# Trends in Quantification of HbA1c Using Electrochemical and Point-of-Care Analyzers
## 6 Multi-Analyte Sensors  
In an effort to overcome the limitations accompanying the diagnosis of diabetes based solely on HbA1c measurements, multi-analyte measurements have been gaining traction recently. One strategy is to simultaneously measure total Hb and HbA1c. Not only does this strategy reduce errors owing to differences in basal Hb levels, it can also provide information on the anemic status of the individual. There are certain sensors designed to detect both the total Hb (tHb) and HbA1c in the blood sample, keeping in mind the fact that in real samples, the HbA1c is measured in terms of HbA1c% to total Hb. Several potentiometric field-emission transmitter (FET) sensor chips fabricated by Micro-Electro-Mechanical-Systems (MEMS) and Complementary Metal-Oxide-Semiconductor Transistor (CMOS) techniques have been reported to quantify both tHb and HbA1c [53; 54; 55; 56]. In a recent study [62], an aptasensor employed a novel interface with aptamers displaying high affinity for tHb and HbA1c for quantification.  
A three-dimensional paper-based electrochemical impedance device (3D-PEID) has been reported for simultaneous sensing of tHb and HbA1c [48]. The electrode surface comprised egg-shell membranes (ESM) modified with APBA and haptoglobin to detect HbA1c and tHb, respectively. [PERSON] et al. [34] designed an interface by using chitosan (CS) and tetraethyl silica (TEOS) to immobilize the carbon nanotubes on screen-printed electrodes for tHb detection, while HbA1c was detected using an APBA-modified reticulated vitreous carbon (RVC) electrode.  
In another study, molecular imprinted conducting nano-cubes were employed to detect HbA1c and tHb. The sensor platform contains dual molecularly imprinted nano-cubes with PAPBA for HbA1c, along with poly-rhodamine B (for tHb) deposited on carbon paste-coated aluminum foil for detection [67]. Recently, [PERSON] et al. [40] developed  
Figure 9: Schematic illustration of a WS\({}_{2}\) NP\(-\)fabricated nano-biosensor based on the FAO principle for the HbA1c sensor in diabetic patients. Copyright CC BY\(-\)NC\(-\)ND 4.0 [86].  
a simple platform for detecting tHb (in blood samples) by immobilizing MWCNT in SPCE using Nafion, while HbA1c in diluted blood samples can be detected in a separate modified platform.  
Measurement of HbA1c along with other diabetic markers may offer higher diagnostic accuracy, for instance, a novel heterojunction nanohybrid interface comprising electrospun TiO\({}_{2}\) nanowires and carboxylic acid-functionalized graphene (G-COOH), along with a composite of gold nanoparticles (Au NPs) and PAPBA. The nanoninterface was denoted as TiO\({}_{2}\)(G)NW@PAPBA-Au HJNH and was drop-cast on a pre-cleaned indium tin oxide (ITO) electrode, and the working electrode was used to non-enzymatically detect glucose by the photoelectrochemical method and HbA1c through the electrochemical method [47]. The analytes from the sample were captured on the electrode surface by PAPBA. The detection range for glucose was between a wide range of 0.5 and 28 mM, while the sensor was able to quantify HbA1c between 2 and 10% with a LoD of 0.11 mM and 0.17%, respectively. Though two key markers of diabetes were detected by this sensor, the upper limit of detection for HbA1c could be extended for better clinical utility. Further, the sensor requires clinical validation for establishment of its diagnostic utility in clinics. Recently, an electrochemical PoC device with disposable electrodes modified with chemical capture agents was successfully employed to quantify Hb, HbA1c, and glycated albumin from serum samples, as well as microalbumin and creatinine from urine samples. This integrated detection device enabled superior diagnostic efficiency for anemia, diabetes, and diabetic kidney disease [87].