## 1 Introduction
### Advantages of Glucose Sensing without the Enzyme  
Enzymatic and non-enzymatic electrochemical glucometers are the two mainly glucose-sensing approaches. Enzymatic approaches, in principle, depend on the oxidation of glucose molecules by the utilization of recognition enzymes such as GOx or glucose dehydrogenase (GDH), which results in the generation of detectable compounds such as O\({}_{2}\), CO\({}_{2}\), or H\({}_{2}\)O\({}_{2}\). The detection mechanism relies on typical current values relative to the concentration of the original glucose when interacting with the surface of the sensor. Although enzyme-based glucometers have dominated the industry of glucose biosensors for decades, there are several critical challenges that prohibit their further advancement. Particularly, they suffer from low thermal and chemical stability issues because of the enzymatic protein nature. Even if GOx is more stable than other enzymes, it is highly vulnerable to environmental factors such as pH (constrained to the pH range from 2 to 8), temperature (below 44 \({}^{\circ}\)C), and humidity levels. Moreover, the easy deactivation of GOx in the presence of some detergents such as sodium n-dodecyl sulfate at low pH and hexadecyltrimethylammonium bromide at high pH, leads to a quick deactivated GOx [25; 26]. The instabilities of GOx chemically and thermally stand as a barrier for continuous monitoring during the fermentation process in the enzymatic biosensor. The stability of the enzymatic biosensor is required, which means complex fabrication strategies of the enzyme within the polymers, covalent cross-linking of the enzyme, sol-gel entrapment of enzyme, etc. [27; 28; 29; 26].  
Three generations of glucose biosensors suffered from the arising limitation of the performance where the sensors depend on pH value, enzyme activity and interference, electrode surrounding, (temperature and humidity), etc. The short-term stability of enzymatic glucose sensors creates a problem for the users (single-time disposable usage), in addition, it is not possible to avoid the harsh thermal and chemical conditions during the fabrication, storage, and usage of enzymatic glucose sensors. The high-cost fabrication and short lifetime of enzymatic glucose biosensors are problems for most diabetes patients, and this explains why non-enzymatic glucose biosensors attract extraordinary research interest.  
Figure 3: Summary of glucose electrooxidation mechanisms: Presented as enzymatic (first-, second-, and third-generation sensors) and non-enzymatic (so-called herein “fourth-generation” sensors).  
The non-enzymatic glucose biosensors are promising for the fourth-generation of analytical GOx, in which the electrodes can oxidize the glucose in the sample without enzymatic needs [30; 31]. However, the non-enzymatic glucose biosensor is based on the electrocatalysts activity to oxide the glucose without enzymes, such as metals (Au, Ni, Cu, Pd, etc.), metal oxides (CuO, RuO2, etc.), alloys (PtPb, PtRu, etc.), complex (nickel hexacyanoferrate, etc.), and carbon (graphene, diamond, nanotubes, etc.).  
Investigating the right material composition of the electrodes are the keywords to get a good output of these types of biosensors such as high sensitivity, low cost, and stability. Recently emerging, a class of graphene-based non-enzymatic glucose sensor electrodes with nanoparticles, metals, metal oxides, alloys, and polymers would meet these scientific demands such as cost-effectiveness, synthesis approach, biocompatibility, stability, electron-transfer kinetics, and sensitivity [32; 33; 34; 35; 36; 37].