Functionalized Porous Silicon Surfaces as DESI-MS Substrates for

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Functionalized porous silicon surfaces as DESIMS substrates for small molecules analysis Nicolas V. Schwab, Moriam O. Ore, Marcos N. Eberlin, Sylvie Morin, and Demian R. Ifa Anal. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Nov 2014 Downloaded from http://pubs.acs.org on November 5, 2014

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Analytical Chemistry

Functionalized porous silicon surfaces as DESIMS substrates for small molecules analysis Nicolas V. Schwab1,2,•, Moriam O. Ore1,•, Marcos N. Eberlin2, Sylvie Morin*1 and Demian R. Ifa,1* 1

Departament of Chemistry, York University, Toronto, Ontario, M3J 1P3, Canada.

2

ThoMSon Mass Sectrometry Laboratory, University of Campinas — UNICAMP, Campinas, SP, 13085-970, Brazil. • These authors contributed equally to this work.

KEYWORDS: DESI, porous silicon, mass spectrometry, porosity ABSTRACT In desorption electrospray ionization mass spectrometry (DESI-MS), the type of surface in addition to low gas and solvent flow rates help avoid the ‘splashing of solvent’ or ‘washing effect’ where samples are promptly removed from the surface by the spray. These effects operate on smooth surfaces and generally result in unstable signals as the spray moves over the spot. The aim of this work is to compare the performance of functionalized porous silicon surfaces (pSi) for small molecules analysis with regard to the stability of the signal and the limits of detection (LODs) observed in DESI-MS. The results shown that functional groups like 1-decene and Heptadecafluoro-1,1,2,2Tetrahydrodecyl Trimethoxysilane on pSi surfaces provides a good alternative for dried spot analysis by DESI-MS, improving stability of the signal and the LODs. This is possible because the dual process containing the weak sample-surface interactions of the hydrophobic characteristic of the functional groups and increasing the surface area of interaction between the sample and the thin solvent film created by the DESI spray, resulting in more effective dissolution of the analyte in the spray solvent without fast removal of the sample.

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INTRODUCTION Desorption electrospray ionization (DESI) is one of the most used ambient techniques in mass spectrometry that allows direct surface sample analysis without or with minimal sample preparation.1,2 In DESI, charged droplets created by the solvent spray under a nitrogen flow and high voltage hits the surface dissolving the sample, followed by splashing on the arrival of subsequent droplets with the emission of secondary droplets which are directed to mass spectrometer. The DESI mechanism involves a droplet pickup process followed by ESI-like desolvation of the secondary droplets and formation of gas-phase ions.3,4 With relative simplicity source, fast analysis (just few seconds) and high sensitivity, DESI-MS has been successfully used for analysis of many different samples.5,6 Despite the simplicity there are several important parameters for DESI ion source optimization, which are responsible for spectra quality. The optimization of the geometry of the system, nebulizing gas pressure, solvent flow and capillary voltage have been documented.6,7 For spot analysis, the auxiliary surface is an important parameter that needs to be evaluated for good quality spectra. The type of the surface helps to avoid the ‘splashing of solvent’ where samples are promptly removed from the surface by the spray, this effect operating on smooth surfaces generally result in unstable signals as the spray moves over the spot.8 A study carried out by Ifa et al.9, using different PTFE substrates showed that the porosity of the material avoids sample being swiftly washed away from the surface and making the signal more stable leading to little sample spot-to-spot carryover. Volny et al.10, suggests that surface energy (wettability) is an important factor controlling droplet behavior on the surface and based on the results presented proposed that hydrophobic materials have the potential to be excellent DESI substrates. Porous silicon (pSi) is a high surface area semiconducting material suitable for the development of biosensors.11-13 Due to its properties of photoluminescence it has potential applications for the design of optoelectronics devices and also has an interesting application as substrates for desorption/ionization mass spectrometry techniques.14 Desorption/ionization mass spectrometry (DIOS-MS) on silicon substrate is a matrix-free technique that has been successful used for small and large molecules analysis.15 The main advantages of using pSi substrates is the ability to control morphology, porosity, porous layer thickness and chemical properties. pSi substrate can be fabricated from crystalline silicon using known experimental methods for a particular application. For example, functionalized surfaces can be produced through thermal hydrosilylation16 and silylation process.17 Such reactions lead to the formation of chemically stable bonds linked monolayers containing functional groups. These functional substrates are already reported for use in desorption/ionization assisted by laser in mass spectrometry applications. Morin et al.18, created alkyl monolayer films as functional groups on pSi as MALDI-MS substrates for selective binding of proteins from complex mixtures. They related that the functional groups could serve as platforms to selectively capture and sequester large molecules from complex mixtures for 2 ACS Paragon Plus Environment

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identification and enrichment of low abundant biological molecules. Siuzdak et al. used silylation chemistry on porous silicon to provide ultrahigh sensitivity and analyte specificity with DIOS-MS analysis.19 The present paper discusses the use of functionalized pSi surfaces with different porosities by DESI-MS for small molecules analysis with regard to the LOD, signal stability and cross contamination. The LOD can be taken as an indicator of sensitivity since improvements in the sensitivity of the method bring about better LODs. In a previous study,9 it was observed that porous Teflon is a better surface compared to the commercially available printed Teflon slides. In the present work, an initial test showed that the total ion counting (TIC) from pSi using just methanol was even higher compared to the porous Teflon. For this reason, we focused our work on porous silicon surfaces.

EXPERIMENTAL pSi Etching Conditions. To create porous surfaces, silicon crystalline (Virginia semiconductors) wafers were first etched with hydrofluoric acid (HF) and anhydrous ethanol mixture in Teflon etch cell galvanostatically under different conditions to produce and control the pore size diameter as follow: Micropores: Porous silicon film diameter smaller than 2 nm, formed using 1Ω cm (100) p-type silicon substrate etching current of 8.3mA/cm2 for 30sec, in 1:1 (HF: Ethanol) solution. Mesopores: 1mΩ cm (100) p-type silicon substrate, etching current of 8.3mA/cm2 for 30sec, in 3:1 (HF: Ethanol) solution. Macropores: 15-100Ω cm (100) p-type silicon substrate, etching current of 8.3mA/cm2 for 40min, in (HF (10%): Ethanol (72%) solution). Chemical modification of pSi surfaces: Thermal hydrosilylation: To avoid the fast oxidation of the freshly etched H-terminated porous silicon substrates were then reacted thermally with 1-decene reagents in Schlenk tubes under argon in order such reaction lead to the formation of thermally and chemically stable Si–C bond creating an hydrophobic surface. The freshly etched porous silicon surface was placed under argon in a Schlenk tube containing 1-decene reagent and allowed to react at 150 °C for 3 h then the functionalized surface was rinsed with ethanol followed by rinsing with dichloromethane. Finally, the sample was dried under a gentle stream of argon. Silylation. The derivatization process involved the modification of hydroxyl groups present on the porous silicon surface with Heptadecafluoro-1,1,2,2-Tetrahydrodecyl Trimethoxysilane (HFTHDTMS) (Gelest Inc.) by thermal oxidation of the freshly etched porous surface carried out at 300 °C for 4 min followed by aqueous oxidation in nitric acid containing oxidizing solution (1:1:5) (H2O2:HNO3:H2O) at 80°C for 5 min,



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then addition of 50 µl of the silylating agent for 30 min at 100 °C. Surface was then rinsed with ethanol and dried with argon. Characterization of pSi surfaces: Porous materials are classified into several kinds by their size. Microporous materials have pore diameters of less than 2 nm and macroporous materials have pore diameters of greater than 50 nm; the mesoporous category thus lies in the middle. To distinguish the pore size of the substrate scanning electron microscopy images of pSi surfaces were acquired using a FEI Quanta 3D Peg, scanning electron microscope and a Nicolet 6700 Fourier transform infrared spectrometer (FT-IR) (Thermo Scientific) equipped with a Harrick Cricket accessory for diffuse reflectance was used to confirm the surface functionalization. Instrumentation: DESI-MS. The experiments were conducted using a Finnigan LTQ linear ion trap mass spectrometer (Thermo Scientific) and coupled to a lab-built DESI source with a 2D moving stage. The LTQ operating parameters were as follow: spray voltage, 5 kV; MS injection time, 150 ms; the automatic gain control (AGC) was turned on and 2 microscans were summed to create each spectrum. The DESI source conditions were as follow: nitrogen sheath gas pressure, 100 psi; incident angle, 51 º; tip-to-surface distance, 2 mm; tip-to-inlet distance, 5-7 mm. Methanol was used as spray solvent and delivered by the instrument syringe pump at a volumetric flow rate of 3 µL/min. Measurements were obtained by continuously scanning the DESI spray across the surface varying the speed according to the experiment. Sample preparation: Stock solutions of Propranolol, Angiotensin, Acetylcholine, Testosterone, Verapamil, Roxithomycin, Ibuprofen, Chloramphenicol purchased from Sigma-Aldrich and Diazepam, Cocaine, Oxycodone from Cerilliant (Round Rock, Texas), were prepared in deionized water LC-MS grade at concentration of 1 µg/mL and employed for serial dilutions in water providing final concentrations of 0.5, 1, 10 and 100 ng/mL. All the spotted samples on the pSi surfaces were allowed to dry at room temperature prior to analysis.

RESULTS AND DISCUSSION To evaluate the efficiency of porous silicon surfaces as substrate by DESI-MS analysis, three different surfaces were produced. Changing the etching parameters such as current density, etching solution and etching time, affects the surface morphology allowing fabrication of porous silicon films with different pores sizes diameters. The Figure 1 show the microscopy imaging of the porous silicon created using the conditions described at experimental section.


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A)

B)

C)

Figure 1. Plan and cross section view imaging by scanning electron microscopy of (A) microporous; (B) mesoporous and (C) macroporous of pSi surfaces. Every pSi surface generated by anodization process are hydride terminated, hydrophobic and very unstable when handled for several minutes in the air, it oxidizes easily resulting in the formation of a thin native oxide layer, therefore treatments should be performed to create stable surfaces. The oxidation changes the chemical interaction of the sample-to-surface creating hydrophilic surfaces due the Si-OH bonds formed and will create a strong interaction of the sample droplets with the substrate compromising the performance of the experiments. The spot size is important to determine the analyte 5 ACS Paragon Plus Environment


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concentration per unit area, as well as amount of material available to be sampled by a DESI impact plume. Best detections levels can be reached if the sample is concentrated in an area smaller than the spray spot size.20 Thermal hydrosilylation was one of the routes used to modify pSi with Si-C bonds and improve its aqueous stability producing a dense monolayer of alkene species covering the pSi surface and protecting from degradation. The substrate as soon as etched by HF was cleaned with ethanol and placed in Schlenk tubes with 1-decene reagent under argon for 3 hours at 150 ºC, creating a purely hydrophobic surface. After, the chip was rinsed using portions of ethanol and dichloromethane follow by drying with argon. The created surfaces also can be used several times in DESI-MS analysis after washing without any memory effects from previous sample applications. To investigate the effect of different pore size surfaces on the ionization efficiency in DESI a model sample was prepared by mixing four different compounds (cocaine, propranolol, verapamil and acetylcholine) with final concentration of 200 ng/mL for each one. Aliquots of 1 µL of the mixed sample were deposited in each surface and left to dry at room temperature, after a line is scanned trough the spot at 350 µm/s using a lab built moving stage and methanol as DESI solvent spray. The highest total ion current related at spot area was chosen to compare the desorption/ionization efficiency in common surfaces used by DESI analysis like porous PTFE and PMMA sheets (see Figure S1 at support information). The micro and meso porous silicon surfaces gave better signal intensities under same conditions. During the experiment, a difference of the stability of the signal intensities between the unprocessed non-porous silicon and the pSi surfaces was observed. Porous surfaces always produce a good signal during analysis that lasts for at least one minute of sampling at same spot while the opposite is observed for the non-porous silicon surfaces, the signal of the analyte is not stable and persists just for a few seconds. To understand this effect a simple test was made, a dried spot from 5 µL of cocaine and chloramphenicol solution deposited on these surfaces was analyzed by running the DESI spray ten times over the same line. The test was performed in triplicate using the moving stage at 800 µm/s. The desorption/ionization signal intensities were evaluated in the positive mode for cocaine and the negative for chloramphenicol. It is interesting to note at Figure 2 the difference between the signals intensities along the repetitions, the amount of sample desorbed on the non-porous silicon surfaces decreases exponentially whereas the porous silicon surfaces did not change as much after ten repetitions.


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Flat

Relative Intensity (%)

Micro

Meso

Macro

A)

100 80 60 40 20 0 0

2

4

6

8

10

Number of repetitions (#) Flat

Micro

Meso

Macro

B)

100


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80 60 40 20 0 0

2

4

6

8

10

Number of repetions (#)

Figure 2. Signal stability analysis of an aliquot of 5 µL of a 1 µg/mL solution of (A) cocaine and (B) chloramphenicol after ran 10 times in triplicate. Each point represents 3 replicates analysis of the highest intensities per repetition of the compounds ion peaks. The intensities were normalized for each surface.

The desorption on porous silicon surfaces cause a long and stable analyte ion signal and we hypothesize that the spray of methanol creates pools of solvent on the surface. These pools are then pushed against the pores by subsequent spray droplets without getting inside the pores due to the hydrophobicity of the surface. This process would create turbulences in the pools improving the solubility of the analytes previously crystalized on the surface. This mechanism improves the desorption/ionization efficacy without fast removal of the sample maintaining a stable and high signal throughout time. For the non-porous silicon surfaces, the opposite happens a very unstable signal is observed due to instantaneous removal of the sample from the surface. 7 ACS Paragon Plus Environment


The carryover test was performed in DESI-MS for the silicon substrates; 1µL of 4 different analytes at 1 µg/mL was deposited in a line with around 1 mm of distance between each droplet. After drying, the sample was scanned by DESI over the spots at 350 µm/s of scan rate. The extracted-ion chromatogram obtained from the compounds were plotted to evaluate the cross contamination, this problem occurs when the thin layer of solvent containing dissolved analyte is pushed along the surface or splashed. The Figure 3 demonstrates the experiment for functionalized micro-porous and nonporous silicon surface, it is clearly evident along the scan rate the overlapping of peaks on non-porous surfaces and this effect was completely minimized over the porous surfaces. The porosity of pSi surfaces probably acts as a barrier to the spreading solvent, thereby decreases carryover and the same quality was observed for macro and meso pores, the graphs can be seen at support information. Cocaine

Verapamil

Oxycodone

Acetylcholine

100


A)

50

0 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Time (min) Cocaine

Verapamil

Oxycodone

Acetylcholine

100

B) Relative Intensity (%)

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50

0 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Time (min)


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Figure 3. Extracted-ion chromatogram intensities of Cocaine, Verapamil, Oxycodone and Acetylcholine solution at 1µg/mL. Aliquots (1µL of each solution) were deposited in a straight line about 1 mm apart on (A) micro-porous and (B) non-porous surface.

The results clearly show a significant improvement in sample ionization on porous surfaces to current problems in analysis by DESI-MS. The comparison of the mass spectra acquired for the mixed solution evidently shows the high efficiency of desorption/ionization on the pSi surfaces. The hydrophobic surface functionalization with 1-decene helps to increase the analytical signal of the molecules when at the same time the porosity avoids the fast removal of samples due the desorption. Further, we evaluate such effects modifying the pSi surfaces with HFTHDTMS by silylation process. The HFTHDTMS consists of fluorinated carbon chains and the reaction occurs when the pSi surface is oxidized through thermal and aqueous oxidation followed by deposition of the reagent on the surface and heating for 30 min. These fluoro-alkyl groups express a highly hydrophobic behavior than 1-decene, thereby improving even the desorption of polar compounds and enhancing the sensitivity. To evaluate the lowest limit of detection several compounds were tested and compared with different surfaces produced. The experiment was perfomed with a non-porous silicon surface and microporous surfaces functionalized with 1-decene and HFTHDTMS. The etching conditions to produced micro-porous film was chosen for subsequent functionalization due the previously experiments showing higher signal intensities at same condition for this surface compared with others (Figure S1). The table 1 show the LOD for several ordinary compounds on distinct surfaces. Five different concentrations of each compound, ranging from 0.5 ng/mL to 1 µg/mL were deposited in a straight line and the DESI spray scanned across the dried spots. The detection method was made by MS/MS mode and the ion current used for data analysis.



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Table 1. Lowest concentrations detected for representative compounds on different surfaces Compound

Acetylcholine

Polarity

+

Colisson Energy 30

Precursor → Product (m/z) +

146 [M+H] → 87 +

LOD (ng/mL) Non-porous Silicon Wafer

1-decene-micro-pSi

HFTHDMS-micro-pSi

100

1

0.5

Propranolol

+

27

260 [M+H] → 183

1

0.5

0.5

Testosterone

+

20

289 [M+H]+ → 253

1000

10

10

Diazepam

+

22

285 [M+H]+ → 257

Cocaine Oxycodone

+ +

14 30

100

10

1

+

10

0.5

0.5

+

1

0.5

0.5

+

304 [M+H] → 182 316 [M+H] → 298

Verapamil

+

23

455 [M+H] → 182

100

1

1

Roxithomycin

+

20

837 [M+H]+ → 679

10

1

0.5

Angiotensin

+

20

524 [M+H]2+ → 784

Ibuprofen Chloramphenicol

-

20 27

100

10

10

-

1000

100

100

-

10

10

1

205 [M-H] → 161 321 [M-H] → 257

For the eleven compounds tested the non-porous silicon surface gave higher limit of detection than the two functionalized pSi surfaces. The porous surfaces give similar LOD for most of the compounds but HFTHDTMS-pSi provides better limit of detection for four of the compounds tested. It is important to mention that silylation process proves to be easier, simpler and faster to produce when compared with thermal hydrosilylation process.

CONCLUSION The functionalized pSi surfaces provides a good alternative as auxiliary surface by DESI-MS analysis, improving the stability of the signal and the LODs. This is possible because the weak sample-surface interactions due to the hyprophobic characteristic favoring desorption of the analyte. The porosity of the surface allows higher surface area interaction between the dried spot and the thin solvent film created by DESI spray while avoiding the fast consumption due to splashing effect of the sampling, resulting in a more effective dissolution of the analyte and contributes. The performed experiments gave a lower limit of detection for several compounds tested and the background ions results from the compounds at room atmospheric pressure. No difference was observed comparing the micro, meso and macro surfaces (Figure 2) in terms of signal intensity, suggesting that more investigation is necessary in order to fabricate porous surfaces to act as microwells. Possible instrument and solvent impurities did not show in any of the investigated pSi surface suppressing ionization of the analytes. The produced functionalized pSi surfaces


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can be reused for several times after analysis without any memory effect by rinsing the surface with methanol and water. The use of different solvents and the flow rate conditions can change the efficiency of ionization depending on the functionalization groups. The experiments performed using only methanol as spray solvent gave the best results. The hydrophobic behavior of the functionalized groups could increase or decrease the wettability of the surface under different pore sizes conditions. Low wetting surfaces enable less contact between the surface and the solution and could be further investigate for better improvement of the quality of analysis by DESI-MS.21 Further experiments will be done to investigate the surface wettability and to elucidate the mechanism responsible for the results obtained. The use of high speed imaging is also intended. The investigated functionalized pSi surfaces could be suitable for several applications such as quantitation analysis in real samples and specially for blotting or imprint techniques in imaging analysis as an alternative methodology for soft and/or irregular tissues sections.22 Besides, specific functional groups can be produced on porous surfaces at relatively low cost in order to enhance the selective analysis of a variety of compounds. These new surfaces could potentially be commercialized bringing analytical advantages to DESI users.

ASSOCIATED CONTENT Support Information Mass spectrum of several analysis on different surfaces and meso and macroporous cross contamination tests. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]; Phone: +1 416 736-2100 ext.33555. ; [email protected]; Phone : +1 416 736-2100 ext.22303.

ACKNOWLEDGMENT We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Brazilian Science Foundation’s CAPES (Proc. 0293/13-0) for financial assistance. 11 ACS Paragon Plus Environment


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Functionalized Porous Silicon Surfaces as DESI-MS Substrates for

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