Uncovering the Formation of Color Gradients for Glucose Colorimetric

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Uncovering the formation of color gradients for glucose colorimetric assays on microfluidic paper-based analytical devices by mass spectrometry imaging Soraia Vasconcelos de Freitas, Fabrício Ribeiro de Souza, Jorge Candido Rodrigues Neto, Géssica A. Vasconcelos, Patrícia Verardi Abdelnur, Boniek G. Vaz, Charles S. Henry, and Wendell K. T. Coltro Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b02384 • Publication Date (Web): 06 Sep 2018 Downloaded from http://pubs.acs.org on September 6, 2018

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Analytical Chemistry

Uncovering the formation of color gradients for glucose colorimetric assays on microfluidic paper-based analytical devices by mass spectrometry imaging Soraia V. de Freitas†, Fabrício R. de Souza†, Jorge C. Rodrigues Neto†,‡, Géssica A. Vasconcelos†, Patrícia V. Abdelnur†,‡, Boniek G. Vaz†, Charles S. Henryǁ and Wendell K. T. Coltro†,⸹,* †

Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, 74690-900, Goiânia, GO, Brazil. Embrapa Agroenergia, Empresa Brasileira de Pesquisa Agropecuária, 70770-901, Brasília, DF, Brazil. ǁ Colorado State University, 80523, Fort Collins, CO, USA. ⸹ Instituto Nacional de Ciência e Tecnologia de Bioanalítica, 13084-971, Campinas, SP, Brazil. ‡

ABSTRACT: This study describes the use of mass spectrometry imaging with matrix-assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI) to understand the color gradient generation commonly seen in microfluidic paper-based analytical devices (µPADs). The formation of color gradients significantly impacts assay sensitivity and reproducibility with µPADs but the mechanism for formation is poorly understood. The glucose enzymatic assay using potassium iodide (KI) as a chromogenic agent was selected to investigate the color gradient generated across a detection spot. Colorimetric measurements revealed that the relative standard deviation for the recorded pixel intensities ranged between 34 and 40%, compromising the analytical reliability. While a variety of hypotheses have been generated to explain this phenomenon, few studies have attempted to elucidate the mechanisms associated with its formation. Here, mass spectrometry imaging using MALDI and DESI was applied to understand the non-uniform color distribution on the detection zone. MALDI experiments were first explored to monitor the spatial distribution of the glucose oxidase and horseradish peroxidase mixture, before and after lateral flow assay with and without KI. MALDI(+)-TOF data revealed uniform enzyme distribution on the detection spots. On the other hand, after the complete assay DESI(-) measurements revealed a heterogeneous shape indicating the presence of iodide and triiodide ions at the zone edge. The reaction product (I3-) is transported by lateral flow towards the zone edge, generating the color gradient. Mass spectrometry imaging has been used for the first time to prove that color gradient forms as result of the mobility small molecules and not the enzyme distribution on µPAD surface.

Colorimetric detection has been widely used with microfluidic paper-based devices (µPADs) for clinical studies,1–4 rapid diagnostics,5–7 environmental analyses,8–10 food quality control11–13 and forensic chemistry.14–16 The increasing popularity can be attributed to the possibility of getting fast results using inexpensive readout systems such as desktop scanners, smartphones, and digital cameras.17–20 The inherent portability of electronic devices for image capture and the potential use of mobile applications for performing colorimetric detection on µPADs could be powerful for point-of-care testing.5,6,9,17,19 While colorimetric detection is attractive for simplified detection, color gradient and/or lack of color uniformity on the detection zones is a significant problem for many assays, especially when they are performed with the flow. In general, chromogenic agents or target biomolecules spotted on paper may travel towards the detection zone edges during the reaction, developing a non-uniform coloration. This problem compromises the readout reliability and consequently the quantitative results.21–26 Different authors have proposed methods for improving colorimetric detection on µPADs. Garcia and co-workers demonstrated that paper surface oxidation enables the conversion of hydroxyl into aldehyde groups allowing for the covalent attachment of enzymes to the paper surface. A colorimet-

ric assay for glucose and uric acid performed on chemically modified µPADs revealed noticeable improvements in the color uniformity.23 Evans et al. investigated the effects of different chromatography and filter paper grades on the analytical performance of µPADs.24 Based on their report, the best analytical performance is obtained using thinner materials like Whatman grade 1 filter and chromatography papers as they promote faster solution transport and therefore better color uniformity. The same group also described the modification of µPADs with silica nanoparticles previously functionalized with 3-aminopropyltriethoxysilane to improve color uniformity.27 This strategy enabled stronger adsorption of enzymes on the surface and minimized the color gradient often observed on native µPADs. Figueredo et al. reported the incorporation of magnetic nanoparticles, multiwalled carbon nanotubes (MWCNT), and graphene oxide (GO) on µPADs as strategies to solve the lack of homogeneity often seen in the color measurements.25 All the tested nanomaterials provided improvements in color uniformity and sensitivity for glucose assays. The reported advances may be associated with physical adsorption of different nanomaterials to the paper surface. Gabriel and co-workers also showed that the formation of chitosan films on paper zones creates a favorable microenvironment for the direct electron transfer (DET) between enzymes

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and reactive surface.26 When compared to native µPADs, the faster DET on chitosan-modified µPADs provided better color uniformity. Morbioli and co-workers reported that the rational design of µPADs in a three-dimensional configuration could enable a uniform permeation of fluids along the cellulose matrix.28 The authors systematically investigated the effect of the hydrodynamic resistance of the path traveled by the fluid on the color distribution. McCann et al. studied the distribution of proteins spotted on µPADs and their interaction with 3MM chromatography paper.29 The authors observed that the color intensity was proportional to the amount of protein immobilized on the paper surface. In their report, homogeneous blue spots were always obtained due to the staining with Coomassie blue, thus indicating no coffee ring effect for the proteins. Despite recent advances, the underlying mechanism leading to the color formation is poorly understood. A complete understanding would increase the analytical performance (reproducibility, sensitivity, etc) and accelerate commercialization of this technology. The current study describes a systematic investigation of the color gradient formation on µPADs using the mass spectrometry imaging techniques known as matrixassisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI). Colorimetric assays for glucose detection based on the enzymatic reaction with glucose oxidase (GOx) was chosen as a model due to its wide application on µPADs and, consequently, well-known properties. MALDI and DESI were successfully employed to visualize the spatial distribution of enzymes and chromogenic agent in the paper surface, respectively.

EXPERIMENTAL SECTION

Chemicals and materials. Potassium iodide (KI), glucose oxidase (from Aspergillus niger, 181 U mg−1) (GOx), horseradish peroxidase (73 U mg−1) (HRP), D(+)glucose, isopropyl alcohol, sodium phosphate dibasic anhydrous, sodium phosphate monobasic, acetonitrile, formic acid and sinapinic acid (SA), sodium periodate, hydrogen peroxide, N-(3dimethylaminopropyl)-N‫׳‬-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were acquired from Sigma Aldrich Co. (Saint Louis, MO, USA). Methanol was received from Tedia Company, Inc (Fairfield, OH, USA). Analytical solutions were prepared using ultrapure water processed through a water purification system (Direct-Q® 3, Millipore, Darmstadt, Germany) with a resistivity equal to or higher than 18.2 MΩ cm without further purification. Whatman chromatography paper (grade 1) was purchased from GE Healthcare Life Sciences (Chicago, IL, USA). Fabrication of µPADs. Paper-based devices were fabricated by laser cutting24 using CHR Whatman paper (grade 1). The layout was drawn using CorelDraw version X8 and cut by commercial CO2 laser engraver (model Mini 24, 30 W, Epilog Laser Systems, Golden, CO, USA) using 600-dpi resolution, 30% power, and 30% speed. µPADs were designed to contain three detection zones and one control zone. All zones (diameter = 5 mm each) were interconnected by microfluidic channels (2 mm wide). The lengths of microfluidic channels from detection zones to the intersection and from the control zone to the intersection were 8 and 7 mm, respectively. To avoid contamination, µPADs were immersed in isopropyl alcohol for 5 min and dried at room temperature prior to the addition of each solution.

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Chemical modification of the paper surface. To compare the enzyme distribution on native and chemically modified µPADs, the paper surface was oxidized according to a procedure reported by Garcia and co-workers23. In brief, µPADs were immersed in 0.5 mol L-1 NaIO4 solution for 30 min in the dark. Then, the µPADs were washed in ultrapure water and allowed to dry at room temperature. Next, 0.75 µL aliquots of a mixed solution containing EDC (0.1 mol L-1) and NHS (0.1 mol L-1) were spotted on the detection zones before the addition of the glucose enzymatic assay compounds and allowed to dry at room temperature for 20 min before glucose assay. Glucose enzymatic assay. The glucose enzymatic assay was performed according to the procedure described by Martinez et al.19 Briefly, 1 µL aliquot of 0.6 mol L-1 KI solution was spotted on all detection zones and dried at room temperature for 10 min. Then, 1 µL aliquot of a solution containing GOx (120 U mL-1) and HRP (30 U mL-1) prepared in 100 mmol L-1 phosphate buffer (pH 6.0) was added on all detection zones and allowed to dry at room temperature for 10 min. Lastly, 12 µL aliquot of standard glucose solution (8 mmol L1 ) was added in the channel intersection to reach the detection zones by lateral flow. Hydrogen peroxide assay. A colorimetric assay for detecting hydrogen peroxide was carried out on µPADs to evaluate the color gradient formation. For this purpose, an 1 µL aliquot of 0.6 mol L-1 KI solution was spotted on all detection zones and dried at room temperature for 10 min. Then, 12 µL of 8 mmol L-1 hydrogen peroxide standard solution was added in the channel intersection to reach the detection zones by lateral flow. Matrix-Assisted Laser Desorption/Ionization (MALDI). MALDI(+)-TOF imaging experiments were performed on an UltrafleXtreme MALDI-TOF mass spectrometer (Bruker Daltonik GmbH Life Sciences, Bremen, Germany) using flexControl software (version 3.4) for image acquisition and flexImaging (version 4.0) for image processing. To investigate the enzyme spatial distribution, the scanned mass range varied between 40 and 160 kDa, with a detector gain of 20x, a reflector voltage of 2659 V, and an 80 µm smart beam laser in 2,000 Hz frequency. The sample rate was of 1.25 GS/s, with a medium real-time smoothing. A baseline offset adjustment of 2.8% and an analog offset of 3.1 mV was applied. The standard matrix solution consisted of 10 mg/mL SA (sinapinic acid) prepared in 30% acetonitrile/0.1% formic acid. To monitor the enzymes distribution, 3 µL of the matrix were spotted on the detection zones. Desorption electrospray ionization (DESI). DESI(-) experiments were carried out using a lab-built prototype DESI ion source coupled with a QExactive™ (Thermo Scientific™, Bremen, Germany) mass spectrometer (MS). The MS parameters used in all analyses were: resolving power of 70,000, scan range of (m/z) 100 to 300, and a maximum injection time of 200 ms. The ion automatic gain control was set to 5e6, and the capillary temperature was 275 °C. DESI geometry parameters were optimized to obtain the best signal intensity and the final conditions used were tip-to-surface 2 mm, tip-to-MS inlet 4 mm, and incidence angle 52º. The surface scanning speed was 200 µm.s-1, and the vertical line distance (step size) was 200 µm resulting in a pixel size of 200 µm. Methanol was used as a solvent and delivered at a flow rate of 5 µL.min-1, and the nitrogen gas pressure was 150 psi. The MS data were converted using Firefly v.2.2.00 software (Prosolia Inc., Indianapolis, IN) and the images were generated using the open source Biomap 3X software (https://ms-imaging.org/wp/biomap/).


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Analytical Chemistry

RESULTS AND DISCUSSION

Color gradient generation. The colorimetric enzymatic assay for glucose was chosen to investigate the mechanism of color gradient generation due to its broad use in the established literature.19 The assay is based on the conversion of glucose to gluconic acid (GA) and hydrogen peroxide catalyzed by the enzyme GOx. This reaction occurs in the presence of HRP which catalyzes the reduction of the hydrogen peroxide and the oxidation of iodide to molecular iodine, causing the formation of a brown color.19 Under flow conditions, the sample solution travels across the paper until reaching the detection zone previously spotted with the chromogenic and enzyme solutions. In this region, the development of a brown coloration with a uniform distribution over the entire zone is expected. Many studies in the literature have demonstrated that the color generation does not occur homogeneously across the paper.23-25,27 The common explanation for this phenomenon is that the spotted reagents (mainly enzymes) are carried along with the glucose solution towards the zone edges/borders by the fluidic transport, especially when they are not well attached to the paper surface. Figure 1 displays a typical optical image obtained illustrating this effect. For the glucose assay performed at a concentration of 8 mmol L-1, the color gradient was calculated dividing the absolute standard deviation by the mean pixel intensity value generated in the Corel Photo-Paint software using the RGB scale. The resulting values for the three detection zones displayed in Figure 1B range from 34 to 40%, reflecting the color change across the entire zone. This effect compromises the quantitative analysis and consequently the analytical reliability once the concentration information is directly extracted from the color intensity generated on entire zone.

image (Figure 2D) was also recorded for the glucose assay performed on paper surface previously oxidized with periodate and chemically activated with EDC/NHS. For all four images in Figure 2, the enzymes distribution appears to be uniform across the entire detection zone. It is important to highlight that both enzymes were imaged separately. Although they present different mass values (80 kDa/monomer for GOx and 44 kDa for HRP), no difference was observed experimentally based on the mass spectra. The images displayed in Figure 2 were generated using all data recorded between 102 to 110 kDa, where the most abundant peaks were observed at m/z 104 kDa (see Figure S-2). Based on the results achieved by MALDI experiments, note that enzymes with m/z values between 102 and 110 kDa are uniformly distributed on the detection zones, i.e., they were not transported to the zone edges underflow assay, as previously hypothesized.23–27

Figure 2. MALDI(+) images showing the spatial distribution in the detection zone containing (A) GOx/HRP prior to lateral flow assay, (B) GOx/HRP and (C, D) GOx/HRP plus KI after lateral flow for glucose detection. Images (C) and (D) were recorded using native and oxidized paper surfaces, respectively.

Figure 1. Optical images showing the µPAD (A) before and (B) after glucose assay performed at a concentration of 8 mmol L-1 using KI as the chromogenic agent.

MALDI(+)-TOF imaging. MALDI imaging was explored to study the enzymes spatial distribution on the detection zones. To confirm that the papers surfaces were free of contamination and to assure the reliability of MALDI to spatially monitor the chosen enzymes on paper surface, an image of the pure paper detection zone, i.e., without any modification or spotted solution, was imaged by MALDI (Figure S-1). To analyze reagent and product concentrations on the µPADs, detection zones were individually spotted with different solutions and sequentially analyzed. Figure 2A shows a MALDI image of the detection zone spotted with GOx/HRP only. Figures 2B and 2C show two MALDI images obtained after the glucose assay on detection zones spotted with GOx/HRP and GOx/HRP plus KI, respectively. In addition, a MALDI

DESI(-) MS imaging. Once MALDI-TOF demonstrated that enzymes remained uniformly distributed across paper during flow experiments, DESI MS imaging was explored to analyze the distribution of the chromogenic agent and/or the reaction products on the paper surface. DESI images displayed in Figures 3A and 3B show the spatial distribution of I- in the detection zones after the glucose enzymatic assay performed in both native and oxidized µPADs. Note a heterogeneous color distribution in both substrates. In addition, the profile observed by imaging was similar to that seen in the digital image exhibited in the corner of each DESI image. To demonstrate that the color gradient is generated by the movement of I- ions, a colorimetric assay for hydrogen peroxide was performed using KI and chromogenic agent. As can be observed in the DESI images depicted in Figures 3C and 3D, the spatial distribution in both native and oxidized µPADs revealed behavior similar to that seen for the enzymatic assay. Considering the images presented in Figures 3A-3D (m/z 126.904), it is clearly demonstrated that the movement of Iions plays a strong effect on the color gradient formation. In addition, colorimetric assays for glucose and hydrogen peroxide were performed in both native and oxidized paper-based devices. As denoted in Figure 3B and 3D, the color gradient


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was less pronounced than those observed in Figures 3A and 3C. This may be attributed to a stronger electrostatic interac-

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tion between chromogenic agents and paper surface rather than effective covalent attaching.

Figure 3. DESI imaging showing the spatial distribution of (A-D) I- (m/z 126,904) and (E-H) I3- in the detection zones created on native and oxidized paper surfaces. Images labeled as (A, B) and (E, F) show the spatial distribution recorded for the glucose colorimetric assay performed at a concentration of 8 mmol L-1. Images labeled as (C, D) and (G, H) display the spatial distribution for the hydrogen peroxide assay performed at a concentration of 8 mmol L-1. For all DESI images, optical images for all the experiments were also presented.

As is well known, the colorimetric reaction to detect glucose in the presence of both GOx and HRP enzymes leads to the formation of molecular iodine, and its interaction with the excess of I- spotted on the paper surface can promote the formation of triiodide ions (I3-). In this way, DESI imaging was also explored to investigate the spatial distribution of I3- in the detection zone. A MS spectrum was initially recorded allowing the identification of two main peaks with m/z values equal to 126.904 and 380.714, thus successfully confirming the presence of I- and I3- ions, respectively. In this way, the m/z 380.714 was selected to generate the DESI images showed in Figures 3E-3H. As can be noted, color gradients for glucose and hydrogen peroxide were recorded with behavior quite similar to those seen in Figures 3A-3D, indicating the presence of I3- in the heterogeneous shape at the zone edge. This achievement successfully supports the hypothesis that the color gradient is formed mainly by the movement of iodide and triiodide ions to the zone edges under lateral flow. One of the strategies to minimize the formation of color gradients refers to the possibility of adding the indicator after the enzymatic assay. For this purpose, 1 µL of KI solution was added on the detection zone 10 min after completed the enzymatic reaction, i.e., directly into a zone containing 1 µL aliquot of GOx/HRP and glucose solution that had been transported by flow. This experiment was carried out to investigate the color distribution in the detection zone and to test our hypothesis related to the color gradient generation. The results achieved by DESI-MS imaging are presented in Figure 4. As shown in Figure 4A, the generated color also exhibits a slight gradient with darker intensity in the edges. The color gradient was calculated considering the pixel intensity recorded for the three detection zones and the achieved values ranged from 13 to 15%. Although DESI-MS imaging has provided a uniform distribution of the iodide ion (Fig. 4B), the presence of a small gradient is due to the principle hypothe-

sized previously. When the indicator is added to the zone, the solution located at the edges evaporates faster than the one located in the middle of the zone because of air contact. Therefore, it moves from the center to the edges to supply the evaporated water, developing a brown coloration with higher intensity at the edges due to a high concentration of I3-.30 the strategy of using multiple additions of chromogenic indicators on the detection zone has been used to minimize the coffee ring or washed away effects.31 Likewise, the data presented in Figures 3A-3H show that the color gradient is generated by the fluidic transport of I- and mainly I3-.

Figure 4. (A) Optical and (B) DESI-MS images showing the color generation and distribution (m/z 126.904) in the detection zone, respectively, keeping the addition of KI after completed the enzymatic reaction.

CONCLUSIONS In summary, we reported for the first time a systematic study about the coffee ring or washed away effect formation on paper-based devices, exploiting complementary mass spectrometry imaging techniques to understand the real reason for


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Analytical Chemistry the lack of uniformity often observed. MALDI and DESI imaging techniques were successfully explored to accomplish all the involved steps in the enzymatic assay for the colorimetric detection of glucose. Based on the reported data, MALDI(+)-TOF has indicated that both GOx and HRP enzymes are uniformly distributed before and after lateral flow assay. On the other hand, DESI(-)-MS experiments generated useful information showing that the lack of color uniformity is due to the fluidic transport of the I- and I3-. This hypothesis has been supported by colorimetric assays for detecting glucose and hydrogen peroxide. This achievement demonstrates that the anchoring of chromogenic agents is the most crucial step to ensure reliable analytical information from colorimetric measurements. Lastly, this current study has successfully revealed that the paper oxidization does not lead the uniform distribution of enzymes on the paper surface. While many reports have achieved improvement on the color uniformity and intensity,23,25,26 this may be most probably associated with the stronger interaction between chromogenic agents and paper surface.

ASSOCIATED CONTENT

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Supporting Information MALDI-TOF MS data for the native paper surface without spotted solution and enzymatic solution containing GOx and HRP, DESI MS data for I- and I3-.

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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

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Author Contributions

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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

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ACKNOWLEDGMENT This work was supported by CNPq (grant no. 308140/2016-8), CAPES (grant no. 3363/2014), FAPEG and INCTBio. C.S.H. acknowledges support from Colorado State University.

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