Sabine Szunerits
email: sabine.szunerits@univ-lille1.fr

Rabah Boukherroub

Graphene-based nanomaterials in innovative electrochemistry

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Introduction

Electrochemical science has become a discipline of wide scientific and technological interest due to the important role in present-day technologies. Batteries, fuel cells, supercapacitors, electrochromic devices, gas separation membranes, and sensors are some examples of applications of electrode materials. The success in electrochemical technology is largely due to the continued design and development of novel material electrodes that meet the needs of modern society. Emerging two-dimensional nanomaterials, including next to graphene, h-BN, MoS 2 , NbSe 2 , TiS 2 , TaS 2 , WS 2 , WSe 2 , TaSe 2 , etc., metal-organic frameworks (MOFs) and many more, are at the forefront of interest because of their superior potential for electrochemically driven applications in many different fields [START_REF] Chen | Emerging two-dimensional nanomaterials for electrochemical hydrogen evolution[END_REF][START_REF] Wang | 2D nanomaterials based electrochemical biosensors for cancer diagnosis[END_REF][START_REF] Khan | Twodimensional (2D) nanomaterials towards electrochemical nanoarchitectonics in energy-related applications[END_REF][START_REF] Boukherroub | Graphene based biosensors Interface Focus[END_REF]. The success of graphenebased electrode materials, such as chemical vapor deposition produced graphene as well as chemically derived graphene derivatives, in numerous electrochemical based technologies (Figure 1) is due to a number of factors, which are key to most of the applications [START_REF] Boukherroub | Graphene based biosensors Interface Focus[END_REF][START_REF] Ambrosi | Electrochemistry of Graphene and Related Materials[END_REF][START_REF] Mao | Carbon Nanofiber-, Carbon Nanotube-and Graphene-Based Electrochemical Systems for Sensing, Electrocatalysis, and Energy Storage[END_REF][START_REF] Mao | Remarkably High Heterogeneous Electron Transfer Activity of Carbon-Nanotube-Supported Reduced Graphene Oxide[END_REF].

Graphene (G)

ANODE/CATHODE IN BATTERIES

Li-ion batteries Na-ion batteries

ELECTROANALYTICAL PLATFORMS

Sensors Biosensors

TRIGGERABLE RELEASE PLATFORM

Drug delivery

FLEXIBLE ELECTODES and ELECTRONICS

Skin electrodes Wearable sensors

ELECTROCATALYTIC APPLICATIONS

Hydrogen evolution Oxygen reduction

ENERGY STORAGE DEVICES

Supercapacitors

Reduced graphene oxide (rGO)

Porous rGO (prGO)

Figure 1: Graphene interfaces for innovative electrochemical based applications. Indeed, graphene exhibits a large surface area, which can be further tuned through the generation of porous structured graphene and incorporation of dopants. Additionally, graphene as a highly conjugated network (-conjugation) bears hydrophobic properties providing an ideal platform for immobilizing organic and inorganic molecules in an easy manner. Graphene exhibits also high conductivity and mediates electron transfer mostly at its edge planes [8]. Those properties have made graphene of potential interest for electrochemical and biosensing oriented applications. To evaluate graphene's performance as an electrode material, the heterogeneous electron transfer (ET) rate between graphene and a redox mediator has to be determined and compared with its naturally occurring counterpart 3-D graphite. [START_REF] Velicky | Electron transder kinetics on mono and mulitlayer graphene[END_REF][START_REF] Ritzert | Kinetics of interfacial electron transfer at single-layer graphene electrodes in aqueous and nonaqueous solutions[END_REF] The literature offers some contrasting views on the reactivity of mono and multilayered graphene. Accelerated kinetics data are reported on mechanically exfoliated monolayer graphene compared to bilayer graphene and graphite. [START_REF] Valota | Electrochemical behavior of monolayer and bilayer graphene[END_REF][START_REF] Li | Elecrochemistry of individual monolayer graphene sheets[END_REF] Guell et al. observed increased ET kinetics with increasing number of CVD stacked graphene flakes (from 1 to 7) using a ferrocene derivative as a mediator. However, no increased ET was observed at the edges or steps in comparison to the basal plane. [START_REF] Guell | Correlations in heterogenopus electron transfer at monolyaer and multilayer graphene[END_REF] To shed more light into the electrochemistry of graphene, Velicky et al. determined the electron transfer rates of three redox mediators on mechanically exfoliated graphene layers (1-100) supported on insulating Si/SiO 2 substrates. A large variation in kinetics is observed across the basal plane of the same flake, indicating that local surface conditions affect the electron transfer kinetics. While the growing number of commercial sources of graphene represents certainly an important step towards the commercialization of graphene-based materials in the near future, for a large number of electrochemical applications, it is not graphene but chemically derived reduced graphene oxide (rGO) which is used. In contrast to pristine graphene, rGO contains lattice defects and residual oxygen-containing groups. While these defects impact on the electrical readout, they are actually beneficial to achieve fast heterogeneous electron transfer.

Additionally, the presence of oxygen-containing groups offers plenty of opportunities for covalent immobilization of surface ligands to target specific sensing or drug delivery applications [8,[START_REF] Zhou | Electrochemical Sensing and Biosensing Platform Based on Chemically Reduced Graphene Oxide[END_REF]. The promising electrochemical characteristics such as large potential window, fast electron transfer kinetics and increased capacitance of rGO based materials together with their low cost of production make them ideal materials for electrochemicaldriven applications [START_REF] Zhou | Electrochemical Sensing and Biosensing Platform Based on Chemically Reduced Graphene Oxide[END_REF][START_REF] Tang | Preparation, Structure, and Electrochemical Properties of Reduced Graphene Sheet Films[END_REF]. This article is not aiming to discuss in details all the different recent examples of rGO based electrochemical applications ranging from energy to electroanalytical and biosensing driven applications. It should be seen as a general review to a broad audience interested in graphene based electrochemistry and its different aspects. The review will thus highlight some important works with details to be found in the respective articles. It will also address certain aspects to further enhance the use of graphene nanomaterials in innovative electrochemical designs.

Recent examples from the literature

Energy driven applications: Energy storage and energy conversion

The development of novel materials for energy storage is of great importance to fulfill the increasing demand of energy. Lithium ion batteries are highly promising devices for powering portable electronics and also electrical vehicles. Currently, the use of graphite anodes with a theoretical capacity of 372 mAh g -1 has become insufficient to satisfy the increasing energy and power densities demand, making the search for efficient and stable anode materials possessing high lithium capacity of high importance. Mullins and co-workers developed a composite of N-doped rGO and nanocrystalline tin sulfides and tested it as anode in lithium batteries [START_REF] Youn | Simple Synthesis of Nanocrystalline Tin Sulfide/N-Doped Reduced Graphene Oxide Composites as Lithium Ion Battery Anodes[END_REF]. When cycling at a specific rate of 0.2 A g -1 , a Coulombic capacity of 562 mAh g -1 was retained after the 200 th cycle, which is believed to be due to the presence of conductive rGO cushioning the stress associated with the expansion of lithiation of Sn. Lin et al. reported a composite lithium metal anode composed of 7 wt.% layered rGO with nanoscale gaps that can host metal lithium. The composite exhibited low dimensional variations (20%) during cycling, good mechanical flexibility next to retaining up to 3.390 mA g -1 of capacity in a carbonate electrolyte [START_REF] Lin | Layered reduced graphene oxide with nanoscale interlayer gaps as a stable host for lithium metal anodes[END_REF]. Graphene encapsulated Si microparticles were proposed by Li as anode in lithium ion batteries, where the graphene cage acts as a flexible and mechanically strong buffer during deep galvanostatic cycling, allowing the microparticles to expand and fracture within the cage while retaining electrical connectivity on both the particle and electrode levels.

Among the new battery chemistries being developed, sodium-ion batteries are considered to be the most promising ones due to similar intercalation chemistry to Li-ion ones and natural abundance of sodium resources. Anodes of rGO, with uniformly anchored Fe 2 O 3 single crystallites with a particle size of ≈300 nm displayed a reversible capacity of 610 mAh g -1 at 50 mA g -1 , high coulombic efficiency (71% for the first cycle) and a good cyclability with 82% capacity retention after 100 cycles, suggesting a potential feasibility for sodium-ion battery [START_REF] Li | In Situ Grown Fe 2 O 3 Single Crystallites on Reduced Graphene Oxide Nanosheets as High Performance Conversion Anode for Sodium-Ion Batteries[END_REF]. The Na + intercalation/de-intercalation properties of mesoporous WO 3-x encapsulated in N-doped macroporous graphene, formed by heat treatment of a co-assembly of amine-functionalized mesoporous silica/metal oxide and GO with subsequent silica removal, were recently demonstrated by Kim et al. [START_REF] Kim | General Synthesis of N-Doped Macroporous Graphene-Encapsulated Mesoporous Metal Oxides and Their Application as New Anode Materials for Sodium-Ion Hybrid Supercapacitors[END_REF].

To tackle the challenge in the preparation of high-capacity electrode materials with good structural stability and flexibility, Mo et al. proposed a 3D interconnected porous nitrogendoped graphene foam (NGF) with encapsulated Ge quantum dots@nitrogen-doped graphene (Ge-QD@NG), exhibiting high specific capacity of 1.220 mAh g -1 and long cycling capability [START_REF] Mo | 3D nitrogen-doped graphene foam with encapsulated germanium/nitrogen-doped graphene yolk-shell nanoarchitecture for high-performance flexible Li-ion battery[END_REF]. It is well recognized that the ever-growing demands in future flexible electronics such as wearable devices, portable implants, biomedical products, have aroused a worldwide research interest in the development of electrodes that maintain their conductivities under repeated stretching deformation. A solid-state electrochemical capacitor was recently developed using wavy rGO displaying a specific capacitance of 67.25 mF cm -2 at a current density of 1 mA cm -2 , and excellent stability [START_REF] Xu | Highly Conductive Stretchable Electrodes Prepared by In Situ Reduction of Wavy Graphene Oxide Films Coated on Elastic Tapes[END_REF].

Next to batteries, supercapacitors (SC) are the key devices for energy storage due to their high specific capacitance, high power density, ultrafast charging/discharging rate, extremely low internal discharge, long cycle life (300.000 cycles) and low cost [START_REF] Simon | Materials for Electrochemical Capacitors[END_REF][START_REF] Chee | Flexible Graphene-Based Supercapacitors: A Review[END_REF]. We reported recently on an all solid-state SC using N-doped porous rGO with a specific capacity of 230 F g -1 at 1 A g -1 current density and good capacitance retention up to 88% even after 10.000 galvanostic charge/discharge cycles recorded at 5A g -1 (Figure 2A) [START_REF] Chee | Flexible Graphene-Based Supercapacitors: A Review[END_REF]. While symmetric SC have many reported outstanding properties, asymmetric designs using graphene-based materials as negative electrode materials allowed widening the negative working potential range. A high performance asymmetric SC using MnCo 2 O 4 nanofibers as anode and N-doped rGO aerogels as cathode was proposed [START_REF] Pettong | High-Performance Asymmetric Supercapacitors of MnCo 2 O 4 Nanofibers and N-Doped Reduced Graphene Oxide Aerogel[END_REF]. The MnCo 2 O 4 nanofibers store negative charges such as solvated OH -, while the N-doped rGO aerogel stores positive charges, providing an operating potential of 1.8 V with energy and power densities of 54 Wh kg -1 and 9851 W kg -1 , respectively and 85.2 % capacity retention over 3.000 cycles. The charge storage mechanism of the spinel-type oxide materials remains however unclear, even though synchrotron-based X-ray absorption spectroscopy (XAS) was used to determine the oxidation states of Co and Mn at the MnCo 2 O 4 electrode after being electrochemically tested.

Last but not least, microbial fuel cells are perceived as a promising renewable power source harvesting electricity from organic matter by microorganisms. Their practical application is still greatly impeded by their lower power density compared to conventional fuel cells, mainly due to the sluggish extracellular electron transfer and low bacteria loading. 3D hierarchically structured porous MWCNTs/rGO nanohybrids were found to be useful anode materials for the growth of rich bacterial biofilms, displaying a power density of 789 mW m -2 in Shewanella putrefaciens CN32 microbial fuel cells (Figure 2B), being 6-fold higher than that of conventional carbon cloth [START_REF] Zou | Tailoring hierarchically porous graphene architecture by carbon nanotube to accelerate extracellular electron transfer of anodic biofilm in microbial fuel cells[END_REF].

Catalytic driven reaction

Metal nanoparticle-rGO composites have been largely investigated as advanced electrode materials due to their interesting electrocatalytic features. Introduction of rGO to the catalytic system enhances the catalytic activity not only due to its large surface area, high conductivity and excellent electrochemical properties, but also as rGO stabilizes efficiently the catalytic nanostructures from aggregation. Such nanocomposites have found widespread applications for green and renewable sources of energy, including electrochemical water splitting reaction, putting oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) at the forefront of interest. Similarly, the oxygen reduction reaction (ORR) is important to renewable energy technologies, including fuel cells and metal-air batteries. Platinum based catalysts have long been used for ORR and HER, and carbon supported platinum (Pt/C) is still one of the bench mark catalysts [START_REF] Nie | Recent advancements in Pt and Pt-free catalysts for oxygen reduction reaction[END_REF]. Indeed, based on its adsorption energetics of the H atom, platinum is the optimal material for fuel cell electrocatalysis. The high cost of platinum and low catalytic efficiency due to CO poisoning along with thermal instability remain nevertheless the major limiting factors for enhancing the energy-conversion efficiency in fuel cells and other energy driven devices. Non-Pt group electrocatalysts and even metal-free catalysts have shown their efficiency towards the different electrocatalytic processes [START_REF] Khan | Twodimensional (2D) nanomaterials towards electrochemical nanoarchitectonics in energy-related applications[END_REF]. For example, CoMn oxide nanoparticles (Co:Mn ratio of 2:1) supported over N-doped porous reduced graphene displayed ORR activity under basic conditions comparable to that of commercial Pt/C catalyst (Figure 2C), where the high activity was attributed to the cooperative effect arising from the metal entities and the defects in N-doped porous rGO [START_REF] Sing | Efficient and Durable Oxygen Reduction Electrocatalyst Based on CoMn Alloy Oxide Nanoparticles Supported Over N-Doped Porous Graphene[END_REF].

PdAg particles embedded on ZrO 2 /porous carbon/rGO nanocomposites resulted in electrodes with excellent activity for the dehydrogenation of formic acid with 100% hydrogen selectivity [START_REF] Song | Metal-Organic Framework Templated Porous Carbon-Metal Oxide/Reduced Graphene Oxide as Superior Support of Bimetallic Nanoparticles for Efficient Hydrogen Generation from Formic Acid[END_REF]. Zheng et al. demonstrated that g-C 3 N 4 @N-doped reduced graphene oxide was a highly efficient metal-free HER catalyst [START_REF] Zheng | Hydrogen evolution by a metal-free electrocatalyst[END_REF]. Tri-doped rGO (nitrogen, phosphorus, fluorine), obtained by thermal activation of a mixture of polyaniline-coated GO and ammonium hexafluorophosphate, was found to exhibit excellent electrocatalytic activities for ORR, OER and HER and could be used as an OER-HER bifunctional catalyst for oxygen and hydrogen gas production in an electrochemical water-splitting unit, which was powered by an integrated Zn-air battery based on an air electrode made from the same electrocatalyst for ORR (Figure 2D) [START_REF] Zhang | Nitrogen, Phosphorus, and Fluorine Tri-doped Graphene as a Multifunctional Catalyst for Self-Powered Electrochemical Water Splitting[END_REF].

Sensing and biomedical applications

The attractive properties of rGO based nanomaterials have paved more recently the way for the fabrication of a wide range of electrochemical based biosensors with improved analytical performance [START_REF] Bunyakul | Combining Electrochemical Sensors with Miniaturized Sample Preparation for Rapid Detection in Clinical Samples[END_REF][START_REF] Ibau | Current advances and future visions on bioelectronic immunosensing for prostate-specific antigen[END_REF][START_REF] Turcheniuk | Gold-graphene nanocomposites for sensing and biomedical applications[END_REF]. The underlying principle of an electrochemical sensor is to convert a biological binding event into a measurable electrical signal. This approach is represented by electron transfer between the rGO coated interfaces and an electroactive species, which can be either the molecule to be analyzed or a species, whose electrochemical signal correlates with the presence of the target analyte. Aspects governing electron transfer on graphene coated electrodes become of importance to obtain large output signals, allowing to reach low detection limits needed when analyzing clinical samples. Impressive electrocatalytic performance was obtained on multi-layered graphene flakes coated Si wafers in response to biomolecules such as dopamine and ascorbic acid due to the large area of edge planes that are available on such an interface to allow rapid heterogeneous electron transfer [START_REF] Shang | Catalyst-Free Efficient Growth, Orientation and Biosensing Properties of Multilayer Graphene Nanoflake Films with Sharp Edge Planes[END_REF]. The other advantages of rGO in the electroanalytical context is the high surface area of rGO supporting the integration of a high density of analyte specific ligand. Nickel [START_REF] Subramanian | Preparation of reduced graphene oxide-Ni(OH) 2 composites by electrophoretic deposition: application for non-enzymatic glucose sensing[END_REF] and copper oxide [START_REF] Maaoui | Copper oxide supported on three-dimensional ammonia-doped porous reduced graphene oxide prepared through electrophoretic deposition for non-enzymatic glucose sensing[END_REF] supported on rGO or ammonia-doped porous rGO allowed non-enzymatic glucose sensing due to the electro-catalytic properties of the nanostructures for glucose under alkaline conditions with a 0.25 µM detection limit in the case of using N-doped prGO/CuO modified electrodes (Figure 3A) [START_REF] Maaoui | Copper oxide supported on three-dimensional ammonia-doped porous reduced graphene oxide prepared through electrophoretic deposition for non-enzymatic glucose sensing[END_REF]. In a similar manner, non-enzymatic sensing of hydrogen peroxide can be achieved using Pt NPs modified rGO-chitosan-ferrocene carboxylic acid structures, [START_REF] Bai | Nonenzymatic electrochemical biosensor based on Pt NPs/RGO-CS-Fc nano-hybrids for the detection of hydrogen peroxide in living cells[END_REF] hollow TiO 2 -rGO microspheres encapsulating hemoglobin, [START_REF] Liu | Hollow TiO 2 modified reduced graphene oxide microspheres encapsulating hemoglobin for a mediator-free biosensor[END_REF] or Au@Prussian blue core-shell structures embedded onto rGO, [START_REF] Zhang | Free-standing and flexible graphene papers as disposable non-enzymatic electrochemical sensors[END_REF] with detection limits in the nanomolar range.

Real-time quantitative monitoring of biomarkers, a specific class of biological substances whose expression in serum and saliva correlates with a certain illness, has become essential for early detection of the disease, directing personalized treatments and analysis of treatment efficacy. An immunosensing platform for the electrochemical detection of oral cancer, based on anti-IL8/Au NPs-rGO coating, was recently proposed [START_REF] Verma | Anti-IL8/AuNPs-rGO/ITO as an Immunosensing Platform for Noninvasive Electrochemical Detection of Oral Cancer[END_REF]. Porous rGO electrodes modified with anti-gliadin antibodies using 1-pyrenecarboxylic acid as linker molecule to porous reduced graphene oxide (prGO) allowed for sensitive sensing of gliadin in food samples (Figure 3B) [START_REF] Chekin | Reduced Graphene Oxide Modified Electrodes for Sensitive Sensing of Gliadin in Food Samples[END_REF]. We have also demonstrated that an rGO modified electrode can analyze the level of folic acid protein in human serum with a picomolar detection limit, [START_REF] He | Detection of folic acid protein in human serum using reduced graphene oxide electrodes modified by folic-acid[END_REF] while molybdenum disulfide-rGO hybrid electrode allowed the direct detection of folic acid in human serum with a limit of detection 10 nM [START_REF] Chekin | MoS 2 /reduced graphene oxide as active hybrid material for the electrochemical detection of folic acid in human serum[END_REF]. rGO and/or porous rGO modified electrodes are also highly adapted as general platforms for the efficient on-demand delivery of a variety of drugs using electrochemical triggered approach (Figure 3C), as shown for the controlled delivery of a therapeutic protein such as insulin, [START_REF] Teodorescu | Electrochemically stimulated drug release from flexible electrodes coated electrophoretically with doxorubicin loaded reduced graphene oxide[END_REF] an anticancer drug like doxorubicin,[46] ondansetron, an antagonist to prevent nausea and vomiting caused by chemotherapy, [START_REF] Boulahneche | On demand electrochemical release of drugs from porous reduced graphene oxide modified flexible electrodes[END_REF] as well antibiotics such as ampicillin [START_REF] Boulahneche | On demand electrochemical release of drugs from porous reduced graphene oxide modified flexible electrodes[END_REF]. Porous rGO (prGO) has, in addition, found its interest for the analysis of protein aggregation in pharmaceutical formulations (Figure 3D) [START_REF] Vasilescu | Porous reduced graphene oxide modified electrodes for the analysis of protein aggregation. Part 1: Lysozyme aggregation at pH 2 and 7.4[END_REF].

Opinion for potential users of graphene in electrochemical methods

The rich electrochemistry of graphene is due to its intrinsic favorable properties to molecules of aromatic structure, where  stacking interactions can result in enhanced and better defined electrochemical signals [START_REF] Shang | Catalyst-Free Efficient Growth, Orientation and Biosensing Properties of Multilayer Graphene Nanoflake Films with Sharp Edge Planes[END_REF], and the ease by which catalytic sites in form of nanoparticles and others can be irreversible anchored onto graphene-based materials. While there has been tremendous progress in the development of graphene based materials, there is still room for further research on the determination of underlying reasons for the activity of graphene, such as the insight which established that ORR catalysis on N-doped graphene stems from the electron-deficient carbon neighboring pyridine nitrogen. In the case of electrochemical sensors, even though a large amount of graphene based sensors are reported in the literature exhibiting good sensing characteristics, the performance in real biological samples, where next to a variety of other proteins high salt concentrations are present, is often not considered and information is largely lacking. These are only one of the different challenges to overcome, in order to bring some of the current sensors into real biomedical applications. The realization of graphene-based, next-generation electrochemical guided applications, depends in addition essentially on a reproducible, large-scale production of graphene. The large scale production of monolayer graphene films by of chemical vapor deposition (CVD) in uniform and homogenous manner remains a key challenge. The limited mechanical properties and stability of CVD graphene in solution are one of the most significant obstacles for its use in graphene-based flexible devices. The mass production of high-quality GO and rGO, achieved by chemical oxidation/reduction and exfoliation of lowcost graphite, is on the other hand a promising way to connect to real-world applications and commercialized products. Much effort has thus been more lately devoted into assembling well dispersed multifunctional chemically reduced graphene oxide nanosheetes onto and into ordered macrostructures without loss of their electrochemical properties and keeping mechanical strength and conductivity. Such flexible light-weight and functional materials are of interest for classical energy driven applications (fuel cells, Li-ion batteries, supercapacitors) as well as wearable energy systems and sensors.

CONCLUSION AND OUTLOOK

The above examples are not an exhaustive list of applications where graphene based materials have resulted in innovative electrochemical applications. It is rather a collection of relevant examples from the literature from different research teams with different perspectives and should serve as triggering further interest in graphene-based electrochemistry. They were chosen as they underline important advancements where graphene was the core of the improvement. It is with no doubt, that this field is currently advancing mainly by developing and finding the miracle material. Basic electrochemical concepts remain mainly untouched, but are essential in understanding mechanistic aspects and potential limitations/advantages of different graphene nanostructures. With the rapid progress that has been made in the last two years on the synthetic aspects of graphene related materials together with advances in in situ spectroscopic methods and powerful theoretical modeling, it is certain that the next five years will be fruitful for advancing graphene-based electrochemical technological inventions. One of the limitations of graphene-based materials remains certainly the variation of the chemical composition and metal contamination, depending on the origin of the graphite precursor and oxidation process conditions. Although for certain applications, this would not affect much their performance, for catalytic and electrocatalytic applications, the nature and concentration of metal contaminant can have a huge impact on the performance and reproducibility of the electrode material.

Figure 2 :

 2 Figure 2: Selected examples for energy and electrocatalytic driven applications: (A) Electrochemical testing of an all solid-state supercapacitor device fabricated with N-doped porous rGO: (a) Plots of the energy density and power density as a function of chargedischarge current density and (b) demonstration of flexibility of the device with different bending states (reprint with permission from Ref.[31]); (B) Mechanism of anodic biofilm on enhanced bioelectrocatalysis; (C) (left) ORR using CoMn/N-doped prGO (2:1) as cathode catalyst, (right) power density of a primary Zn-air battery using this cathode catalyst [27]; (D) (left) Schematic of electrochemical water splitting, (right) O 2 and H 2 production volume as a function of water splitting time (reprint permission from Ref.[30]).

Figure 3 :

 3 Figure 3: Selected examples of the use of rGO and prGO modified electrodes for biomedical applications: (A) Non-enzymatic glucose sensing: (left) CV of N-doped prGO/CuO electrode in the absence and presence of glucose (800 µM) in 0.1 M NaOH, (middle) EDX analysis of N-doped prGO/CuO electrodes, (right) Amperometric response to 1 mM glucose and 10 mM interfering species such as ascorbic acid (AA), uric acid (UA), dopamine (DA), cysteine (Cys), fructose, galactose in 0.1 M NaOH [37]; (B) (left) Differential pulse voltammograms of anti-gliadin modified prGO electrodes in the absence and presence of gliadin using Fe(CN) 6 3-(5 mM)/PBS (0.1 M) as a redox couple, (right) SEM image of prGO based immunosensor [42]; (C) Schematic illustration of formation of drug loaded graphene based electrodes and electrochemically triggered on demand release; (D) (left) Change in oxidation current density of a lysozyme solution (700 µM) submitted to forced degradation at pH 2 and pH 7.7, (right) AFM image of a fresh lysozyme solution and an aged one [48].

Acknowledgements

This work has emanated in part from research conducted with the financial support from the Centre National de la Recherche Scientifique (CNRS), the University of Lille, the Hauts-de-France region, the CPER "Photonics for Society", the Agence Nationale de la Recherche (ANR) through FLAG-ERA JTC 2015-Graphtivity and the EU through the Marie Sklodowska-Curie action (H2020-MSCA-RISE-2015, PANG-690836).


Sabine Szunerits
email: sabine.szunerits@univ-lille1.fr

Rabah Boukherroub
email: rabah.boukherroub@univ-lille1.fr

Graphene based biosensors

Keywords:

Reliable data obtained from analysis of DNA, proteins, bacteria and other disease related molecules or organisms in biological samples has become a fundamental and crucial part of human health diagnostics and therapy. The development of non-invasive tests that are rapid, sensitive, specific and simple would allow preventing patient discomfort, delay in diagnosis, and the follow-up of the status of the disease. Bioanalysis is thus a progressive discipline for which the future holds many exciting opportunities. The use of biosensors for the early diagnosis of diseases has become widely accepted as a point-of-care diagnosis with appropriate specificity in short time. To allow a reliable diagnosis of a disease at an early state, highly sensitive biosensors are required as the corresponding biomarkers are generally expressed at very low concentrations. In the past 50 years, various biosensors have been researched and developed encompassing a wide range of applications. This contrasts to the limited number of commercially available biosensors. When it comes to sensing of biomarkers with the required picomolar (pM) sensitivity for real time sensing of biological samples only a handful of sensing systems have been proposed, being often rather complex and costly. Lately, graphene-based materials have been considered as superior over other nanomaterials for the development of sensitive biosensors. The advantages of graphene based sensor interfaces are numerous, including enhanced surface loading of the desired ligand due to the high surface-to-volume ratio, excellent conductivity and small band gap beneficial for sensitive electrical and electrochemical read outs, as well as tuneable optical properties for optical read outs such as fluorescence and plasmonics. In this paper, we review the advances made in the last years on graphene based biosensors in the field of medical diagnosis

Introduction

Biosensors are analytical devices that convert a biochemical/biological reaction into a measurable physicochemical signal, which is proportional to the analyte concentration. A typical biosensor consists thus of two elements: a surface linked biological component that interacts selectively with the analyte of interest in blood or serum and a transducer for the detection of the analyte binding event on the surface. The major advantage of using biosensors as compared to other conventional biochemical assays such as immunoassays and PCR-based strategies is the fast response time (normally several minutes) along with high specificity. The first biosensor reported dates back to the work by Leland C. Clark, considered as the father of biosensors. Based on his experience on the oxygen electrode [1], he proposed making electrochemical sensors more intelligent by entrapping enzymes such as glucose oxidase onto the oxygen electrode using dialysis membrane [2]. This glucose analyser became commercially available in 1975 in the form of an amperometric sensor. The idea of fixing antibodies rather than enzymes to the sensor transducer has emerged in the early 80's with the work by Lieberg et al. [3]. This work paved the way for the commercial success of surface plasmon resonance (SPR) biosensors (Biacore Technology, launched in 1990); these devices rely on monitoring the change in the plasmonic signal upon antibody-antigen affinity reactions in real time. Since then various biosensors have been developed encompassing a wide range of applications.

One of the many remaining challenges in biosensor development concerns the efficient and selective capture of the biological recognition event. In order to achieve the often requested picomolar (pM) detection limit for biological analyte, nanomaterials have been intensively investigated as candidates for transducer coatings. The possibility to enhance the quantity of bioreceptors immobilisation with consequently improved signal readout makes this biosensor approach greatly appealing. Among the different nanomaterials considered [4], graphene and its various forms such as graphene oxide (GO), reduced graphene oxide (rGO), graphene nanoribbons (GNR), etc have received worldwide attention for the development of biosensors. Different sensing mechanisms including optical, electrochemical, or electrical can be employed with graphene based biosensors, in the following noted as G-biosensors. In the case of electrochemical (amperometric, voltammetric, impedimetric) G-biosensors and electrical sensing concepts (graphene based field effect transistors (G-FET), the high electron transfer rates, high charge-carrier mobility and low electrical noise levels are of uttermost importance for highly sensitive detection of biomarkers and other biological analytes in serum and blood samples [5,6]. Furthermore, chemically derived graphene derivatives can exhibit a high density of edge-plane-like defect sites, providing many active sites for electron transfer to chemical and biological species [5]. Also, the high optical transparency of graphene monolayers makes them ideal materials for optical based G-biosensors and highly beneficial to improve the sensing performance of plasmonic sensors [7]. The fluorescence quenching ability of GO resulted in the development of several fluorescence resonance energy transfer (FRET) based G-biosensors [8]. Graphene has also shown to be an emerging material as surface enhanced Raman (SERS) substrate due to its ability to generate strong chemical enhancement [9]. Independent on the detection method adopted, the presence of hydrophobic domains or -systems on graphene-based transducers renders them excellent supporting layers for biomolecules' immobilization. However, the control of non-specific interactions becomes even more important when compared to other sensing surfaces, especially when analysing biological liquids [10]. Improvement in the fabrication of non-fouling graphene transducers is one of the essential steps in the development of high performance G-biosensors [10].

To obtain a general overview on the results achieved in this field, some of the key works around the development of point-of-care sensing in biological fluids using G-biosensors will be highlighted here. As the examples of G-biosensors are countless, the focus will be on the direct detection of small molecules such as glucose and dopamine, DNA, and protein biomarkers (e.g. folic acid protein, lysozyme, prostate specific antigen) using immunosensing and pathogen detection. It is hoped that this brief overview of G-biosensors and its interest for the biomedical field will stimulate further research activities together with commercialization of some of proposed concepts to help advancing personalized care.

Preparation of graphene based biosensors

A number of different approaches for the synthesis of graphene and its derivatives such as graphene oxide (GO), reduced graphene oxide (rGO), porous reduced graphene oxide (prGO), and graphene nanoribbons (GNRs) are available in the literature (Figure 1). Large area single and few layer high-quality graphene nanosheets can be produced by chemical vapour deposition (CVD) methods on nickel or copper and are commercially accessible. Such graphene sheets are nowadays routinely transferred to any transducer interface using mainly PDMS-supported transfer processes [11]. The high quality of CVD graphene and the possibility to obtain mono-and bilayer modified electrical interfaces makes such electrodes advantageous for G-FETs and plasmonic biosensing. The use of chemically derived GO and rGO nanosheets, obtained from graphite precursor through solution-based exfoliation aiming at weakening the van der Waals forces between the graphene layers, is the most commonly used synthetic approach for the construction of G-biosensors. It is a relatively cheap method for obtaining GO/rGO on a large-scale, with the additional benefit of possible modulation of the morphology and porosity of the nanosheets. Furthermore, doping with non-metallic elements such as nitrogen, sulphur, or boron allows to modulate the electronic structure of these materials and leads in general to improved electrical and electro-catalytic properties. Reduction of the GO flake size results in better dispersible structures of 3-20 nm in size consisting of no more than 5 layers; these structures exhibit a high surface area and termed graphene quantum dots (GQDs) [12].

Different techniques such as drop-casting, spin-coating, electrostatic interaction between positively charged interfaces and the negatively charged GO/rGO nanosheets, electrophoretic deposition (EPD) and electrochemical reduction of GO can be employed to coat electrical as well as inert surfaces with the chemically derived graphene materials. The method of choice depends on the thought after application and the employed transducer element. Table 1 gives a short list of selected biomedical analytes of interest together with the method employed for their detection and the limit of detection which can be reached, most of them being discussed in more details in this review.

C. ELECTRODE PREPARATION Graphene Transfer, Drop-casting, Electrostatic interaction, Electrophoretic deposition (EDP), Electrochemical reduction (ER), etc,

Porous rGO 1 µm

GC-prGO (drop-casting)

Au-rGO (EPD)

1 µm 1 µm

Au/PDDA/GO (electrostatic)

Au-graphene (transfer)

1 µm 1 µm

GC-prGO (ER)

D. Some selected SEM images of graphene-coated interfaces B. STRUCTURE OF GRAPHENE-BASED MATERIALS

E. coli

Graphene-anti-E. coli FET 10 cfu mL -1 [23] EC: electrochemistry; GO: graphene oxide; GQDs: graphene quantum dots; GO x : glucose oxidase; Au NPs: gold nanoparticles; DPV: differential pulse voltammetry; PDDA: poly(diallyldimethylamonium); PSA : prostate specific antigen.

G-biosensors for glucose and dopamine

One challenging and important molecule to monitor is glucose. Increase in glucose levels is critical for human health as hyperglycemia, defining diabetes, leads to premature death caused by macrovascular and microvascular complications. A close monitoring of the blood glucose concentration can largely help to manage diabetes. Tremendous efforts have been put into the development of efficient and reliable methods for glucose sensing. Graphene based glucose sensors are generally built by immobilizing glucose oxidase (GO x ) onto the graphene surface such as the graphene-FET proposed by Huang at al. (Figure 2A) [24]. In this work, GO x was covalently lined via its amine groups to 1-pyrenebutanoic acid succinimidyl ester, where the pyrene end is firmly attached to graphene through - stacking interactions. Measuring a change in conductance allowed glucose detection down to 0.1 mM. Although the use of GO x allows for high selective detection towards glucose, non-enzymatic glucose sensors based on the integration of electro-catalytic sites for glucose, often in the form of nanoparticles, onto graphene have been pursued [13,25,26]. While these sensors are less selective to glucose and need to be for the most part operated in an alkaline medium, they display several advantages such as better stability than GO x -based interfaces and often improved sensitivity with detection limits in the low µM to nM range. In the case of N-doped porous reduced graphene oxide loaded with Cu NPs (N-prGO-Cu NPs) the improved sensitivity to glucose is attributed to the electro-catalytic behaviour of the CuO/CuOOH couple (Figure 2B). In the presence of glucose, the redox peak of Cu(0)/Cu(I) stays unchanged, while the peak of the Cu(I)/Cu(II) transition is decreased reflecting the formation of Cu(I)-glucose complex. The band at +0.4V is strongly increased, in line with the activity of Cu(III) in basic medium (Figure 2B) [27].

A different non-enzymatic glucose sensing approach based on the use of graphene quantum dots (GQDs) modified with boronic acid substituted bipyridine ligands, which serve as fluorescence quencher upon electrostatic interaction with GQDs was proposed [14] (Figure 2C). When glucose is added to the system, the boronic acid moieties are converted to tetrahedral anion glucoboronate esters, which neutralize the net charge of the bipyridinium, thus greatly diminishing the quenching effect and recovering the fluoresence intensity of the GQDs (Figure 2C). Another small biomolecule of interest is dopamine. It is one of the crucial catecholamine neurotransmitter widely found in serum samples at concentrations between 10 nM and 1 µM. Abnormal levels can result in a variety of diseases (Huntington's disease, Parkinson's disease, Schizophrenia) with high levels increasing the risk of high blood pressure related diseases. Rapid and accurate detection of dopamine at low cost has thus become of demand in clinical diagnostics. The electrochemical activity of dopamine makes its electrochemical detection rather appealing. However, uric acid (UA), ascorbic acid (AA) and serotine (ST) are coexisting with dopamine in the extracellular fluids of the central nervous system in mammals at even higher concentrations and can be oxidized at a potential close to that of dopamine. The excellent electrochemical properties of graphene for dopamine together with chemical enhancement via - stacking interactions have enabled the development of dopamine specific G-sensors even in the presence of high concentrations of AA, UA and ST [28,29] (Figure 2D). Extremely low LOD could be achieved using electrochemically reduced GO in combination with polyvinylpyrrolidone capable of detecting 0.2 nM dopamine in the presence of 1 mM AA [15].

DNA sensing with G-biosensors

The need for a rapid and sensitive DNA analysis is an important issue in clinical diagnosis.

Major studies have focused on the sequence-specific recognition of ssDNA and on the detection of single nucleotide polymorphisms (SNP). SNP is a common form of genomic variation occurring in every 100-300 base pairs and related to many major diseases and disorders, such as Parkinson's disease, Alzheimer's disease, diabetes and various cancers. The development of analytical approaches for selective DNA sensing has consequently been strongly pursued with the believe that low-cost systems suitable for DNA analysis could revolutionise modern health care. Electrodes modified with graphene oxide nanowalls (GON) with preferred vertical orientation [17] or graphene nanoplatelets [30] are capable to catalytically oxidize the four DNA bases simultaneously, resulting in DNA sensors with a LOD as low as 9.4 zM [17] (Figure 3A). The fluorescence quenching ability of GO was exploited by several research groups for the detection hybridization events. When a dye-labelled ssDNA is immobilized via non-covalent binding onto GO, the fluorescence is quenched; this non-covalent interaction is reversible. ssDNA interaction with GO occurs thus via  stacking, hydrophobic interactions and hydrogen bonding. Even though both, GO and ssDNA, are negatively charged, DNA can be adsorbed on GO in buffers containing a high concentration of salts to screen electrostatic repulsion [31]. In dsDNA the nucleotide bases are hidden in the helical structures, preventing their effective interaction with the GO surface in contrast to ssDNA. In the presence of a complementary DNA (cDNA) target, a duplex is formed, disturbing the GO-ssDNA interaction and resulting in a release of the formed dsDNA upon which fluorescence is restored (Figure 3B). This approach has been recently used in combination with ssDNA modified GQDs for fluorescence resonance energy transfer (FRET) based DNA sensing [16] (Figure 3B.). This concept was further applied to surface plasmon resonance (SPR) based DNA sensing [11] (Figure 3C). Gold nanostars modified with ssDNA were integrated into commercially available graphene coated SPR chips. As dsDNA has a lower affinity to graphene, hybridized targets are released from the graphene surface, resulting in a negative shift of the SPR signal which allows an easy discrimination between mismatched DNA and offers a label-free approach for DNA detection with a LOD of 500 aM over a linear dynamic range up to 10 nM [11].

The feasibility of G-FET based sensors for nucleic-acid based analytes has been shown by Zheng et al. [18]. Peptide nucleic acid (PNA) was non-covalently immobilized to the graphene channel and hybridization with target DNA produced a left-shift in the Dirac point with a LOD of 10 fM [18]. Dontschuk et al has shown in addition the interest of G-FETs for DNA sequencing [32]. They demonstrated experimentally that GFETs are able to measure distinct coverage-dependent conductance signatures upon adsorption of the four different DNA nucleobases, a result that was attributed to the formation of an interface dipole field.

G-based sensors for protein biomarkers

Protein biomarkers are specific molecules existing in blood or tissues, whose measurement or identification is very critical and efficient in the prediction, diagnosis, and monitoring of cancer and many other diseases. Clinical utility of biomarkers to diagnose disease requires the capability to measure femto-to picoMolar concentrations of these, which is also important to understand cellular processes and to search for new protein biomarkers. The detection limits of the prevailing analytical protocols (e.g. ELISA-enzyme linked immunosorbent assay) for biomarker detection lags far behind the requirements for clinical utility and research. Graphene-based immunoassay platforms, where specific antibodies are immobilized onto graphene to capture selectively the biomarker analyte, have shown on the other hand excellent sensitivity [33] (Figure 4). For example, we have recently demonstrated that postfunctionalization of rGO modified electrodes by simple immersion into a solution of folic acid allowed for the development of an electrochemical based sensor for folic acid protein with a 4A) and a plasmonic sensor with 5 fM detection limit [20]. Levels of folic acid protein in serum can increase up to 22 pM in metastic diseases. Given that human serum is free of folic acid proteins, detection of this protein in serum serves as an early stage cancer diagnostic step. A rGO based FET modified with prostate specific antigen-α1-antichymotrypsin (PSA-ACT) was used by Kim et al. to detect fM levels of PSA with a dynamic range over 6-orders of magnitude [22] (Figure 4B). Surface plasmon resonance (SPR) based read out was used by Cosnier and co-workers for the detection of cholera toxin on graphene coated gold chips modified with pyrene-nitrilotriacetic acid (NTA) with a detection limit of 5 pg mL -1 [34]. We showed recently the suitability of Micrococcus lysodeikticus modified GO-coated SPR interfaces to sense serum lysozyme levels with a limit of detection of 3.4 nM [19] (Figure 4C). Lysozyme, an enzyme found in biological fluids is upregulated in leukaemia, renal diseases as well as a number of inflammatory diseases. While lysozyme concentration in serum of healthy people ranges from 27 to 301 nM, patients suffering from Inflammatory Bowel Disease show microMolar levels of lysozyme. Recently, a multifunctional nanoplatform based on magnetic-plasmonic nanoparticles attached to GO allowed for the sensitive detection of Alzheimer disease biomarkers (-amyloid , tau proteins) down to 100 fg mL -1 [21] (Figure 2D). These examples highlight the efficient use of G-biosensor for protein analysis.

One main hurdle of all these sensors when performing tests in human serum samples, often not evoked in the literature, is linked to the high non-specific interaction between the graphene surface and serum proteins. We have compared a number of different strategies to reduce nonspecific binding of clinical serum samples spiked with lysozyme (100 µM) on rGO [20] (Figure 4E). While simple immersion into serum decreased strongly the anti-fouling properties of graphene, rGO modification with pyrene-PEG units have shown to result in the best non-fouling interface [20,35].

Bacteria and Viruses

The specific and sensitive detection of pathogenic microorganisms remains a big scientific challenge and a practical problem of enormous significance. Pathogen diagnosis is currently based on culturing the microorganism on agar plates with the disadvantage of being long (minimum of 24 h) and ignoring viable but non-cultural cells. G-FET biosensors have been successfully applied for the detection of bacteria and their metabolic activities. CVD graphene modified with anti-E. coli antibodies allowed E. coli concentrations as low as 10 cfu mL -1 to be detected [23]. Graphene oxide in combination with E. coli O157:H7 antibody-conjugated quantum dots was used as pathogen-revealing agent by exploiting the universal high efficient long-range quenching properties of GO; a LOD of 3.810 3 cfu mL -1 was achieved [36]. Graphene printed onto water-soluble silk and modified with antimicrobial peptides allowed bioselective detection of bacteria at single-cell levels remotely [37].

Conclusion and perspectives

We tried to review the most recent advances on graphene based biosensors by selectively highlighting a variety of different examples for the detection of some molecules of biomedical interest. Routinely, such sensors achieve a picomolar detection limit, with some even reaching the low femtomolar concentration range. The possibility that a large range of different detection methods can be employed with graphene based sensors is of high advantage, as depending on the looked after final application, sensor size and read out can be customised at will. There is however still an urgent need for moving beyond research by developing new concepts for achieving even better sensitivity and selectivity, in order to bring some of the current sensors into real biomedical applications. Even though a large amount of sensors reported in the literature exhibit good storage stability and repeatability, important for complex sensors involving nanomaterials and manual step preparations, the performance in real biological samples is often not reported. As non-specific interactions are of primary concern on graphene based interfaces, this lack of information together with the large-scale reproducibility of the fabrication of graphene biosensor interfaces are probably two of the most crucial limiting factors for current commercialization. When it comes to in vivo application of some of the sensing concepts, graphene based biosensors are still in their infancy. Toxicity and biocompatibility issues still need to be addressed carefully to avoid any undesired secondary health effects. Current in vivo and in vitro assessments of the biostability of the sensors are encouraging and promising for further technological transfer.

Different challenges are still to overcome. The collaboration between material scientists, chemists, physicists as well as engineers and medical personal is of fundamental importance to drive this field further and to propose graphene based biosensors as point-of-care alternatives for patients. The success of any new biosensor material lies in addition on its reproducibility and possible industrial scale production. The emergence of a number of companies providing mono-and bilayered graphene nanosheets on several interfaces, graphene oxide (GO), reduced graphene oxide (rGO) and even modified matrixes has been an additional motivation for using graphene for biosensor applications.

Figure 1 :

 1 Figure 1: Construction of graphene-based biosensor interfaces: (A) Current preparation methods, (B) Chemical structures of different graphene derivatives widely used for biosensing; (C) Methods for the transfer of graphene-based materials to solid substrates; (B) SEM images of graphene coated interfaces using different deposition methods and different graphene precursors

Figure 2 :

 2 Figure2: G-based sensors of small molecules such as glucose and dopamine: (A) CVD graphene modified with glucose oxidase (GO x ) using a bifunctional pyrene linker for the construction of a G-FET for glucose (reprint with permission from Ref.[23]); (B) Nonenzymatic glucose sensor operating under basic conditions based on N-doped porous reduced graphene oxide loaded with Cu NPs (N-prGO-Cu NPs) (reprint with permission from Ref.[27]); (C) Graphene quantum dots (GQDs) modified with boronic acid substituted bipyridine ligands for non-enzymatic glucose sensing under physiological conditions (reprint with permission from Ref.[14]); (D) Differential pulse voltammetry of ascorbic acid (1 mM), serotine (1 mM) and dopamine (1 mM) and a mixture of all three (0.1 M) on glassy carbon electrodes modified with hydrazine reduced GO (reprint with permission from Ref.[28]).

2 Non

 2 ) O +OH - Cu(III)OOH+ e - Cu(III) + glucosse Cu (II) + + D-glucono-1,5-lactone +H 2 O

Figure 3 :

 3 Figure 3: DNA sensing with G-biosensors: (A) Single DNA electrochemical biosensing using graphene nanowalls (GNW): SEM image of GNWs formed by electrophoretic deposition onto graphite rod, differential pulse voltammograms of dsDNA (0.1 µM) in PBS (0.1 M, pH 7) on different interfaces (reprint with permission from Ref.[17]); (B) Mechanism of DNA interaction with GO (reprint with permission from Ref.[31]) and FRET based DNA sensing using graphene quantum dots and graphene oxide (reprint with permission from Ref[16]); (C) Graphene-SPR based DNA sensing: TEM image of a gold nanostructure together with change in SPR signal upon incubation with cDNA and mismatched DNA[11].

Figure 4 :

 4 Figure 4: G-biosensors for protein sensing using: (A) Electrochemical sensor for folic acid protein: DPV upon addition of increasing concentrations of folic acid proteins (reprint with permission from Ref. [10]); (B) G-FET for the analysis of prostate biomarkers (reprint with permission from Ref. [22]); (C) Graphene-SPR based sensing for lysozyme: AFM image of Au-(PDDA/GO) 2 interface modified with Micrococcus lysodeiktikus and change in SPR responses to different concentrations of lysozyme added to fetal bovine serum (reprint with permission from Ref. [19]); (D) Concentration dependent SERS spectra from tau protein conjugated nanoplatform after magnetic separation together with SEM image of core-shell nanoparticle attached hybrid GO and HR-TEM picture (reprint with permission from Ref.[21]).

Folic

Table 1 :

 1 Selected examples of most performing graphene based biosensors for different analytes.

	Analyte	Sensor design	detection	LOD	Ref
	glucose	3D graphene foam-Co 3 O 4 nanowires	EC	20 nM	[13]
	glucose	Graphene+GO x	FET	0.1 mM	[6]
	glucose	GQDs-bipyridine boronic acid	fluorescence 1 mM	[14]
	dopamine	rGO-polyvinylpyrrolidone	EC	0.2 nM	[15]
	DNA	GO and GQD-ssDNA	FRET	75 pM	[16]
	DNA	Graphene-Au NPs-ssDNA	SPR	500 aM	[11]
	DNA	GO nanowalls	DPV	9.6zM	[17]
	DNA	graphene	FET	10 fM	[18]
	lysozyme	Au/PDDA-GO-Micrococcus lysodeikticus	SPR	3.4 nM	[19]
	Folic acid	Au-rGO	DPV	1 pM	[10]
	Folic acid	graphene	SPR	5 fM	[20]
	β-amyloid	Magnetic/plasmonic GO	SERS	100 fg mL -1 [21]
	PSA	rGO	FET	1 fM	[22]

A.

PRODUCTION METHODS Mechanical Exfoliation, Liquid-based Exfoliation, CVD growth Graphene Graphene Oxide (GO) Reduced graphene oxide (rGO)

Acknowledgements

Financial supports from the Centre National de la Recherche Scientifique (CNRS), the University Lille 1, the Hauts-de-France region, the CPER "Photonics for Society", the Agence National de la Recherche (ANR) through FLAG-ERA JTC 2015-Graphtivity, and the EU union through the Marie Sklodowska-Curie action (H2020-MSCA-RISE-2015, PANG-690836) and Graphitivity are acknowledged.