments. The combination of the CE and miniature MS could certainly provide a much improved performance for chemical analysis. As a demonstration, a mixture of peptides, MRFA and angiotensin II was analyzed using the miniature CE/MS system. Optimized experiment conditions were applied, viz. nano-ESI tip diameter ∼ 11 μm, distance between CE capillary outlet and nano ESI tip L ∼ 1 mm, sample loading duration 15 s, CE capillary length 40 cm, and potential across the CE capillary 7 kV. Ionized by the nano-ESI source, protonated MRFA (m/z 524.3) doubly protonated angiotensin II (m/z 524.1) could not be well resolved in MS spectra if directly analyzed using the miniature MS (Figure 5a). With the miniCE/MS system, MRFA and angiotensin II could be well separated by CE prior to the MS analysis by the miniature MS, D
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Figure 5. Isobaric ion analyses. (a) Mass spectrum for the mixture of MRFA (singly charged) and angiotensin II (doubly charged). (b) CE chromatograph of MRFA and angiotensin II. Insets: isolated mass spectra of MRFA and angiotensin II, respectively. (c) Tandem MS of MRFA. (d) Tandem MS of angiotensin II.
Figure 6. (a) Nano-ESI mass spectrum of the mixture vitamin B1 and angiotensin I. (b) CE chromatography results. Insets: mass spectra of vitamin B1 and angiotensin I, respectively.
both vitamin B1 and angiotensin I could be observed when
as shown in Figure 5b. To further confirm the two chromatography peaks in Figure 5b, tandem MS experiments were also performed (Figure 5c and 5d), which confirm that the first peak corresponds to MRFA ions and the second peak corresponds to angiotensin II ions. Avoiding Charge Competition Effects. In an ESI source, the ionization efficiency differences between different ions would cause huge ion intensity differences in a mass spectrum, which is typically referred as the charge competition effects.48 With the single-stage vacuum chamber and a simplified ion transfer device (DAPI rather than complicated ion optics), sensitivity of the miniature MS would be not as good as a labscale instrument. The loss of sensitivity will then aggravate the charge competition effects. Figure 6a shows the nano-ESI mass spectrum of vitamin B1 (50 μg/mL) and angiotensin I (125 μg/ mL) mixture, in which the mass peak of angiotensin I was buried in the background due to the charge competition effects, as well as the low sensitivity of the mini-MS. With the help of CE separation in front, vitamin B1 and angiotensin I could be separated before undergoing the ionization process, therefore, avoiding the charge competition effects. As shown in Figure 6b,
using the mini CE/MS system.
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CONCLUSIONS
In this work, an integrated miniature CE/MS system was developed. A 100% electrically driven CE system was coupled with a DAPI-RIT MS system through a sheath liquid interface design. The system was further optimized with respect to different instrument parameters, including matching the flow rates of CE and nano-ESI, minimizing dilution and peak tailing effects, improving the chromatography separation resolution under limited voltage conditions. Performance of the CE/MS was demonstrated in the analysis of isobaric ions and avoiding charge competition effects in the nano-ESI source. As demonstrated with the proof-of-principle study, further development of the system and associated analytical method would provide a potentially powerful analytical tool. E
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ASSOCIATED CONTENT
S Supporting Information *
Details on the flow rate, CE peak narrowing effect, detection limit and CE separation voltage. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Wei Xu. E-mail:
[email protected]. Phone: +86-01068918123. Author Contributions ⊥
These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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REFERENCES
This work was supported by National Natural Science Foundation of China (21205005), Ministry of Science and Technology of China (2012YQ040140-07 and 2011YQ0900502), 1000-Talent Plan of China.
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