A Review of Electrochemical Sensors for the Detection of Glycated Hemoglobin

Abstract

Glycated hemoglobin (HbA1c) is the gold standard for measuring glucose levels in the diagnosis of diabetes due to the excellent stability and reliability of this biomarker. HbA1c is a stable glycated protein formed by the reaction of glucose with hemoglobin (Hb) in red blood cells, which reflects average glucose levels over a period of two to three months without suffering from the disturbance of the outside environment. A number of simple, high-efficiency, and sensitive electrochemical sensors have been developed for the detection of HbA1c. This review aims to highlight current methods and trends in electrochemistry for HbA1c monitoring. The target analytes of electrochemical HbA1c sensors are usually HbA1c or fructosyl valine/fructosyl valine histidine (FV/FVH, the hydrolyzed product of HbA1c). When HbA1c is the target analyte, a sensor works to selectively bind to specific HbA1c regions and then determines the concentration of HbA1c through the quantitative transformation of weak electrical signals such as current, potential, and impedance. When FV/FVH is the target analyte, a sensor is used to indirectly determine HbA1c by detecting FV/FVH when it is hydrolyzed by fructosyl amino acid oxidase (FAO), fructosyl peptide oxidase (FPOX), or a molecularly imprinted catalyst (MIC). Then, a current proportional to the concentration of HbA1c can be produced. In this paper, we review a variety of representative electrochemical HbA1c sensors developed in recent years and elaborate on their operational principles, performance, and promising future clinical applications.

Keywords: HbA1c sensor; cyclic voltammetry; diabetes; electrochemical impedance spectroscopy; electrochemical sensor; fructosyl valine sensor.

Figure 2

(A) Electrochemical sensor based on the HbA1c and GO_x competition mechanism, as well as the ΔCV responses of HbA1c (this figure was adapted from [35] with some modifications); (B) Electrochemical sensors based on 4-MPBA specific recognition and the ΔCV responses of HbA1c (this figure was adapted from [42] with some modifications); (C) Recognition of HbA1c of PBA-PQQ/ERGO/GC electrode and linear calibration plot of I_d value vs. the concentration of HbA1c (this figure was adapted from [40] with some modifications).

Figure 5

(A) An FAO/AuNP-PTA-TiO₂ nanocomposite was prepared on an ITO electrode (this figure was adapted from [92], with some modifications); (B) Preparation method of the FAO/PtNPs/RGO-NWCNT nanocomposite (this figure was adapted from [94], with some modifications); (C) CHIT-GO-AuNPs-FPOX nanocomposites were prepared on an FTO glass plate (this figure was adapted from [104], with some modifications).

Figure 1

Classification of electrochemical sensors for HbA1c detection.

Figure 3

(A) SELEX was used to screen suitable molecules bound to HbA1c. (B) The manufacture and measurement of the HbA1c sensor (reprint permission has been requested from [52], and it was also adapted from [53]). (C) SWV diagram and calibration curve of suitable aptamers of Hb and HbA1c junctions at different concentrations (reprint permission has been requested from [52]).

Figure 4

(A) Schematic diagram of HbA1c microsensor; (B) Mixed SAMs method; (C) Seed mediated growth nano-gold method; (D) HbA1c test strip prepared by SAM and nanotechnology; (E) Voltage responses of three kinds of immunosensor in the simulated blood sample to HbA1c (reprint permission of A~E has been requested from [63,64]).

Figure 6

(A) The working principle of the molecularly imprinted sensor; (B) A molecularly imprinted sensor that specifically recognizes FV (this figure was adopted from [108]).