Philippe Corcia
email: corcia@med.univ-tours.fr

Stéphane Beltran

Salah Eddine Bakkouche

Philippe Couratier

Therapeutic news in ALS

Keywords:

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

1 Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression.

There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death.

We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.

Introduction:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of both upper (UMN) and lower (LMN) motor neurons in motor cortex, brainstem and spinal cord. This causes weakness and wasting of muscles in all four limbs and the bulbar territory. Death classically occurs once respiratory muscles become involved [START_REF] Brown | Amyotrophic Lateral Sclerosis[END_REF].

ALS is no longer considered as a pure motor neuron disorder since 15-50% of patients develop cognitive disturbances, ranging from cognitive impairment to typical fronto-temporal lobar dementia (FTLD) related to injury of the frontal and temporal cortices [START_REF] Burrell | The frontotemporal dementia-motor neuron disease continuum[END_REF]. Disease incidence is around 2.5/100.000 and the lifetime risk is estimated around 1/300 for men and 1.400 for women [START_REF] Brown | Amyotrophic Lateral Sclerosis[END_REF]. The prognosis of ALS is fatal in all cases with a median duration of survival from first symptoms to death of 36 months (3).

Around 5-10% of ALS cases are considered familial (FALS) with a familial history of motor neuron diseases or FLTD affecting first or second-degree relatives (4). Since 1993 and the identification of pathogenic mutations in the SOD1 gene, more than 30 genes have been linked to ALS [START_REF] Rosen | Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis[END_REF][START_REF] Renton | State of play in amyotrophic lateral sclerosis genetics[END_REF]: among them, four (C9orf72, SOD1, TARDBP, FUS) explain around 60% of FALS cases [START_REF] Renton | State of play in amyotrophic lateral sclerosis genetics[END_REF]. The remaining cases are considered sporadic.

Although there are no phenotypic differences between sporadic and familial ALS, some features appear rather linked to familial cases: FALS populations may be distinguished from sporadic cases by younger age of onset (50 vs 63 years), predominance of lower limbs onset, and disease duration which exhibits a bimodal survival curve with the majority of cases lasting less than two years or more than five years [START_REF] Camu | Genetics of familial ALS and consequences for diagnosis. French ALS Research Group[END_REF].

To date, there are no reliable diagnostic and prognostic biomarkers for ALS. Diagnosis relies on exclusion of all ALS-mimicking diseases [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]. Diagnostic certainty remains, to date, neuropathological, depending on the presence of inclusion bodies in the cytoplasm in spinal cord and brainstem LMN [START_REF] Ince | Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology[END_REF]. These inclusions are labeled by ubiquitin. TDP-43 has been identified as the principal component of these ubiquitinated inclusions which is found in 97% of all ALS cases; SOD1 and FUS are found in 2% and 1% of the inclusions respectively [START_REF] Scotter | TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets[END_REF].

Only two drugs are currently labeled for ALS: riluzole and edaravone which is available in only a few countries worldwide (USA, Canada, Japan, and Switzerland in Europe) [START_REF] Bensimon | ALS/Riluzole Study Group. A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis. ALS/Riluzole Study Group[END_REF][START_REF] Group | Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well-defined patients with amyotrophic lateral sclerosis: a randomised, doubleblind, placebo-controlled trial[END_REF]. Riluzole principally acts as an anti-glutamatergic drug while edaravone acts as an antioxidant. Since the therapeutic effect of these drugs remains modest with only an extension of survival of a few months, there is an urgent need for new treatments that would have greater impact on the natural history of the disease. Although numerous molecules have been tested in ALS over the last 30 years, none have shown a positive effect in this disease [START_REF] Mitsumoto | Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?[END_REF]. Among all the hypotheses put forward, important aspects to be stressed include disease heterogeneity concerning age of onset (from 17 to 95 years), site of onset, prominence of UMN or LMN involvement, and disease duration extending from less than one year (in the case of ALS linked to A5V SOD1 mutation) to decades (in the case of ALS linked to D91A SOD1 mutation) [START_REF] Renton | State of play in amyotrophic lateral sclerosis genetics[END_REF]. Disease heterogeneity is also the result of a complex pathophysiology in which glutamate excitotoxicity, neuroinflammation, mitochondrial dysfunction, protein misfolding and aggregation, defect in axonal transport, disturbances of the DNA/RNA machinery, and oxidative stress interact with each other in motoneuron death processes [START_REF] Van Es | Amyotrophic lateral sclerosis[END_REF]. It is currently obvious that ALS is not determined by a unique cause but, conversely, occurs is the consequence of a combination of complex cellular, molecular and genetic interactions which trigger and sustain motoneuron death [START_REF] Brown | Amyotrophic Lateral Sclerosis[END_REF][START_REF] Van Es | Amyotrophic lateral sclerosis[END_REF].

Evolving clinical and research approaches to ALS therapeutics have led to numerous clinical trials which allowed emergence of new therapeutic options. Over the last years, numerous trials have been run in ALS testing either old drugs in a new indication or compounds directed at new pathological pathways responsible for motoneuron death (Fig. 1).

Here we present an overview of clinical trials, emphasizing the main therapeutic approaches currently developed in ALS.

NEW INDICATION FOR OLD DRUGS

Certain drugs prescribed for decades in non-neurological indications can also present potential therapeutic effects on neuronal function and survival. These unknown properties might have meaningful effects in neurological disorders.

TUDCA-ALS

Tauro-ursodeoxycholic acid (TUDCA), indicated in chronic cholestatic liver and gallstone diseases is well-known to gastroenterologists. TUDCA is orally available and passes through the blood-brain barrier.

It has been shown that TUDCA is neuroprotective in motor neuron-neuroblastoma hybrid cells expressing mutant SOD1 (mutations A4V and G93A) against NO toxicity [START_REF] Hofmann | The continuing importance of bile acids in liver and intestinal disease[END_REF].

Moreover, the interest for TUDCA in ALS came forward due to its potent inhibition of apoptosis via interference with the mitochondrial pathway of cell death, resulting in an inhibition of oxygen-radical production, and reducing endoplasmic reticulum stress and caspase activation [START_REF] Amaral | Bile acids: regulation of apoptosis by ursodeoxycholic acid[END_REF]. Two phase II studies showed promising results in ALS which justified initiating a phase III trial. The first showed that UDCA is well tolerated, measured at a meaningful serum level after oral intake of an appropriate dose, and detected in cerebrospinal fluid [START_REF] Parry | Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic acid in patients with amyotrophic lateral sclerosis[END_REF]. The second study was a proof-of-concept phase II trial which showed that the slope of progression of the ALSFRS-r scale was 7 points/year smaller in the group treated by riluzole+TUDCA vs riluzole [START_REF] Elia | Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis[END_REF]. Following these promising results, a European double-blinded placebo-controlled phase III study was designed to carry on these studies (NCT03878654). This trial is in progress and aims to determine whether TUDCA at the dose of 2g daily will slow disease progression. 440 patients are expected to be enrolled.

TAMOXIFEN

Tamoxifen has been approved for the treatment of breast cancer for a long time. Its mode of action involves a selective modulation of estrogen receptors. In addition to this anti-neoplastic effect, tamoxifen also shows neuroprotective properties by modulating inflammatorymediated damage and promoting autophagy [START_REF] Chen | Tamoxifen for amyotrophic lateral sclerosis: a randomized double-blind clinical trial[END_REF]. A randomized, double-blind, placebocontrolled phase II study was conducted in 18 ALS patients followed for 12 months. The primary endpoint was disease duration. The results have just been published: in the tamoxifen group (40 mg/d), disease progression was slightly decreased but not significantly [START_REF] Chen | Tamoxifen for amyotrophic lateral sclerosis: a randomized double-blind clinical trial[END_REF].

LEVOSIMENDAN

Levosimendan was first developed in cardiology for the treatment of heart failure. The mechanism of action of this drug relies on a selective binding to troponin C and subsequent sensitization of fast and slow skeletal muscles [START_REF] Haikala | Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension[END_REF]. Levosimendan improves submaximal contraction of diaphragm fibers (both slow and fast muscle fibers) by around 20% in patients with chronic obstructive pulmonary disease [START_REF] Van Hees | Levosimendan improves human diaphragm function[END_REF]. In addition, levosimendan prescribed intravenously, was shown to improve the neuromechanical efficiency and contractility of human diaphragm function in healthy subjects [START_REF] Doorduin | The calcium sensitizer levosimendan improves human diaphragm function[END_REF]. Owing to these compelling findings on diaphragm muscle function, a randomized, double-blind, placebo-controlled, crossover, threeperiod study with six months open-label follow-up was conducted in ALS. The primary endpoint was the slow vital capacity (SVC) percentage measured in the sitting position. This study did not show a positive effect of levosimendan on SCV. Since the drug was well tolerated, and considering the conclusions of the post-hoc analysis in favor of a possible dosedependent therapeutic effect on supine SCV, a phase III study has been conducted to assess the efficacy of levosimendan at the dose of 1-2 mg daily after 48 weeks of treatment on SCV (NCT03948178) [START_REF] Al-Chalabi | Levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, doubleblind, placebo-controlled trial[END_REF]. The open-labeled phase of the study is expected to be completed in the next weeks and the results should be published soon.

MASITINIB

Masitinib is an oral tyrosine kinase inhibitor available for the treatment of mastocytosis. This compound has exhibited promising results in animal (rat) models of ALS (SOD1-G93A). The interest in ALS came from its neuroprotective effect on neurons thanks to immunomodulatory properties which target in particular activated microglia and mast cell activity, in both central and peripheral nervous systems [START_REF] Dubreuil | Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT[END_REF][START_REF] Davis | Comprehensive analysis of kinase inhibitor selectivity[END_REF]. Among all the publications focused on this compound in ALS, the results of the double-blind study, placebo-controlled randomized phase II/III study which enrolled 394 patients receiving either riluzole (100mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d fostered the proposal of a larger study. The primary endpoint was the slope of decline of the ALSFRS-R scale during the 48 weeks of the study [START_REF] Mora | Masitinib as an addon therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial[END_REF]. First, this study showed that masitinib was well tolerated and safe at both dosages. Second, there was a positive effect of masitinib in ALS highlighted by a gain of 3.4 points (9.2 vs. 12.6, p=0.016) on the slope of the ALSFRS-r score after 48 weeks: this corresponds to a 27% slowing in the rate of functional decline. Of note, the positive effect was more meaningful in the fast progressor group (slope of progression ≥1.1 /month) at the dose of 4.5 mg/kg/d. A multicentric, randomized, double-blind, placebocontrolled, parallel groups, phase III study is expected to start soon in Europe and North America simultaneously: almost 500 ALS patients are planned to be enrolled in this study which should last 24 months.

DEFERIPRONE

This trial stems from literature in favor of a role for iron in neurodegenerative diseases and mainly in ALS [START_REF] Veyrat-Durebex | Iron metabolism disturbance in a French cohort of ALS patients[END_REF]. Iron is a cofactor of several enzymes involved in motoneuron machinery such as mitochondria aerobic metabolism. Moreover, serum iron, ferritin and transferrin were shown to be increased in ALS patients compared to controls [START_REF] Veyrat-Durebex | Iron metabolism disturbance in a French cohort of ALS patients[END_REF]. Of note, postmortem studies which showed iron accumulation in the central motor tract in ALS patients made the hypothesis of the role of iron in ALS strong enough to allow a clinical trial focused on iron metabolism [START_REF] Adachi | usefulness of SWI for the detection of iron in the motor cortex in amyotrophic lateral sclerosis[END_REF]. Finally, the neuroprotective effect and the longer survival in ALS mouse models treated by iron chelators strongly supported initiation of a clinical trial in human ALS [START_REF] Wang | Prevention of motor neuron degeneration by novel iron chelators in SOD1 G93A transgenic mice of amyotrophic lateral sclerosis[END_REF].

FAIRALS is a randomized, double-blind, placebo-controlled study which aims to assess the efficacy of an iron chelator, deferiprone, in ALS. This study conducted by the French ALS Centre of Lille is currently ongoing. 240 participants are expected to be included, half of whom will receive 600 mg/d of deferiprone taken over 12 months (NCT03293069).

FASUDIL

Rho kinase (ROCK) recently became a matter of interest in ALS. This serine/threonine kinase has two isoforms whose isoform ROCK2 is highly expressed in the central nervous system, more importantly with age [START_REF] Komagome | Postnatal changes in Rho and Rho-related proteins in the mouse brain[END_REF]. ROCK plays a key role in triggering the signal of axonal degeneration once it is activated by the binding of axonal growth inhibitory molecules to their specific receptors [START_REF] Komagome | Postnatal changes in Rho and Rho-related proteins in the mouse brain[END_REF]. ROCK inhibitors have already been assessed in neurodegenerative diseases and demonstrated both a neuroprotective and pro-regenerative effect in Parkinson's disease (PD) models [START_REF] Lingor | ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis[END_REF].

ROCK inhibitors significantly improved survival and motor function in the SOD1(G93A) mouse model of ALS when initiated at a presymptomatic stage [START_REF] Tönges | Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis[END_REF].

Fasudil is a small ROCK-inhibitor molecule first developed for the treatment of vasospasm following subarachnoid hemorrhage (SAH). In the central nervous system, the effects of Fasudil were assessed in a phase III trial in patients with acute ischemic stroke, which showed a significant improvement of clinical outcome [START_REF] Shibuya | Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial[END_REF].

Although the underlying mechanisms remain to be understood, Fasudil currently emerges as a promising drug prompting proposal of a clinical trial in ALS. A phase IIa, multiple-center, randomized, double-blind, controlled, prospective, dose-finding, exploratory, interventional study is expected to start soon in ALS. Fasudil will be administrated intravenously twice daily for 20 treatment days. There will be three arms: 30 mg/d, 60 mg/d and a placebo group. The primary objective of this study will be the assessment of tolerability and safety.

Non-chemotherapeutic trials

Would it be possible to improve the survival of ALS patients with suitable nutrition?

Over the last 20 years, there were numerous lines of evidence stressing that malnutrition is a major pejorative factor in ALS. Following the publication of the French team of Limoges which highlighted 20 years ago that malnutrition increased by seven the risk of death in a period of seven months [START_REF] Desport | Nutritional Status Is a Prognostic Factor for Survival in ALS Patients[END_REF], a huge body of literature confirmed that malnutrition and low body mass index are both correlated with shorter survival in ALS [START_REF] Desport | Nutritional Status Is a Prognostic Factor for Survival in ALS Patients[END_REF]. On the other hand, a high-fat high calorie intake diet (HFCD) was shown to improve the evolution of ALS in mouse models [START_REF] Wills | Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial[END_REF]. Two European trials have been focused on diet in ALS: the French study named NUTRALS (NCT02152449) is still ongoing and deals with the effect of oral nutritional supplementation in the functional status of ALS patients.

The second trial, LIPCAL-ALS (NCT02306590), was conducted in Germany and the results have been published recently [START_REF] Ludolph | Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis[END_REF]. This trial evaluated the efficacy of HFCD (addition of 45g of fat intake and 405 Kcal daily) on disease duration. Two hundred and one patients were enrolled and followed for 18 months. There was no evidence of a positive effect of HFCD in this population but post-hoc analysis would suggest a prolonged survival in fast-progressor patients after 18 months: the survival probability was 0.62 in the HFCD group vs 0.38 in the control group: this meant a significant hazard ratio of 0.5 (Cox proportional hazard regression model, p=0.02).

BIOTECHNOLOGY HUMANIZED MONOCLONAL ANTIBODIES

Prescription of monoclonal antibodies is obvious in dysimmune disorders, which seems, at first sight, unsuitable in neurodegenerative diseases and, in fine in ALS.

Interest for monoclonal antibodies, like ravulizumab, in ALS came from the huge body of literature on neuroinflammation in ALS. This opened new ways for therapeutic research targeting the microglia and the complement cascade.

There is a growing literature showing that the innate immune complement system drives neuroinflammation in ALS. Besides microglia activation, neuroinflammation is also involved in ALS because of the role of the complement system both in the onset and the progression of motor neuron death in ALS: this has been also matter of important reports which highlighted an impairment of the control processes regulating complement cascade activation in the central nervous system: this led to focus on promising therapeutic targets in ALS via an action on the immune system. One key target of the complement cascade in ALS is C5. This relies on an accumulation of evidence over the last 20 years of a key role for this component in the pathophysiology of ALS: both the deletion of C5aR1 (a specific C5 signaling receptor) and the injection of a C5aR1 antagonist improved survival in a SOD1 mouse model of ALS, strongly supporting a key role for this protein in motoneuron death in ALS [START_REF] Parker | Revisiting the role of the innate immune complement system in ALS[END_REF]. Furthermore, functional and survival benefits of C5 signaling blockade have been demonstrated in animal models of ALS. These findings strongly support the inhibition of C5 of the complement complex to be a promising avenue for the treatment of ALS.

Ravulizumab is a recombinant, humanized monoclonal antibody with high specificity against human C5 component. It acts by blocking the complement activation and is currently approved in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

In ALS, a phase III, randomized, double-blind, placebo-controlled, multiple-center study to evaluate the safety and efficacy of ravulizumab should start recruitment soon in France. An open labeled extension will complete the 50 weeks of the randomized controlled trial. The primary objective of this study is to evaluate the effect of ravulizumab compared with placebo on ALS functional rating scale-revised (ALSFRS-R) score (NCT04248465).

SPECIFIC ANTIBODIES

Protein aggregation is an aberrant process due to misfolding which promotes self-association of a protein. This self-association leads to oligomerization and then to fibrils by polymerization. Due to misfolding, the hydrophobic sites of the protein are accessible to the hydrophobic cellular environment.

Misfolded protein is one of the hallmarks of neuropathological findings in ALS with the presence of TDP-43, C9orf72 dipeptide repeats, phosphorylated neurofilaments, FUS and SOD1 inclusions in motoneurons [START_REF] Parakh | Protein Folding Alterations in Amyotrophic Lateral Sclerosis[END_REF]. These pathological deposits probably exert a toxic effect on neurons. Over the last years, therapeutic strategies have focused on blockade of this abnormal process. Several trials target the misfolding process by specific antibodies to misfolded SOD1 protein (α-miSOD1), fragment of antibodies directed to a specific region of TDP-43, to vaccines against unfolded SOD1 and small molecules which enhance the expression of heat shock proteins and, consequently, promote autophagy, such as colchicine and arimoclomol (review in 38).

ANTISENS-OLIGONUCLEOTIDES

Gene therapies have made remarkable progress over the last decade, leading to changes in the course of numerous diseases which were incurable until now. These therapeutic approaches perfectly fit with what clinicians were searching for: a targeted treatment based, in this situation, on the genetic status.

The rationale of this approach relies on the fact that lowering the burden of mutated SOD1 protein in ALS linked to SOD1 mutation may improve the disease prognosis. First trials on antisense oligonucleotides (ASOs) have been launched more than 10 years ago. Since 2010, numerous phase I and phase II trials have been conducted in ALS. ASOs stimulate the degradation of RNA by specific targeting and/or can also correct splicing defects or block miRNA [START_REF] Schoch | Antisense oligonucleotides: translation form mouse models to human neurodegenerative diseases[END_REF].

Following the impressive action of nusinersen in spinal muscular atrophy, major hopes have been put in the development of ASO directed to SOD1 and C9orf72 mutants. A phase III trial is currently underway assessing the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of tofersen in ALS adults with a SOD1 mutation (NCT02623699). The study is expected to be completed in July 2021. In parallel, a phase I study that will evaluate the long-term safety and tolerability of BIIB078 in ALS patients with abnormal C9orf72 expansion will also start soon (NCT04288856). This study is expected to be achieved in July 2023.

REGENERATING THERAPEUTICS

Transplantation of stem cells gives the opportunity to bring neurotrophic factors into the central nervous system. This might make it possible to re-settle regions affected by the motoneuron degenerative process. To date, there are too many issues that need to be resolved before this approach could appear promising in ALS: among the many uncertainties, the type of cells, the mode of administration, and the number of cells to transplant are still under debate [START_REF] Goutman | Stem cell treatments for amyotrophic lateral sclerosis (ALS): A critical overview of early phase trials[END_REF].

Conclusion: How to proceed for success?

We are currently in an enthusiastic period for ALS clinical trials: there are numerous trials that are ongoing or expected to start soon, evaluating promising drugs tested either in a new indication or specifically developed for ALS. This hopeful period does not have to mask that many issues need to be resolved before we will be able to develop a curative drug for ALS.

As pointed out by numerous clinicians, many elements remain problematic: the design of clinical trials would probably be usefully focused on homogenous (phenotypically? pathophysiologically? genetically?) groups of patients. We also have to define more relevant and suitable primary endpoints in order to evaluate efficacy; we have to use more accurate parameters than survival or delay from symptoms until use of NIV 22h daily.

does not perfectly fit with humans ALS on neuropathological aspects: this probably explains a large proportion of failures for drugs that show efficacy on animal models. We also need to reconsider trials in animals that started before the onset of the disease; it is clearly impossible to transpose the results to humans who will be treated once the disease has caused weakness and amyotrophy.

In 2018, a conference was held in Airlie House. The revised Airlie House ALS Clinical Trials Consensus Guidelines published after this meeting should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS (41).

Figure 1 .

 1 Figure 1. Mode of action of the candidate drugs presented in this review.


Yan Zhang
email: yan.zhang@insa-lyon.fr

Laurence Seveyrat

Laurent Lebrun

Correlation between dielectric, mechanical properties and electromechanical performance of functionalized graphene / polyurethane nanocomposites

Keywords: Graphene and other 2D-materials, Polyurethane, Polymer-matrix composites (PMCs), Electrical properties, Electromechanical behavior

Introduction

Electroactive polymers (EAPs) are used in a wide range of applications such as artificial muscles, sensors, microfluids and robotics, for their lightness, easy elaboration, and flexibility [START_REF] Carpi | Standards for dielectric elastomer transducers[END_REF][START_REF] Chen | Electronic Muscles and Skins: A Review of Soft Sensors and Actuators[END_REF][START_REF] Pelrine | Dielectric Elastomer Artificial Muscle Actuators: Toward Biomimetic Motion[END_REF][START_REF] Bar-Cohen | Electroactive polymer actuators and sensors[END_REF]. However, due to their relatively small dielectric constant, the application of EAPs are limited by the high driven electric field required. For this reason, research aiming at improving the electromechanical performance is of great interest [START_REF] Romasanta | Increasing the performance of dielectric elastomer actuators: A review from the materials perspective[END_REF][START_REF] Panahi-Sarmad | Graphene-based composite for dielectric elastomer actuator: A comprehensive review[END_REF][START_REF] Wongtimnoi | Improvement of electrostrictive properties of a polyether-based polyurethane elastomer filled with conductive carbon black[END_REF][START_REF] Carpi | Silicone-poly(hexylthiophene) blends as elastomers with enhanced electromechanical transduction properties[END_REF]. Among the electronic EAPs, polyurethane (PU) is a promising candidate thanks to its low cost as well as balanced properties among which can be mention the electric field-induced strain, mechanical modulus and temperature behavior. The studied PU elastomer presented a specific structure with a mix of hard and soft segments. Thermodynamic incompatibility of the two types of segments led to a phase separation favoring a high-level electromechanical performance [START_REF] Wongtimnoi | Improvement of electrostrictive properties of a polyether-based polyurethane elastomer filled with conductive carbon black[END_REF][START_REF] Diaconu | Properties of polyurethane thin films[END_REF][START_REF] Diguet | Physical modeling of the electromechanical behavior of polar heterogeneous polymers[END_REF].

The total strain S can be expressed in terms of the Maxwell effect due to the electrostatic interaction between charged electrodes, and electrostriction, which is linked to the change in material properties with strain. The strain is related to the applied electric field E with a quadratic equation:

= + = (1)
A previous study on this polyurethane showed that the Maxwell effect is the main mechanism involved in the total strain [START_REF] Zhang | On a better understanding of the electromechanical coupling in electroactive polyurethane[END_REF]. Its electromechanical performance thus depends directly on the ratio of the dielectric constant (εr') to the mechanical Young's modulus (Y), so the electromechanical coefficient M31 can be expressed as [START_REF] Kracovsky | A few remarks on the electrostriction of elastomers[END_REF]:

= (2)
Consequently, increasing the dielectric constant is a convenient way to improve the performance of a PU actuator. Several approaches can be employed for this, including the incorporation of fillers. In the case of insulating fillers, large quantities are required which in turn gives rise to a significant increase in Y, to the detriment of M31. For conductive fillers and especially nanosized ones, a lower content can be sufficient giving rise to a moderate mechanical reinforcement. Many authors linked the beneficial effect of the conductive fillers to Maxwell-Wagner-Sillars interfacial polarization [START_REF] Fook | Transparent flexible polymer actuator with enhanced output force enabled by conductive nanowires interlayer[END_REF][START_REF] Tsangaris | Electric modulus and interfacial polarization in composite polymeric systems[END_REF][START_REF] Sun | Interfacial polarization and dielectric properties of aligned carbon nanotubes/polymer composites: The role of molecular polarity[END_REF]. Consequently, it would be interesting to increase the quantity of interfaces by raising the filler content. The main issue is to preserve the insulating characteristic of the composite for which functionalization of the fillers can offer a suitable solution.

Research on composites of carbon nanotubes, graphene, carbon black have been reported for actuation applications [START_REF] Panahi-Sarmad | Graphene-based composite for dielectric elastomer actuator: A comprehensive review[END_REF][START_REF] Wongtimnoi | Improvement of electrostrictive properties of a polyether-based polyurethane elastomer filled with conductive carbon black[END_REF][START_REF] Park | Actuating single wall carbon nanotube-polymer composites: Intrinsic unimorphs[END_REF][START_REF] Li | Large dielectric constant of the chemically functionalized carbon nanotube/polymer composites[END_REF]. Graphene is of particular interest, due to the extensive electron mobility and a large specific surface area in favor of interfacial polarization. Moreover, the functionalization of fillers favors the dispersion as well as the cohesion with the polymer matrix [START_REF] Ramanathan | Functionalized graphene sheets for polymer nanocomposites[END_REF]. Therefore, in this work, oxygen-functionalized graphene nanoplatelets (OFG) were chosen to prepare PU/OFG composites.

An investigation was performed of the microstructural, mechanical and dielectric properties of PU/OFG nanocomposite films, in order to better understand how these properties affect the electromechanical coefficient M31. Solution tape casting was used for the film elaboration. OFG weight contents were varied in the range 0-14.60 wt%. The impact of nanoplatelets on the PU microstructure was investigated by SEM and DSC analyses, and the dielectric and mechanical properties were characterized. Frequency, temperature and electric field ranges were chosen so as to separate the various mechanisms involved in the polyurethane properties, while considering the conditions for driving actuators. The electromechanical coefficients were evaluated by bender displacement measurements, and compared to the values calculated by equation [START_REF] Chen | Electronic Muscles and Skins: A Review of Soft Sensors and Actuators[END_REF].

Their difference was discussed, especially in terms of conductivity/MWS relaxation contribution and the different dielectric behavior of PU and PU/OFG composites under a high electric field.

Experimental

Materials and preparation

Polyurethane granules (PU, Estane 58887 NAT 038, 1.13 g cm -3 , 87 shore A) and oxygenfunctionalized graphene nanoplatelets (OFG, Graphene Supermarket, oxygen HDPlas TM , planar size 0.3-5 µm, thickness <50 nm) were used to prepare PU/OFG composite films. The PU used in this work was a block copolymer, consisting of 4,4-methylene diphenyl diisocyanate (MDI), 1,4-butanediol (BDO) as hard segments, and poly(teramethylene) oxide (PTMO) as soft segments. Firstly, the PU granules were preheated at 80°C for 3 h following the recommendation of the supplier. Suitable content of OFG nanoplatelets were dispersed in N,Ndimethylformamide (DMF, Honeywell D158550) using an ultrasonic processor with a 7-mm sonotrode (Hielscher UP400S, amplitude 0.7, cycle 1, 40 min). Next, PU granules were dissolved in a DMF/OFG mixture with mechanical stirring and were heated at 80°C for 3h under reflux. The obtained homogenous solution (20 wt% PU in DMF) was left aside during 24 h after which the solution was applied to a glass plate by tape casting, followed by overnight heating at 60°C. A second treatment at 125°C for 3h was applied to remove the residual solvent and ensure the same thermal history. Films with a thickness of around 100 µm and a ratio of OFG to PU ranging from 0 to 14.60 wt% were finally obtained.

Microstructural characterization

The morphology of the PU/OFG composites was observed with a Zeiss Supra Scanning Electron Microscope (SEM) under high vacuum, at a low accelerating voltage of 1 kV.

Observations were performed on cryofractured (cross-section) surfaces of the films.

Thermal properties were obtained with Differential Scanning Calorimetry (Setaram DSC 131

Evo) under a nitrogen atmosphere. A sample around 20 mg was encapsulated in a 120-µL aluminum crucible. It was first cooled down to -120 °C, then heated to 220 °C, and finally cooled down to ambient temperature. Heating and cooling ramps were carried out at a rate of 10 °C min -1 .

Mechanical characterization

The mechanical properties of the films were characterized by a setup consisting of a Newport translation table, a motion microcontroller (XPS), and a 10-N force sensor (Doerler Mesures LC102TC). Films with dimensions of 60 mm in length and 10 mm in width were held on one side with a fixed clamp and on the other side with a mobile clamp, with and without the application of an electric field (function generator, amplifier trek 10/10). A low strain of 1 % was applied to the samples at a speed of 0.4 % s -1 . The strain as well as the stress response of the samples was detected by the motion controller and the force sensor. The Young's modulus of the composite films (Y) was determined on the linear part of the curve from the ratio of stress to strain.

Dielectric characterization

Gold electrodes (20 mm diameter, 26 nm thickness) were coated on both surfaces of the films by sputtering (Cressington 208HR). Dielectric spectroscopy was carried out using a Schlumberger Solartron 1255 impedance/gain phase analyzer and a 1296 dielectric interface.

The dielectric constant and conductivity were determined in the frequency range of 0.1Hz -1MHz.

Temperature measurements were performed under liquid nitrogen using a cryostat (Optistat DN2 Oxford Instruments) and a temperature controller (Oxford ITC503). Measurements were performed in a temperature range of 180-350 K and a frequency range of 0.1 Hz -1MHz, at 1 VRMS.

The dielectric constant was also recorded at high levels of electric field in the range 0.7-10 MV m -1 at 0.1 Hz. A unipolar AC voltage was generated by the impedance/gain phase analyzer, amplified by a Trek 10/10 amplifier, and applied to the sample.

Electromechanical characterization

The composite films were coated with a 26-nm gold electrode on both surfaces, and then attached to a rigid substrate (Mylar, RS 785-0792, 100 µm) with double-sided tape (3M, ATG 969, 100 µm). The electromechanical coefficient M31 of the obtained cantilever was evaluated with the help of a laboratory-built characterization bench (Fig. 1).

Fig. 1. Setup for the measurement of the electromechanical coefficient M31.

One end of the unimorph cantilever structure was clamped in the device, with the other end free to move. The active area was 40 mm x 10 mm x 0.1 mm. A unipolar AC electric field of 10

MVm -1 at 0.1 Hz was applied to the sample with the help of a function generator (Agilent 33220A) and a high-voltage amplifier (Trek 609-6). When the electric field was applied, a transverse elongation was generated in the polymer film, forcing the cantilever to bend. The tip displacement δ of the free end was measured by a laser sensor (3RG7056-3CM00-PF Pepperl+Fuchs), and the field-induced strain S31 could then be calculated from the measured displacement δ, with consideration taken to the configuration geometry and material properties.

The M31 coefficient was deduced from S31. Details of the calculations can be found in [START_REF] Zhang | On a better understanding of the electromechanical coupling in electroactive polyurethane[END_REF].

At least four samples of each composition were used for the dielectric, mechanical and electromechanical measurements, except for the thermally dependent dielectric measurements. The planar size (l) and thickness (d) of the OFG nanoplatelets were determined statistically from the SEM analysis. A planar size of 1.56± 0.64 µm and a thickness of 115± 83 nm were obtained. The planar size was in the range given by the supplier, while the thickness was greater than 50 nm, in agreement with the observed stacked platelets. The mean aspect ratio (Af= l/d) was 14.

Results and discussions

Microstructure of PU and PU/OFG composites

Fig. 3 depicts an example of DSC thermograms for PU and a PU/OFG composite. The thermal properties of all the compositions are given in Table 1.

- Four main thermal events could be observed during the temperature evolution. The first thermal event at -40/-50°C was related to the glass transition of the soft segments (SS) in PU, giving an indication of the separation state between soft and hard segments (HS). Globally, the Tg values did not vary considerably with the OFG content: only a moderate increase was noted at high contents. This increase could be an indication of a higher quantity of HS dissolved in the soft domains and thus a higher degree of HS-SS mixing [START_REF] Martin | The effect of average soft segment length on morphology and properties of a series of polyurethane elastomers. I. Characterization of the series[END_REF]. The endotherm in the range 40-80°C, which can be associated to local restructuring of HS units within the hard micro-domains [START_REF] Koberstein | Simultaneous SAXS-DSC study of multiple endothermic behavior in polyether-based polyurethane block copolymers[END_REF] was not affected by the presence of OFG even if a slight modification was observed with OFG contents of 12.63 wt% and 13.13 wt%.

There were two possible interpretations for the bimodal endotherm (Tm1 and Tm2) in the range 130-180°C. The first one was the micro-mixing of non-crystalline or semi-crystalline hard and soft phases followed by the fusion of crystalline HS [START_REF] Koberstein | Simultaneous SAXS-DSC study of multiple endothermic behavior in polyether-based polyurethane block copolymers[END_REF]. The second was the fusion of crystalline HS with the two peaks related to two lengths of HS [START_REF] Martin | The effect of average soft segment length on morphology and properties of a series of polyurethane elastomers. I. Characterization of the series[END_REF]. In both cases, the increase of the crystallinity was linked to an increase of Tm1 and Tm2 and the global melting enthalpy ΔHf.

In our case, the crystallinity could be considered to be unchanged, since the ΔHf was almost constant versus the OFG content, and no significant change of the Tm1 nor Tm2 value was observed. Due to the nature of the OFG fillers (nanoplatelets) and its random dispersion, the Halpin-Kardos model was chosen to predict the Young's modulus according to (3):

Mechanical properties

= ( ! " # ) ( %! " # ) + & ( ! ' # ) ( %! ' # ) (3)
where Y and Ym are the Young's Modulus of respectively the composites and the matrix, Φf is the volume fraction of fillers, which was calculated assuming a density of 2.2 g cm -3 for OFG and 1.13 g cm -3 for PU, Af is the aspect ratio, whose average value was determined to be 14 earlier in this work, and µL and µT are geometry factors, according to (4) and [START_REF] Romasanta | Increasing the performance of dielectric elastomer actuators: A review from the materials perspective[END_REF].

( ) = % ⁄ ⁄ (4) ( + = % ⁄ ⁄ (5)
Here, Yf is the Young's modulus of the fillers. This model assumes that a perfect adhesion between polymer and filler.

Both the experimental and predicted values increased linearly with the introduction of OFG, and the predicted values were reasonably close to the experimental ones. The increase in Young's modulus with the OFG content was moderate. For example, an increase of 30 % was obtained with 10.25 wt% OFG loading. As there was an uncertainty regarding the Yf due to the fact that the Young's modulus usually decreases with the number of graphene layers due to the slippage between the layers [START_REF] Lee | Elastic and frictional properties of graphene[END_REF], 3 values were employed for the model: 1 TPa for a monolayer [START_REF] Lee | Measurement of the elastic properties and intrinsic strength of monolayer graphene[END_REF], 350 GPa as published for a 10-layer graphene sample [START_REF] Gong | Optimizing the reinforcement of polymer-based nanocomposites by graphene[END_REF] and for the lowest value of 4.5 GPa corresponding to the Young's modulus of graphite [START_REF] Pierson | Handbook of Carbon, Graphite, Diamonds and Fullerenes[END_REF]. Among the possible physical values for Yf, the best fit was obtained for the lowest value.

Possible reasons can be the decrease of Yf induced by the functionalization, as reported in literature [START_REF] Zheng | Effects of functional groups on the mechanical and wrinkling properties of graphene sheets[END_REF], and the moderate interfacial adhesion between the polymer and the nanoplatelets, which is in good agreement with the SEM micrographs. This effect was indeed not considered by the model, and consequently, the mechanical reinforcement was moderate, in favor of a large electric field-induced strain. conduction, Maxwell Wagner Sillars (MWS) polarization and/or electrode polarization [START_REF] Carpi | Silicone-poly(hexylthiophene) blends as elastomers with enhanced electromechanical transduction properties[END_REF][START_REF] Li | Large dielectric constant of the chemically functionalized carbon nanotube/polymer composites[END_REF][START_REF] Dang | Giant dielectric permittivities in functionalized carbon-nanotube/ electroactive-polymer nanocomposites[END_REF];

Dielectric properties

and the second one, less pronounced, around 10 4 Hz, generally attributed to dipolar relaxation.

Figure 5(b) depicts the variation of the loss tangent (ratio of the imaginary part εr" to the real part εr' of the dielectric constant) versus frequency for various OFG contents. As for the pure PU films, as the frequency increased, the nanocomposites exhibited a large decrease in loss tangent followed by a moderate increase. The decrease observed for low frequencies was linked to the end of the contribution of electrode polarization, MSW polarization and/or conduction to the dielectric properties whereas the increase at medium frequencies was due to other dipolar relaxations. For frequencies below 10 Hz, lower loss tangent values were obtained for all composites as compared to pure PU.

Generally, conductive fillers increase the loss tangent of the composites [START_REF] Wongtimnoi | Improvement of electrostrictive properties of a polyether-based polyurethane elastomer filled with conductive carbon black[END_REF][START_REF] Park | Actuating single wall carbon nanotube-polymer composites: Intrinsic unimorphs[END_REF][START_REF] Li | Large dielectric constant of the chemically functionalized carbon nanotube/polymer composites[END_REF]. Only very few papers have reported on lower dielectric losses with conductive fillers [START_REF] Fredin | Substantial recoverable energy storage in percolative metallic aluminum-polypropylene nanocomposites[END_REF]. This decrease could certainly be associated to the functionalization of graphene. The insulating layer formed by the plasma functionalization may have played an effective role since the oxygen functionalization created carbonyl, hydroxyl and other functionalities on the surface of the conductive platelets.

Fig. 5(c) presents the variation of the dielectric constant versus OFG content, at 0.1 Hz. The dielectric constant increased with the OFG content and this occurred to a greater extent after 10.25%. The attained value of the dielectric constant was about four times higher than that of the PU film.

Below the percolation threshold, the experimental data can be modeled by [START_REF] Bouazzaoui | Nonuniversal percolation exponents and broadband dielectric relaxation in carbon black loaded epoxy composites[END_REF]:

, -= , . -(1 - . . 1 ) %2 (6)
Here, εrm' is the dielectric constant of the polymer matrix, mc is the percolation threshold, and q is the critical exponent.

At 0.1 Hz, a percolation threshold of 13.34 wt% and a q exponent of 0.32 were obtained. This percolation threshold was situated in the upper part of the percolation rate range reported for composites with conductive fillers [START_REF] Marsden | Electrical percolation in graphene -polymer composites[END_REF]. According to the literature, typical values for the q exponent are 1, 1.3 and 0.7 for 1D, 2D and 3D space dimensions [START_REF] Stauffer | Introduction to percolation theory[END_REF][START_REF] Myroshnychenko | Effective complex permittivity of two-phase random composite media: A test of the two exponent phenomenological percolation equation[END_REF][START_REF] Grannan | Critical behavior of the dielectric constant of a random compostie near the percolation threshold[END_REF][START_REF] Nan | Physics of inhomogeneous inorganic materials[END_REF], respectively. q values below 0.5 have also been reported and attributed to a 3D network of fillers [START_REF] Bouazzaoui | Nonuniversal percolation exponents and broadband dielectric relaxation in carbon black loaded epoxy composites[END_REF]. The q value of 0.32 obtained in this work can be related to a 3D distribution of OFG nanoplatelets, which was confirmed by the SEM micrograph.

Fig. 6(a) presents the real part of the conductivity (σ') of PU and PU/OFG composites as a function of the angular frequency (ω). The curve of conductivity of both PU and PU/OFG composites consisted of two parts, namely, a low-frequency plateau, followed by a monotonously increasing part at higher frequency. In this higher frequency range, the conductivity increased when raising the OFG content, which was consistent with higher conduction values of the graphene fillers. For concentrations beyond 14.60%, the global conductivity exhibited a sharp increase in accordance with a percolating system.

According to Jonscher's law [START_REF] Jonscher | The "universal" dielectric response[END_REF], the conductivity σ' can be described as:

σ'= σDC + Aω n ( 7
)
where A is a constant and n is the power exponent. The DC conductivity σDC corresponds to the value measured for the plateau. The n exponent was obtained using the slope of the curve representing log (σ' -σDC) as a function of log ω (data not shown). The n exponent was in the range 1 to 1.1, except for 14.60 wt% with n near 0.8.

Despite that the exponent is limited to n≤ 1 in the original Jonscher's law, reports on n values higher than unity exist in polymers with ionic-like conduction mechanisms [START_REF] Li | Trap modulated charge carrier transport in polyethylene/graphene nanocomposites[END_REF][START_REF] Papathanassiou | Universal frequency-dependent ac conductivity of conducting polymer networks[END_REF]. For a higher OFG content near the percolation threshold, the n exponent value diminishes which can indicate the contribution of electronic hopping conduction.

Fig. 6(b) depicts the evolution of σDC versus the OFG content. The observed trend was similar to that obtained for the loss tangent: an initial decrease for low and moderate OFG contents followed by an increase for higher contents in the vicinity of the percolation threshold. The evolution was therefore quite different from what has been described in several papers on EAP composites with carbon fillers [START_REF] Li | Large dielectric constant of the chemically functionalized carbon nanotube/polymer composites[END_REF][START_REF] Khurram | Correlation of electrical conductivity, dielectric properties, microwave absorption, and matrix properties of composites filled with graphene nanoplatelets and carbon nanotubes[END_REF], which reported a monotonic increase of DC conductivity when increasing the content of conductive fillers. Since σDC is related to the transport of free charges from one electrode to another, it can be assumed that the OFG would behave as traps for the charged mobile species with an efficiency correlated to the distance between them. In addition, the isolating layer created by the functionalization can also contribute to the decrease of the conductivity, as it did for loss tangent. For a moderate OFG content, the distance between two neighboring traps was high enough to disturb the charge transport but this capability decreased as the distance was reduced, thus leading to new paths for the charge displacement.

Near the percolation threshold, an electronic conduction can have an important role through the tunnel effect.

Temperature-dependent experiments were conducted for a more thorough interpretation of the charge carrier transport in these materials. It was important to pay particular attention to these features since they occur near room temperature and can help with the interpretation of the electromechanical performance of such EAPs. Fig. 7 presents the evolution of the imaginary part of the dielectric constant ɛr" and the modulus M" in the temperature range from -100 to 80 °C. The dielectric modulus M" formalism [START_REF] Mccrum | Anelastic and dielectric effects in polymeric solids[END_REF] (equation ( 8)) can be used to highlight relaxation phenomena not observed with ɛr", especially at low frequencies when high dielectric constant and conductivity values can mask the phenomena. and are not affected by fillers. In addition, the temperature range is below that used for actuators.

For all these reasons, attention was paid to the last peak in the vicinity of room temperature. This peak was highly dependent on OFG content, with the position of the maximum varying from 0 to 25 °C. A mix of interfacial polarization (MWS), conduction and/or electrode polarization was associated to this range. To go deeper in the interpretation and obtain information on the type of charges involved in this process, two studies were conducted: the variation of DC conductivity with temperature, and the treatment of the relaxation phenomena in the range from -10°C to 35°C after subtracting the σDC part.

Fig. 8(a) presents the evolution of the log of σDC versus 1/T. In the temperature range -10 °C to 35 °C, log σDC exhibited a near linear relation with 1/T. The temperature range was chosen so as not to consider other phenomena such as the α relaxation. The linear evolution agreed with the Arrhenius law:

-5678 9: (;

) = 5678 < + = > ? @ + (9)
where σ0 is the pre-exponential factor, Ea is the activation energy of DC conduction, and KB is the Boltzman constant. Relaxation peaks were visible in the corrected spectra, revealing the MWS relaxation. They were fitted using the double stretched Havriliak-Negami relaxation function [START_REF] Havriliak | A complex plane analysis of α-dispersions in some polymer systems[END_REF]:

, * (B) = , C + ∆E FGH(IJK) L M N (10)
where , C is the dielectric constant at high angular frequency far from the relaxation peak, ∆, is the dielectric dispersion, τ is the characteristic relaxation time, and α and β are related to the asymmetry and broadness of the spectra, respectively. The Havriliak-Negami fitting results on conduction-free loss relaxation are presented in Fig. 10 at ambient temperature (298 K). The dielectric dispersion ∆ɛ increased non-linearly with the OFG content, going from 2 for the pure PU to 5-6 for low and moderate OFG contents, and then abruptly grew for contents in the vicinity of the percolation threshold. This was evidence of a MWS polarization contribution nonproportional to the OFG content, and it was consequently indirectly correlated to the number of interfaces. ɛ∞ presented a slight increase versus OFG content, indicating that contrarily to what is generally assumed other relaxations, such as α and β relaxations, may have contributed. This point is currently under investigation.

The relaxation time τ remained in the range 1.0-1.5 s, and was not significantly influenced by the OFG content. The parameter α was equal to 1 for all the compositions, evidencing that the distribution of the relaxation time was symmetric, whereas the β parameter lay in the range 0.4-0.65, displaying a significant broadness of the distribution. Both for PU and the PU/OFG composites, the MWS polarization did not relax at a single frequency. From the temperature dependence of the relaxation time (data not shown), the activation energy was determined to be in the range 0.1-0.35 eV. The Ea was not greatly affected by the OFG content and the low values obtained indicated a high dipole mobility. The predicted M31-1V increased with the filler content, first at a moderate level and then more dramatically near the percolation threshold. This is in good agreement with the large increase of the dielectric constant, which is more important than the increase of Young's modulus. The evolution of the measured M31 exhibited a different trend. The measured M31 values of the composites were lower than the ones of pure PU, and it decreased slightly with the OFG content.

Electromechanical properties

The measured M31 values of pure PU were highly dispersed. It is noteworthy that the measurement conditions in terms of temperature and frequency were also those where a very large variation of dielectric properties was observed. The inability of the ɛr'/Y law to predict the measured data can also be linked to the fact that the dielectric constant and the Young's modulus can depend on the electric field. Given that EAPs work at electric fields from a few to hundreds of MV m -1 , it was essential to investigate the dielectric and mechanical properties under high electric fields. Fig. 12(b) presents the evolution of the real part of the dielectric constant as a function of applied electric field for PU and two composites at 0.1 Hz. Their dielectric behavior was different: the dielectric constant of the pure PU was three-fold of that at moderate electric fields before stabilizing at a value near 20 at 10 MV m -1 . The increase was lower for PU-10.25wt%-OFG, and for PU-12.63wt%-OFG, a decrease was observed. Fig. 12(c) presents an example of a strain-stress curve, measured with and without a 10-MV m -1 electric field for pure PU. The curves without and with an electric field were parallel, indicating that the electric field had no influence on the Young's modulus.

The evolution of the measured M31 coefficients and new predicted values of M31 from data measured at 10 MV m -1 (namely M31-E) were then plotted and can be seen in Fig. 12(d). The M31-E coefficient was successful in predicting the higher M31 of pure PU compared to the composites, while M31-1V did not. For the PU/OFG composites, neither M31-1V nor M31-E were able to predict the measured coefficients, or the decrease in measured M31 versus OFG content. The difference between the experimental and calculated coefficients increased with the OFG content. This observation can be correlated with the increase in ∆ɛ and ɛ∞ parameters due to the MWS relaxation. The depolarizing field induced by the interfacial polarization could indeed diminish the applied field, leading to a competition between the increase in dielectric constant and the effective electric field seen by the polymer.

In addition, fluctuations in the temperature range harboring the maximum of the relaxation peak could produce strong variations in dielectric properties, leading to a dispersion of the measured M31. As discussed previously in this paper, the moderate mechanical interfacial adhesion could also affect the strain transmission and reduce the macroscopic electric field-20 induced strain.

Conclusions

The mechanical, dielectric and electromechanical properties of PU/OFG composites with various OFG content were investigated, with attention paid to the properties at low frequency and temperatures between -20 and 35°C, where most EAP actuators and energy harvesters work.

The 3D distribution of nanoplatelets in the composites was confirmed by SEM analysis as well as the percolation law. The mechanical reinforcement remained modest probably due to a moderate adhesion between polymer and graphene nanoplatelets, highlighted by SEM and in agreement with over-estimated values predicted from the Halpin-Kardos model. DSC experiments revealed that the microstructure of polyurethane was not really affected by the presence of functionalized graphene, indicating the extrinsic role of the fillers on the properties.

As excepted, a large increase of the dielectric constant was obtained near the percolation threshold, as well as a decrease versus frequency. The variation in DC conductivity versus OFG content supported the fact that the OFG behaved as traps for the charged mobile species with the efficiency correlated to the distance between traps. The obtained activation energy lay in a range 0.7-0.9 eV, regardless of the OFG content, pointing at an ionic origin of the conduction.

A detailed study was carried out on the dielectric relaxation peak at low frequency, near room temperature, after removing the contribution of the DC conduction. Havriliak-Negami fitting indicated a Maxwell Wagner Sillars polarization contribution. It was however not proportional to the OFG content, and consequently not directly correlated to the number of interfaces.

A comparison of the experimentally determined M31 and the calculated M31 revealed the importance of taking the dielectric constant values under the same conditions as those used to drive actuators. The dielectric constant measured at high electric fields gives a better prediction of the electromechanical coefficient M31 of pure PU at low frequency, but does not completely explain the decreasing M31 of the composites. A possible explanation for this could be that the interfacial polarization decreased the electric field seen by the composites and counterbalanced the increase in dielectric constant. Other factors, such as a moderate mechanical interfacial adhesion as well as temperature fluctuations around the maximum of the relaxation peak, could also explain the values of the M31 coefficients.

Fig. 2

 2 Fig.2presents an example from the SEM analysis of the composite containing 10.25 wt% of

Fig. 2 .Fig. 2 (

 22 Fig. 2. SEM micrographs of a cryofractured (cross section) surface of the PU-10.25 wt%-OFG.

Fig. 3 .

 3 Fig. 3. DSC thermograms of PU and PU-12.63 wt%-OFG.

Fig. 4 (Fig. 4 .

 44 Fig.4(a) gives an example of a stress-strain curve of the PU/OFG composites. Fig.4(b)

Fig. 5 (

 5 Fig. 5(a) presents the evolution of the real part of the dielectric constant (εr') for different OFG

Fig. 5 .

 5 Fig. 5. (a) Variation of the real part of the dielectric constant ɛr' and (b) the loss factor tanδ as a

Fig. 6 .

 6 Fig. 6. (a) Conductivity of PU/OFG composites versus frequency, (b) DC conductivity versus

Fig. 7 .

 7 Fig. 7. Dielectric relaxations of PU/OFG composites at 0.1 Hz (a) imaginary part of the dielectric

Fig. 8 .Fig. 9 (

 89 Fig. 8. Evolution of the DC conductivity of PU and the PU/OFG composites: (a) log σDC versus

Fig. 9 .

 9 Fig. 9. Evolution of (a) the imaginary part of the dielectric constant εr" and (b) εr" without the

Fig. 10 .

 10 Fig. 10. Havriliak-Nagami fitting parameters versus OFG content for the MWS relaxation at ambient temperature (from DC conduction-free dielectric data): (a) dielectric dispersion ∆ɛ, (b) high frequency dielectric constant ɛ∞, (c) relaxation time τ, (d) spectra broadness parameter β.

Figure 11 Fig. 11 .

 1111 Figure 11 depicts the variation of S31 versus the square of electric field amplitude for PU and

Fig. 12 .

 12 Fig. 12. (a) M31 of PU/OFG composites measured at 10 MV m -1 , 0.1 Hz and M31 calculated with

Table 1 .

 1 Thermal properties of PU-OFG films from DSC experiments.

	wt%	TgSS	ΔCp	Tm1-2	ΔHf
	OFG	(°C)	(mW)	(°C)	(J/g)
	0 -50.0 1.2 147-169 12.8
	2.77 -45.2 1.3 147-169 13.1
	5.40 -48.9 1.3 150-168 11.6
	10.25 -47.5 1.1 147-170 12.6
	12.63 -45.8 1.2 150-169 11.2
	13.13 -41.1 1.1 147-173 11.2

Acknowledgement

The Authors thank the Centre Lyonnais de Microscopy (CLYM) for the SEM analysis. Yan Zhang thanks the China Scholarship Council for financial support during her PhD studies.