Research ArticleENGINEERING

A thermal activated and differential self-calibrated flexible epidermal biomicrofluidic device for wearable accurate blood glucose monitoring

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Science Advances  27 Jan 2021:
Vol. 7, no. 5, eabd0199
DOI: 10.1126/sciadv.abd0199
  • Fig. 1 Design of the flexible epidermal biomicrofluidic device for continuous blood glucose monitoring.

    (A) Photo of the real application of the proposed device. (B) Detailed structure of the integrated epidermal biomicrofluidic device. (C) Photo of the fabricated flexible glucose detection patch. (D) Detailed structure of the temperature control component. (E) Detailed structure of the glucose detection patch consisting of an ISF extraction electrode pair (EE, extraction electrode; AE, auxiliary electrode), a glucose sensor (WE, working electrode; RE/CE, reference electrode/counter electrode), and a differential Na+ sensor (SWE, Na+ WE; SRE, Na+ RE). (F) Working mechanism of the integrated flexible epidermal biomicrofluidic device (photo credit: Zhihua Pu, Tianjin University).

  • Fig. 2 Thermal activation to improve the efficiency of transdermal ISF extraction.

    (A) Schematic diagram of the mechanism of transdermal ISF extraction and the formation of the epidermal biomicrofluidic system. (B) Photo of the fabricated flexile ISF EE pair. (C) Photo of the fabricated flexible heating wires and temperature sensors. (D) Normal skin impedance changes over time with and without thermal activation. (E) Correlations between the ISF extraction rate and extraction current density with and without thermal activation. (F) Correlations between the ISF extraction time and extraction current density with and without thermal activation when the desired amount of extracted Na+ is 100 nmol. (G) The temperature change with time under different applied voltages. (H) Temperature measurement results from the fabricated sensor and the commercial sensor. (I) Temperature test results from the temperature sensor when the fabricated epidermal temperature control component is in operation (photo credit: Zhihua Pu, Tianjin University).

  • Fig. 3 Characterization of the fabricated flexible epidermal electrochemical glucose sensor.

    (A) Prototype of the fabricated flexible electrochemical glucose sensor including a WE and a CE (also serving as the RE). (B) Cross-sectional structure of the WE of the glucose sensor, including the flexible polyimide (PI) film substrate; gold electrode layer to transfer electrons to the detector; three-dimensional nanostructure of graphene and platinum nanoparticles (PtNPs) to enhance the electron transfer rate to improve the sensitivity; Prussian blue (PB) layer to reduce the working potential versus RE to 0 V to reduce the interference currents; GOx layer to enable selective detection of glucose; and Nafion layer to prevent GOx leakage, acting as an electrochemical reaction microtank, and make the device biocompatible with skin. (C) Field emission scanning electron microscopy (SEM) image of the Au WE surface. (D) SEM image of the graphene/Au WE surface. (E) SEM image of the PtNPs/graphene/Au WE surface. (F) Energy-dispersive spectroscopy (EDS) of the Au WE surface. (G) EDS of the graphene/Au WE surface. (H) EDS of the PtNPs/graphene/Au WE surface. (I) Amperometric responses to the addictive 0.5 mM H2O2 at an applied potential of −0.2 V versus RE for the different sensor configurations without modified PB layer (n = 5). (J) Amperometric responses of the sensor configuration with the PtNPs/graphene/Au WE before and after printing of the PB layer (n = 5). (K) Amperometric measurements of glucose solutions via the proposed flexible sensor (n = 6). (L) Selectivity of the glucose sensor [the addition of different analytes to 0.1 M PBS: 0.2 mM glucose, 0.1 mM dopamine (DA), 0.1 mM ascorbic acid (AA), and 0.1 mM uric acid (UA)] (photo credit: Zhihua Pu, Tianjin University).

  • Fig. 4 In vivo experiments using the proposed epidermal biomicrofluidic technique and the device.

    (A) Photo of the fabricated flexible differential Na+ sensor. (B) Structure of the WE of the Na+ sensor, from the bottom-up, includes a flexible PI substrate layer, a gold electrode layer, a poly(3,4-ethylenedioxythiophene) (PEDOT) layer, an Na+-selective membrane layer, and a Nafion layer. (C) Structure of the RE of the Na+ sensor, from the bottom-up, includes a flexible PI layer, a gold electrode layer, an Na+ reference membrane layer, and a Nafion layer. (D) Amperometric measurements in glucose solutions for the proposed flexible electrochemical glucose sensor at room temperature and 37°C (n = 6). (E) Test of the Na+, showing voltage changes as the Na+ concentration at room temperature and 37°C (n = 6). (F) Glucose measurement results from the fabricated epidermal biomicrofluidic device, and the fingertip blood glucose measured by a commercial glucometer (for one volunteer). The glucose concentrations obtained by the proposed system are delayed by approximately 10 min compared with those obtained by the glucometer due to the physiological delay between the glucose concentrations in ISF and in blood (36). (G) Glucose detection results without differential Na+ correction (for the same volunteer). (H) Glucose detection results with differential Na+ correction and with cathodic Na+ correction (for another volunteer who is sweaty). (I) Plot of predicted glucose concentration versus reference glucose concentration on the Clarke error grid with differential Na+ correction. (J) Plot of predicted glucose concentration versus reference glucose concentration on the Clarke error grid without correction. (K) Plot of predicted glucose concentration versus reference glucose concentration on the Clarke error grid with cathodic Na+ correction only (results from all seven volunteers) (photo credit: Zhihua Pu, Tianjin University).

Supplementary Materials

  • Supplementary Materials

    A thermal activated and differential self-calibrated flexible epidermal biomicrofluidic device for wearable accurate blood glucose monitoring

    Z. Pu, X. Zhang, H. Yu, J. Tu, H. Chen, Y. Liu, X. Su, R. Wang, L. Zhang, D. Li

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    The PDF file includes:

    • Thermal activation to facilitate ISF extraction
    • Flexible epidermal temperature control component
    • Flexible electrochemical glucose sensing
    • Glucose measurement correction model based on Na+ monitoring
    • Figs. S1 to S27
    • Tables S1 to S7
    • References

    Other Supplementary Material for this manuscript includes the following:

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