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Cited by 151Biosensors and Analytical DetectionOcular Surface and Contact LensElectrowetting and Microfluidic Technologies

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Paper-based microfluidic system for tear electrolyte analysis

Open access
Yetisen, Ali K., Jiang, Nan, Tamayol, Ali, Ruiz-Esparza, Guillermo U., Zhang, Yu Shrike, Medina-Pando, Sofía, Gupta, Aditi, Wolffsohn, James S., Butt, Haider, Khademhosseini, Ali, Yun, Seok-Hyun·2017·Lab on a Chip
DOI 10.1039/c6lc01450jPMC PMC5433427
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Abstract

This article describes a paper-based microfluidic system that quantifies the concentrations of tear electrolytes using a smartphone-based reader.

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Figures

Fig. 1 Principle of operation of the paper-based microfluidic system for the quantitative analysis of electrolytes in tear film.
Fig. 1 Principle of operation of the paper-based microfluidic system for the quantitative analysis of electrolytes in tear film.CC BY · PubMed Central
Fig. 2 Fluid dynamics characterization of G1 paper-based microfluidic devices at 24 °C. (a) Wicking distances of G1 strips as the width was varied from 2.0 to 5.0 mm. (b) The effect of increase in fluid viscosity from 1.0 to 10.0 mPa s on wicking distance in G1 strips (20 mm in length and 2 mm in width). Fluid viscosities were varied by changing the concentration of glucose (10 μL) from 0.5 to 3.0 mol L–1. (c) Wicking distances as the number of branches was increased from 1 to 4 within 60 s. Sample volume was 10 μL. (d) Photographs of paper-based microfluidic devices with different numbers of branches (1 to 4). Scale bar = 4 mm. (e) Bright-field microscopic image of G1 matrix. Scale bar = 50 μm. (f) Photographs of a four-channel paper-based microfluidic device, where Rhodamine B solution (10 mmol L–1) was used to show fluid diffusion as a function of time. Scale bar = 4 mm. Error bars represent standard error of the mean (n = 3).
Fig. 2 Fluid dynamics characterization of G1 paper-based microfluidic devices at 24 °C. (a) Wicking distances of G1 strips as the width was varied from 2.0 to 5.0 mm. (b) The effect of increase in fluid viscosity from 1.0 to 10.0 mPa s on wicking distance in G1 strips (20 mm in length and 2 mm in width). Fluid viscosities were varied by changing the concentration of glucose (10 μL) from 0.5 to 3.0 mol L–1. (c) Wicking distances as the number of branches was increased from 1 to 4 within 60 s. Sample volume was 10 μL. (d) Photographs of paper-based microfluidic devices with different numbers of branches (1 to 4). Scale bar = 4 mm. (e) Bright-field microscopic image of G1 matrix. Scale bar = 50 μm. (f) Photographs of a four-channel paper-based microfluidic device, where Rhodamine B solution (10 mmol L–1) was used to show fluid diffusion as a function of time. Scale bar = 4 mm. Error bars represent standard error of the mean (n = 3).CC BY · PubMed Central
Fig. 3 Na+ and K+ ion measurements using fluorescent crown ether derivatives in buffer solutions (Tris, pH 7.4, 150 mmol L–1) at 24 °C. (a) Chelation mechanisms of fluorescent (i) diaza-15-crown-5 and (ii) diaza-18-crown-6 with monovalent metal ions. (b) Selectivities of diaza-15-crown-5 (λ ex/λ em: 485/528 nm) and diaza-18-crown-6 (λ ex/λ em: 360/460 nm) (25 μmol L–1) for mono/divalent ions (100 mmol L–1) in aqueous solutions (n = 3). (c) The effect of pH on fluorescence readouts at constant Na+ and K+ ions (100 mmol L–1), and diaza-15-crown-5 and diaza-18-crown-6 (25 μmol L–1) concentrations in aqueous solutions (n = 3). Quantifications of 16-fold diluted (d) Na+ and (e) K+ ions on G1 matrix at a constant probe concentration (25 μmol L–1) (n = 6). Insets show the quantifications of non-diluted Na+ and K+ ions on G1 matrix (n = 3). Shadows in Fig. 3c–e show the physiological pH, Na+ and K+ ion concentration range. Error bars represent standard error of the mean.
Fig. 3 Na+ and K+ ion measurements using fluorescent crown ether derivatives in buffer solutions (Tris, pH 7.4, 150 mmol L–1) at 24 °C. (a) Chelation mechanisms of fluorescent (i) diaza-15-crown-5 and (ii) diaza-18-crown-6 with monovalent metal ions. (b) Selectivities of diaza-15-crown-5 (λ ex/λ em: 485/528 nm) and diaza-18-crown-6 (λ ex/λ em: 360/460 nm) (25 μmol L–1) for mono/divalent ions (100 mmol L–1) in aqueous solutions (n = 3). (c) The effect of pH on fluorescence readouts at constant Na+ and K+ ions (100 mmol L–1), and diaza-15-crown-5 and diaza-18-crown-6 (25 μmol L–1) concentrations in aqueous solutions (n = 3). Quantifications of 16-fold diluted (d) Na+ and (e) K+ ions on G1 matrix at a constant probe concentration (25 μmol L–1) (n = 6). Insets show the quantifications of non-diluted Na+ and K+ ions on G1 matrix (n = 3). Shadows in Fig. 3c–e show the physiological pH, Na+ and K+ ion concentration range. Error bars represent standard error of the mean.CC BY · PubMed Central
Fig. 4 Quantification of divalent metal ions in buffer solution (Tris, pH 7.4, 150 mmol L–1) at 24 °C. (a) Chelation mechanism of o-acetanisidide with divalent metal ions. (b) Fluorescence readouts of o-acetanisidide (λ ex/λ em: 485/528 nm) in the presence mono/divalent metal ions in aqueous solutions (n = 3). (c) The effect of pH on fluorescence readouts of o-acetanisidide (25 μmol L–1) at constant Mg2+ and Ca2+ ion concentrations (100 mmol L–1) in aqueous solutions (n = 3). (d) Fluorescence intensity readouts of Mg2+ and Ca2+ ions (100 mmol L–1) as the concentration of o-acetanisidide were varied from 3–50 μmol L–1 (n = 3). (e) Quantification of 16-fold diluted Ca2+ ions on G1 matrix at a constant o-acetanisidide concentration (25 μmol L–1) (n = 6). Insets show the quantification of non-diluted Ca2+ ions on G1 matrix (n = 3). Shadows in Fig. 4c and e show the physiological pH and Ca2+ ion concentration range. Error bars represent standard error of the mean.
Fig. 4 Quantification of divalent metal ions in buffer solution (Tris, pH 7.4, 150 mmol L–1) at 24 °C. (a) Chelation mechanism of o-acetanisidide with divalent metal ions. (b) Fluorescence readouts of o-acetanisidide (λ ex/λ em: 485/528 nm) in the presence mono/divalent metal ions in aqueous solutions (n = 3). (c) The effect of pH on fluorescence readouts of o-acetanisidide (25 μmol L–1) at constant Mg2+ and Ca2+ ion concentrations (100 mmol L–1) in aqueous solutions (n = 3). (d) Fluorescence intensity readouts of Mg2+ and Ca2+ ions (100 mmol L–1) as the concentration of o-acetanisidide were varied from 3–50 μmol L–1 (n = 3). (e) Quantification of 16-fold diluted Ca2+ ions on G1 matrix at a constant o-acetanisidide concentration (25 μmol L–1) (n = 6). Insets show the quantification of non-diluted Ca2+ ions on G1 matrix (n = 3). Shadows in Fig. 4c and e show the physiological pH and Ca2+ ion concentration range. Error bars represent standard error of the mean.CC BY · PubMed Central
Fig. 5 Quantification of pH values in buffer solutions (Tris, 150 mmol L–1) at 24 °C. (a) Principle of operation of seminaphtorhodafluor. (b) Fluorescence intensity readouts as the concentration of seminaphtorhodafluor (λ ex/λ em: 530/590 nm) was varied from 3–50 μmol L–1 at pH = 7.4 in aqueous solutions (n = 3). (c) Quantification of Tris buffer pH (inset) and 16-fold diluted Tris buffer (150 mmol L–1, pH = 7.4) on G1 matrix at a constant seminaphtorhodafluor concentration (25 μmol L–1) (n = 6). Insets show the quantification of non-diluted Tris buffer on G1 matrix (n = 3). Shadows in Fig. 5c show the physiological pH range. (d) Relative fluorescence intensity readouts of mono/divalent ions at a constant concentration of seminaphtorhodafluor (25 μmol L–1) at pH 7.4 (n = 3). Error bars represent standard error of the mean.
Fig. 5 Quantification of pH values in buffer solutions (Tris, 150 mmol L–1) at 24 °C. (a) Principle of operation of seminaphtorhodafluor. (b) Fluorescence intensity readouts as the concentration of seminaphtorhodafluor (λ ex/λ em: 530/590 nm) was varied from 3–50 μmol L–1 at pH = 7.4 in aqueous solutions (n = 3). (c) Quantification of Tris buffer pH (inset) and 16-fold diluted Tris buffer (150 mmol L–1, pH = 7.4) on G1 matrix at a constant seminaphtorhodafluor concentration (25 μmol L–1) (n = 6). Insets show the quantification of non-diluted Tris buffer on G1 matrix (n = 3). Shadows in Fig. 5c show the physiological pH range. (d) Relative fluorescence intensity readouts of mono/divalent ions at a constant concentration of seminaphtorhodafluor (25 μmol L–1) at pH 7.4 (n = 3). Error bars represent standard error of the mean.CC BY · PubMed Central
Fig. 6 Microfluidic system for tear fluid analysis. (a) Paper-based microfluidic device impregnated with fluorescent probes. Scale bar = 2 mm. (b) Sample collection and dilution device using a capillary tube. Scale bar = 1 cm. (c) The schematic of the portable readout device. Scale bar = 1 cm. (d) The use of the portable readout device for capturing the image of the fluorescent probes. Scale bar = 1 cm. (e) Photograph of the interlayer groove to place the paper-based microfluidic device. Scale bar = 4 mm. (f) Screenshot of the smartphone app capturing an assay image. Scale bar = 1 cm. Red square (1 × 1 mm2) in the magnified screenshot (blue dashes) shows the selected sensing region. Scale bar = 1 mm.
Fig. 6 Microfluidic system for tear fluid analysis. (a) Paper-based microfluidic device impregnated with fluorescent probes. Scale bar = 2 mm. (b) Sample collection and dilution device using a capillary tube. Scale bar = 1 cm. (c) The schematic of the portable readout device. Scale bar = 1 cm. (d) The use of the portable readout device for capturing the image of the fluorescent probes. Scale bar = 1 cm. (e) Photograph of the interlayer groove to place the paper-based microfluidic device. Scale bar = 4 mm. (f) Screenshot of the smartphone app capturing an assay image. Scale bar = 1 cm. Red square (1 × 1 mm2) in the magnified screenshot (blue dashes) shows the selected sensing region. Scale bar = 1 mm.CC BY · PubMed Central
Fig. 7 Quantifications of electrolytes in artificial tear fluid using the smartphone readout system: (a) Na+ ions, (b) K+ ions, (c) Ca2+ ions and (d) H+ ions sensing. Scale bars = 2 mm. Insets in (a) and (b) show Na+ ion concentration in the range of 130–150 mmol L–1 and K+ ion concentration in the range of 24–26 mmol L–1. Error bars represent standard error of the mean (n = 6). Curves (red dashes) were fitted using eqn (3). Shadows show the physiological Na+, K+, Ca2+ ion concentration and pH ranges.
Fig. 7 Quantifications of electrolytes in artificial tear fluid using the smartphone readout system: (a) Na+ ions, (b) K+ ions, (c) Ca2+ ions and (d) H+ ions sensing. Scale bars = 2 mm. Insets in (a) and (b) show Na+ ion concentration in the range of 130–150 mmol L–1 and K+ ion concentration in the range of 24–26 mmol L–1. Error bars represent standard error of the mean (n = 6). Curves (red dashes) were fitted using eqn (3). Shadows show the physiological Na+, K+, Ca2+ ion concentration and pH ranges.CC BY · PubMed Central
Fig. 8 Quantitative analysis of simulated artificial tear samples. (a) Sub-type differentiation of dry eye: inferred (a) Na+, (b) K+, (c) Ca2+ ion concentrations and (d) different stages of dry eye. *: p < 0.05, **: p < 0.01, ***: p < 0.001, compared with control. Error bars represent standard error of the mean (n = 3).
Fig. 8 Quantitative analysis of simulated artificial tear samples. (a) Sub-type differentiation of dry eye: inferred (a) Na+, (b) K+, (c) Ca2+ ion concentrations and (d) different stages of dry eye. *: p < 0.05, **: p < 0.01, ***: p < 0.001, compared with control. Error bars represent standard error of the mean (n = 3).CC BY · PubMed Central

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Citations

Cites

Show all 40 references

Research works printed but not linked: 6

  1. Craig, 1997, Optom. Vis. Sci., 74, 8, 10.1097/00006324-199701000-00014 · DOI
  2. Holly, 1984, Trans. Ophthalmol. Soc. U. K., 104, 374
  3. King-Smith, 2000, Invest. Ophthalmol. Visual Sci., 41, 3348
  4. Begley, 2000, Optom. Vis. Sci., 77, 40, 10.1097/00006324-200001000-00012 · DOI
  5. Hamano, 1991, Nippon Ganka Kiyo, 42, 719
  6. Gilbard, 1994, Int. Ophthalmol. Clin., 34, 27, 10.1097/00004397-199403410-00005 · DOI

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Metadata

Authors
Yetisen, A. K., Jiang, N., Tamayol, A., Ruiz-Esparza, G. U., Zhang, Y. S., Medina-Pando, S., Gupta, A., Wolffsohn, J. S., Butt, H., Khademhosseini, A., & Yun, S.-H.
Affiliations
  • Brigham and Women's Hospital (US)
  • Biomaterials Innovation Research Center
  • Harvard–MIT Division of Health Sciences and Technology (US)
  • Aston University (GB)
  • University of Birmingham (GB)
  • Harvard University (US)
Corresponding author
  • Yetisen, Ali K.
  • Yun, Seok-Hyun
ORCID
Venue
Lab on a Chip
Publisher
Royal Society of Chemistry (RSC)
Published
2017
Volume
17
Issue
6
Pages
1137-1148
ISSN
  • 1473-0189 (ISSN-L)
  • 1473-0197
DOI
10.1039/c6lc01450j
PMC
PMC5433427
OpenAlex
W2588545273
Cited by
151
References
40
Citations by year
2026: 11 · 2025: 15 · 2024: 17 · 2023: 8 · 2022: 17 · 2021: 26 · 2020: 21 · 2019: 16 · 2018: 14 · 2017: 5
FWCI
6.90
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Lab on a Chip (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aston Publications Explorer (Aston University) (acceptedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (201929/Z/16/Z)
  • Royal Society
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Biosensors and Analytical Detection
  • Health Sciences › Medicine › Ophthalmology › Ocular Surface and Contact Lens
  • Physical Sciences › Engineering › Electrical and Electronic Engineering › Electrowetting and Microfluidic Technologies
Keywords
paper-based microfluidics, dry eye, pH measurement
MeSH terms
Electrolytes, Equipment Design, Humans, Paper, Potassium, Sodium, Tears, Dry Eye Syndromes, Microfluidic Analytical Techniques

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