Research ArticleMATERIALS SCIENCE

Molecularly selective nanoporous membrane-based wearable organic electrochemical device for noninvasive cortisol sensing

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Science Advances  20 Jul 2018:
Vol. 4, no. 7, eaar2904
DOI: 10.1126/sciadv.aar2904
  • Fig. 1 Schematic representation of noncovalent imprinting process and corresponding surface characterizations by microscopy.

    (A) Molecular memory is introduced on the sensor surface by copolymerizing functional monomer and cross-linker in the presence of the analyte, which acts as a molecular template. After elution of the analyte, complementary binding sites are revealed complimentary in size and shape to template by creating molecular memory on the surface that allows specific rebinding of the target molecule. The recognition sites obtained in this manner have binding affinities approaching those demonstrated by antibody-antigen systems. Tapping-mode atomic force microscopy (AFM) analysis of cortisol-selective polymer (B) and its corresponding control (C). Scanning electron microscopy (SEM) images of cortisol-selective polymer (D and F) and its control (E and G) with two different magnifications. Pore size distribution for cortisol-imprinted (H) and nonimprinted polymers (NIPs) (I). The BJH method was applied to calculate pore size distribution from experimental isotherms using the Kelvin model of pore filling. The method applies only to the mesopore and small macropore size range.

  • Scheme 1 Schematic drawings of the patch-type wearable cortisol sensor.

    The integrated wearable sensor consists of several important layers from bottom to top as follows: (i) laser-patterned microcapillary channel arrays for sweat acquisition (bottom layer), (ii) sample reservoir to assist sample delivery, (iii) sensor layers composed of the OECT device on the flexible SEBS elastomer substrate with the PEDOT:PSS semiconductor layer and the MSM, and (iv) polyethylene-based hydrophobic protection layer.

  • Fig. 2 Schematic representation of membrane integration and device characteristics.

    (A) Schematic drawing of integration of MSM to OECT device consisting of PEDOT:PSS channel coated on an indium tin oxide glass substrate with the cortisol-selective membrane separating the PEDOT:PSS channel from the electrolyte solution, gated with an Ag/AgCl electrode. Device characteristics demonstrated by output and transfer curves before (B and C) and after (D and E) membrane integration. The output and transfer curve measurements were conducted in artificial sweat solutions.

  • Fig. 3 Testing of MS-OECT device for ex situ analysis.

    (A) Schematic drawings of planar-gated MS-OECT device on the SEBS substrate for drain current measurements. PDMS, polydimethylsiloxane. Ex situ measurement for MSMs (inset: control membrane) (B) and their corresponding calibration curves (the calibration curve for high-to-low concentration is based on fig. S6B, and the highlighted area shows the physiological range of cortisol in human sweat) (C). The measurements were conducted in artificial sweat with increasing concentrations of cortisol. The selectivity of the MS-OECT device was evaluated in the presence of structural analogs of cortisol including progesterone, cortisone, and testosterone in artificial sweat. The measurement was started with 0.005 mM cortisol, and it was gradually increased up to 5.0 μM. The concentrations of interferent were increased step-wise for progesterone (Pr-C1, 0.025 μM; Pr-C2, 0.5 μM), cortisone (Cr-C1, 0.025 μM; Cr-C2, 0.5 μM), and testosterone (Tes-C1, 0.025 μM; Tes-C2, 0.5 μM) to ensure that they do not involve a binding process (D). The drain current measurement of each run is shown in fig. S25.

  • Fig. 4 Ex situ real sample analysis using skin-like microfluidic device.

    (A) Schematic drawing of skin-like microfluidic device with a photograph of the device while being flexed, and an optical micrograph of the device surface. Scale bar, 500 μm. Drain current measurements of molecularly selective (B) and control (C) membrane-integrated devices for ex situ analysis and their corresponding calibration curves (D). (E) Real sample analysis and comparison with standard cortisol ELISA for two subjects for three repetitive measurements for each subject.

  • Fig. 5 Analytical performance of the wearable cortisol sensor.

    (A) MS-OECT device applied to male volunteer’s forearm. The device was tested by spraying artificial sweat with increasing concentrations of cortisol on volunteer’s forearm and measuring the corresponding output current (B) to obtain a calibration curve (C). (D) The real-time response of both the molecularly selective and control devices was measured after completing physical exercise by mounting electrical contacts to the wearable sensor device. The cortisol response was recorded using the output measurement, and data were represented as a change of drain current (ΔID) at a low voltage, which substantially reduces the possibility of electrical shock. The cortisol concentration was measured using sweat directly from the skin, and the results were compared with the best fit of (B) [relative standard deviation (RSD) = 35% for n = 2]. RSD, relative SD. (E) The data obtained showed a good correlation with the standard cortisol ELISA method for cortisol detection with an RSD of 5% for two measurements.

  • Table 1 Optimization conditions.

    Optimization conditions.. Formulations used to design cortisol-selective polymers.

    The values are calculated by taking the ratio of slope of each sensor calibration curve for each molecularly imprinted and nonimprinted control polymer (Fig. 3, B and C, and figs. S1 to S5). The starting concentration of cortisol is 0.2 mmol in each condition. Control polymers are not included in the table; they were prepared exactly as corresponding selective polymer but without the template. AIBN, azobisisobutyronitrile.

    MembraneMonomerCross-linkerInitiatorSolventRatio*ConditionsSensing factor
    A1618MAAEDMAAIBNAcetonitrile1:6:18UV, 4°C, 30 hours4.2
    M1618MAAEDMAAIBNMethanol1:6:18UV, 4°C, 30 hours5.1
    D1618MAAEDMAAIBNDCM1:6:18UV, 4°C, 30 hours5.4
    D1630MAAEDMAAIBNDCM1:6:30UV, 4°C, 30 hours10.1
    D1660MAAEDMAAIBNDCM1:6:60UV, 4°C, 30 hours2.2
    D1630RTMAAEDMAAIBNDCM1:6:30UV, room
    temperature,
    30 hours
    6.7

    *Molar ratio of template/functional monomer/cross-linker.

    †Calculated based on each sensor device’s performance to express imprinting efficiency.

    Supplementary Materials

    • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/4/7/eaar2904/DC1

      Supplementary Materials

      Fig. S1. Ex situ device testing for A1618 and A1618C.

      Fig. S2. Ex situ device testing for M1618 and M1618C.

      Fig. S3. Ex situ device testing for D1618 and D1618C.

      Fig. S4. Ex situ device testing for D1630 and D1630C.

      Fig. S5. Ex situ device testing for D1630RT and D1630RTC.

      Fig. S6. Reversibility test for unsaturated device.

      Fig. S7. Reversibility test for saturated device.

      Fig. S8. SEM characterization of MIP.

      Fig. S9. SEM characterization of NIP.

      Fig. S10. Drain current measurements without PVC matrix.

      Fig. S11. Drain current measurements in 10% PVC matrix.

      Fig. S12. Drain current measurements in 25% PVC matrix.

      Fig. S13. Washing tests by cyclic voltammetry.

      Fig. S14. Diffusion characteristics of the MS-OECT.

      Fig. S15. Diffusion characteristics of the NS-OECT.

      Fig. S16. Selectivity tests.

      Fig. S17. Bending tests.

      Fig. S18. Stretchability tests.

      Fig. S19. The reusability tests.

      Fig. S20. SEM characterization of microchannel arrays.

      Fig. S21. The performance of acquisition layer.

      Fig. S22. The reusability test for on-body real sample analysis.

      Table S1. BET characteristics.

      Note S1. Nanopore formation in MIP.

      Note S2. Rationale for MIP design.

      Note S3. Diffusion characteristics of MSM.

    • Supplementary Materials

      This PDF file includes:

      • Supplementary Materials
      • Fig. S1. Ex situ device testing for A1618 and A1618C.
      • Fig. S2. Ex situ device testing for M1618 and M1618C.
      • Fig. S3. Ex situ device testing for D1618 and D1618C.
      • Fig. S4. Ex situ device testing for D1630 and D1630C.
      • Fig. S5. Ex situ device testing for D1630RT and D1630RTC.
      • Fig. S6. Reversibility test for unsaturated device.
      • Fig. S7. Reversibility test for saturated device.
      • Fig. S8. SEM characterization of MIP.
      • Fig. S9. SEM characterization of NIP.
      • Fig. S10. Drain current measurements without PVC matrix.
      • Fig. S11. Drain current measurements in 10% PVC matrix.
      • Fig. S12. Drain current measurements in 25% PVC matrix.
      • Fig. S13. Washing tests by cyclic voltammetry.
      • Fig. S14. Diffusion characteristics of the MS-OECT.
      • Fig. S15. Diffusion characteristics of the NS-OECT.
      • Fig. S16. Selectivity tests.
      • Fig. S17. Bending tests.
      • Fig. S18. Stretchability tests.
      • Fig. S19. The reusability tests.
      • Fig. S20. SEM characterization of microchannel arrays.
      • Fig. S21. The performance of acquisition layer.
      • Fig. S22. The reusability test for on-body real sample analysis.
      • Table S1. BET characteristics.
      • Note S1. Nanopore formation in MIP.
      • Note S2. Rationale for MIP design.
      • Note S3. Diffusion characteristics of MSM.

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