**6. Future Perspectives**

Limited research development has been made with regard to the fabrication of advanced nanomaterials with bifunctional property for NEGHS. Further improved research and development are necessary to make the commercialization of implantable in vivo and portable in vitro NEGHS devices, which require the improvement of practical, affordable, advanced nanomaterial-based electrocatalysts with multifunctional reactivity. The current research review addresses multiple directions for the achievement of non-enzymatic bifunctional electrode platforms. Electrochemical sensing parameters of advanced nanomaterial with bifunctional electrodes are dependent upon the electrode potential, bandgap, surface defects, synergetic effect, and surface area of the nanocomposites. However, the influence of these issues on NEGH sensing is not addressed in the literature and provides opportunities for the future development of biodevices. Since the multienzymatic properties of nanomaterials have attracted wider research interest, the catalytic (glucose) and peroxidase (H2O2) activity of nanomaterial should be effectively optimized and promoted for the best performance of NEGH sensors. The essential electrochemical mechanism in NEGH sensing with the same electrode material should be established using theoretical and analytical models with relevant laboratory experiments. Current studies on NEGH sensors mostly focus on the electrocatalyst performance of advanced nanomaterials and limit the understanding of the influence of nanomaterial morphology on glucose and H2O<sup>2</sup> quantification and the interaction with bio-analytes. To overcome this, researchers should focus on the development of nanomaterials in different morphologies, such as dots, tubes, fibers, spheres, and core-shells, and a detailed study should be undertaken to improve the surface area and conductivity, which could have a positive influence on the development of NEGH sensors. The modified electrodes show catalytic activity in acidic or basic conditions, which limit the practical application of NEGH sensors. In this context, studies must be done on the oxidation and reduction mechanisms at neutral pH conditions by considering novel nanomaterials. The use of biopolymers as bio-catalytic centers are tolerable to achieve highly sensitive and selective NEGH sensors, and distinct consideration should be given to building electrode platforms with improved robustness and enhanced electro catalytic activity. NEGH sensor-based nanomaterials as catalysts have been demonstrated to be very reasonable; conversely, it is essential to design new schemes for the synthesis, functionalization, and fabrication of nanomaterials to acquire more accurate quantification of glucose and H2O2. Several sequential steps involved in the preparation of electrodes for a conventional modified electrode based on NEGH sensing, including cumbersome electrode cleaning, polishing and washing, binder and solvent selection, catalyst preparation, and loading process, have increased the time and cost of NEGH sensing electrodes. Furthermore, to establish contact between the working electrode and catalyst using a binder remains another challenge for the performance of NEGH sensing. This could be avoided by developing binder-free, freestanding bare electrodes, ink/screen printed electrodes and the in situ fabrication/modification of advanced nanomaterials as modified electrodes that make possible the preparation of disposable NEGH sensing electrodes. Moreover, another compelling research direction is in the preparation of metal/metal oxide morphologies with emerging carbon materials (g-C3N4, graphene, CNTs, black phosphorous, and activated carbon, etc.) to form new functional materials. For commercialization, an important prospect is the prolongation of lifetime of the sensors, even though the non-enzymatic sensors are more stable than enzymatic sensors, they lack in the corrosion property/unstable in humid conditions, which requires researchers to focus on anticorrosive nanomaterials. Current challenges in improving efficiency of the NEGH sensors can be overcome by optimizing the selectivity, working potential, linearity, sensitivity and working pH conditions. Though some NEGH sensors are good in neutral pH conditions with low detection limits, their linear range of detection may be questionable. The low detection range sensors are not useful in day-to-day diabetes management and hence few reports have been applied in various real-time applications such as sensing in antibiotic lotions, milk, and glucose-based fuel cells, etc. The selectivity of NEGH remains a huge problem, which means that the oxidation of interference compounds such as AA, DA, and UA chlorine ions and other carbohydrates at the same working

potential affects the glucose and H2O<sup>2</sup> determinations. Transition metal/metal-oxide-based sensors have shown significant progress in selectivity issues and electrode fouling problems due to reasonable isoelectric point values. From the reported literature on NEGH sensors the sensitivity was improved using different strategies and the novel combination of nanomaterials. Sensor sensitivity is dependent on on working potential, electro kinetics and electrolyte conditions. However, different research groups have performed sensing under their own optimized conditions, which necessitates a uniform protocol for sensing operations. In addition, to improving the sensitivity by optimizing the properties of advanced nanomaterials, the selectivity performance should be more focused to achieve stability, repeatability, and practical evaluation of glucose and H2O2. The dual in-line sensor requires a clear mechanism with suitable working conditions in neutral pH. The use of the same electrode material for multiple applications is essential to reduce the cost and will make commercialization easy. The dual sensor requires a clear electro catalytic mechanism for sustainable development, and it can be achieved by operating the electrodes at the same working potential (positive/negative). In short, the bifunctional, electro-catalyst-based NEGH sensing technology must be extended from the laboratory to the field by proper implementation to boost sustainable electronic devices.

#### **7. Conclusions**

Non-enzymatic glucose and H2O<sup>2</sup> (NEGH) electrochemical sensors can be developed based on metals, metal oxides, bimetallic/metal oxide insole, and in combinations with graphene, graphene oxide, carbon nanotubes, graphitic carbon nitride, and polyaniline materials. Several important parameters, such as working potentials, sensitivity, linear range, and selectivity need to be considered for the development of better NEGH sensing, and advanced nanomaterials have been recently suggested as an effective electrocatalyst. This review provides a vital summary of previous NEGH sensing studies and discusses the current state and comparative characteristics of different NEGH sensing modified electrodes to detect both glucose and H2O<sup>2</sup> in dual in-line monitoring systems. The metal nanocomposites exhibited excellent catalytic activity and notable NEGH sensing performances in terms of detection limits and linear ranges of glucose and H2O2. Especially, the development of transition metal chalcogenides (TMDs) such as NiN2, CoN2, Cu2S, CoS, and V2S has overcome the limitations of poor conductivity, less active sites, low stability, low electron transfer, wide band gap and over potential issues. The metal oxide nanocomposites are low cost and highly tolerable in neutral pH conditions compared to metal nanocomposites. However, the metal oxides, such as Cu2O, CuO, NiO and Co3O4, in NEGH sensing have limitations like poor conductivity and structural instability during operation. These limitations could be overcome by designing unique morphologies, which show excellent performance with high sensitivity and selectivity. Bimetallic nanocomposites generally have better electro-catalytic activity and conductivity compared to other nanocomposites. Bimetallic nanocomposites with a porous nanostructure are mostly fabricated by using the dealloying method for NEGH sensing. Modifying the morphology of bimetallic into nanowires/plates/spheres, and nanofibers altered the potential window to avoid interference of electrodes in achieving high selectivity. Among bimetallic nanocomposites, bimetallic nitrides (BMN) have attracted attention due to their exceptional redox property, superior conductivity, and high corrosion resistance and mechanical strength. Screen-printed electrodes modified metal (oxide)/metal oxide nanocomposites and enhanced electrochemical NEGH sensing, has promoted research in real-time applications and overcame the limitations of portability and instability. The perovskite-type ferrites with rGO solved agglomeration, stability and poor conductivity issues and improved mass and electron transfer between electrode and electrolyte to further enhance linear ranges, sensitivity and selectivity. Even though substantial improvements in NEGH sensors have been made based on exploration of carbon and non-carbon-based nanocomposites, additional efforts are essential to deeply understand the mechanism of glucose oxidation and reduction/oxidation of H2O<sup>2</sup> and NEGH sensing at the same working potential, and to further improve the optimization of sensing parameters in real-time applications. This comprehensive review aims to strengthen the understanding of nanomaterials for

NEGH sensing and provide a fundamental foundation to explore novel nanomaterials and innovative ideas to revolutionize the sensing of both glucose and H2O<sup>2</sup> leading to commercialization and clinical application of NEGH sensors.

**Funding:** This work was supported by an NPRP grant from the Qatar National Research Fund under the grant number NPRP11S-0110-180247. The statements made herein are solely the responsibility of the authors.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

Diabetes mellitus (DM); Non-enzymatic glucose and H2O<sup>2</sup> (NEGH); enzymatic glucose and H2O<sup>2</sup> sensing (EGHS); Multiwalled carbon nanotubes (MWCNTs); Gold Nanobipyramids (AuNBP); Graphitic carbon nitride quantum dot (g-CNQD); Silver nanoparticle (Ag NPs); Sodium hydroxide (NaOH); paraffin wax-impregnated graphite electrode (PIGE); Glassy carbon electrode (GCE); Copper nanoparticle (Cu NPs); Copper sulphide nano rods (Cu2S NRs); Nickel nitride (Ni3N); Graphene aerogels (GA); Cobalt sulphide (CoS); Three dimensional (3D); Nitrogen (N<sup>2</sup> ); Nitrogen doped graphene (NG); cobalt nitrate nanowire (Co3N NW); Ammonia (NH<sup>3</sup> ); Cobalt(II) nitrate hexahydrate (Co (NO<sup>3</sup> )2 .6H2O); Ammonium fluoride (NH4F); Cobalt (Co); Nickel (Ni); Ascorbic acid (AA); Uric acid (UA); L-Dopamine (L-dopa); Sodium, Potassium, Chlorine ions (Na+, K<sup>+</sup> and Cl<sup>−</sup> ions); vanadium sulfide (VS<sup>2</sup> ); graphitic carbon nitrate (g-C3N<sup>4</sup> ); Gold (Au), Vanadium (V); Vanadium sulphide (V2S); Tetra-Cobalt(II) carboxamide-PEG2-biotin phthalocyanine (CoTPEG2BAPc); Ordered mesoporous silica (OMCs); bis(acetylacetonate) oxo vanadium (VO(acac)<sup>2</sup> ); 4-(pyridine-40-amido) thiol phenol (PATP); Copper oxide (CuO); Cuprous oxide (Cu2O); Tetraamminecopper(II) sulfate monohydrate (Cu(NH<sup>3</sup> )4 <sup>2</sup>+); Copper hydroxide (Cu(OH)<sup>2</sup> ); Polyamic acid (PAA); Polyaniline (PANI); One dimensional (1D); X-ray diffraction (XRD); Ti mesh (TM); poly(acrylic acid) (PAA); High pressure Liquid chromatography–mass spectrometry (HPLC-MS); saturated calomel electrode (SCE); Ethylenediaminetetraacetic acid (EDTA); Fluorine doped Tin Oxide (FTO); Urea (UR); Sucrose (SU); Sodium borohydride (NaBH<sup>4</sup> ); polyvinyl pyrrolidone (PVP); N, N-dimethylformamide (DMF); Copper chloride (CuCl<sup>2</sup> ); Copper sulfate (CuSO<sup>4</sup> ); Potassium hydroxide (KOH); metal-organic framework (MOFs); Electro reduced grapheme oxide (ERGO); Platinum (Pt); Palladium (Pd); Chromium (Cr); Iron (Fe); Aluminium (Al); Molybdenum disulfide (MoS<sup>2</sup> ); Iron nitride (Fe3N); Carbon screen-printed electrodes (CPEs); La0.6Sr0.4Fe0.8O3-d (LSF); La0.6Sr0.4Co0.2Fe0.8O3-d (LSCF); LaNi0.6Co0.4O<sup>3</sup> (LNC); Co0.4Fe0.6LaO<sup>3</sup> (CFL); LaNiO<sup>3</sup> Nanofibers (LNFs); Nanoporous gold (NPG); Silicon dioxide (SiO<sup>2</sup> ); Zinc oxide (ZnO)

#### **References**


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