International Journal of Mass Spectrometry 312 (2012) 201–207

Contents lists available at ScienceDirect

International Journal of Mass Spectrometry

journal homepage: www.elsevier.com/locate/ijms

Paper spray ionization devices for direct, biomedical analysis using mass
spectrometry
Qian Yang a , He Wang a , Jeffrey D. Maas b , William J. Chappell b , Nicholas E. Manicke c ,
R. Graham Cooks c,d,∗ , Zheng Ouyang a,d,∗∗
a
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
b
Department of Electrical and Computer Engineering, Purdue University, West Lafayette, IN 47907, USA
c
Department of Chemistry, Purdue University, West Lafayette, IN 47907, West Lafayette, IN 47907, USA
d
Center for Analytical Instrumentation Development, Purdue University, West Lafayette, IN 47907, USA

a r t i c l e i n f o a b s t r a c t

Article history: Paper spray ionization has been developed as a direct, fast and low-cost sampling and ionization method
Received 1 March 2011 for qualitative and quantitative mass spectrometric (MS) analysis of complex mixtures. Analyte ions
Received in revised form 22 May 2011 are generated by applying a high voltage and a small volume (∼10 ␮L) of spray solvent onto a porous
Accepted 24 May 2011
substrate. The sample can be preloaded onto the paper or mixed into the spray solution. The geometry of
Available online 1 June 2011
the paper and the method of supplying the necessary internal standard are important factors that affect
the ionization efficiency and subsequently the sensitivity and quantitation accuracy of the analytical data.
Keywords:
As the cut angle of the paper tip is changed, the spray plume, the total spray current and the electric field
Clinical analysis
Ambient ionization
intensity at the tip all vary correspondingly, with resulting differences in signal intensity. Sample load is
Electrophoresis another important factor for obtaining a stable MS signal and accurate quantitative results. The optimal
Paper spray sample load was found to be dependent on the paper size. The dissolution and spray process was also
In situ analysis investigated and analyte transfer on paper was shown to be largely associated with bulk solution flow
toward the spray tip. The information gathered from these systematic studies provides guidance for the
design and optimization of a disposable sample cartridge for paper spray MS, a device which potentially
is suitable for fast clinical analysis, especially for point-of-care diagnostics.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction newborn screening for inborn errors of metabolism [6,7], such as

fatty acid oxidation disorders or aminoacidopathies; (iii) foren-
Mass spectrometry (MS) is a powerful method for analyzing sic and clinical toxicology [8] and (iv) proteomics [9]. Although
complex mixtures, especially when augmented by tandem mass there are many well-established analytical methods for detecting
spectrometry (MS/MS). The development of electrospray ioniza- biomarkers in serum and tissue utilizing antibody-based detection
tion (ESI) [1] and atmospheric pressure chemical ionization (APCI) methods such as enzyme-linked immunosorbent assay (ELISA),
[2], allowed the techniques of liquid chromatography (LC) and MS development of robust antibody reagents for specific biomarkers
to be combined to form a relatively robust and highly practica- is difficult and time-consuming [10]. In comparison with these
ble method that is now widely used [3]. The LC/MS and LC/MS/MS biochemical or immunological analytical technologies, the major
methods are currently used for quantitative and qualitative analysis advantages of MS in clinical applications include the speed of anal-
for pharmaceutical and clinical applications as well as for biolog- ysis, the high specificity, especially for mixtures, the low limit of
ical studies. Particular areas of application include (i) therapeutic detection (LOD), and lack of any requirement for analyte-specific
drug monitoring (TDM) [4,5], for example, for treatments involv- reagents (ASRs) [11]. All of these factors make MS a versatile tool
ing immunosuppressants, antiretrovirals, and antidepressants; (ii) for rapid and high-throughput analysis.
Currently MS analysis provides significant amounts of informa-
tion about complex samples, but the use of MS systems in routine
∗ Corresponding author at: Department of Chemistry, Purdue University, 560 Oval clinical laboratories could be increased significantly if some current
Drive, West Lafayette, IN 47907, USA. Tel.: +1 765 494 5263; fax: +1 765 494 9421. limitations could be removed. One bottleneck is the complexity
∗∗ Corresponding author at: Weldon School of Biomedical Engineering, Purdue
of the required sample pretreatment before MS analysis, which
University, West Lafayette, IN 47907, USA. Tel.: +1 765 494 2214;
typically involves labor-intensive and time-consuming sample
fax: +1 765 496 1912.
E-mail addresses: [email protected] (R.G. Cooks), [email protected] manipulations including extraction, purification and chromato-
(Z. Ouyang). graphic separation. Another limitation is the expertise required for

1387-3806/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijms.2011.05.013
202 Q. Yang et al. / International Journal of Mass Spectrometry 312 (2012) 201–207

MS operation and data interpretation. Widespread use of MS for of physical variables on its analytical performance. The geometry,
pharmaceutical and clinical applications is likely to result from the structures and materials of the substrate and the operating param-
availability of more user-friendly MS analytical systems. eters of the paper spray were all investigated. The first observation
The emergence of a new family of ionization techniques, the made was that spray only occurs at sharp tips at the paper edge,
ambient ionization methods [12], addresses this need. These meth- such as the four corners of a square. The spray could be eliminated
ods include desorption electrospray ionization (DESI) [13], direct from one or more points by rounding the corners (Fig. 1a). The angle
analysis in real time (DART) [14] and many others [15–17]. These of the paper tips plays a key role in the generation of the spray. To
methods have simplified MS analysis by allowing the generation investigate the effect of tip angle in paper spray, paper substrates
of analyte ions directly from ordinary samples under ambient con- with a variety of shapes were designed and cut precisely using a
ditions without sample preparation or prior separation steps. The laser as shown in Fig. 1b. Each shape consisted of two parts: a tiny
barriers to MS analysis of samples in their native states are being salient with one of the five different angles (30◦ , 60◦ , 90◦ , 120◦ and
overcome by these strategies. Many groups have reported encour- 150◦ ) in the front and an identical large circular part behind it. It
aging results in the direct analysis by various ambient ionization was found that the spray occurred only at the salient. The area of the
methods of pharmaceutical drugs [18–24], illicit chemicals [25–31] circular part was constant for all the shapes and was much larger
and biological molecules in complex matrices [32–36]. than the salient area to ensure that the solvent evaporation pro-
As a new branch of the ambient ionization, the recently devel- cess was comparable for each design. Accordingly, the difference
oped method of paper spray ionization (PS) has been shown to have in MS signal observed with these substrates was mainly due to the
some promising features and a wide range of applications [37–41]. differences in tip angle.
The capability of paper spray for direct analysis of crude biolog- A cocaine solution of 15 ␮L volume (1 ␮g/mL in methanol/water,
ical samples has been demonstrated with urine [38], dried blood 1:1, v/v) was applied to each paper substrate, and the shape of spray
spots (DBS) [40], whole blood [37], and tissue samples [41], all plume, the abundance of the protonated cocaine ion (m/z 304) and
of which are highly important for clinical applications. Numerous the total spray current were recorded (Fig. 1d). The diameter of
drugs in dried blood spots, including dextrorphan, amitriptyline, the spray plume was observed to decrease as the angle increased,
imipramine, citalopram, and imatinib, have been directly analyzed thus and a larger proportion of the charged droplets population
from paper substrates using paper spray. This demonstrated that was directed into the MS inlet (Fig. 1c). However, no spray could
paper spray can be used as an effective alternative to standard be observed for the tip with an angle 150◦ . Moreover, the tolerance
extraction procedures [42] and also to newer methods including of the signal to the positioning of the paper became smaller with
DESI [43] and liquid microjunction surface sampling probes (LMJ- larger angles and the larger the angle, the shorter the critical dis-
SSP) [44]. Linear responses for these drugs were recorded by PS-MS tance needed to produce the spray. It is interesting that the change
across a concentration range of at least three orders of magnitude, in peak intensity of the cocaine fragment ion m/z 182 with angle is
fully covering their therapeutic ranges [39]. Limits of quantita- not monotonic (Fig. 1e). The same behavior is observed for the pro-
tion for each of these drugs were around 1 ng/mL in whole blood tonated molecule, m/z 303 although the total ion current intensity
[39]. Various methods for applying internal standard (IS) have been steadily increased for 30–90◦ and then decreased. The onset voltage
investigated, including printing the paper with the IS before load- for paper spray increased continuously as the angle was increased.
ing the blood sample, soaking a punched out section of a DBS with It was 3 kV for tips with a 30◦ and 60◦ angle and increased to 4 kV
the IS, and using a spray solvent containing the IS [40]. for tips with angle 90◦ and 120◦ . At spray voltages exceeding 6 kV,
In this paper, a systematic characterization of paper spray severe corona discharge occurred.
devices was conducted. Several factors, including the geometry of The total current increased as the spray voltage increased and
the paper triangle and the sample loading, were shown to have the 30◦ tip always gave the highest current (Fig. 1f). The electric field
an impact on the ionization efficiency of paper spray. The concept at the spray tip was numerically calculated using the finite element
of making paper spray disposable sample cartridges has also been analysis tool COMSOL Multiphysics 4.1 (COMSOL, Inc., Burlington,
implemented based on the knowledge acquired from the charac- MA) (Fig. 1g–h). The boundary conditions were set to be 4.5 kV at
terization study. the paper tip and 0 V at the MS inlet, corresponding to the operating
condition in the experiments. The potential distribution for angle
60◦ is shown in Fig. 1g. A zoom-in view of the electric field for
2. Experimental
angle 30◦ is shown in the inset of Fig. 1h. The highest electric field
strength was found to be at the of the paper tips, which supports
Chromatography paper used for paper spray was purchased
the observation that spray only occurs at the sharp corners of the
from Whatman (Whatman International Ltd., Maidstone, England).
paper substrates (Fig. 1a). The field strength at the tip of the paper
Bovine whole blood (with sodium citrate as anticoagulant) was pur-
spray is plotted as a function of the angle in Fig. 1h. As expected,
chased from Innovative Research (Novi, MI). All other reagents were
electric field density is higher at the tips of paper cut to smaller
purchased from Sigma–Aldrich (Milwaukee, WI) and used without
angles, which is favorable for generating the spray (Fig. 1c).
further purification. Methanol/water solution (1:1, v/v) was used
Sample load is another important factor that affects paper spray
as the solvent for paper spray unless otherwise noted. Mass anal-
ionization. Solutions of 1 ␮g/mL imatinib and 1 ␮g/mL imatinib-
ysis was performed using a Thermo Fisher LTQ mass spectrometer
d8, pre-mixed in bovine whole blood, were used to explore
(Thermo Fisher Scientific Inc., San Jose, CA). The temperature of
the relationship between sample load and paper substrate size
the MS capillary inlet was typically set at 150 ◦ C and the tube lens
for quantitative analysis. Three homologous paper triangle sub-
voltage was set at 65 V. Tandem mass spectra were recorded using
strates (T1, T2, T3) of different areas were prepared: they were
collision-induced dissociation (CID) and product ion scans were
7.5 mm × 8 mm for T1 paper substrates, 11.9 mm × 12.7 mm for T2
recorded. The voltage used for paper spray ionization was 4.5 kV
paper substrates, and 16.8 mm × 17.9 mm for T3 paper substrates
in positive mode, unless otherwise noted.
so that the area ratio of T1, T2 and T3 was 1:2.5:5. The spray sol-
vent volumes applied to substrates T1, T2, and T3 were 10, 25,
3. Results and discussion 50 ␮L MeOH:water (1:1), which is proportional to their areas. For
each size of paper substrate, three different blood sample amounts
This study sought to achieve a systematic characterization of (0.5, 1.25, 2.5 ␮L) were preloaded in the middle of the substrate
the paper spray mass spectrometry experiment and the effects which were then dried and tested. Two key characteristics, MS sig-
 Q. Yang et al. / International Journal of Mass Spectrometry 312 (2012) 201–207 203

Fig. 1. (a) Spray plumes on a rectangular paper substrate. (b) Paper substrates with different tip angles of 30◦ , 60◦ , 90◦ , 120◦ or 150◦ . (c) Spray plumes recorded for paper
substrates with tip angles of 30◦ , 60◦ , 90◦ and 120◦ . (d) MS and MS/MS spectra of 1 ␮g/mL cocaine in MeOH:water (1:1) as spray solvent, paper substrate with a tip angle
90◦ , spray voltage 4.5 kV. (e) Peak intensity of cocaine fragment ion m/z 182 and (f) total spray current as a function of the spray voltage. (g) Simulated potential distribution
simulation (tip angle = 60◦ ). (h) Electric field strength at the paper substrate tip as a function of tip angle. Inset: zoomed-in view of electric field distribution at a paper
substrate tip (tip angle = 30◦ ).
204 Q. Yang et al. / International Journal of Mass Spectrometry 312 (2012) 201–207

Fig. 2. Peak intensity of imatinib fragment ion m/z 394 (a) and imatinib/imatinib-d8 ratio (b) as a function of sample load for different paper sizes (T1: 5 mm × 8 mm; T2:
11.9 mm × 12.7 mm; and T3: 16.8 mm × 17.9 mm). 1 ␮g/mL imatinib and imatinib-d8 in whole bovine blood.

nal intensity and the ratio between the signal for the drug (imatinib)
and its internal standard (imatinib-d8), were investigated.
The peak intensity of the imatinib fragment ion m/z 394 gen-
erally increased as the blood sample amount increased for each
paper substrate size (Fig. 2a). However, 1.25 ␮L and 2.5 ␮L samples
loaded onto the T1 substrate gave similar MS signal intensities. The
T2 and T3 substrate behaved unexceptionally. It is concluded that
the T1 substrate had already reached its maximum extraction limit
(its saturation sample load) for volumes between 1.25 and 2.5 ␮L.
Since the MS signal intensity of the T2 and T3 paper substrates was
still rising at 2.5 ␮L sample load, the T2 and T3 substrates should
have unique saturation sample loads that are higher than that for
the T1. For 1.25 ␮L sample load, the signal intensity dropped as the
size of paper substrate increased due to the larger volume of spray
solvent, which helped to dilute the blood sample and lowered the
signal of the analyte, whereas for the 2.5 ␮L sample load, the trend
was opposite in that the highest signal intensity appeared using the
T3 paper substrate. Moreover, for the same sample-to-solvent ratio
of 0.5 (0.5 ␮L blood on T1, 1.25 ␮L blood on T2 and 2.5 ␮L blood on
T3), the larger paper tips yielded much improved signal intensities.
To eliminate various sources of error in quantitation, the ratio
between the drug and its internal standard, instead of the absolute
signal intensity of the drug, was used to determine the concen-
tration of the drug in blood. In Fig. 2b, the dashed line represents
the theoretical ratio between the drug and its internal standard.
Most of the ratios measured were found to be in agreement with
the theoretical values except for the 0.5 ␮L blood on the T2 and T3
paper substrates. This deviation from the theoretical ratio appears
to be because 0.5 ␮L blood was too little to provide accurate quan-
titative results using the larger T2 and T3 paper substrates. This
indicates that each substrate size also has a minimum sample load
requirement for quantitative analysis.
The process of analyte dissolution and distribution with the
spray solution on the paper was also studied. Consideration was
given to three processes by which the analytes might be transferred
during paper spray: (1) capillary action/wetting, (2) electrophoresis
and (3) bulk solution movement as a surface liquid film. An equilat-
eral triangle paper substrate with length along each side of 3 cm and
three analytes (caffeine, imatinib and bradykinin 2–9) were used
for the study (Fig. 3). The three corners of the large paper triangle
were cut after the paper had dried for each test, and the peak inten-
sities of fragment ions (m/z 138 for caffeine, m/z 394 for imatinib,
and m/z 404 for bradykinin 2–9) were recorded for each corner of
each triangle (Fig. 4a).
Transport by capillary action was examined by applying 100 ␮L
of solvent slowly to the middle of the paper to wet the whole
paper. Under these conditions, analytes moved through the paper
only by capillary action. As shown in the upper panel of Fig. 4b, Fig. 3. MS/MS spectra of caffeine, imatinib and bradykinin 2–9 using paper spray
similar signal intensities were obtained for all three compounds ionization.
 Q. Yang et al. / International Journal of Mass Spectrometry 312 (2012) 201–207 205

Fig. 4. (a) Schematic illustration of the experimental design for studying the analyte dissolution and transfer on paper (F: front; L: left; R: right). (b) Distributions of caffeine
(red), imatinib (green) and bradykinin 2–9 (blue) on paper under different conditions. Peak intensities for the transitions m/z 195 → 138 for caffeine, m/z 494 → 394 for
imatinib and m/z 453 → 404 for bradykinin 2–9 were monitored. (For interpretation of the references to color in text, the reader is referred to the web version of the article.)

(caffeine, imatinib and bradykinin) at all three corners, which sug- (stereo lithography apparatus) [45]. SLA resin Nanoform 15120
gests that the analytes were evenly distributed by capillary action. (DSM Somos) was chosen as the cartridge material as it has a
To examine the contribution of electrophoretic flow, electrodes high glass-transition temperature and is relatively chemically inert,
were attached to the base and the apex of the large paper trian- especially to organic solvents [46]. The cartridge consisted of three
gle and a DC electric current of 100 nA was established between main parts: holder, lid and electrode (Fig. 5a). A paper substrate
these electrodes during the same wetting process as described was sandwiched between the holder and the lid, with its sharp tip
above. The electric current was equivalent to that under normal extending through the front opening to allow unimpeded spray.
paper spray condition. An even distribution was observed again, The lip structure was used to protect the paper tip from damage
as shown in the middle panel in Fig. 4b, and this result indicates during the handling of the cartridge. The lid could be opened easily
that electrophoretic transfer does not play a significant role. Lastly, or locked onto the holder through the side clips, which allowed the
normal paper spray was implemented, so that capillary and elec- paper inside could be replaced as necessary. Through the hole in
trophoretic effects operated in addition to bulk solution movement the lid, sample and solvent could be applied to the paper substrate.
due to the driving force of the spray leaving the tip. Since a relatively A bolt through a nut embedded in the cartridge was in contact with
large amount of solvent was added to wet the paper, excess solvent the paper to allow application of the high voltage.
formed a liquid film on the paper surface. As the spray occurred at The paper substrate was cut into a polygon (Fig. 5b) with the
the tip of the paper, the solvent was consumed and the liquid on spray tip having the sharpest angle of less than 90◦ , which sup-
the paper was pulled toward the spraying tip. As shown in the bot- pressed spray from the other corners. Since bulk solvent movement
tom panel in Fig. 4b, higher signal intensities were observed at the is critical for signal intensity, five props (three on the bottom and
spraying tip for all three analytes. This demonstrates the significant two on the lid) were fabricated to support the large paper tip
role of bulk solvent movement in transferring analyte. (Fig. 5c). This design prevents paper bending due to wetting by the
With the knowledge gained from the studies described above, large amount of solvent. The configuration of interlaced props with
a paper spray cartridge was designed and fabricated using SLA curved surfaces minimized the contact area between the resin and
206 Q. Yang et al. / International Journal of Mass Spectrometry 312 (2012) 201–207

Fig. 5. (a) Paper spray cartridge design. (b) Design of the paper substrate (red: spray point). (c) Support of the paper substrate with props inside cartridge. (d) Cartridge
fabricated using SLA. (e) MS and MS/MS spectra of 1 ␮g/mL imatinib in whole bovine blood using paper spray cartridge with MeOH:water (1:1) as spray solvent, spray voltage
4.5 kV. (For interpretation of the references to color in text, the reader is referred to the web version of the article.)

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