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Towards Quantitative Chemical Analysis Using a Ruler on Paper: An Approach to Transduce Color to Length Based on Coffee-Ring Effect Dagan Zhang, Biao Ma, Litianyi Tang, and Hong Liu Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b03790 • Publication Date (Web): 02 Jan 2018 Downloaded from http://pubs.acs.org on January 3, 2018
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Analytical Chemistry
Towards Quantitative Chemical Analysis Using a Ruler on Paper: An Approach to Transduce Color to Length Based on Coffee-Ring Effect Dagan Zhang, Biao Ma, Litianyi Tang and Hong Liu* † State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China. ABSTRACT: We report a quantitative analytical method using naked eyes. The method is based on the coffee-ring effect on paper which converts a colored solution to stains on the paper. It is found that the width of the colored stains is correlated to the concentration of analyte so that quantitative analysis can be accomplished using a ruler. The influence of the shape and lamination of the paper reservoir to the test results is studied to find the optimal one for unambiguous analysis. It is also found that the sample color doesn’t cause interference to the test. The applicability of the method to quantitative chemical analysis is demonstrated by detection of glucose.
Color-based detection on paper has long been utilized for rapid and on-site chemical analysis.1-3 For example, litmus paper has been used for pH test since the 16th century.4 For color-based tests, the amount of analyte is indicated by the color resulting from a chemical or biological reaction.510 But color is a complex signal, which is characterized by hue, value and saturation.11 The perception of color by human eyes is influenced by a range of subjective and objective factors (e.g. background light and individual difference in color perception) that may introduce uncertainty to the test results.12-14 For example, in lateral-flow tests (e.g. pregnancy test) that are widely used for diagnostics, the appearance of a colored test line on a nitrocellulose membrane indicates the presence or absence of an analyte (yes/no answer for diagnostics).15 But the boundary between the yes and no answers is not well defined and susceptible to difference in subjective interpretation of individuals. For urine dipsticks, a reference color bar is often printed on the packaging material so that one can compare the test results with the reference for semi-quantitative detection.16 But the color of the test result is often slightly different from the printed color which makes interpretation of the test result quite subjective. For quantitative color-based tests, an image recording device (i.e. a digital camera or a scanner) or a spectrometer is often involved.17-19 Using the image device, a photograph of the reaction zone is taken, and the color of the zone is digitized which can be represented by three values ranging from 0-255 for red, green and blue (RGB) channels, respectively.20-23 Unfortunately, the photographs taken by different cameras or scanners are considerably different. Even using the same one, the color of the photographs is still affected by a range of parameters which may need to be carefully controlled for accurate measurement.24 Spectrometer is relatively expensive and delicate which
Scheme 1. Schematic illustration showing the principle for quantitative analysis on paper based on the coffee-ring effect. requires trained personnel to operate, so it is less suitable for point-of-care analysis than portable devices.7 For almost all of the color-based tests, the background color of the sample (e.g. blood or urine) may result in interference to the tests, so sample pretreatment such as centrifugation is often required.25 For rapid and on-site chemical analysis, the development of methods to transduce test results into signals that can be unambiguously measured using naked eyes is highly relevant.14,26-28 Here we demonstrate that the transduction of color-based test result into length can be simply accomplished based on the well-known coffee-ring effect (Scheme 1).29-36 A coffee ring is a pattern left by drying a drop of coffee on a substrate. Because the liquid near the edge of a droplet on the substrate evaporates faster than that near the center, a capillary flow arises which brings solutes from the center of the droplet to the edge. The flow leads to the formation of ring-shaped stain on the substrate after complete evaporation of the liquid. The coffeering effect have been used for a variety of applications such as
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Figure 2. (a) Optical photographs of paper strips after completion of the glucose tests. The concentration of glucose in the sample is indicated. (b) Color intensity measured as a function of distance from the edge after the completion of test. The glucose concentration in the sample was 10 mM.
Figure 1. (a) Optical photographs of circle paper reservoirs after completion of the glucose tests. The concentration of glucose in the sample is indicated. (b) Color intensity measured as a function of distance from the edge after the completion of test. The glucose concentration in the sample was 10 mM. nanofabrication,37,38 nanochromatography,39 mass spectroscopy,40 surface-enhanced Raman spectroscopy and preconcentration for biosensing.41-44 For our method, an aqueous sample was introduced onto the paper strip which was preloaded with test reagent. After reacting in a dry chamber for 10 min, the color resulting from the reaction was converted into width of a colored ring on the paper. So the test result can be directly measured using naked eyes with the aid of a ruler and correlated to the concentration of analyte in the sample. (Detailed experimental procedure can be found in the Supporting Information) As a demonstration, glucose is quantitatively detected using this method without using any instruments. We believe this method can be further used for development of various kinds of visualized quantitative colorimetric assays using naked eyes, so it is promising for point-of-care testing under resource-limited conditions. We used starch-iodide paper for detection of glucose. GOx was preloaded on the paper for catalyzing the oxidation of glucose by oxygen and production of H2O2. The H2O2 oxidized the iodide to iodine which was converted to triiodide anion and formed a complex with starch, producing an intense blue/purple color. Conventionally, the color intensity was measured using an imaging device or a spectrometer for quantitative detection. Here we let the reaction mixture on the paper to dry. We found that a colored
ring formed in the paper reservoir (Figure 1a). The forming of the ring was because the solution near the edge of the reservoir evaporated faster than that in the middle leading to a flow of the solution from the center to the edge to replenish the evaporated water. The colored starchtriiodide particles were brought to the edge with the flow and were concentrated on the edge as water evaporated. Note that a homemade dry chamber with silica gel desiccant was used as the reaction chamber to maintain a constant humidity for all assays. Before each assay the chamber was sealed for more than 120 min. For point-of-care applications, the whole test strip can be packaged and stored in a sealed and dry environment which is routinely used in test strip industry. As shown in Figure S1 in the Supporting Information, the relative humidity was kept at about 17%, which ensured the reproducibility of the tests. Usually, the colored particles tend to aggregate into a narrow ring on a solid substrate (e.g. a glass slide). However, in our case the paper substrate was highly porous, and the starch was in the form of nanoparticles in the paper as shown in Figure S2 in the Supporting Information. The evaporation-driven flow brought starch nanoparticles to the edge. Some of the nanoparticles were stuck in the micropores of the paper so that the width of the ring can be much wider than that on the solid substrate. This is a critical feature for further development of coffee-ring based analytical method because the width of ring can be easily measured using naked eyes. As shown in Figure 1a, the width of the ring increased with increasing concentration of glucose. This was reasonable because the glucose reacted with dissolved oxygen and the preloaded reagents to produce the colored starchtriiodide nanoparticles. Higher concentration of glucose in the sample led to more colored nanoparticles which were entrapped in the porous paper to form a wider ring. For quantitative detection, we measured the width of the ring, which was calculated as (d0-d)/2 (d0 is the outer diameter of the ring which was 6.0 mm and d is the inner diameter of the ring as shown in Figure 1a). The width of the ring was correlated to the glucose concentration, and was linearly correlated to logarithm of glucose concentration from 1.0 mM to 20 mM (Figure S3).
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Analytical Chemistry
Figure 3. (a) Optical photographs of partially laminated paper strips after completion of the glucose tests. The concentration of glucose in the sample is indicated. (b) Color intensity measured as a function of distance from the edge after the completion of test. The glucose concentration in the sample was 10 mM. Blue dashed lines show where the lamination was on the strip. Because of the geometry of the reservoir shown in Figure 1a, the colored nanoparticles were evenly distributed around the circle. This led to a problem that the change in ring width is relatively small (0-1.5 mm for glucose concentration from 0 mM to 20 mM), which means the sensitivity for detection was low. To solve this problem, we tried to change the shape of the detection reservoir while keeping the other conditions the same. We fabricated a starch-iodide paper strip (20 × 1.4 mm) which had the same area as the circle paper reservoir had. Similarly, the evaporation at both ends of the paper strip was faster than that in the middle, leading to an evaporation-driven flow of solution from the center of the strip to both ends. Different from the ring stain formed on the circle reservoir, two colored bands formed near both ends of the paper strip (Figure 2a). Because the colored nanoparticles were concentrated near both ends rather than distributed around the circle, the width of the colored bands was larger than that of the ring formed on the circle reservoir. As shown in the Figure S4, the width of the colored band was correlated to the glucose concentration, and was linearly correlated to logarithm of glucose concentration from 1.0 mM to 20 mM. Note that the width of the colored bands changed from 0-9.0 mm for glucose concentration from 0 to 20 mM, so the sensitivity for detection of glucose increased by 6 times compared with the circle reservoir. However, for unambiguous quantitative detection, a clear boundary, where the color intensity decreases from the maximum to zero, is required to measure the width. As shown in Figure 2b, the boundary of the colored band was not as clear as that of the ring formed on circle reservoir, which made measurements of the band width relatively subjective, and therefore considerable uncertainty can be introduced into the test results. Since the colored band formed because of the evaporation-driven flow on the paper strip, the direction of the flow had a dramatic influence on the colored band on the paper strip. The evaporation-driven flow on the paper strip shown in Figure 2a was not uniform, which blurred the boundary of the colored band. For accurate quantitative
Figure 4. (a) Width of the colored band (d0-d)/2 as a function of glucose concentration. Inset: the width as a function of logarithm of the glucose concentration. The error bars represent standard deviation for three replicated measurements. (b) Optical photographs of partially laminated paper strips after completion of the lactate tests. The concentration of lactate in the sample is indicated. (c) Width of the colored band (d0-d)/2 as a function of lactate concentration. Inset: the width as a function of logarithm of the lactate concentration. The error bars represent standard deviation for three replicated measurements. (d) Optical photographs of the partially laminated paper strips after completion of the glucose tests. The concentration of glucose in the sample is indicated. One of the samples contained 22 µM sunset yellow as the interferent. testing, a clear color boundary is required. We hypothesized that a more clear color boundary can be obtain by laminating the paper strip to have a more uniform evaporation-driven flow. To demonstrate that, we partially laminated the paper strip leaving only both ends of the strip exposed to the air. For this case, water can only evaporate from the ends of the paper strip resulting in a uniform evaporation-driven flow from the center of the paper to the ends (Figure 3a). Note that the increased reaction time can also lead to a blurred boundary due to diffusion of the colored species in the reaction mixture. But this effect should not be dominant, because of the small diffusion constant of the triiodide-starch nanoparticle complex. As shown in Figure 3, a well-defined boundary was obtained due to the uniform evaporation-driven flow on the partially laminated paper strip. The color intensity measured at different locations of the reservoir for detection of 10 mM glucose was plotted in Figure 1b, 2b, 3b. For all three paper reservoirs, the color intensity decreased from about 200 to 0 with increasing distance from the edge. But the color boundary on the partially laminated paper strip
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was more obvious than that of the paper strip without lamination. Although the color boundary on the circle paper reservoir was almost as clear as that of the partially laminated paper strip, the change in the width was too small to be measured using naked eyes as previously discussed. Therefore, the partially laminated paper strip should be the optimal reservoir for the coffee-ring based chemical analysis. In this case, the reaction time increased as the paper strip was partially laminated, so the number of colored nanoparticles produced was increased which resulted in wider colored bands than the one without lamination (Figure 3b). The sensitivity for detection of glucose was further enhanced due to the increased width of the colored bands. (Figure 4a). For detection of glucose, the width of the colored band was measured using a ruler which was linearly correlated to logarithm of glucose concentration from 1.0 to 20 mM (Figure 4a). The limit-of-detection, calculated as three times the standard deviation of the blank divided by the slope of the calibration curve, was 0.020 mM. The reproducibility of the testing method was also acceptable which was demonstrated by replicated test in a week (Figure S5). The maximum coefficient of variability is 8.2%. Meanwhile, we also validated our method with lactate (Figure 4b). For detection of lactate, the width of the colored band was measured using a ruler which was linearly correlated to logarithm of lactate concentration from 1.0 to 20 mM (Figure 4c). The limit-of-detection was 0.025 mM. So our method can definitely be used for many targets. For all color-based assays, the background color of the sample (e.g. blood or urine) will result in interference to the tests, so sample pretreatment such as centrifugation is required. For the detection method we developed, the color test result was transduced into width of the colored band so that the interference of the background color of the sample can be avoided. To demonstrate this, we prepared a sample containing 22 µM sunset yellow as the interferent. The test result of the sample was compared with that of the same sample but without the interferent. As shown in Figure 4d, although the yellow-colored interferent did change the color of the band formed on the paper which will cause interference to a conventional colorimetric assay, the width of the colored band didn’t change. Human blood plasma sample was also tested and the results agreed well with that of standard method (Figure S6). So our method can be useful for testing colored samples without any pretreatment.
ASSOCIATED CONTENT Supporting Information Information about chemicals, materials, experimental procedures, and additional Figures. This material is available free of charge on the ACS Publications website.
AUTHOR INFORMATION Corresponding Author
[email protected] Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We gratefully acknowledge financial support from Chinese Recruitment Program of Global Experts, Innovative and Entrepreneurial Talent Recruitment Program of Jiangsu Province, the National Natural Science Foundation of China (21405014, 21327902, 21635001), the Natural Science Foundation of Jiangsu (BK20140619), the Science and Technology Development Program of Suzhou (ZXY201439), State Key Project of Research and Development (2016YFF0100802).
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