# Trends in Quantification of HbA1c Using Electrochemical and Point-of-Care Analyzers
## 2 Sensors for Quantification of HbA1c  
The emerging field of sensors offers a wide versatile platform for the detection of various analytes, which can be tailored based on the desired analyte, employing appropriate detection elements. Sensors comprise a sensing element that responds to the analyte and a transducer that produces the readable output. If the sensing element involves a chemical molecule, the sensor is classified as a chemical sensor, while those that employ biomolecules such as enzymes, antibodies, aptamers, oligonucleotides, etc., are classified as biosensors [23]. While chemical sensors are cost-effective and stable, they do not possess the specificity and sensitivity of biosensors [23]. Sensors are also classified based on the transduction element as optical, electrochemical, electrical, calorimetric, and piezoelectric sensors. Among the various transduction methods, electrochemical sensors are widely employed for analytical applications due to the simple operation, rapid response, cost  
Figure 1: Scheme illustrating the formation of HbA1c by non-enzymatic glycation of hemoglobin via Amadori rearrangement. effectiveness, portability, and ease of fabrication [24]. Though there are several reports of HbA1c quantification using optical [25], photoacoustic [26], electrochemical piezoelectric [27], chemiluminescence [28], photoelectric [29], magnetic immunoassay [30], etc., majority of the reports have focused on electrochemical methods of transduction owing to their merits. This review focuses only on the progress in electrochemical strategies for HbA1c measurement. The electrochemical sensors can be further classified as potentiometric sensors, that measure the charge potential accumulated in the working electrode, amperometric sensors, that measure the change in current due to reduction and oxidation of electroactive species in the system at a constant potential, voltamtor sensors, that measure the current change at a defined potential window, and impedimetric sensors, that detect changes in the capacitance and charge conductance at the electrode/electrolyte interface [31]. In order to improve the sensitivity, response times, and detection range of the electrochemical sensors, the earlier generations of electrochemical sensors employed an electron transfer agent or a redox mediator, while the current generation of sensors employ direct electron transfer on an electrode surface that is modified with nano-dimensional particles. These nanointerfaces offer amplified electro-catalytic, electron transfer, and conductivity owing to their structural characteristics. Nanostructures of various sizes, shapes, and chemical nature have been explored as interface materials. Further, these nanostructured interfaces also serve as immobilization matrices with a high surface area for retaining biological capture elements such as enzymes and antibodies, thereby augmenting the specificity, sensitivity, and detection range of the biosensor. Electrochemical measurements of HbA1c have been carried out by both chemical and biosensors. In the chemical method, the conventional cis-diol interaction between boronate and the sugar moiety of HbA1c is exploited for the detection of HbA1c, while biosensors quantify the redox changes or current flow variations owing to interactions between HbA1c and the biological recognition elements, such as antibodies or enzymes. Additionally, HbA1c has also been quantified in an indirect method which involves the detection of fructosyl-valine (FV), a small peptide generated by digesting HbA1c by oxidation using the enzyme fructosyl amino acid oxidase (FAO), resulting in the generation of H2O2, which is measured electrochemically [32]. The present review includes science citation indexed articles published from the year 2000 to present in Science Direct, PubMed, and Google Scholar on electrochemical sensors for HbA1c. Sensors fabricated with either chemical or biological sensing elements have been considered for the review.