Plasmonic Schirmer Strip for Human TearBased Gouty Arthritis Diagnosis Using SurfaceEnhanced Raman Scattering Moonseong Park, Hyukjin Jung, Yong Jeong, and Ki-Hun Jeong* Department of Bio and Brain Engineering and KAIST Institute for Optical Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea S Supporting Information *
ABSTRACT: Biomarkers in tear fluid have attracted much interest in daily healthcare sensing and monitoring. Recently, surface-enhanced Raman scattering (SERS) has enabled highly sensitive label-free detection of small molecules. However, a highly stable straightforward tear assay with superior sensitivity is still under development in tear collection and analysis. Here we report a plasmonic Schirmer strip for on-demand, rapid, and simple identification of biomarkers in human tears. The diagnostic strip features gold nanoislands directly and evenly formed on the top surface of cellulose fibers, which maintain a hygroscopic nature for an efficient collection of tear production as well as provide plasmonic enhancement in SERS signals for identification of tear molecules. The uric acid in human tears was quantitatively detected at physiological levels (25−150 μM) by using SERS. The experimental results also clearly reveal a strong linear correlation between uric acid level in both human tears and blood for gouty arthritis diagnosis. This functional paper strip enables noninvasive diagnosis of disease-related biomarkers and healthcare monitoring using human tears. KEYWORDS: Schirmer strip, SERS, paper, tear, gouty arthritis detection of tear biomarkers with low Raman activity14 due to time-consuming15 and additional data processing.16,17 Paper contains cellulose nanofiber and microfiber matrices whose hygroscopic micro/nanopores induce strong capillarydriven lateral flow.18−21 Recently, this distinctive feature has been further utilized for paper-based SERS techniques such as chromatographic SERS,22 flexible scaffolding SERS format,23 and SERS swabs.24 However, these approaches employ silver nanoparticles as plasmonic nanostructures, which are easily oxidized due to high reactivity and large surface-to-volume ratio.7 Besides, their toxicity further restricts long-term healthcare monitoring applications.25,26 Here we report a plasmonic SERS Schirmer strip for rapid, label-free, and on-demand bioassays of tear molecules. The plasmonic strip contains Au nanoislands on the top surface of cellulose fiber matrices for highly sensitive SERS detection of tear constituents (Figure 1a). Like conventional Schirmer test strips measuring tear production, this particular configuration maintains the hygroscopic micro/nanopores for an efficient collection of human tears by inserting a paper strip into the lower eyelid of the human eye (Figure 1b). In addition, the
H
uman tears contain assorted biochemical molecules such as proteins, metabolites, organic acids, or ions.1−4 Some disease-associated biomarkers in the tears offer many opportunities for daily healthcare monitoring, diagnosis, or physiological function research through rapid and low-cost tear fluid assays. For instance, the glucose level in tear fluid shows a strong positive relationship with that in the blood.3 Besides, the uric acid in tears and in the blood plays a key role as a diagnostic indicator for antioxidant status in the eye4 and gouty arthritis,5 respectively. For decades, mass spectrometry,2 ferric reducing ascorbate assay,4 and amperometric electrochemical sensors3 have extensively contributed to the biomarker diagnosis in human tear fluid. However, a pointof-care diagnostic platform for tear biomolecule assays is still challenging due to time-consuming, bulky, and high-cost equipment. Surface-enhanced Raman scattering (SERS) allows the detection of extremely small amounts of biochemical molecules without fluorescent labeling.6−8 Localized surface plasmons, i.e., the collective oscillation of free electrons in metal nanostructures, significantly enhance an incident light field within electromagnetic hot spots between nanostructures.9,10 Recently, plasmon-enhanced SERS-based biosensors allow highly sensitive and label-free detection of various biomolecules.11−13 However, most previous works still struggle with the SERS © 2016 American Chemical Society
Received: September 13, 2016 Accepted: December 14, 2016 Published: December 14, 2016 438
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Figure 1. Plasmonic Schirmer strip for SERS-based tear screening. (a) Schematic diagram of a plasmonic Schirmer strip. The Schirmer test provides a direct and efficient collection of tears. 3D volumetric electromagnetic hot spots from Au nanoislands on the cellulose micro/nanofibers enable highly sensitive SERS detection of biomolecules with low Raman activity. SEM images of (b) a plasmonic Schirmer strip and (c) cellulose nanofibers covered with Au nanoislands in Volmer−Weber mode. Au nanoislands uniformly cover the top surface of cellulose micro/nanofiber matrices. The inset clearly shows hygroscopic micro/nanopores for capillarydriven lateral flow.
Figure 2. Plasmonic resonance wavelength (PRW) and SERS enhancement of a plasmonic Schirmer strip. (a) Control of Au nanoislands in Volmer−Weber mode on cellulose micro/nanofibers depending on the film thickness and the deposition rate. The left four figures are SEM images of a plasmonic Schirmer strip with a film thickness of 4, 6, 8, and 10 nm at 0.5 Å/s, and the right figures are the SEM images for different deposition rates of 0.2, 0.5, 1.0, and 2.0 Å/s at 8 nm. Precisely controlled deposition of a Au thin film forms the Au nanoislands in Volmer−Weber mode. The binary images in the insets clearly show the change in formation of the Au thin film. For the film thickness, the formation of Au became nanoislands from 4 to 8 nm with decreasing nanogaps, and it became a nanofilm rather than nanoislands for a 10 nm film thickness. For the deposition rate, the formation of Au became nanoislands rather than a nanofilm for higher deposition rates. (b) PRW of a plasmonic Schirmer strip depending on the film thickness (bottom axis, black) and the deposition rate (top axis, red). The dotted line (left axis) with an empty symbol and the solid line (right axis) with a filled symbol indicate practically measured PRW from extinction spectra and calculated PRW using the FDTD method, respectively. The PRW becomes close to an excitation wavelength of 633 nm for the film thickness of 8 nm and the deposition rate of 0.5 Å/s for both the measured and the calculated PRW. (c) Peak intensity variation of SERS signals from Rhodamine 6G (R6G) depending on the film thickness (bottom axis, dotted line) and the deposition rate (top axis, dash dotted line). The SERS signals from R6G are maximized when the PRW has the closest value of the excitation wavelength (633 nm), i.e., Au nanoislands with 8 nm film thickness and 0.5 Å/s deposition rate. In particular, the Au nanoislands with 8 nm film thickness include the narrowest nanogaps, which generate strong plasmon resonance for detection of small molecules.
hierarchical structures of cellulose fibers amply create highly dense nanogap-rich Au nanoislands with three-dimensional (3D) electromagnetic hot spots and thus induce strong plasmonic enhancement of both incident and scattered light from target molecules (Figure 1c).
RESULTS AND DISCUSSION The plasmonic Schirmer strip was simply fabricated on Whatman chromatography paper by using thermal evaporation of a Au thin film. Depending on the film thickness and the deposition rate, a Au thin film in Volmer−Weber mode directly forms the nanoislands on the top surface of cellulose fibers due to the strong coupling of Au atoms with each other rather than with the cellulose (Figures 2a and S1).12,13,27 The scanning electron microscope (SEM) images clearly show nanogap-rich Au nanoislands on the top surface of cellulose fibers. Au film thicknesses from 4 to 10 nm were fabricated under a constant deposition rate of 0.5 Å/s. The film thicknesses were selected from the minimum thickness securing intense localization of incident light28 to the maximum thickness for Au nanoisland formation without Au nanofilm formation. Au deposition rates from 0.2 to 2.0 Å/s were used under a constant Au film thickness of 8 nm. The deposition rates were selected from the minimum value without error during the thermal evaporation to the maximum value with securing the quality of deposition. The nanogaps between Au nanoislands on a single cellulose fiber or neighboring fibers create volumetric electromagnetic hot spots and thus result in strong plasmonic enhancement of SERS signals.22,29−32 The binary inset figures transferred from the SEM images show the formation change of the Au thin film from nanoislands to nanofilms depending on the film thickness and the deposition rate (see detailed parameter changes in Figure S4). The plasmon resonance wavelengths (PRWs) of Au nanoislands were measured from the extinction spectra and well matched the calculated PRWs (Figures 2b, S2, and S3) based on the finite-difference time-domain (FDTD) method (see Experimental Methods). The PRWs become red-shifted
from 4 to 8 nm in film thickness due to the increased nanoisland size, whereas they become blue-shifted from a deposition rate of 0.5 to 2.0 Å/s due to the decreased nanoisland size (Figure S4).28 The Au nanoislands for either 10 nm in film thickness or 0.2 Å/s in deposition rate become almost a nanofilm with cracks by filling the nanogaps between nanoislands with blue-shifted PRWs.33 Rhodamine 6G (R6G) was used as a reference molecule to demonstrate the plasmonic enhancement of SERS signals depending on the PRW (Figures 2c and S5). All the major SERS peaks of R6G at 610, 1357, and 1501 cm−1 exhibit the maximum values as the PRW becomes close to an excitation wavelength of 633 nm. Except for the film 439
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strip width of 5 mm helps an efficient collection of tears without the edge effect, and the folding crease clearly indicates the folding line for the conventional Schirmer test.34 The hygroscopic nature of the plasmonic Schirmer strip and the conventional Schirmer strip was compared by using plasmonic strips with different area fractions of Au nanoislands. Both the plasmonic Schirmer strip and the conventional Schirmer strip were prepared on Whatman chromatography paper by using a paper stencil mask during thermal evaporation and then cut to 0.5 cm × 6 cm. Absorbed crystal violet (CV) dyes were eluted by ethanol as eluent for 10 min. The measured migration length of ethanol and the retention factor of CV are about 40.3 mm and 0.956 for all the plasmonic Schirmer strips with different area fractions of Au nanoislands of 0, 0.25, 0.5, 0.75, and 1, respectively. The experimental results clearly demonstrate that the transport properties of cellulose fiber matrices remain constant because Au nanoislands are only covered on the top surface of the cellulose fiber matrices (Figure 3b). SERS-based tear assays were first conducted with an artificial tear solution for quantitative SERS detection. Assorted tear constituents of peroxidase, albumin, lysozyme, immunoglobulin G (IgG), histamine, sialic acid, urea, citric acid, ammonia, sodium, potassium, and bicarbonate at physiological levels in human tears16 were mixed together in deionized water for an artificial tear solution (Figure 4a; see Experimental Methods). As a target molecule, uric acid of different concentrations was respectively added into the artificial tear solution. The quantitative SERS detection of uric acid at different concentrations in the artificial tear solution was performed by using the peak intensity ratios of major SERS peak intensities at 660, 756, and 1342 cm−1 relative to those at 25 μM (Figures 4b and S6a). Each peak refers to skeletal ring deformation, out-ofplane N−H bending and ring vibration, and in-plane N−H bending, respectively.35 The average level of uric acid in human tears is 68 ± 46 μM,4 and the measured peak intensities were normalized by the base level36 of uric acid in human tears at 25 μM for compatibility with a commercial Raman system. The experimental results clearly demonstrate the SERS detection of uric acid from 25 to 150 μM. This detection range inspires the
thickness of 10 nm resulting in a Au nanofilm, the nanogap spacing decreases as the film thickness increases, and therefore the SERS peak intensities become apparently increased.22 As a result, Au nanoislands of 8 nm in film thickness and 0.5 Å/s in deposition rate were finally selected for the plasmonic Schirmer strip in this experiment. The plasmonic Schirmer strip features a layout similar to that of a commercial Schirmer test strip (Figure 3a). The strip was
Figure 3. Hygroscopic nature of a plasmonic Schirmer strip. (a) Photographic image of plasmonic Schirmer strips, which include the predetermined patterns of Au nanoislands to avoid direct contact between Au nanoislands and the human eye for safety. (b) Hygroscopic properties depending on Au nanoislands. The migration length of the eluent and the retention factor of crystal violet were measured for different patterned area fractions of Au nanoislands. Au nanoislands placed on the top surface of the cellulose fiber matrices maintain the same hygroscopic nature. The inset optical image exhibits the plasmonic Schirmer strips after the elution, which clearly demonstrates no significant variation in retention factor for different area fractions of Au nanoislands.
prepared on 5 × 35 mm Whatman chromatography paper with Au nanoislands 10 mm away from the folding crease for eye safety and a millimeter scale indicating the amount of tears. The
Figure 4. SERS-based tear screening using a plasmonic Schirmer strip. (a) Molarities of constituents in the artificial tear solution. Uric acid at different concentrations was spiked into the solution. (b) SERS detection of uric acid in the artificial tear solution using a plasmonic Schirmer strip. Uric acid acts as a diagnostic biomarker for gout, toxocara, retinoblastoma, and conjunctivitis. The SERS signals from each target molecule increase as the concentration increases. The plasmonic Schirmer strip enables SERS detection of tear constituents, and it further determines whether the concentrations of uric acid are normal or excessive. (c) Correlation between uric acid level in tears and in blood. The SERS peak intensity ratio at 1342 cm−1 was used to estimate the uric acid level in human tears. The plasmonic Schirmer strip reveals the linear relationship between uric acid level in tears and blood, which further aids in the diagnosis of gouty arthritis. 440
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Methods. Fabrication of Plasmonic Schirmer Strips. The micro/ nanofabrication of plasmonic Schirmer strips includes thermal evaporation of a Au thin film on a paper substrate. Delicate control of film thickness and deposition rate enables formation of Au nanoislands in Volmer−Weber mode. The film thickness was controlled from 4 to 10 nm, and the deposition rate was controlled from 0.2 to 2.0 Å/s. Numerical Analysis. The numerical calculation of an electric field distribution and PRW for Au nanoislands on a cellulose layer was performed by using a finite-difference time-domain method (FDTD Solutions, Lumerical Computational Solutions, Inc.). The physical dimensions of Au nanoislands for each condition were extracted from the inset binary images of Au nanoislands on cellulose fiber matrices (Figure 2a). The optical properties of cellulose fiber matrices were acquired in ref 39. Properties of the Plasmonic Schirmer Strip. Extinction spectra were calculated as 1 − (Rplasmonic Schirmer strip/Rpaper) after the intensity values of reflected light intensity R from the plasmonic Schirmer strip and Whatman chromatography paper were measured using a chargecoupled device (CCD)-based UV−vis near-infrared (NIR) microspectrometer (SpectraPro 2300i, Princeton Instruments, Trenton, NJ, USA) coupled with an inverted confocal laser scanning microscope (CLSM, Axiovert 200M, Carl Zeiss Co. Ltd. Seoul, Korea). A lightemitting diode (LED) was used as light source. Hygroscopic nature was measured by elution of crystal violet on the 0.5 cm × 6 cm plasmonic Schirmer strips using ethanol as an eluent for 10 min. Artificial Tear Solution. Artificial tear solution was prepared as follows: First, ammonium bicarbonate (2.9 mM) and potassium bicarbonate (23.1 mM) were added in deionized water as a buffer stock solution. Histamine solution (90 μM) and a mixture solution of peroxidase (1.32 μM), IgG (0.2 μM), and sodium citrate (0.3 mM) were separately prepared in the buffer stock solution. The histamine solution (10 μL), the mixture solution (1 mL), lysozyme (0.02 mM), urea (6.27 mM), and sialic acid (1.14 mM) were added into 8.89 mL of the buffer stock to prepare the artificial tear solution. Uric acid of different concentrations was respectively added into the artificial tear solution. SERS Measurement. SERS signals were measured by a CCD-based UV−vis NIR microspectrometer coupled with an inverted CLSM. A 632.8 nm HeNe laser with 5 mW power was used as excitation source with an integration time of 5 s for R6G with two times accumulation and 40 s for the artificial tear solution. All the experimental results were measured five times and then averaged. Human Tear Test. Tear fluid samples were obtained from 16 participants including 11 normal people, four people at risk for gouty arthritis, and one person taking a uric acid depressant due to gouty arthritis. The ages of participants ranged from 20 to 31, and people with eye diseases or diabetes and who regularly take drugs were excluded during the recruitment of participants. Less than 0.5 mL of human tear fluid was obtained from each participant using the plasmonic Schirmer strip until the tear fluid reached the mark for sufficient wetting, and then SERS signals from the tear fluid were measured. Blood samples were also taken by the KAIST Clinic Pappalardo Center to measure uric acid levels in the blood for comparing to the SERS signals from uric acid in tear fluid. The measurement of uric acid level in the blood was carried out by the KAIST Clinic Pappalardo Center using a Hitachi 7180 (Hitachi HighTechnologies Corporation, Tokyo, Japan) with L-type UA M (Wako Pure Chemical Industries, Ltd. Osaka, Japan). All procedures were carried out under the approval of the KAIST Institutional Review Board (IRB, approval number KH2016-19).
label-free measurement of normal or abnormal levels of uric acid in human tears. SERS-based human tear screening was finally performed for noninvasive diagnosis of gouty arthritis. Sixteen volunteers participated in both SERS detection of the uric acid level in tears and enzymatic detection of the uric acid level in the blood (see Experimental Methods). The uric acid level in human tears was precisely projected by comparing the major peak intensity ratios of SERS signals from uric acid in human tears with those from the uric acid in the artificial tear solution (Figure S6b,c). The uric acid level in tears is apparently higher than 95 μM for the risk group of gouty arthritis and is lower than 95 μM for normal participants. The strong linear correlation between the uric acid levels in the tears and the blood was apparently revealed by using the plasmonic Schirmer strip (Figure 4c). Note that the uric acid level in the blood is clinically higher than 420 μM (7 mg/dL) for hyperuricemia, which is a high risk for gouty arthritis.5,37 The experimental results also obviously indicate the excessive level of uric acid in tears for the risk group of gouty arthritis and the normal level of uric acid in tears for 11 normal participants and one patient taking a uric acid depressant due to gouty arthritis. In particular, the gouty arthritis patient taking a uric acid depressant exhibited normal levels of uric acid both in tears and in blood, which clearly supports that this tear screening is effective for measuring the uric acid level. A clinical diagnosis for gouty arthritis often includes invasive procedures such as taking a blood sample, which takes a long time, or taking a synovial fluid sample for observation of uric acid crystals, which substantially hinder the rapid diagnosis and continuous monitoring.37,38 However, this method offers a simple, noninvasive, on-demand, rapid, and label-free detection of uric acid in human tears for diagnosis of gouty arthritis.
CONCLUSION To conclude, this work has successfully demonstrated the quantitative SERS detection of uric acid in human tears by using a plasmonic Schirmer strip. Au nanoislands in Volmer− Weber mode were directly formed on cellulose micro/ nanofiber matrices by controlling the film thickness and the deposition rate during thermal evaporation. This particular configuration not only provides highly sensitive SERS detection of biomarkers in tears due to the volumetric electromagnetic hot spots but also maintains the direct and efficient collection of human tears owing to the hygroscopic nature of cellulose fiber matrices. The plasmonic Schirmer strip allows the rapid, simple, low-cost, label-free, and point-of-care detection of the uric acid level in human tears, and furthermore it provides a diagnostic guideline for monitoring diverse biomarkers in human tears such as glucose, cortisol, and ascorbic acid. EXPERIMENTAL METHODS Materials. Rhodamine 6G (99%), crystal violet solution (1 wt %), peroxidase from horseradish, albumin from human serum (≥96%), human lysozyme, immunoglobulin G (IgG, ≥95%), urea (99.0− 100.5%), histamine (≥97%), sialic acid (≥98%), L-ascorbic acid (≥99.0%), sodium citrate tribasic dihydrate (≥99.0%), ammonium bicarbonate (≥99.0%), potassium bicarbonate (99.7%), uric acid (≥99%), and Whatman chromatography paper were obtained from Sigma-Aldrich Korea Ltd. (Yongin-si, Gyeonggi-do, Korea). Au source (99.999%) was obtained from Taewon Scientific Co. Ltd. (Seoul, Korea). Color bar Schirmer tear test strips were purchased from Koryo Eyetech Co. Ltd. (Seoul, Korea). All the chemicals were used without further purification.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.6b06196. Details of control of Au nanoislands in Volmer−Weber mode including nanoisland size and nanogap size, numerical analysis for plasmon resonance wavelength, 441
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(14) Kneipp, K.; Kneipp, H.; Itzkan, I.; Dasari, R. R.; Feld, M. S. Surface-Enhanced Raman Scattering and Biophysics. J. Phys.: Condens. Matter 2002, 14, R597−R624. (15) Filik, J.; Stone, N. Drop Coating Deposition Raman Spectroscopy of Protein Mixtures. Analyst 2007, 132, 544−550. (16) Reyes-Goddard MSc, J. M.; Barr, H.; Stone, N. Surface Enhanced Raman Scattering of Herpes Simplex Virus in Tear Film. Photodiagn. Photodyn. Ther. 2008, 5, 42−49. (17) Villa, J. E. L.; Poppi, R. J. A Portable SERS Method for the Determination of Uric Acid Using a Paper-Based Substrate and Multivariate Curve Resolution. Analyst 2016, 141, 1966−1972. (18) Pardee, K.; Green, A. A.; Takahashi, M. K.; Braff, D.; Lambert, G.; Lee, J. W.; Ferrante, T.; Ma, D.; Donghia, N.; Fan, M.; Daringer, N. M.; Bosch, R.; Dudley, D. M.; O’Connor, D. H.; Gehrke, L.; Collins, J. J. Rapid, Low-Cost Detection of Zika Virus Using Programmable Biomolecular Components. Cell 2016, 165, 1255− 1266. (19) Martinez, A. W.; Phillips, S. T.; Whitesides, G. M. ThreeDimensional Microfluidic Devices Fabricated in Layered Paper and Tape. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 19606−19611. (20) Shin, J. H.; Park, J.; Kim, S. H.; Park, J.-K. Programmed Sample Delivery on a Pressurized Paper. Biomicrofluidics 2014, 8, 054121. (21) Park, J.; Shin, J. H.; Park, J.-K. Pressed Paper-Based Dipstick for Detection of Foodborne Pathogens with Multistep Reactions. Anal. Chem. 2016, 88, 3781−3788. (22) Jung, H.; Park, M.; Kang, M.; Jeong, K.-H. Silver Nanoislands on Cellulose Fibers for Chromatographic Separation and Ultrasensitive Detection of Small Molecules. Light: Sci. Appl. 2016, 5, e16009. (23) Lee, C. H.; Hankus, M. E.; Tian, L.; Pellegrino, P. M.; Singamaneni, S. Highly Sensitive Surface Enhanced Raman Scattering Substrates Based on Filter Paper Loaded with Plasmonic Nanostructures. Anal. Chem. 2011, 83, 8953−8958. (24) Yu, W. W.; White, I. M. Inkjet-Printed Paper-Based SERS Dipsticks and Swabs for Trace Chemical Detection. Analyst 2013, 138, 1020−1025. (25) Hwang, E. T.; Lee, J. H.; Chae, Y. J.; Kim, Y. S.; Kim, B. C.; Sang, B.-I.; Gu, M. B. Analysis of the Toxic Mode of Action of Silver Nanoparticles Using Stress-Specific Bioluminescent Bacteria. Small 2008, 4, 746−750. (26) Yoon, H.-J.; Lee, E.-S.; Kang, M.; Jeong, Y.; Park, J.-H. In vivo Multi-Photon Luminescence Imaging of Cerebral Vasculature and Blood-Brain Barrier Integrity Using Gold Nanoparticles. J. Mater. Chem. B 2015, 3, 2935−2938. (27) Koch, R.; Winau, D.; Führmann, A.; Rieder, K. H. GrowthMode-Specific Intrinsic Stress of Thin Silver Films. Phys. Rev. B: Condens. Matter Mater. Phys. 1991, 44, 3369−3372. (28) Peng, S.; McMahon, J. M.; Schatz, G. C.; Gray, S. K.; Sun, Y. Reversing the Size-Dependence of Surface Plasmon Resonances. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 14350−14534. (29) Qin, L.; Zou, S.; Xue, C.; Atkinson, A.; Schatz, G. C.; Mirkin, C. A. Designing, Fabricating, and Imaging Raman Hot Spots. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 13300−13303. (30) Chen, G.; Wang, Y.; Yang, M.; Xu, J.; Goh, S. J.; Pan, M.; Chen, H. Measuring Ensemble-Averaged Surface-Enhanced Raman Scattering in the Hotspots of Colloidal Nanoparticle Dimers and Trimers. J. Am. Chem. Soc. 2010, 132, 3644−3645. (31) McMahon, J. M.; Li, S.; Ausman, L. K.; Schatz, G. C. Modeling the Effect of Small Gaps in Surface-Enhanced Raman Spectroscopy. J. Phys. Chem. C 2012, 116, 1627−1637. (32) Shanthil, M.; Thomas, R.; Swathi, R. S.; Thomas, K. G. Ag@ SiO2 Core-Shell Nanostructures: Distance-Dependent Plasmon Coupling and SERS Investigation. J. Phys. Chem. Lett. 2012, 3, 1459−1464. (33) Doron-Mor, I.; Barkay, Z.; Filip-Granit, N.; Vaskevich, A.; Rubinstein, I. Ultrathin Gold Island Films on Silanized Glass. Morphology and Optical Properties. Chem. Mater. 2004, 16, 3476− 3483.
extinction spectra, SERS signals from R6G, and SERS signals from artificial tear solution and human tears (PDF)
AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. ORCID
Ki-Hun Jeong: 0000-0003-4799-7816 Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS This work was financially supported by Samsung Research Funding Center of Samsung Electronics under project number SRFC-IT1402-02. This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2016013061). REFERENCES (1) Gelstein, S.; Yeshurun, Y.; Rozenkrantz, L.; Shushan, S.; Frumin, I.; Roth, Y.; Sobel, N. Human Tears Contain a Chemosignal. Science 2011, 331, 226−230. (2) Perumal, N.; Funke, S.; Pfeiffer, N.; Grus, F. H. Proteomics Analysis of Human Tears from Aqueous-Deficient and Evaporative Dry Eye Patients. Sci. Rep. 2016, 6, 29629. (3) Yan, Q.; Peng, B.; Su, G.; Cohan, B. E.; Major, T. C.; Meyerhoff, M. E. Measurement of Tear Glucose Levels with Amperometric Glucose Biosensor/Capillary Tube Configuration. Anal. Chem. 2011, 83, 8341−8346. (4) Choy, C. K. M.; Benzie, I. F. F.; Cho, P. Ascorbic Acid Concentration and Total Antioxidant Activity of Human Tear Fluid Measured Using the FRASC Assay. Invest. Ophthalmol. Visual Sci. 2000, 41, 3293−3298. (5) Dehghan, A.; Köttgen, A.; Yang, Q.; Hwang, S.-J.; Kao, W. H. L.; Rivadeneira, F.; Boerwinkle, E.; Levy, D.; Hofman, A.; Astor, B. C.; Benjamin, E. J.; Van Duijn, C. M.; Witteman, J. C.; Coresh, J.; Fox, C. S. Association of Three Genetic Loci with Uric Acid Concentration and Risk of Gout. Lancet 2008, 372, 1953−1961. (6) Chen, Y.; Cruz-Chu, E. R.; Woodard, J. C.; Gartia, M. R.; Schulten, K.; Liu, G. L. Electrically Induced Conformational Change of Peptides on Metallic Nanosurfaces. ACS Nano 2012, 6, 8847−8856. (7) Losurdo, M.; Bergmair, R.; Dastmalchi, B.; Kim, T.-H.; Giangregroio, M. M.; Jial, W.; Bianco, G. V.; Brown, A. S.; Hingerl, K.; Bruno, G. Graphene as an Electron Shuttle for Silver Deoxidation: Removing a Key Barrier to Plasmonics and Metamaterials for SERS in the Visible. Adv. Funct. Mater. 2014, 24, 1864−1878. (8) Hwang, J.; Lee, S.; Choo, J. Application of a SERS-Based Lateral Flow Immunoassay Strip for the Rapid and Sensitive Detection of Staphylococcal Enterotoxin B. Nanoscale 2016, 3, 66−72. (9) Zijlstra, P.; Paulo, P. M. R.; Orrit, M. Optical Detection of Single Non-Absorbing Molecules Using the Surface Plasmon Resonance of a Gold Nanorod. Nat. Nanotechnol. 2012, 7, 379−382. (10) Butet, J.; Brevet, P.-F.; Martin, O. J. F. Optical Second Harmonic Generation in Plasmonic Nanostructures: from Fundamental Principles to Advanced Applications. ACS Nano 2015, 9, 10545− 10562. (11) Hong, S.; Lee, M. Y.; Jackson, A. O.; Lee, L. P. Bioinspired Optical Antennas: Gold Plant Viruses. Light: Sci. Appl. 2015, 4, e267. (12) Oh, Y.-J.; Jeong, K.-H. Glass Nanopillar Arrays with NanogapRich Silver Nanoislands for Highly Intense Surface Enhanced Raman Scattering. Adv. Mater. 2012, 24, 2234−2237. (13) Park, M.; Oh, Y.-J.; Park, S.-G.; Yang, S.-B.; Jeong, K.-H. Electrokinetic Preconcentration of Small Molecules within Volumetric Electromagnetic Hotspots in Surface Enhanced Raman Scattering. Small 2015, 11, 2487−2492. 442
DOI: 10.1021/acsnano.6b06196 ACS Nano 2017, 11, 438−443
Article
ACS Nano (34) Lecault, V.; VanInsberghe, M.; Sekulovic, S.; Knapp, D. J. H. F.; Wohrer, S.; Bowden, W.; Viel, F.; McLaughlin, T.; Jarandehei, A.; Miller, M.; Falconnet, D.; White, A. K.; Kent, D. G.; Copley, M. R.; Taghipour, F.; Eaves, C. J.; Humphries, R. K.; Piret, J. M.; Hansen, C. L. High-Throughput Analysis of Single Hematopoietic Stem Cell Proliferation in Microfluidic Cell Culture Arrays. Nat. Methods 2011, 8, 581−586. (35) Pucetaite, M.; Velicka, M.; Pilipavicius, J.; Beganskiene, A.; Ceponkus, J.; Sablinskas, V. Uric Acid Detection by Means of SERS Spectroscopy on Dried Ag Colloidal Drops. J. Raman Spectrosc. 2016, 47, 681−686. (36) Cho, H.; Lee, B.; Liu, G. L.; Agarwal, A.; Lee, L. P. Label-Free and Highly Sensitive Biomolecular Detection Using SERS and Electrokinetic Preconcentration. Lab Chip 2009, 9, 3360−3363. (37) Shibasaki, K.; Kimura, M.; Ikarashi, R.; Yamaguchi, A.; Watanabe, T. Uric Acid Concentration in Saliva and Its Changes with the Patients Receiving Treatment for Hyperuricemia. Metabolomics 2012, 8, 484−491. (38) McCarty, D. J.; Hollander, J. L. Identification of Urate Crystals in Gouty Synovial Fluid. Ann. Intern. Med. 1961, 54, 452−460. (39) Kasarova, S. N.; Sultanova, N. G.; Ivanov, C. D.; Nikolov, I. D. Analysis of the Dispersion of Optical Plastic Materials. Opt. Mater. 2007, 29, 1481−1490.
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