# A Review of Electrochemical Sensors for the Detection of Glyated Hemoglobin
## 2 Direct Type Electrochemical HbA1c Sensors
### Amperometric Sensors
The HbA1c captured on the electrode surface led to the reduction in the oxidation peak current of PQQ, because the protein molecules hinder the electron transfer pathway. Within the HbA1c concentration range of 9.4-65.8 \(\mu\)g/mL, the peak current decreased linearly by differential pulse voltammetry (DPV). Similarly, carbon electrodes coated with polyaniline boric acid nanoparticles were also used to determine HbA1c in a label-free manner [41]. The peak current varied according to a linear relationship with the logarithm of HbA1c concentration within the range of 0.975-156 \(\mu\)M, with high selectivity. In recent years, some novel electrochemical HbA1c sensors have been reported. A reticulated vitreous carbon (RVC) electrode was modified with 3-aminophenylboronic acid, chitosan (CHIT), and tetraethyl silica (TEOS) [32]. The biosensor was employed to detect HbA1c in clinical samples, and comparison showed that the detection results were basically the same as those from automatic biochemical analysis. In 2018, a molecularly imprinted polymer (MIP) flexible sensor was reported to simultaneously detect HbA1c and Hb by specifically capturing targets through non-covalent bonding and a cis-diol structure [43]. The linear ranges for detecting HbA1c and Hb were 0.2-230 ng/mL and 0.5-200 ng/mL, respectively. The sensor was successfully applied to determine the concentration of HbA1c in blood samples collected from women with gestational diabetes and healthy pregnant women. A novel graphene-doped titanium dioxide (TiO\({}_{2}\))-based heterojunction nano hybrid material (H)NH) was modified by poly(3-aminophenylboric acid) (PAPBA) and gold nanoparticles (AuNPs) [44]. The boric acid group in PAPBA was used to capture HbA1c. When the content of HbA1c ranged from 2.0% to 10%, the signal was directly proportional to the electrocatalytic reduction current of H\({}_{2}\)O\({}_{2}\), and the detection limit was 0.17%. In 2019, another type of unlabeled electrochemical sensor was developed for HbA1c detection. In this sensor, 4-mercaptophenyl boric acid (4-MPBA)-modified screen-printed electrodes modified by gold nanoflowers (AuNFs) were used as the sensing electrodes [42] (Figure 2B). The linear range for detecting HbA1c was 5-1000 \(\mu\)g/mL or 2-20% of the content, and the results demonstrated that the sensor had good specificity and stability. In addition, the use of a 16-channel screen-printed electrode and the considerably reduced detection time and cost endowed this sensor with significant performance superiority over other existing HbA1c detection methods in terms of pretreatment and operation procedures. Recently, to improve the electrode surface electron transmission capacity, [PERSON] et al. designed a three-dimensional antifouling nano-biosensing surface based on bovine serum albumin (BSA) and glutaraldehyde(GA) cross-linking and then used the HbA1c antibody and 3-aminophenyl boronic acid (APBA) to functionally modify the surface [45]. The presence of non-glycated hemoglobin (HbAo) resulted in a linear dynamic range of 2-15%, which facilitated label-free POCT detection of HbA1c. A redox medium was fixed on the surface of a nanocomposite, which contained pTTBA and N,S-doped porous carbon (NSPC), to fabricate HbA1c sensors [46]. This system could accurately separate and detect Hb and HbA1c in blood samples. The linear dynamic ranges of Hb and HbA1c were 1.0 \(\times\) 10\({}^{-6}\)-3.5 mM and 3.0 \(\times\) 10\({}^{-6}\)-0.6 mM, respectively. **Ferrocene-based. ** Ferrocene (Fc)-modified electrodes may be promising for the construction of current sensors because of the reasonable stability and structural versatility of Fc derivatives [23; 47; 48]. In a recent study, [PERSON] et al. reported a novel scheme that made full use of the redox ability of ferrocene difformylcysteine (Fc[CO-Cys(Trt)-OMe]\({}_{2}\)) and ferrocene glutathione (Fc[CO-Glu-Cys-Gly-OH]) [49]. The two derivatives were adsorbed on the surface of electrodes modified by AuNPs, and the performance of the sensor was quantitatively characterized.