Chip-CE/MS using a flat low-sheath-flow interface

Research Article

Chip-CE/MS using a flat low-sheath-flowinterface

A chip-CE/ESI/MS interface based on a low-sheath-flow design has been developed.

A flat low-sheath-flow interface was fabricated to facilitate the coupling with a CE

microchip. The interface consists of a PMMA reservoir block, a PMMA platform and

a replaceable ESI sprayer. A CE interface was constructed by using a wire-assisted epoxy-

fixing method to connect a 1.5 cm connecting capillary to the end of chip-CE channel.

The opposite end of the connecting capillary was tapered to approximately 40 mm od to fit

tightly inside the back end of a removable fused-silica capillary ESI sprayer, which was

also tapered to give a 10 mm orifice. With this 1.5 cm connecting capillary, the sheath

liquid flowed coaxially around the connecting capillary to create a low dead volume liquid

junction at the interface between the connecting capillary and the ESI emitter. An

advantage of the current design over existing chip-based CE/MS interfaces is that ESI

emitter can easily be replaced. The analytical utility of this microdevice was demonstrated

by the analysis of two synthetic mixtures: a series histamine antagonists and a mixture of

synthetic peptides.

Keywords:

Chip-CE/MS / Flat low-sheath-flow interface / PMMA microchipDOI 10.1002/elps.200800271

1 Introduction

CE is widely accepted as a high-performance separation

technique that has been applied to the analysis of several

molecular classes including DNA, proteins, peptides and

drugs. CE offers numerous practical advantages such as

high separation efficiency, high speed and low sample

consumption. In recent years, CE analysis has moved

beyond the traditional fused-silica column format and is

now frequently performed in separation channels fabricated

within microchips. The motivation behind microchip-based

CE is that it can execute high resolution separations in a

short time period (several hundred seconds), permits

integration of sample preparation and analysis in a single

device, and allows fabrication of high-density arrays for

increased throughput.

Many chip-based ESI/MS devices have been proposed

[1–3]. A common feature of these devices was that the

electrospray voltage was directly applied to the sample

reservoir to drive sample solution to the sprayer. In contrast

to infusion analysis, successful operation of a chip-CE/ESI/

MS system requires independent optimization and

control of the voltages delivered for CE and ESI. Thus, an

important feature of any CE/MS interface is the means by

which electrical voltage is applied to the CE outlet/ESI

electrode.

Over the past two decades, a variety of CE/ESI/MS

interfaces have been reported. These interfaces can be

classified into three broad categories: sheath flow [4–7],

sheathless [8–10] and liquid junction interfaces [11, 12]. The

sheath flow interface is the most popular CE/MS interface.

In a conventional sheath flow interface, the outlet of the CE

capillary is simply inserted into the ESI probe. With this

configuration, electrical connection to the CE outlet is

achieved using a sheath liquid that mixes with the CE buffer

at the CE outlet through outer coaxial stainless steel tubing

[4, 5]. Because of its ability to modify running buffer before

spraying, the sheath flow interface accommodates a wide

range of buffer systems [13, 14].

Unlike column CE/MS, which often adopts a sheath

liquid approach, the sheathless interface is the most popular

design for chip-based CE/MS applications [15–19].

Comparatively few reports have appeared in the literature

utilizing a sheath liquid design for chip-based CE/MS. The

incorporation of a sheath liquid for chip-based CE/MS

generally occurs by one of two approaches: the utilization of

an external connection [20–22] or through an integrated

design [23]. The first use of an external connection was

reported by Harrison and co-workers [22]. In this micro-

device, a 10–40 cm capillary was used to couple the chip to a

conventional coaxial sheath flow interface. More recently,

Zheng et al. [21] used a similar approach to couple chip-CE

Fu-An LiJu-Li HuangGuor-Rong Her

Department of Chemistry,National Taiwan University,Taipei, Taiwan

Received April 25, 2008Revised June 20, 2008Accepted June 23, 2008

Correspondence: Professor Guor-Rong Her, Department ofChemistry, National Taiwan University, No. 1, Section 4,Roosevelt Road, Taipei 106, TaiwanE-mail: [email protected]: 1886-2-23638058

& 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.electrophoresis-journal.com

Electrophoresis 2008, 29, 4938–49434938

to an IonSprayTM MS interface. A sheath liquid design

using the concept of free-standing liquid junction was first

proposed by Wachs and Henion [24] for coupling to a

microchip. In this design, the sprayer utilized a free-stand-

ing liquid junction and a dynamic flowing ‘‘liquid bridge’’

formed by the surface tension resulting from the continuous

flow of a suitable sheath liquid (2–6 mL/min). An integrated

sheath liquid interface was reported by Sikanen et al. [23],

who used negative photoresist SU-8 to fabricate an inte-

grated CE/ESI microchip. The sheath flow interface was

created within the microchip using standard lithographic

processes.

A common problem with a sheath liquid interface

is its high sample dilution factor. Because the flow rate

of a polymeric chip is typically low (�50–100 nL/min),

excessive dilution occurs using standard sheath flow

rates that are commonly in the range of a few microliters

per minute.

Among the published sheath flow chip-CE/MS

approaches [20–22], one design [20] employed the concept of

a low-sheath-flow (low dilution) approach. In this approach,

a PEEK tee unit was used to connect the CE chip

to a nanoESI spray emitter using a delivery capillary in

combination with a sheath liquid transfer line. The sheath

liquid flow rate was optimized to be about 200 nL/min.

Unfortunately, in this design the chip was fixed to the

interface making it difficult to replace a clogged or damaged

ESI sprayer.

The concept of using a removable ESI sprayer has

been proposed in chip-CE/MS [25, 26]. An advantage of

using a removable ESI emitter is that the ESI emitter

can be easily replaced. In this paper, we present

a microdevice for CE/ESI/MS analysis consisting of a

PMMA-CE microchip and a flat low-sheath-flow ESI/MS

interface with a removable ESI sprayer. A flat low-sheath-

flow interface was fabricated to facilitate the coupling

with a PMMA-CE microchip. A small piece of fused silica

affixed to the PMMA chip was used to connect the

PMMA chip to removable ESI emitter. A reservoir fabricated

from PMMA was used to deliver the sheath liquid coaxially

to the transfer line to the ESI emitter. The device

was designed to have a removable ESI sprayer and low

sample dilution factor. Results are presented from

the analysis of representative mixtures to illustrate the

potential of this new device.

2 Materials and methods

2.1 Materials and sample preparation

The PMMA plates were obtained from Chi Mei (Tainan,

Taiwan). The fast fixing epoxy resin (4 min) was obtained

from Kuo Sen (Taipei, Taiwan). Fused-silica tubing was

obtained from Polymicro Techniques (Phoenix, AZ,

USA). Glacial acetic acid, ammonium hydroxide and

methanol (HPLC grade) were purchased from J. T. Baker

(Phillipsburg, NJ, USA). Peptide standard mixture, carbi-

noxamine, pheniramine, chloropheniramine, bromophenir-

amine, doxylamine, formic acid and 48% HF were obtained

from Sigma-Aldrich Chemical (St. Louis, MO, USA).

The running buffers for peptide and histamine antagonist

analysis were 1% acetic acid aqueous solution and 80 mM

formic acid adjusted to pH 3.5 with ammonium hydroxide,

respectively. Before use, the solution was filtered through

a 0.22-mm syringe filter (Pall Gelman Laboratory, Ann

Arbor, MI, USA). The concentration of peptide mixture

and histamine antagonist mixture were 20 pmol/mL

and 20 mg/mL in running buffer, respectively. Deionized

water (Milli-Q Water System, Millipore, Bedford, MA, USA)

was used in the preparation of the buffer solution

and sheath liquid. All chemicals were used without further

purification.

2.2 Microchip fabrication

The PMMA chip, shown in Fig. 1A, consisted of two

PMMA plates (65 mm� 25 mm� 2 mm) with a 45 mm

separation channel (from the injection cross to the channel

exit) and a 15 mm injection channel (7.5 mm from the

sample reservoir to the injection cross and 7.5 mm from

the injection cross to the sample waste reservoir). The

exit of the separation channel is connected to a small

piece of fused-silica capillary as a connecting capillary

between the CE microchip and the flat low-sheath-

flow interface.

The method for fabricating the PMMA-CE microchip

was based on our previous work [27]. Briefly, the channel on

the PMMA microchip was fabricated by hot imprinting

method based on a silicon master, and closed by thermally

bonding with a covering PMMA plate. The silicon master

was created using standard photolithographic procedures

and deep reactive ion etching performed in a Surface

Technologies Systems machine (STS, Newport, UK). To

imprint the channels, the silicon template with protruding

features was used to imprint the channel pattern onto 2.0-

mm-thick PMMA substrates. The hot imprinting and

bonding processes were performed in a gas chromatography

oven (GC-17A, Shimadzu, Japan). Before the imprinting,

the PMMA surfaces were cleaned by soaking the plate in

isopropanol, and then rinsed thoroughly with deionized

water in an ultrasonic bath. Blank PMMA plate and silicon

master were sandwiched between two glass plates (5-mm

thick) by a homemade clamp device, and were placed into an

oven at 1401C for 10 min. Prior to bonding, three access

holes (3 mm in diameter) were drilled through the cover

plate (4 mm in thickness). The two PMMA plates were

bonded by application of appropriate pressure and heat

(1001C) using the same clamp device. After 10 min, the

clamp device was removed, and the bonded chip was

annealed at 1001C for another 5 min. After cooling to room

temperature, the PMMA chip was ready for coupling of the

ESI sprayer.

Electrophoresis 2008, 29, 4938–4943 Microfluidics and Miniaturization 4939


2.3 The attachment of a connecting capillary to the

CE chip

The connection between the exit of the microchannel and

the connecting capillary is by means of a wire-assisted

epoxy-fixing method [27]. A 5-cm tungsten wire (30-mm

diameter, S.I.S., Ringoes, NJ, USA) was first cleaned with

methanol, and then inserted throughout a 3-cm length

fused-silica capillary (50-mm id; 375-mm od). One end (about

1 cm) of the wire was inserted into the outlet of the PMMA

channel. The 3-cm capillary was then fixed on the chip using

fast fixing epoxy resin. After the epoxy was cured, the wire

was withdrawn from the device.

Next, a small weight (about 50 g) was attached to the

capillary end of the microdevice, and the capillary was

drawn to a taper tip using a propane–butane microtorch. To

make �40 mm tip, the tapered tip was etched in 48%

aqueous hydrogen fluoride solution for �1.5 min. Following

etching, the capillary was washed with deionized water.

2.4 The fabrication of a flat low-sheath-flow

interface

As shown in Fig. 1b, the low-sheath-flow interface consisted

of a PMMA sheath liquid reservoir block (25 mm�8 mm� 10 mm), a PMMA plate (75 mm� 25 mm�1.0 mm) and an ESI sprayer. An enlarged cartoon of the

interface is shown in Fig. 1C. A sheath liquid reservoir was

created using a 3-mm od driller and drilled to 9 mm in

depth. Two channels with different dimensions were drilled

through the PMMA block and across the sheath liquid

reservoir. The larger channel (870-mm id) was used for

inserting an ESI sprayer. A 1.0 cm� 700 mm id� 850 mm od

fused-silica capillary with a tapered tip (10 mm orifice) was

used as the ESI sprayer. A tapered end is created at the end

of the larger channel (Fig. 1C) so that the end of the sprayer

will not be inserted into the reservoir. The smaller channel

(400-mm id) was used for inserting the connecting capillary

(�375-mm od) into the low flow interface. A platinum wire

(250-mm od) was inserted into the reservoir and immersed

in the sheath liquid to provide the voltage necessary for ESI

operation. The sheath liquid was delivered to the reservoir

continuously by a syringe pump.

2.5 Chip-CE/ESI/MS analysis

Prior to the chip-CE/ESI/MS analysis, the CE chip was slid

into the interface as shown in Fig. 1D. The reservoirs in

the CE chip were then filled with the sample solution

and running electrolyte respectively, and the electrophoresis

voltages were supplied by platinum electrodes immersed in

the electrolyte from two high voltage power supplies

(CZE1000R and CZE2000, Spellman, Hauppauge, NY,

USA). The ESI voltage was provided by the LTQ ion

trap mass spectrometer (ThermoFinnigan, San Jose, CA,

USA). Four different sets of voltages were applied to

the various reservoirs during loading and separation

steps. During sample loading, the voltages were applied

as follows: reservoir B 10.8 kV; reservoir S 10.8 kV; ESI 1

1.2 kV; reservoir SW 0 V and reservoir B 11.2 kV; reservoir

S 11.0 kV; ESI 11.2 kV; reservoir SW 0 V for peptides and

histamine antagonists loading, respectively. The voltages

during separation were applied as follows: reservoir B 1

3.5 kV; reservoirs S and SW 13.0 kV; ESI 11.2 kV and

reservoir B 13.5 kV; reservoirs S and SW 12.0 kV;

ESI 11.2 kV for the peptide mixture and the histamine

antagonists separation, respectively. All chip-CE/ESI/MS

analyses were carried out using a computer controlled

power supply and a relay arrangement through an in-house-

written LabView program (National Instruments, TX, USA).

40 µm tip

10 µm orifice

ESI sprayer

Sheath liquid reservoir

Connectingcapillary

Sheath liquid transfer line

Pt wire

BSW

S

15 mm 45 mm 15 mm

25 mm

67 mm

10 mm

8.0 mm

A B

C D

Figure 1. Schematic diagramsof the chip-CE low-sheath-flowESI/MS device. (A) Layout of thePMMA-CE chip with a connect-ing capillary. (B, buffer reser-voir; S, sample reservoir;SW, sample waste reservoir).(B) The low-sheath-flow inter-face. (C) An enlarged diagramof the low-sheath-flow inter-face. The sprayer tip wastapered to �10 mm. (D) The CEmicrochip was slid into the low-sheath-flow interface.

Electrophoresis 2008, 29, 4938–49434940 F.-A. Li et al.


The mass spectrometer used for this study is a linear ion

trap (LTQ) equipped with a nanoelectrospray ionization

source (ThermoFinnigan). The microchip device was

mounted on the nanoelectrospray source, and fine posi-

tioning of the spray tip was achieved by using a XYZ stage.

System control and data collection were done by Xcalibur

software version 2.0. On-line chip-CE/ESI/MS was

performed in the positive-ion full-scan mode. For all

experiments, the maximum ion injection time was 50 ms,

and one scan consisted of one microscan.

3 Results and discussion

3.1 A flat low-sheath-flow interface for chip-CE/MS

To achieve improved sensitivity, a low-sheath-flow approach

was adopted in this study. The low flow interface we have

developed [28] for capillary column CE was found to be not

suitable as the interface for chip-CE. In the low flow

interface, the sheath liquid reservoir is a microcentrifuge

tube. To avoid the spillage of sheath liquid from the

interface, the tube was placed �451 with respect to the

sampling cone of the mass spectrometer. This arrangement

did not cause a problem for the connecting of a capillary

column because the length of the CE column is long enough

(430 cm) to bend and be readily inserted into the sheath

liquid reservoir. However, a polymeric chip provides very

little flexibility. To position the chip with 1.5 cm connecting

capillary directly through the microcentrifuge tube into the

ESI sprayer is not a suitable arrangement because it is better

to operate chip-CE horizontally to avoid any siphon effect

within the chip. To solve the problem mentioned above, a

flat low-sheath-flow interface is developed to place the CE

chip horizontally related to the sampling cone of mass

spectrometer.

The flat low-sheath-flow interface shown in Fig. 1B

consisted of a PMMA sheath liquid reservoir block, a PMMA

platform and a low flow ESI sprayer. The PMMA platform is

used to fix the reservoir block and is also served as a holder

to facilitate the chip-CE/MS operation. Because of the plat-

form, the PMMA chip can be easily slid into the interface for

chip-CE/MS operation (Fig. 1D).

Based on the current monitoring method [29], the EOF of

a PMMA-CE chip was measured to be about 65 nL/min,

which is significantly smaller than the EOF of capillary CE

(�200 nL/min). It is known that the size of the orifice deter-

mines the optimal flow rate of a sprayer. To trade-off between

minimum sample dilution and robustness, the orifice of the

ESI sprayer was chosen to be 10 mm which is significantly

smaller than the low flow interface used in capillary CE

(25 mm). The optimal flow rate for a 10-mm tip was �100 nL/

min and thus the dilution factor was less than 2.

The CE microchip was connected to the low-sheath-flow

ESI interface through a 1.5-cm connecting capillary

(Fig. 1A). A wire-assisted method was used to attach a

connecting capillary to the CE chip. The metal wire serves

two major functions. First, the wire provides a simple

method for inter-channel alignment. Second, during the

fixing process, because the wire is in the separation channel,

the epoxy resin will not flow into the channel and thus avoid

blocking the channel. During the analysis, the connecting

capillary was inserted through the reservoir, and into the

ESI sprayer as shown in Fig. 1C.

Initially, a non-tapered capillary of 375 mm od� 50 mm

id was used as the connecting capillary column. However,

the electropherograms indicated that the peak width

was significantly wider than the data obtained with a

sheathless approach (data not shown). Because a non-

tapered 375 mm od capillary cannot penetrate to the very end

of the sprayer, the increase in peak width was believed to be

due to the dead volume between the tip of the connecting

capillary and the orifice of the sprayer. To reduce the dead

volume, the end of the capillary was tapered to �40 mm od

so that the capillary can be inserted to the very end of the

ESI sprayer. With this modification, the resolution was

found to be similar to that obtained from a sheathless chip-

CE approach.

In comparison with sheathless chip-CE/MS, this low-

flow chip-CE/MS approach provides several advantages.

First, it provides the flexibility of buffer selection and elim-

inates the need for a conductive coating. Second, the 40-mm

tip-connecting column is much stronger than the 10-mm tip

used in sheathless CE/MS approach. Third, because of the

PMMA platform, one can easily withdraw the old/damaged

chip and insert a new chip into the interface. Fourth, the

sprayer can be easily replaced if there is a need of a new ESI

sprayer. In sheathless chip-CE/MS, the replacement of an

ESI tip requires inter-channel alignment, fixing with epoxy

and the application of a conducting coating.

3.2 Practical consideration of the interface

As mentioned in Section 3.1, the optimal flow rate of a

10 mm tip was �100 nL/min. To achieve a flow rate

exceeding 100 nL/min, it was found that the ESI voltage

had a profound effect on the flow rate of sheath liquid.

Under the condition that the separation column was

inserted to the very end of the sprayer, the relationship

between ESI voltage and sheath liquid flow rate is shown in

Fig. 2. As can be seen from Fig. 2, the sheath liquid flow

rate is generally increased with the applied voltage and at a

voltage of 1.1 kV would reach the optimal flow rate for a 10-

mm sprayer. However, 1.1 kV voltage was found to be not the

optimal voltage for CE/MS operation. Considering the ESI

efficiency, electrospray stability and sheath liquid flow rate,

an ESI voltage of 1.2 kV was chosen as the ESI voltage in

this study.

Since the sheath liquid reservoir was placed near the

heated (�2751C) sampling capillary of the LTQ mass spec-

trometer, the high temperature environment was found to

cause the evaporation of the volatile sheath liquid. To ensure

having enough sheath liquid during CE/MS operation, the



sheath liquid was continually delivered to the sheath liquid

reservoir by a syringe pump. In this study, the flow rate of

the sheath liquid was �70 nL/min (total flow rate �130 nL/

min) when the ESI voltage was set at 1.2 kV. However, due

to thermal evaporation, a flow rate of 500 nL/min was

needed to maintain a constant liquid level in the sheath

liquid reservoir.

Solvent compatibility is an issue when using polymers

such as PMMA for fabrication of the sheath liquid reservoir.

Fortunately, the composition of the sheath liquid (50%

MeOH) was found to be compatible with PMMA. According

to our experience, PMMA is stable up to 80% MeOH.

Another issue, which required attention, was leakage of

the sheath liquid. This phenomenon occurred when the

hole for inserting the connecting capillary was not sealed.

Two factors, high organic solvent content and high sheath

liquid level, were found to correlate with leakage. The

former is due to the reduced surface tension and the latter is

the result of the liquid pressure. Experimental study

revealed that leakage could be avoided if the content of

methanol was less than 80% and the height of the sheath

liquid was less than 5 mm.

3.3 Chip-CE/MS analysis of histamine antagonists

and peptides

The performance of the flat low-sheath-flow interface was

investigated for the analysis of selected histamine antago-

nists. Figure 3 displays results form the analysis of a

histamine antagonist mixture using chip-CE/MS utilized a

flat low-sheath-flow interface. The histamine antagonists

were separated within 1.5 min. The RSD of the peak

height and peak area were 5.6 and 6.2%, respectively

(n 5 3), and the peak widths of the histamine antagonists

ranged from 1.8 to 4.2 s. The performance characteristics

appear in Table 1. The detection limit and plate numbers

of the histamine antagonists analysis were in the

range of 3.0–5.0 ng/mL and 4.02� 104–2.04� 105,

respectively.

This device also showed its versatility in the analysis of

peptides. The extracted ion electropherograms of a standard

peptide mixture is shown in Fig. 4. Although the peptides

were not completely resolved, the co-migrating components

could be resolved by their difference in mass. The micro-

device was also evaluated for the analysis of a more

complicated peptide mixture obtained from a proteolytic

digestion of cytochrome C (20 pmol/mL). Detection was

performed in full MS scan mode with a scan range of m/z330–1500. The m/z values observed for the tryptic fragments

were compared to m/z values predicted from the known

protein sequence. A sequence coverage of 88.5% was

obtained in this experiment.

0

50

100

150

200

250

300

350

0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7ESI voltage (kV)

Shea

th f

low

rat

e (n

L/m

in)

Figure 2. Plot of sheath flow rate versus ESI voltage. The studywas performed using a 1 cm�700 mm id� 850 mm od fused-silicatubing tapered to 10 mm od and filled with sheath liquid. A 50-mmtungsten wire was inserted into sprayer to provide electricalcontact for electrospray. The flow rate of sheath liquid wasestimated based on the rate of the consumption of sheath liquid,methanol/water/acetic acid (50:50:1 v/v/v).

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3

50

100

50

100

50

100

50

100

50

100

Rel

ativ

e A

bund

ance

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3Time (min)

50

100

50

100

50

100

50

100

50

100

Doxylaminem/z = 271.2

Pheniraminem/z = 241.2

Chloropheniraminem/z = 275.1

Bromopheniraminem/z = 319.2, 321.2

Carbinoxaminem/z = 291.2

Figure 3. Chip-CE/MS analysis of a mixture of histamineantagonists. The extracted ion electropherograms: pheniramine(m/z 241.2), doxylamine (m/z 271.2), chloropheniramine (m/z275.1), carbinoxamine (m/z 291.2) and bromopheniramine (m/z319.2, 321.2). Conditions: BGE, 80 mM formic acid (pH 3.5).Sheath liquid: methanol/water/formic acid (50:50:1 v/v/v).

1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3Time (min)

50

100

50

100

50

100

Rel

ativ

e A

bund

ance

50

100

50

100

GY

1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3Time (min)

50

100

50

100

50

100

Rel

ativ

e A

bund

ance

50

100

50

100

1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3Time (min)

50

100

50

100

50

100

Rel

ativ

e A

bund

ance

50

100

50

100m/z=239.4

VYVm/z=380.3

[leu5]-Enkephalinm/z=556.4

[Met5]-Enkephalinm/z=574.3

Angiotensin IIm/z=523.8

Figure 4. Chip-CE/MS analysis of a mixture of five peptides. Theextracted ion electropherograms: angiotensin II (m/z 523.8), GY(m/z 239.4), VYV (m/z 380.3), [Leu5]-enkephalin (m/z 556.4) and[Met5]-enkephalin (m/z 574.3). Conditions: BGE, 1% v/v aceticacid. Sheath liquid: methanol/water/acetic acid (50:50:1 v/v/v).

Electrophoresis 2008, 29, 4938–49434942 F.-A. Li et al.


4 Concluding remarks

A chip-CE/MS approach based on a PMMA-CE microchip

and a low flow interface was proposed. A flat low-sheath-

flow ESI interface has been developed to facilitate the

coupling of chip-CE with ESI/MS detection. The device

offers the advantages associated with a low-sheath-liquid

interface such as buffer selection, low dilution factor and

ease of operation. The CE chip and the low-sheath-flow ESI

interface were connected through a connecting capillary.

Since the 10-mm ESI sprayer is not fixed on the CE

microchip, sprayer replacement can readily occur if the

sprayer becomes clogged or damaged. Consequently,

this interface is more robust than a sheathless design.

The practicality and performance of this device have

been evaluated by the analysis of histamine antagonists

and peptides. The results demonstrate that satisfactory

data can be obtained within a few minutes using this

new device.

This work was supported by the National Research Councilof the Republic of China.

The authors have declared no conflict of interest.

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Table 1. Performance characteristics of histamine antagonist drugs analysis using chip-CE/MS utilized a flat low-sheath-flow interface

Drug W1/2 (min) Migration time (min) Theoretical platesa) LOD (ng/mL)b)

Doxylamine 0.04 1.20 83 300 3.6

Pheniramine 0.04 1.25 90 300 4.4

Chloropheniramine 0.03 1.41 204 300 3.0

Bromopheniramine 0.05 1.44 76 700 5.0

Carbinoxamine 0.07 1.46 40 200 4.0

a) Theoretical plates per meter.

b) S/N 5 3.



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Chip-CE/MS using a flat low-sheath-flow interface