# A Review of Electrochemical Sensors for the Detection of Glyated Hemoglobin
## 3 Indirect Type Electrochemical HbA1c Sensors
### FAO Type  
Currently, FAO has been proven to be reproducible [83; 84; 85] and suitable for simple, convenient, and economical real-time HbA1c detection [85]. The emergence of nanotechnology has led to a new generation of electrochemical biosensors with nanostructured interfaces that enable faster detection with smaller volumes [86]. Currently, a wide range of nanomaterials, such as gold, silver, carbon nanotubes, graphene, and metal oxides, have been successfully applied in biosensors [87]. These materials have excellent properties, such as high biocompatibility, good water dispersibility, and large surface areas [88; 89; 90]. Doping \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Type** & **Electrode/Interface** & **Detection** & **Mechanisms of** & & & \\
**Material** & **Range/Limit** & **Detection** & **Sample** & **References** \\ \hline \multirow{8}{*}{MIP nanocube-modified CP@Al foil/human-enzyme enzyme Probe} & Au electrode/3- & 7.5–20 \(\upmu\)g/mL/ & HbA1c hinders the oxidation current of & 0.1 mM & \\  & mercaptopropionic acid, anti-HbA1c & & 100–250 \(\upmu\)g/mL/ & & PBS/human & \\  & anti-HbA1c & & 7.5 \(\upmu\)g/mL, NA & [Fe(CN)\({}_{6}\)]\({}^{4-/3-}\) & serum & \\  & MIP nanocube-modified CP@Al foil/human-made CP@Al foil/human-made enzyme Probe} & 0.5–100 mM/ & Artificial enzyme catalyzes the oxidation of HbA1c & Human whole blood & [59] \\ \hline \multirow{8}{*}{Potentioetric sensors} & Probe electrode/thioalcohol, AuNPs, anti-HbA1c & Potential difference in sensing chip & HbA1c reagent & [63] \\  & Au electrode/mixed SAMs, EDC\&NHS, anti-HbA1c & 1.6–72.14 & Potential difference in sensing chip & Simulated blood sample & [64] \\ \cline{1-1}  & anti-HbA1c & & ng/mL/NA & & \\ \hline \multirow{8}{*}{Impedimetric sensors} & Interdigital electrode/thiophene-3- & 10–100 \(\upmu\)g/mL/ & HbA1c affects impedance changes & HbA1c & [76] \\ \cline{1-1}  & boronic acid Dual SPCE and magnetic paper/haptoglobin, APBA & 2.3–14\%/0.21\% & HbA1c affects impedance changes & Human whole blood & [77] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: _Cont._nanoparticles into normal materials or substrates can improve the resulting electrochemical properties [91]. [PERSON] et al. [92] formed a stable scaffold with AuNPs and point-like tubular TiO\({}_{2}\); 12-phosphotungstic acid was used as a reductant after depositing well-dispersed AuNPs on TiO\({}_{2}\) nanotubes, which accelerated electron transfer between proteins and conductors (Figure 5A). The response time was only three seconds, and the linear range for HbA1c detection was 0.5-2000 uM. Furthermore, [PERSON] et al. [93] fabricated a fixed nitrogen-doped graphene/AuNP/fluorine-doped tin oxide (FTO) glass electrode based on fructosyl amino acid oxidase (FAO), with a half-life of up to four months. This biosensor could detect HbA1c in human whole blood, exhibiting a low detection limit of 0.2 uM. To further improve the reaction efficiency, [PERSON] et al. [94] synthesized 3D-structured reduced graphene oxide, multi-walled carbon nanotubes, and platinum nanoparticles (PtNPs) (Figure 5B) to coat an Au electrode. Additional reaction sites were exposed, the response time of the sensor was reduced to less than three seconds, and the linear range was 0.05-1000 uM. This sensor had good repeatability and was successfully used to determine the concentration of HbA1c in human blood samples. Moreover, [PERSON] et al. mixed AuNPs-PtNPs and polyindole-5-carboxylic acid (PINSCOOH) and modified them onto the surface of a gold electrode [95], which showed good storage stability and retained 50% of the initial activity after 12 weeks. The unique characteristics of the two different metal nanoparticles helped improve the sensitivity and specificity of the sensor; its linear detection range for FV was 0.1-1000 uM, and its detection limit was 0.2 uM. [PERSON] et al. prepared a film of a ZnO nanoparticle/polypyrrole hybrid [96] and fixed it onto a gold electrode surface with FAO.