Fully printed and self-compensated bioresorbable electrochemical devices based on galvanic coupling for continuous glucose monitoring

Abstract

Real-time glucose monitoring conventionally involves non-bioresorbable semi-implantable glucose sensors, causing infection and pain during removal. Despite bioresorbable electronics serves as excellent alternatives, the bioresorbable sensor dissolves in aqueous environments with interferential biomolecules. Here, the theories to achieve stable electrode potential and accurate electrochemical detection using bioresorbable materials have been proposed, resulting in a fully printed bioresorbable electrochemical device. The adverse effect caused by material degradation has been overcome by a molybdenum-tungsten reference electrode that offers stable potential through galvanic-coupling and self-compensation modules. In vitro and in vivo glucose monitoring has been conducted for 7 and 5 days, respectively, followed by full degradation within 2 months. The device offers a glucose detection range of 0 to 25 millimolars and a sensitivity of 0.2458 microamperes per millimolar with anti-interference capability and biocompatibility, indicating the possibility of mass manufacturing high-performance bioresorbable electrochemical devices using printing and low-temperature water-sintering techniques. The mechanisms may be implemented developing more comprehensive bioresorbable sensors for chronic diseases.

Fig. 1.. Concepts and demonstration of the bioresorbable electrochemical device.

(A) Schematic illustration of the bioresorbable electrochemical device. (B) The mechanism of the three-electrode system for glucose detection with an additional SE and a DO sensor. (C) Representative image of the sensor. (D) System-level diagram showing the electrical components of the system; MCU, Microcontroller Unit. (E) Image of a rat that is wearing the monitoring system on the dorsal. (F) Dissolution processes of the bioresorbable electrochemical device after immersing in phosphate-buffered saline (PBS) solution. PLGA, poly(lactic-co-glycolic acid); cat, catalase; GO_x, glucose oxidase.

Fig. 2.. Characterizations of the bioresorbable electrochemical device.

(A) A schematic of the RE mechanism. (B) Conductivity of Mo-W pastes with different weight ratios and particle sizes. Surface morphology of bioresorbable patterns printed with 25 wt % of Mo MPs (1 μm) and 25 wt % of W MPs (1 μm) before (C) and after (D) sintering. (E) Stability test of different REs in 1× PBS solution for 8 hours against a commercial Ag/AgCl RE. (F) Potential time graph of repeatability measurements for different REs in 1× and 10× PBS solution. (G) Radar plots of the Mo-W REs with different ratios based on five parameters. Stable electrode potential (E_p): the constant potential that can be achieved by the RE under specific experimental conditions. Conductivity (σ): the ability of the RE to conduct electricity in the given electrolyte environment. Time to reach a stable potential (T_S): the duration required for the RE to achieve the E_p. Potential drift (E_Dri): the continuous alteration in potential exhibited by the RE throughout the measurement. Repeatability difference (E_Dif): the disparity in repeatability observed among the RE potentials derived from repeated measurements. (H) Conductivity of the bioresorbable pastes with different Mo particle sizes and concentrations. (I) Cyclic voltammetry curves in pure PBS solution and PBS solution containing 2 mM glucose measured by the bioresorbable glucose sensor.

Fig. 3.. In vitro characterization of the bioresorbable electrochemical device.

(A) Time-dependent current response of the glucose sensor at different glucose concentrations from 0 to 25 mM in PBS solution at 37°C. Selectivity (B), reversibility (C), and mechanical robustness (D) of the bioresorbable electrochemical device. (E) Time-dependent current response of the DO sensor at different DO saturation from 0 to 180%. (F) Real-time responses of the DO sensor from 0 to 100% DO saturation in comparison with a commercial DO sensor. (G) Changes in the current response of the glucose sensor and the DO sensor in the bioresorbable device after being immersed in 5 mM glucose solution with a DO level of 90% for 1 week. (H) Temperature changes measured by the temperature sensor from 25° to 50°C. (I) Real-time responses of the temperature sensor in comparison with a commercial standard thermometer.

Fig. 4.. In vitro and in vivo biocompatibility evaluations.

(A) Fluorescent images of L-929 cells cultured on the bioresorbable electrochemical device for 24, 48, and 72 hours with calcein-AM/PI staining. Green (calcein-AM) for live cells and red (PI) for dead cells. (B) Cell viability of L-929 cells using Cell Counting Kit-8 assay after 24, 48, and 72 hours. (C) Images of the degradation process of the bioresorbable electrochemical device implanted in the subcutaneous tissue over 8 weeks. (D) Images of the degradation process of the external interconnect and wound healing process over 8 weeks. (E) Changes in body weight for control and experimental groups measured weekly for 8 weeks. (F) Results of the blood routine tests for the rats. (G) Results of the blood biochemistry tests for the rats. Control data are collected from three rats acquired from one batch for 8 weeks. (H) Histology images of the heart, kidney, liver, spleen, and lung, stained with hematoxylin and eosin of the control and experimental groups after 8 weeks. Biologically independent rat (A) to (H): control group, n = 3; experimental group, n = 3. WBC, white blood cell; RBC, red blood cell, PLT, platelets; LYM, lymphocytes; Gran, granulocyte; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRE, creatinine.

Fig. 5.. In vivo evaluations of the bioresorbable electrochemical device.

(A) Diagram of an OGTT rat who fasted for 24 hours before the experiment followed by instilling 5% glucose solution into the proximal jejunum of the rat on days 1, 3, and 5. Continuous monitoring results of (B) glucose, (C) DO, and (D) temperature obtained on days 1, 3, and 5. Each measurement has been conducted for 125 min each day. (E) Diagram of a type 1 diabetic rat who has been injected with 1 U of insulin (physiological saline solution) on days 1, 3, and 5. Continuous monitoring results of (F) glucose, (G) DO, and (H) temperature on days 1, 3, and 5. Each measurement has been conducted for 150 min each day. In (A) and (E), n = 3 independent rats.