Direct Trace Element Analysis of Liquid Blood Samples by In-Air Ion

Article pubs.acs.org/ac

Direct Trace Element Analysis of Liquid Blood Samples by In-Air Ion Beam Analytical Techniques (PIXE−PIGE) Robert Huszank,* László Csedreki, and Zsófia Török Institute for Nuclear Research, Hungarian Academy of Sciences (MTA Atomki), P.O. Box 51, H-4001 Debrecen, Hungary ABSTRACT: There are various liquid materials whose elemental composition is of interest in various fields of science and technology. In many cases, sample preparation or the extraction can be complicated, or it would destroy the original environment before the analysis (for example, in the case of biological samples). However, multielement direct analysis of liquid samples can be realized by an external PIXE−PIGE measurement system. Particle-induced X-ray and gamma-ray emission spectroscopy (PIXE, PIGE) techniques were applied in external (in-air) microbeam configuration for the trace and main element determination of liquid samples. The direct analysis of standard solutions of several metal salts and human blood samples (whole blood, blood serum, blood plasma, and formed elements) was realized. From the blood samples, Na, P, S, Cl, K, Ca, Fe, Cu, Zn, and Br elemental concentrations were determined. The focused and scanned ion beam creates an opportunity to analyze very small volume samples (∼10 μL). As the sample matrix consists of light elements, the analysis is possible at ppm level. Using this external beam setup, it was found that it is possible to determine elemental composition of small-volume liquid samples routinely, while the liquid samples do not require any preparation processes, and thus, they can be analyzed directly. In the case of lower concentrations, the method is also suitable for the analysis (down to even ∼1 ppm level) but with less accuracy and longer measurement times.

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technique based on the measurement of characteristic prompt gamma-rays produced in nuclear reactions.16 The IBA analysis of some important light elements (such as Li, Be, B, Mg, Na) sometimes are only feasible by applying PIGE technique instead of PIXE. The emitted X-rays of a light element have such low energy that they will be absorbed by the sample itself, the air, the detector window, among others; however, the emitted gamma photons during PIGE measurements have sufficiently high energy for good detection. Thus, the PIGE method has been widely applied also in geology, environmental sciences, archaeometry, material sciences, and so on.17−19 In many cases, the sample preparation or the extraction can be complicated, it may cause big deviations in the reproducibility, or it destroys the original environment before the analysis (for example, in the case of biological samples, blood, plants, etc.). Because of this, a technique which is fast and could be used directly on sensitive and/or biological samples, needing only one drop of liquid without special preparation, would be advantageous in the appropriate field of science or in practice. Indirect analysis of liquid samples can be realized by the PIXE−PIGE technique. This kind of method has already been used earlier for liquid analysis: drops dried on a filter or on carbon foils and analyzed in a high-vacuum environment.20 However, our purpose is completely different:

he importance of trace elements in human life and their role in different diseases and metabolic states is now wellknown. In enzymes and hormones, they control biological functions, for example, in redox balance (cytochromes) or as antioxidants (Cu/Zn/SOD), among others. However, they can be responsible for various malfunctions when their homeostasis has been changed. The disorders in the Cu and Zn transport are known to have clinical effects,1−3 and the serum copper level and serum zinc level were reported to correlate with various cancers.4−8 Therefore, the determination of trace elements in the diagnosis of certain diseases can be important. The most commonly applied methods for the trace and main element determination, among others, are UV−vis spectroscopy, flame atomic absorption spectrometry (FAAS), inductively coupled plasma atomic/optical emission spectrometry (ICPAES/OES), electrothermal atomic absorption spectrometry (ETAAS), inductively coupled plasma−mass spectrometry (ICPMS), neutron activation, and also ion-beam analytical (IBA) techniques such as Particle-Induced X-ray and Gamma-ray Emission spectroscopy (PIXE, PIGE). PIXE is a wellestablished analytical technique, a powerful tool for rapid, multielement, (quasi) nondestructive analysis.9 It allows simultaneous detection of numerous elements (6 > Z > 92 in vacuum) with high-detection sensitivities, and with a focusing system, the spatial resolution can be as small as a cell.10,11 PIXE systems are particularly suitable for the analysis of biological, geological, environmental, metallurgical, ceramic, and a wide range of other inorganic materials.12−15 PIGE is an analytical © XXXX American Chemical Society

Received: September 8, 2016 Accepted: December 23, 2016 Published: December 23, 2016 A

DOI: 10.1021/acs.analchem.6b03541 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

Figure 1. External microbeam setup for the analysis of liquid samples showing the detectors, sample holder and the exit nozzle (A, B). For the charge measurements a chopper was used inside the chamber, in vacuum.24

analysis. To hold the syringe, a plate and a syringe holder was fabricated and fixed on the beam extracting accessory, so the sample can be placed in the right position and distance in front of the beam with good reproducibility. The distance between the silicon-nitride (Si3N4) exit window (from Norcada, thickness: 200 nm) and the surface of the liquid sample was 1 cm during the analysis. Two X-ray detectors were used to analyze elements, in 135° arrangements relative to the beam direction. In our experiments, a Si(Li) detector (manufactured by e2v Ltd., 50 mm2 active area, 125 eV fwhm resolution at 5.9 keV) was used with a 25 μm Be window and an additional Kapton foil absorber (125 μm for 2.5 MeV and 250 μm thick for 3.5 MeV proton energy) for the heavier elements (from K to U), and a Silicon Drift Detector (SDD) with 8 μm Be window (manufactured by AMPTEK, 25 mm2 active area, 125 eV fwhm resolution at 5.9 keV) was used for the lighter elements (from Na to Zn). The distances of the SD detector and the Si(Li) detector from the sample were 6.2 and 4.2 cm, respectively. For a more detailed description of the experimental setup, see our earlier paper.24 In order to detect light elements, a Canberra-type HPGe gamma-ray detector was used. The detector was placed at 45° relative to the beam direction. The distance between the target surface and the gamma-ray detector was 10.5 cm. A lead shield was used to reduce the laboratory background and the proton induced gamma-ray background which comes from the construction materials of the chamber, the collimators, the slits, and so on. The proton beam was focused to about ∼30 μm, and this was the typical beam size during the whole measurement. The focused ion beam was scanned over the sample surface continuously (the scan size was 1 × 1 mm). In the PIXE process, the X-ray photons are emitted by the ionization collisions between the incident particles and the target atoms. The energy of the X-ray photon is characteristic of the elements present in the liquid. The yield of an X-ray peak (Yi) collected in the X-ray spectrum is proportional to the concentration of the corresponding element (i) and can be given as the following formula 1:

analysis of the liquid samples directly, without sample preparation, at atmospheric pressure (on air). For that purpose, the ion beam can be extracted to the air through a thin foil, which is the so-called external beam setup.21−24 The use of the external PIXE−PIGE technique for the analysis of liquid samples (e.g., water, mineral oils, blood, serum, etc.) has been hardly investigated previously, and only a few examples can be found in the literature.25,26 In this paper, the analysis of standard solutions of several metal salts, and as a potential application, human blood samples (whole blood, blood serum, blood plasma, and formed elements) were introduced. The focused and scanned ion beam creates an opportunity to analyze very small volume samples (∼10 μL). As the sample matrix consists of light elements (in the case of a water solution or biological samples and most of the organic solvents), the analysis is possible at ppm level. Using the external beam setup, the liquid samples require minimal preparation process, and thus, they can be analyzed directly, as they are. Furthermore, on the contrary to the most commonly applied analytical techniques used in trace element analysis, even anions or nonmetallic elements (e.g.: F−, Cl−, Br−, PO43−, SO42−, etc.) can be analyzed directly and simultaneously with this method. However, this new analytical approach needs large and hardly accessible infrastructures, but it can be very useful in the case of samples where the usual analytical methods are difficult to apply or the sample preparation would affect its natural environment.

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EXPERIMENTAL DETAILS Arrangement of the Analysis. The experiments were carried out at the nuclear microprobe facility10 in the Institute for Nuclear Research, Hungarian Academy of Sciences, Debrecen, Hungary using an external beam setup system.24 The energetic ions were produced by a 5 MV single ended Van de Graaff accelerator. In this study, the setup was applied for the analysis of liquid samples. The measurements were carried out on two proton energies (2.5 and 3.5 MeV), under helium flow. The detection limits of several elements were tested and compared at these proton energies. For the liquid sample, a window-less sample holder was introduced (see Figure 1). It is a simple 1 mL plastic syringe, which was cut at the top. It is practical, the sample loading is very simple (such as with a normal syringe) and the liquid sample is stable in it in any position, so it could be placed in front of the ion beam in horizontal position, which is important because the external beam accessory is attached to a horizontal ion beam. The sample surface is open to air, so there is no need to use a window which may reduce the performance of the

Yi = NpNAv

Ci Ω Wi M i 4π

(1)

where Np is the number of the bombarding particles, NAv is the Avogadro’s number, Ci is the concentration of the element i in g/g, Mi is mass of the atom i in AMU, Ω/4π is the solid angle of the detector, and Wi is the effective X-ray production cross sections of the atom i (for more detailed description see refs 27 and28). In the case of the PIGE method, the determination of B


Article


Table 1. Results of the Measured Standard Solutions, Including the Nominal and the Determined Concentrations and the Limit of Detection (LOD) Values at 2.5 and 3.5 MeV Proton Energya 2.5 MeV Si(Li) element

concn [ppm]

P (KH2PO4) K (KH2PO4) S (Na2SO4) Ca (CaCl2) Cl (CaCl2) Cr (K2Cr2O7) Cu (CuSO4·5H2O) Zn Pb (Pb(NO3)2)

299 378 312 321 568 600 320 450 463

measured [ppm]

337 446 556 370 469 392

SDD fit error%

57 53 7 7 4 5 3.5 MeV

LOD [ppm]

measured [ppm]

fit error%

LOD [ppm]

11 67 3 2 5 6

267 337 433 376 668 594 420 512 386

15 4 7 3 4 2 5 5 11

48 13 29 10 20 6 17 21 36

Si(Li)

a

SDD

element

concn [ppm]

measured [ppm]

fit error%

LOD [ppm]

measured [ppm]

fit error%

LOD [ppm]

Cr (K2Cr2O7) Cu (CuOAc2·H2O) Zn Ca (CaCl2) Cl (CaCl2)

303 311 323 300 532

378 295 355 257

6 10 11 16

7 3 4 17

303 312 334 299 528

5 6 8 5 8

8 13 20 17 43

The standard solutions were prepared by dissolving the appropriate amount of compound in Milli-Q water.

the case of the higher concentration standard solutions and about 0.8−1.1 μC in the case of the lower concentration standard solutions and the blood samples. In some cases, at 2.5 MeV proton energy, the collected charges were higher (about 2.5 μC) to get spectra with good statistics (e.g., the highly diluted standard solutions and some blood samples). From these parameters, the measurements times were the following: 5−10 min in case of standard solutions, 20−25 min in case of blood samples with 3.5 MeV, and about 30−40 min with 2.5 MeV energy protons. The uncertainty of the charge determination was taken into account with ±3%. For the evaluation of PIXE spectra, the GUPIXWIN program package was used.31 The calculations were done with the “fixed matrix solution” option assuming a known matrix composition. In the case of the standard solutions, the matrix composition was pure water, while in the case of the blood samples, the ICRU blood standard for matrix composition was used. The limit of detection (LOD) was calculated by the GUPIXWIN software as well, and it is given by31

the concentration of a target element can be realized with standards, using eq 2 (from ref 16); if the target is definitely thick (the thickness is greater than the penetration depth of the incident ions), the distribution of the components are homogeneous, and the produced gamma-photons are not significantly attenuated in the target: Yi = fwi

Yst(Ep)Sst(Ep) Sm(Ep)

(2)

where f wi is the weight fraction of nuclide i in matrix m, Yst is the yield of the gamma photons of i element in the standard under the same experimental condition at beam energy Ep, Sst(Ep) is the stopping power of the standard and Sm(Ep) is the stopping power of the matrix components of the target material at Ep ion energy. The quantitative determination of light elements in liquid samples was carried out applying standard solutions (such as NaF and MgSO4). If the matrix of the sample is not exactly known, the stopping power values (S(E) at the given proton energy) can cause significant inaccuracy in the calculations. In the case of the standard solutions, the matrix is pure water, but in the case of the blood samples, it is a bit different, because of the different organic materials in it. Fortunately, because the organic part of the blood mostly consist of light elements, the calculated stopping power values (S(E)) for water and for blood material (ICRU standard), using the SRIM2013 code,29 differ less than 2.5%. The net area of gamma-ray peaks in the spectra was determined by the Fityk software package.30 The determination of the accumulated charge (number of bombarding particles, Np) on the investigated sample is necessary for the quantitative, direct elemental analysis of PIXE and PIGE methods. In our experiments, the accumulated charge was determined by an in-vacuum beam chopper (the transmission yield is 87.6%), calibrated with a Faraday-cup on each proton energy.24 The typical beam current was about 500−700 pA. The collected charges were about 0.2−0.3 μC in

LOD (ppm) =

3· B Q ·H ·Y1t·ε ·T

(3)

where B is the background area in one fwhm region, Q is the charge in μC, H is the instrumental constant used in conversion of area to concentration (contains solid angle, etc.), Y1t is the theoretical thick target yield of K, L, or M alpha X-rays/μC/ ppm/steradian in the 1 fwhm region centered about the element’s principal peak, ε is the relative detector efficiency, and T is the transmission of X-rays through any absorber that is present. Blood Preparation. In our experiments, EDTA-anticoagulated (K3EDTA) and native (nonanticoagulated) blood were used (male subject, 29). The anticoagulated blood was divided into two parts. One of them was centrifuged with 3000 rpm, and then the upper part was taken as plasma (blood plasma). The other part was used as whole blood. The native blood was C


Article


Table 2. Results of the Measured Standard Solutions with Low Concentration (Series B), Including the Nominal and the Determined Concentrations and the Limit of Detection (LOD) Values at 2.5 and 3.5 MeV Proton Energy 2.5 MeV

3.5 MeV

Si(Li)

Si(Li)

element

concn [ppm]

measured [ppm]

fit error%

LOD [ppm]

concn [ppm]

measured [ppm]

fit error%

LOD [ppm]

Cr Fe Cu Zn

6.0 3.3 3.2 4.5

7.4 3.3 3.6 3.7

17 22 22 24

1.5 0.9 0.4 0.7

3.0 3.0 3.1 3.2

3.7 9.4 2.7 3.2

40 10 18 16

2.8 1.6 0.9 0.8

Figure 2. X-ray spectra of the different fractions of the investigated blood samples measured on 3.5 MeV proton energy with (A) SDD and (B) Si(Li) detectors.

holder syringe, which was then fixed horizontally in a holder, in front of the ion beam for the direct analysis (see Figure 1). First, series A solutions were measured for the calibration and to determine the specific constants (solid angle of the detectors, detector efficiency, etc.) of the system. Afterward, the system constants were evaluated using the results measured on these standard solutions. Table 1 summarizes the results of the measured standard solutions, including the nominal and the determined concentrations and the limit of detection (LOD) values at 2.5 and 3.5 MeV energy. Due to the high uncertainty in the measured calcium and chlorine concentrations evaluated from the Si(Li) detector (caused by the high X-ray background and the applied absorbent foil), the concentration of the lighter elements (Z ≤ 20) were evaluated from the results of the SDD detector only. In the case of the iron(II) solution at higher concentration (∼300 ppm), we experienced precipitation during the analysis. It is caused by an oxidative reaction with hydroxyl radicals (OH) formed by the ion irradiation induced reaction of water molecules, producing iron(III), which precipitates from the solution. Therefore, this element was excluded from the system

also centrifuged with 3000 rpm to obtain the serum (blood serum) and the sediment part as formed elements. In order to avoid and minimize the possible contamination during the sample preparation and storage, standard vacutainer tubes were used for the blood collection, and then the prepared blood samples were stored in Eppendorf tubes until the IBA analysis.

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RESULTS AND DISCUSSION

Properties and Limitation of the Experimental Setup. In order to test the setup properties and limitations of the system, two series of standard solutions were investigated, respectively. The standard solutions prepared with higher (300−600 ppm) elemental concentrations (series A) were used to determine the setup properties, while the others with lower (3−6 ppm) concentrations (series B) were applied to test the limitations of the system. The standard solutions were prepared by dissolving the appropriate amount of compound in Milli-Q water. The list of investigated standards with the nominal and the measured concentrations are shown in Table 1 and Table 2, respectively. The standard solutions were loaded in the sample D


Article


Figure 3. Gamma-ray spectrum of the whole blood measured at 3.5 MeV proton energy. The sodium peaks are at 440 and 1635 keV, and the background peaks are noted as Bg. The peaks at 844 and 1014, as well as at 1779 keV energies can be considered as ion-induced background from the aluminum chopper wing and the Si3N4 exit window, respectively.

their emitted low energy X-rays (by the air, self-absorption, by the applied filter, the detector window, etc.). With the PIGE technique, these light elements can be determined with good sensitivity, in certain cases. In our study, the sodium content of the different fraction of blood was measured. However, the determination of Al and Mg was not possible due to the limit of detection, the high laboratory background, and the applied aluminum material for the beam chopper wings (which was used for the determination of the deposited charge). The γ-ray spectrum of the whole blood is shown in Figure 3. The measured elemental concentrations of the different parts of the blood samples using PIXE−PIGE method are summarized in Table 3.

constant determination. Although the precipitation process was not observable at low iron(II) concentration (in series B solution), for the large discrepancy between the measured and the nominal values, the same process may be responsible. In order to test the limitations of our analytical system, we investigated solutions with concentrations close to the detection limit of the PIXE method (i.e. standards with several ppm concentrations). In our case, we analyzed the series B standard solutions (Cr, Fe, Cu, Zn, see Table 2). In these experiments, we used the results only from the Si(Li) detector system, because it is much more sensitive for elements with higher atomic number, which are mostly the trace elements in biological systems. On the basis of the measurements of the standard solutions, it was found that 3.5 MeV proton energy is more suitable for investigation of liquid materials because of the larger penetration depth to the liquid (it is increased with about 80 μm in the case of water) and the increased X-ray and gammaray yields. Because of this, the ratio of the net peak area and the background can be improved, so the measurement time can be decreased. In conclusion, we found that the method is capable to determine elemental composition of small-volume liquid samples. Furthermore, in the case of lower concentrations, the method is also suitable for the analysis (at even ∼1 ppm level) but with less accuracy and longer measurement time. Trace Element Analysis of Liquid Blood Sample. Trace elements such as F, Si, Cr, Mn, Fe, Co, Cu, Zn, Se, Mo, and I, among others, are distributed in each organ in a characteristic way. There are several papers dealing with the relationship between different diseases and trace element concentration analyzed in high vacuum by the PIXE technique, using a drying or lyophilizing sample preparation method.20 In our study, measurements were carried out using human blood samples including whole blood, formed elements, blood plasma, and blood serum. Given the past experience with the standard solutions, the investigation of the blood samples was done at 3.5 MeV proton energy only. The measurement conditions were the same as in the case of the standard solutions (see Figure 1). Elemental composition of different parts of blood were determined using the combined PIXE− PIGE technique. The X-ray spectra are shown on Figure 2A,B. As depicted in Figure 2A,B, the different fractions of blood can be well separated by its characteristic X-ray spectra. Light elements such Na, Mg, Al sometimes cannot be measured by the PIXE technique because of the absorption of

Table 3. Measured Elemental Concentrations of the Different Parts of the Blood Samples Using PIXE−PIGE Method at 3.5 MeV Energya 3.5 MeV measured concentrations [ppm] P S Cl K Ca Fe Cu Zn Br Na

whole blood

blood plasma

formed elements

blood serum

706 4229 1191 −b 61 1044 3 13 4 2549

138 2632 937 −b 172 6 5 4 3 1810

342 1681 535 1130 18 1346 1.4 15

354 4732 1822 137 429 5 4 5 4 2392

802

a

The average uncertainty of the absolute concentration values measured by PIXE varied between 5-15%, and 17-30% at concentrations below 50 ppm, while in the case of the PIGE measurements it was between 9−12%. bBecause of the potassium content of the applied anticoagulant (K3EDTA), these results were excluded.

Generally, using the combined μ−PIXE-PIGE techniques, the trace elements concentration of biological samples can be determined with minimal sample preparation and at ppm sensitivity. It was found that the concentrations of certain elements measured in the whole blood and the blood serum are in good agreement with the reference data found in the literature.32,33 However, in case of some heavy elements, such E



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as iron, copper, and zinc, the measured values may be higher than the reference values. The reason for this is unknown yet. In the future, further measurements are needed to investigate this aspect.

CONCLUSIONS With this ion beam analytical method, light and heavy elements could be successfully determined in liquid phase, without the need of any sample preparation. Thanks to the light element matrix (H2O), the elements could be detected down to 1 ppm level using about a 10 μL sample. It was found that the analysis with 3.5 MeV proton energy (compared to 2.5 MeV), is more suitable for the investigation of liquid materials because of the larger penetration depth to the liquid (it increases about 80 μm in the case of water) and the increased X-ray and gamma-ray yields. Because of this, the measurement time can be decreased. In conclusion, we found that the method is capable to determine elemental composition of small-volume liquid samples routinely. Nevertheless, in the case of lower concentrations, the method is still suitable for the analysis (down to even ∼1 ppm level) but with less accuracy and longer measurement time. As a possible application, different fractions of blood samples were also measured, and light and trace elements were successfully determined. The samples did not require preparation, they could be measured as is, in liquid form. We found that the concentrations of certain elements measured in the whole blood and the blood serum are in good agreement with the reference data found in the literature. However, in the case of some elements (e.g., iron, copper and zinc), the measured values were higher than the reference values. Further measurements are needed also on biological standard materials to investigate this effect in more detail. With the combined μ−PIXE-PIGE technique, trace element concentration of biological samples can be determined with minimal sample preparation and at ppm sensitivity. Moreover, on the contrary to the most commonly applied analytical methods used in trace element analysis, even anions or nonmetallic elements (e.g.: F−, Cl−, Br−, PO43−, SO42−, etc.) can be determined directly and simultaneously with this method. However, this new analytical approach needs large and sometimes hardly accessible infrastructures, but it may be useful in the case of samples where the common analytical methods are difficult to apply. AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: (+36) 52 509 200 ext. 11394. Fax: (+36) 52 416181. ORCID

Robert Huszank: 0000-0001-9986-2388 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

The technical assistance of the Van de Graaff accelerator operating staff at MTA Atomki is gratefully acknowledged. The authors are grateful to K. Pénzes-Daku for valuable discussions and technical assistance. This work was partly supported by the Hungarian Scientific Research Fund OTKA (K108366). F


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Direct Trace Element Analysis of Liquid Blood Samples by In-Air Ion

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