# A Review of Electrochemical Sensors for the Detection of Glyated Hemoglobin
## 2 Direct Type Electrochemical HbA1c Sensors
### Amperometric Sensors
The ferrocene glutathione sensor was proven to have a stronger catalytic current response to Hb, and the current showed a good linear correlation, with Hb concentrations ranging from 0.1 to 1000 \(\upmu\)g/mL. The relative standard deviation was less than 4.7%, and the recovery rate was between 95.5% and 103.2%. Both properties meet the clinical requirements for Hb analysis. **Appamer-based. ** A nucleic acid aptamer is a sequence of short single-strand DNA or RNA, and aptamers are produced through in vitro selection procedures. Aptamers provide several unique advantages: minimal possibility of chemical synthesis, small batch variability, long shelf life, stability under various conditions, and a variety of available chemical modifications. Therefore, aptamers are now the most promising alternative to  
Figure 2: (**A**) Electrochemical sensor based on the HbA1c and GOx competition mechanism, as well as the \(\Delta\)CV responses of HbA1c (this figure was adapted from [35] with some modifications); (**B**) Electrochemical sensors based on 4-MPBA specific recognition and the \(\Delta\)CV 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 Id value vs. the concentration of HbA1c (this figure was adapted from [40] with some modifications). monoclonal antibodies [50]. Novel aptamers for glycated and total hemoglobin have been selected recently, showing high affinity and specificity [51]. [PERSON] et al. reported a dual sensor for detecting HbA1c and Hb in a finger pick blood sample (1 uL) [17]. The Hb content was determined by measuring the cathode current generated from catalysis with toluidine blue O (TBO), while the HbA1c content was determined by measuring the cathode current produced when HbA1c was captured by the aptamer. The dynamic ranges for detecting Hb and HbA1c were 0.1-10 uM and 0.006-0.74 uM, respectively, and the mean HbA1c values (%) of the proposed method were also proven to be reasonable by comparison with high performance liquid chromatography (HPLC). [PERSON] et al. screened two specific aptamers with dissociation constants of 2.8 nM and 2.7 nM for HbA1c and Hb, respectively, based on the systematic evolution of ligands by exponential enrichment (SELEX) process [52]. Then, the authors fixed the sulfhydryl-modified aptamers onto the surface of array electrodes modified by AuNPs to perform label-free detection of HbA1c and Hb (Figure 3A-C). The sensor had a high sensitivity and detected HbA1c and Hb with detection limits of 0.2 ng/mL and 0.34 ng/mL, respectively. Such an array platform is superior to the existing immunoassay methods due to its simplicity, stability, low sample consumption, and low cost. However, the main disadvantage is that has a complicated operation. This method can detect HbA1c in human whole blood without any pretreatment and has broad applications in the diagnosis of diabetes. blood samples, the effective antifouling ability of the electrode can improve the affinity and specificity of detection. [PERSON] et al. [54] developed a gHb-targeted aptamer (GHA) through a modified SELEX process, and it was used to produce three distinct SAM-SPR-sensing surfaces with and without an antifouling layer. The results showed that the correlation between the HbA1c-targeted aptamer and HbA1c of the sensor surface with antifouling modification was higher than that of the sensor surface without modification, and the interference of nonspecific protein adsorption was reduced. This system illustrates the role of aptamers and antifouling surface modifications in developing effective, low-cost, and rapid HbA1c analyses in blood samples. **Antibody-based. ** Specificity and simplicity are the greatest advantages of this kind of immunosensor, which can satisfy the detection of HbA1c in a complex sample environment. [PERSON] et al.