Prof. Y Slim Elleuch

Alain Lusson

Sebastien Pillet

Kamel Boukheddaden

Dr Younes Abid
email: younes.abid@fss.rnu.tn

Abid

Prof A Lusson

Prof K Boukheddaden

Prof S Pillet

White light emission from a zero-dimensional lead-chloride hybrid material

Keywords: 0D hybrid material, Lead chloride, White light emission, FWHM, CRI

Organic-inorganic hybrid (OIH) materials have emerged as high-performance class of light emitters, which can be used as phosphors for optically pumped white light-emitting diodes (WLEDs). Here, we report a new example of broadband white light (WL) emission from zero-dimensional lead chloride-based OIH material namely (TAE)2[Pb2Cl10](Cl)2 (TAE = tris-(2aminoethyl) ammonium (C6N4H22)). Single crystals of this compound and its corresponding ammonium salt TAE.HCl have been synthesized by slow solvent evaporation method at room temperature and were characterized by X-ray diffraction, optical absorption (OA) and photoluminescence (PL) measurements. The crystal structure shows an isolated lead chloride edge sharing bi-octahedra [Pb2Cl10] 6-interacting with two [TAE] 4+ cations and two Cl - chlorine ions through multiple hydrogen bonds in a triclinic unit cell, which confers to this system its 0D character. Upon UV irradiation at 3.81 eV, (TAE)2[Pb2Cl10](Cl)2 shows a very broadband WL emission resulting from the overlapping of two peaks located at 2.07 eV and 2.83 eV, respectively attributed to photoinduced free excitons confined in Pb2Cl10 inorganic bi-octahedra and the organic cations, respectively. When excited with a 4.66 eV laser, the full width at half maximum of WL band luminescence reaches the unprecedented value of 1.25 eV (247nm), and exhibits the highest CRI value with 96 and a chromaticity coordinates closer to the reference white light. This was mainly attributed to light emission originating from some self-trapped excitonic states caused by structurally highly distorted inorganic subnetwork. The present results enrich the restricted family of hybrid perovskite WL emitters and highlight the importance of the 0D OIH materials for solid-state lighting applications.

conventional lighting sources, has attracted great attentions in recent years. [START_REF]The Promise of Solid State Lighting for General Illumination[END_REF] Realizing WL emission from light-emitting diodes (LEDs) is of particular interest for illumination applications. [START_REF] Wang | Direct White-Light-Emitting Metal-Organic Framework with Tunable Yellow-to-White Photoluminescence by Variation of Excitation Light[END_REF] Different strategies for generating white light are well-known. [START_REF] Kitai | Luminescent Materials and Applications[END_REF][START_REF] Ye | Phosphors in phosphor-converted white light-emitting diodes: Recent advances in materials[END_REF] One can use (i) a combination of red, green, and blue LEDs in a single device; (ii) a blue LED connected to a single or two color conversion phosphors excited by the blue light, and (iii) a UV LED connected to three different phosphors, which emit in the blue, green, and red regions of the visible spectrum, respectively. While these techniques have been widely commercially accepted, the resulting devices suffer from a variety of inevitable drawbacks, such as the spectral overlap of the different constituting phosphors which can result in self-absorption and hence losses of emission efficiency and poor color stability. Especially, white light stability is often described by three main characteristics: (i) the Commission Internationale d'Eclairage "CIE": this is the most widely used method to describe the composition of any color in terms of three primaries (red-green-blue) coordinates; (ii) the Correlated Color Temperature "CCT": which indicates the temperature of a blackbody radiator that is most similar in chromaticity to the light being described, and (iii) the Color Rendering Index "CRI": this is a numerical measure of how true a color appears to the human eye when illuminated with a light source. It can be rated on a scale from 0 to 100, where 100 is a true color representation. [START_REF] Kamtekar | Recent Advances in White Organic Light-Emitting Materials and Devices (WOLEDs)[END_REF] Therefore, a major aim in solid-state lighting research has been concentrated recently in the development of a single-component broadband WL emitting, highly luminescent, and photostable material which achieve the criteria imposed by the above mentioned characteristics. In this context, organic-inorganic hybrid (OIH) materials represent an emerging class of crystalline photoactive materials, which have excellent solution processability with promising astounding physical properties for optoelectronics. [START_REF] Colella | The Bright Side of Perovskites[END_REF][START_REF] Saparov | Organic -Inorganic Perovskites: Structural Versatility for Functional Materials Design[END_REF][START_REF] Stoumpos | Halide Perovskites: Poor Man's High-Performance Semiconductors[END_REF][START_REF] Zhou | Organic-inorganic metal halide hybrids beyond perovskites[END_REF] While early investigations of OIH materials have been mainly focused on the structural and vibrational dynamics, they have been rediscovered over the past two decades and applied in promising optoelectronic fields, [START_REF] Manser | Intriguing Optoelectronic Properties of Metal Halide Perovskites[END_REF][START_REF] Stoumpos | The Renaissance of Halide Perovskites and Their Evolution as Emerging Semiconductors Acc[END_REF] such as light emitting diodes (LED), [START_REF] Chondroudis | Electroluminescence from an Organic-Inorganic Perovskite Incorporating a Quaterthiophene Dye with in Lead Halide Perovskite Layers[END_REF][START_REF] Koutselas | Some Unconventional Organic-Inorganic Hybrid Low-Dimensional Semiconductors and Related Light-Emitting Devices[END_REF][START_REF] Tan | Bright light-emitting diodes based on organometal halide perovskite[END_REF][START_REF] Yuan | Perovskite energy funnels for efficient light-emitting diodes[END_REF][START_REF] Mitzi | Organic-inorganic electronics IBM[END_REF] Field Effect Transistors or thin film transistors (TFT), [START_REF] Mitzi | Organic-inorganic electronics IBM[END_REF][START_REF] Kagan | Organic-Inorganic Hybrid Materials as Semiconducting Channels in Thin-Film Field-Effect Transistors[END_REF][START_REF] Mitzi | High-mobility ultra thin semiconducting films prepared by spin coating[END_REF][START_REF] Mitzi | Solution-processed inorganic semiconductors[END_REF][START_REF] Wang | High-performance transparent inorganic-organic hybrid thin-filmn-type transistors[END_REF][START_REF] Chin | Lead iodide perovskite lightemitting field-effect transistor[END_REF] Solar Cells [START_REF] Kim | Lead Iodide Perovskite Sensitized All-Solid-State Submicron Thin Film Mesoscopic Solar Cell with Efficiency Exceeding 9%[END_REF][START_REF] Etgar | Mesoscopic CH3NH3PbI3/TiO2 Heterojunction Solar Cells[END_REF][START_REF] Burschka | Sequential deposition as a route to high-performance perovskite-sensitized solar cells[END_REF][START_REF] Heo | Efficient inorganicorganic hybrid heterojunction solar cells containing perovskite compound and polymeric hole conductors[END_REF][START_REF] Jeon | Efficient Inorganic-Organic Hybrid Perovskite Solar Cells Based on Pyrene Arylamine Derivatives as Hole-Transporting Materials[END_REF][START_REF] Hao | Lead-free solid-state organic-inorganic halide perovskite solar cells[END_REF][START_REF] Green | The emergence of perovskite solar cells[END_REF][START_REF] Yang | Facile fabrication of large-grain CH3NH3PbI3-xBrx films for high-efficiency solar cells via CH3NH3Brselective Ostwald ripening[END_REF][START_REF] Mcmeekin | A mixed-cation lead mixed-halide perovskite absorber for tandem solar cells[END_REF][START_REF] Yang | Iodide management informamidinium-lead-halidebased perovskite layers for efficient solar cells[END_REF] and Photovoltaics. [START_REF] Bisquert | The Swift Surge of Perovskite Photovoltaics[END_REF][START_REF] Even | Importance of Spin-Orbit Coupling in Hybrid Organic/Inorganic Perovskites for Photovoltaic Applications[END_REF][START_REF] Mosconi | First-Principles Modeling of Mixed Halide Organometal Perovskites for Photovoltaic Applications[END_REF][START_REF] Kamat | Organometal Halide Perovskites for Transformative Photovoltaics[END_REF][START_REF] Escrig | Mixed Iodide-Bromide Methylammonium Lead Perovskite-based Diodes for Light Emission and Photovoltaics[END_REF][START_REF] Bruno | Temperature and Electrical Poling Effects on Ionic Motionin MAPbI3 Photovoltaic Cells[END_REF][START_REF] Samet | Sensitizer-free photon up conversion in (HQ)2ZnCl4 and HQCl crystals: systems involving resonant energy transfer and triplet-triplet annihilation[END_REF] Indeed, the inclusion of such materials into optoelectronics started with the pioneering works of Mitzi et al. [START_REF] Mitzi | Organic-inorganic electronics IBM[END_REF] who successfully assembled LED and TFT devices based on (H2AEQT)PbCl4 and [(PEA)2SnI4] hybrid bidimensional (2D) systems, respectively. Shortly after that, we have witnessed an unpredicted breakthrough and quick evolution in the field of Solar Cells and Photovoltaics, with the realization of highly efficient solid-state hybrid solar cells based on hybrid material absorbers. In fact, recent implementations of OIH absorber with an organic hole conductor enabled Power Conversion Efficiencies (PCEs) greater than 20%, [START_REF] Yang | Facile fabrication of large-grain CH3NH3PbI3-xBrx films for high-efficiency solar cells via CH3NH3Brselective Ostwald ripening[END_REF][START_REF] Mcmeekin | A mixed-cation lead mixed-halide perovskite absorber for tandem solar cells[END_REF][START_REF] Yang | Iodide management informamidinium-lead-halidebased perovskite layers for efficient solar cells[END_REF] and has been recognized as the "next big thing in photovoltaics". [START_REF] Bisquert | The Swift Surge of Perovskite Photovoltaics[END_REF] More recently, the OIH perovskites have interestingly emerged as a highly promising class of light emitters, which can be used as phosphors for optically pumped White Light-Emitting Diodes (WLEDs). [START_REF] Wang | Inorganic-organic hybrid white light phosphors[END_REF] Since these pioneering works, several research groups have reported new examples, achieving great values of the PLQY of 45% and 36% in 1D lead bromide [START_REF] Gautier | Lead Halide Post-Perovskite-Type Chains for High-Efficiency White-Light Emission[END_REF] and 0D lead chloride [START_REF] Yangui | Highly Efficient Broad-Band Luminescence Involving Organic and Inorganic Molecules in a Zero-Dimensional Hybrid Lead Chloride[END_REF] hybrid materials. Moreover, broadband emission FWHM's (Full Width at Half Maximum) reached 0.9 and 0.95 eV in more than one material, [START_REF] Dohner | Intrinsic White-Light Emission from Layered Hybrid Perovskites[END_REF][START_REF] Dohner | Self-Assembly of Broadband White-Light Emitters[END_REF][START_REF] Yuan | Onedimensional organic lead halide perovskites with efficient bluish white-light emission[END_REF] and the CRI exceeded in some case the commercial requirements for indoor illumination, [START_REF] Dohner | Self-Assembly of Broadband White-Light Emitters[END_REF][START_REF] Thirumal | Morphology-Independent Stable White-Light Emission from Self-Assembled Two-Dimensional Perovskites Driven by Strong Exciton-Phonon Coupling to the Organic Framework[END_REF][START_REF] Peng | White-light emission in a chiral onedimensional organic-inorganic hybrid perovskite[END_REF][START_REF] Wu | Broadband whitelight emission with a highcolor rendering index in a two-dimensional organic-inorganic hybrid perovskite[END_REF][START_REF] Ji | The First 2D Hybrid Perovskite Ferroelectric Showing Broadband White-Light Emission with High Color Rendering Index[END_REF][START_REF] Yangui | Hybrid Organic-Inorganic Halides (C5H7N2)2MBr4 (M = Hg, Zn) with High Color Rendering Index and High-Efficiency White-Light Emission[END_REF] where both "warm" and "cold" white light have been generated.

From all these results, some concluding remarks can be drawn. Except for some recently published works, [START_REF] Zhou | Highly Efficient Broadband Yellow Phosphor Based on Zero-Dimensional Tin Mixed-Halide Perovskite[END_REF][START_REF] Dammak | Quasi-white light emission involving Forster resonance energy transfer in a new organic inorganic tin chloride based material (AMPS)[SnCl6[END_REF][START_REF] Yangui | Broadband Emission in a New Two-Dimensional Cd-based Hybrid Perovskite[END_REF][START_REF] Roccanova | Broadband Emission in Hybrid Organic-Inorganic Halides of Group12[END_REF][START_REF] Yangui | Hybrid Organic-Inorganic Halides (C5H7N2)2MBr4 (M = Hg, Zn) with High Color Rendering Index and High-Efficiency White-Light Emission[END_REF] most of the WL emission reported are based on 1D and 2D lead bromide or chloride hybrid materials. The origin of the broadband emission in these OIH was deeply discussed and associated mainly with the presence of a short-range electron-distortion coupling in the strongly deformable lattice which generates self-trapped carriers in the inorganic substructures. [START_REF] Hu | Mechanism for Broadband White-Light Emission from Two-Dimensional (110) Hybrid Perovskites[END_REF][START_REF] Smith | Structural origins of broadband emission from layered Pb-Br hybrid perovskites[END_REF][START_REF] Zhuang | Intrinsic Broadband White-Light Emission from Ultrastable, Cationic Lead Halide Layered Materials Angew[END_REF][START_REF] Mao | White-Light Emission and Structural Distortion in New Corrugated Two-Dimensional Lead Bromide Perovskites[END_REF][START_REF] Peng | Ultrastable, cationic threedimensional leadbromide frameworks that intrinsically emit broadband white-light[END_REF] It was also evidenced that lowering the dimensionality of OIH materials from 2D to 1D to 0D enables a strong quantum confinement of the self-trapped excited states that produce highly efficient below-gap broadband luminescence and give efficient bluish white-light emissions. [START_REF] Hu | Mechanism for Broadband White-Light Emission from Two-Dimensional (110) Hybrid Perovskites[END_REF][START_REF] Yuan | Onedimensional organic lead halide perovskites with efficient bluish white-light emission[END_REF] Also, these single-component white-light emitters have an easily controlled emission, better color-rendering capability, and reproducibility compared to the properties of the multicomponent phosphors. [START_REF] Shang | How to produce white light in a single-phase host?[END_REF] More importantly, it has been proven that the white-light emission intensity remains undiminished after continuous UV irradiation for 30 days under atmospheric conditions (~60% relative humidity). [START_REF] Zhuang | Intrinsic Broadband White-Light Emission from Ultrastable, Cationic Lead Halide Layered Materials Angew[END_REF][START_REF] Peng | Ultrastable, cationic threedimensional leadbromide frameworks that intrinsically emit broadband white-light[END_REF] In this work, we report the synthesis, crystal structure and photophysical properties of a new zero-dimensional organic lead chloride material, namely (TAE)2[Pb2Cl10](Cl)2 (TAE = tris-(2aminoethyl) ammonium (C6N4H22)), showing white light emission properties and exhibiting unprecedented values of 1.25 eV (247 nm) for the FWHM and CRI at 96 with chromaticity coordinates of (0.30,0.33). The temperature-dependence of this emission was also undertaken, on single crystals of (TAE)2[Pb2Cl10](Cl)2 and the corresponding ammonium salt TAE.HCl to investigate the origin and the thermal dependence of the WL performances of the material.

Experimental section

Single crystals of the OIH material (TAE)2[Pb2Cl10](Cl)2 were synthesized by slow solvent evaporation at room temperature. Stoichiometric amounts of PbCl2 and Tris (2-aminoethyl) amine, (NH2CH2CH2)3N, was stirred in aqueous solution of HCl and kept in the dark at room temperature. After two weeks, colorless platelets single crystals were formed. The crystal structure was determined using a supernova 4-circle micro-source diffractometer (Oxford Diffraction) equipped with a two-dimensional ATLAS detector, and using graphite monochromatized MoKα radiation (λ= 0.71073 Å).

All optical measurements were performed on (TAE)2[Pb2Cl10](Cl)2 HOI and its corresponding ammonium salt TAE.HCl. The optical absorption (OA) spectra were measured at room temperature on spin-coated films using a conventional UV-Vis spectrophotometer (HITACHI, U-3300). Photoluminescence (PL) measurements were performed usinga JOBIN YVON HR 320 spectrophotometer under 266 and 375 nm excitation wavelengths, and with 50 mW excitation powers. For temperature dependence measurements, we used a Janis closed cycle cryostat. Photoluminescence excitation (PLE) was recorded at room temperature on a Fluoromax-4spectrofluorimeter equipped with a xenon lamp as anexcitation source.

Crystal Structure

X-rays diffraction experiments performed at room temperature (300K) show that (TAE)2[Pb2Cl10](Cl)2 crystallizes as an OIH material in the triclinic space group P-1 and the relevant crystallographic data are summarized in Table S1 of the supplementary material (SM). As shown in Figure 1, the crystal structure shows discrete [Pb2Cl10] 6-entities, two

[TAE] 4+ cations and two Cl -ions packed in a triclinic unit cell. The [TAE] 4+ cations are located in general positions with their three ammonium groups involved in N-H…Cl hydrogen bonds with the Cl atoms of [Pb2Cl10] 6-groups and Cl -counter ions. In this structure, there exist two different [Pb2Cl10] 6-groups, which are both located on an inversion center forming Pb1 and Pb2 edge-sharing bi-octahedra stacked along the crystallographic a direction. It presents structural strains considering the distortions of the two [Pb2Cl10] 6-bioctahedra building blocks (see Figure S1-S5). These deformations involve modifications in Pb-Cl bond lengths (d) and Cl-Pb-Cl angles (α), and can be quantitatively evaluated using the followings formulas which introduce the octahedral elongation λ oct and octahedral angle variance σ oct 2 : 70

λ oct = 1 6 ∑ (d i d 0 ⁄ ) 2 6 i=1 , σ oct 2 = 1 11 ∑ (α i -90) 2 12 i=1
Here, d i are six independent Pb-Cl bond lengths, d 0 is the mean Pb-Cl bond length and α i are the Cl-Pb-Cl angles. From the structural parameter in [START_REF] Cortecchia | Broadband Emission in Two-Dimensional Hybrid Perovskites: The Role of Structural Deformation[END_REF] ) and reveal the existence high degrees of distortion for both inorganic entities. In this context, it is well known that such distortion plays a crucial role in the formation of self-trapped excitons, which are at the origin broadband emission. [START_REF] Smith | Structural origins of broadband emission from layered Pb-Br hybrid perovskites[END_REF][START_REF] Cortecchia | Broadband Emission in Two-Dimensional Hybrid Perovskites: The Role of Structural Deformation[END_REF][START_REF] Mao | White-Light Emission and Structural Distortion in New Corrugated Two-Dimensional Lead Bromide Perovskites[END_REF][START_REF] Mao | Tunable White-Light Emission in Single-Cation-Templated Three-Layered 2D Perovskites (CH3CH2NH3)4Pb3Br10 -x Clx[END_REF] For a deep analysis of the PL spectrum and in order to investigate the contribution of the organic TAE cation and Pb2Cl10 inorganic anion in the emission process, we have studied under the same conditions the PL spectrum of the organic salt, which exhibits an intense and wide band at 3.07 eV. By comparison of both spectra, one can attribute the two components of the white light emission as follows: The S2 peak at 2.83 is unambiguously associated to the HOMO-LUMO electronic transitions within the organic cation. The 240 meV red shift could be assigned to the interaction between organic and inorganic components in the (TAE)2[Pb2Cl10](Cl)2 leading to tune the band structure and to modify the luminescence properties. [START_REF] Li | Novel <110> Oriented Organic-Inorganic Perovskite Compound Stabilized by N-(3-Aminopropyl)imidazole with Improved Optical Properties[END_REF] Whereas, the S1 peak at 2.07 eV originates from excitonic levels of the Pb2Cl10 bioctahedra, and to boost this assumption, we have recorded the photoluminescence excitation (PLE) spectrum at 2.07 eV (Figure 2(e)). The measurements reveal the presence of a sharp peak at 3.95 eV (313 nm), typically characteristic of the well-known Wannier-type excitons observed in similar compounds based on PbCl6 octahedra. [START_REF] Barkaoui | Yellowish White-Light Emission Involving Resonant Energy Transferin a New One-Dimensional Hybrid Material: (C9H10N2)PbCl4[END_REF][START_REF] Yangui | Highly Efficient Broad-Band Luminescence Involving Organic and Inorganic Molecules in a Zero-Dimensional Hybrid Lead Chloride[END_REF] On the other hand, the very large stokes shift with respect to excitons absorption (1.7 eV) may be interpreted as a result of the strong interaction between the organic and inorganic ions. From an optoelectronic point of view, this material is then assimilated to the self-assembly of two luminescent organic and inorganic ionic entities, placed in very close positions (2 to 3 Å) and having almost equal HOMO-LUMO gaps around (3.95 eV). Such characteristics have been observed in many metal halide hybrids and have been considered to favor strong interactions leading to the emission of broad bands of white light. [START_REF] Samet | Sensitizer-free photon up conversion in (HQ)2ZnCl4 and HQCl crystals: systems involving resonant energy transfer and triplet-triplet annihilation[END_REF][START_REF] Mao | Tunable White-Light Emission in Single-Cation-Templated Three-Layered 2D Perovskites (CH3CH2NH3)4Pb3Br10 -x Clx[END_REF][START_REF] Peng | White-light emission in a chiral onedimensional organic-inorganic hybrid perovskite[END_REF][START_REF] Trabelsi | Optical properties of a new luminescent hybrid material [C6N2H5]3BiCl6 involving a resonance energy transfer[END_REF] It is well known that this type of interaction is characterized by a photoluminescence spectrum strongly dependent on the excitation wavelength. [START_REF] Samet | Sensitizer-free photon up conversion in (HQ)2ZnCl4 and HQCl crystals: systems involving resonant energy transfer and triplet-triplet annihilation[END_REF][START_REF] Peng | White-light emission in a chiral onedimensional organic-inorganic hybrid perovskite[END_REF][START_REF] Trabelsi | Optical properties of a new luminescent hybrid material [C6N2H5]3BiCl6 involving a resonance energy transfer[END_REF] In this context, we carried out photoluminescence measurements under different excitations presented in the right side of Figure 2. For an excitation of 4.66 eV, energy above the organic and inorganic gap, the two entities are excited and their resonant interaction strongly enhances the intensities of both S1 and S2 peaks, giving rise to a single very wide band and a white light of impressive intensity. For an excitation of 3.81 eV, energy included in the organic and inorganic absorption bands tails, the two species are excited and we observe both S1 and S2

resolved peaks, with a lower intensity than the previous one. When exciting by energyof 3.3

eV, only the organic cation is excited and the PL spectrum is reduced to the single band, as if the bioctahedra do not exist.

White-Light Emission

As mentioned above, the studies conducted so far on hybrids based on lead halides have shown that the white light emission mechanisms as well as the profiles of the PL bands depend on many parameters, mainly, the optical activity of the organic cation, the distortion of the inorganic subnetwork and dimensionality. In order to better understand the white light emission mechanism in our material, we have carried out a comparative study of the photophysical characteristics of the materials studied so far. In table 1, we have gathered their main optical characteristics. An overview of these properties shows without ambiguity that for chlorinated and brominated compounds, the lowering in dimensionality is accompanied by a blue shift of the emission peak. Indeed, it was recently demonstrated that lowering the system dimensionality helps in the formation of exciton self-trapping at any exciton-phonon interaction strength, and leads to the observation of broad band luminescence with large stokes shifts. [START_REF] Hu | Mechanism for Broadband White-Light Emission from Two-Dimensional (110) Hybrid Perovskites[END_REF] Furthermore, these studies have shown that the common characteristic to all these materials lies in the fact that the emission of broad bands involves the recombinations of self-trapped excitons, due to the high distortion of the PbX6 octahedra.

As we mentioned in the description of the structure, our material belonging to the lowdimensional 0D HOIM family, does not escape the rule and exhibits a remarkle distortion, stronger than those reported in the literature. In order to probe the contribution of such selftrapped excitonic states in the emission mechanism, we carried out a study of the PL intensity as a function of the excitation power, which presents an excellent tool to confirm the self trapping excitons origin. [START_REF] Dohner | Intrinsic White-Light Emission from Layered Hybrid Perovskites[END_REF][START_REF] Teunis | Pure white-light emitting ultrasmall organic-inorganic hybrid perovskite nanoclusters[END_REF][START_REF] Yuan | Onedimensional organic lead halide perovskites with efficient bluish white-light emission[END_REF] As shown in Figure 4, the intensity of the white light emission excited at 4.66 eV showed a linear dependence on the excitation power density up to 25 MW/cm 2 , suggesting that the current WL emission originated from self-trapped excited states. Such a behavior is in good agreement with previous works, especially the results of Dohner et al. on (N-MEDA)PbBr4 41 and (EDBE)PbBr4. [START_REF] Dohner | Intrinsic White-Light Emission from Layered Hybrid Perovskites[END_REF] We can then conclude, that in addition to the organic and inorganic free excitons involved in the mechanism described above, is added the contribution of the self-trapped excitons. This can explain the impressive intensity of the white light emission, as well as the remarkable width of the PL band. Indeed, in the comparative table, the most remarkable property we can notice in terms of propertiesstructure correlation is the unprecedented width of the emission band of our compound (1.25 eV). To our knowledge, this value stand for the record of the broadening emission observed between overall the WL emitting OIH materials that did not exceed the value of 1 eV.

In order to better illustrate the interesting findings of our 0D OIH material (TAE)2[Pb2Cl10](Cl)2, the white light characteristics, namely the CIE coordinates, the (CCT) and the (CRI), are also presented for comparaison with those of other WL emitting HOI based materials in Table 1. In this study, the (TAE)2[Pb2Cl10](Cl)2 excited with the 4.66 eV laser exhibits CIE coordinates at (0.30, 0.33) very close to the reference coordinates (0.33, 0.33) defined in the CIE chart as the white point or equal energy point (Figure 3). Also, the broad band emission from this material exhibits a CCT of 6741 that affords "cold" white light. Most importantly, the value of the CRI is evaluated at 96, which is the highest value revealed among the other WL emissions from other OIH materials [START_REF] Yangui | Hybrid Organic-Inorganic Halides (C5H7N2)2MBr4 (M = Hg, Zn) with High Color Rendering Index and High-Efficiency White-Light Emission[END_REF] (see Table 1) and exceeds even the high CRI indexes (>90) exhibited by some mixed-phosphor light sources. [START_REF] Kitai | Luminescent Materials and Applications[END_REF][START_REF] Saparov | Organic -Inorganic Perovskites: Structural Versatility for Functional Materials Design[END_REF] Generally, the desired indoor lighting applications typically require values of CRI above 80 and closest to 100 which is, by definition, the black body radiator CRI. [START_REF] Liu | Eu 3+ -doped Tb 3+ metal-organic frameworks emitting tunable three primary colors towards white light[END_REF][START_REF] Wei | A white-light-emitting LnMOF with color properties improved via Eu 3+ doping: analternative approach to a rational designfor solid-state lighting[END_REF] Moreover, from the CRI values depicted in Table 1, we concluded that the highest values are those obtained from chlorided materials and this agree well with the hypothesis conceived by Dohner et al. that chloride substitution improves the material's properties (CRI). [START_REF] Dohner | Self-Assembly of Broadband White-Light Emitters[END_REF] All of these characteristics clearly show the important originality of this new material, and can enable applications sought for many indoor lighting requiring inexpensive and large-area coatings.

Table1. Reported photophysical properties and white light characteristics in some OIH materials.

Compound

Temperature Dependence of WL Emission

To get further information about the stability of excitons, we measured the thermal dependence of the emission spectra of the OIH compound (TAE)2[Pb2Cl10](Cl)2 in the temperature range [10-300 K]. As shown in Figure 5a, significant changes were observed on the behaviors of S1 and S2 PL lines. The integrated intensity of peak S1 continuously decreases as a function of temperature and shows an anomaly around 50 K. We described the quenching of S1 excitonic PL emission as a function of temperature, as a consequence of the competition with a non-radiative channel which described by the Arrhenius-type law, [START_REF] Hong | Dielectric confinement effect on excitons in PbI4-based layered semiconductors[END_REF][START_REF] Jiang | Temperature dependence of photoluminescence from GaAs single andmultiple quantum well heterostructures grown by molecular beam epitaxy[END_REF]

𝐼 𝑃𝐿 = 𝐼 0 1+𝑎𝑒𝑥𝑝( -𝐸 𝑎 𝑘 𝐵 𝑇 ) (1)
where 𝐼 0 is the low-temperature PL intensity, k B is the Boltzmann constant, 𝑎 is the ratio between the radiative and the nonradiative decay rates, and 𝐸 𝑎 is the activation energy. The best fit gives 𝐼 0 = 2.7 × 10 4 ± 480 (a.u), 𝑎 = 25 ± 7 , and 𝐸 𝑎 = 5 ± 0.5 meV. This activation energy presents a good agreement with those measured in similar 2D OIHP such as (C6H11NH3)2PbBr4 [START_REF] Yangui | Optical Investigation of Broadband White-Light Emission in Self-Assembled Organic -Inorganic Perovskite (C6H11NH3)2PbBr4[END_REF] and (C6H5C2H4NH3)2PbI4. [START_REF] Gauthron | Optical spectroscopy of twodimensional layered (C6H5C2H4-NH3)2-PbI4 perovskite[END_REF] On the other hand, S2 PL peak intensity shows three different behaviors as a function of temperature (Figure 5b): first, it decreases until reaching 50 K (region I), then increases between 50 and 180 K (region II) and finally quenches at higher temperature (region III). More importantly, at room temperature (curve b in Figure 5), the emission spectrum of (TAE)2[Pb2Cl10](Cl)2 was dominated by S2 PL band and on cooling, three different behaviors were observed. Indeed, as displayed in the inset of Figure 5b, in the temperature range (I), S1 peak is dominant and the ratio between S1 and S2 increases, then it suddenly decreases in region II, and below 180 K the S1 PL band becomes dominant, and the ratio between S1 and S2 PL intensities stabilizes in region III above 180 K.

Such behavior can be explained by two ways. First, it is well known that excitons stability is much higher at low temperature. [START_REF] Ishihara | Optical properties due to electronic transitions in two-dimensional semiconductors (CnH2n+1NH3)2PbI4[END_REF] Therefore; the intensity of S1 excitonic peak enhances by lowering the temperature and becomes much sharper. Second, the presence of a singularity around 50 K on the thermal behavior of S1 could be the result of structural distortions often observed at low temperature in OIH materials. [START_REF] Dohner | Intrinsic White-Light Emission from Layered Hybrid Perovskites[END_REF][START_REF] Dohner | Self-Assembly of Broadband White-Light Emitters[END_REF][START_REF] Yangui | Optical Investigation of Broadband White-Light Emission in Self-Assembled Organic -Inorganic Perovskite (C6H11NH3)2PbBr4[END_REF] On the other hand, the evidence of three different temperature ranges on the thermal behavior of the integrated intensity of S2 PL band further strengthens the hypothesis of the presence of critical structural changes especially around 50 and 180 K. Moreover, the abnormal increase of the intensity of S2 PL peak between 50 and 180 K is accompanied by the decreases of S1 PL intensity, which suggests the presence of a strong competition in the recombination processes of S1 and S2 PL bands, which can be activated by the presence of structural phase transitions in this temperature range. [START_REF] Yangui | Structural phase transition causing anomalous photoluminescence behavior inperovskite (C6H11NH3)2[PbI4[END_REF] Similar behavior was also found in the temperature dependence of the full width at half maximum (FWHM) of S1 and S2 PL peaks. Indeed, the FWHM of S1 excitonic peak slightly decreases in region I, and then continuously increases as a function of temperature (Figure 5c). Assuming linear electron-phonon coupling and harmonic lattice vibrations, the temperature dependence of the FWHM of S1 PL peak allows estimating the vibrational modes effective frequency coupled to the electronic transition using the following model: 80

Γ(T) = Γ 0 + Γ LO (e E LO k B T -1) -1 + Γ inh e -E b k B T (2)
where, Γ 0 is the emission FWHM at 0 K, E LO is the energy of the longitudinal optical phonon Here, some concluding remarks can be drawn. (i) First, these fitting values are in agreement with those obtained from previous broad emitting 2D perovskites. [START_REF] Dohner | Intrinsic White-Light Emission from Layered Hybrid Perovskites[END_REF][START_REF] Zhuang | Intrinsic Broadband White-Light Emission from Ultrastable, Cationic Lead Halide Layered Materials Angew[END_REF][START_REF] Peng | Ultrastable, cationic threedimensional leadbromide frameworks that intrinsically emit broadband white-light[END_REF] Although the value of Γ LO (170 ± 6 meV) is slightly larger than the ones available in the literature of broad emitting lead bromide perovskites: (130 ± 7 meV) [START_REF] Dohner | Intrinsic White-Light Emission from Layered Hybrid Perovskites[END_REF] and (131 ± 7 meV); 60 however all these values remain considerably larger (up to more than threefold) than those of WL emitting lead chloride based perovskites (49 ± 3 meV). [START_REF] Zhuang | Intrinsic Broadband White-Light Emission from Ultrastable, Cationic Lead Halide Layered Materials Angew[END_REF] The present tendency clearly reveals the existence

Conclusion

In summary, we have synthesized a novel low-dimensional lead chloride-based OIH material by slow solvent evaporation at room temperature. The crystal structure done using single crystal X-ray diffraction shows a 0D structure formed by discrete [Pb2Cl10] 6-entities and two

[TAE] 4+ organic cations located in general positions and two Cl -chlorine ions. The investigations of the photo-physical properties revealed a sharp excitonic absorption and a very broadband WL emission, even at room temperature, consisting of two PL bands (S1 and S2) located respectively at 2.07 and 2.83 eV, attributed respectively, to free excitons confined into the inorganic bi-octahedra Pb2Cl10 and in the organic salts, respectively. This material excited by 4.66 eV irradiation, exhibited a white light emission with record of the emission broadening with 1.25 eV (247 nm) as FWHM and offered the highest CRI value of 96. This is the effect of the supplementary light emissions from self trapped excitons generated within the highly distorted Pb2Cl10 bi-octahedras. We can state now that our material exhibits a very particular case of HOIM by showing a competition of three emission mechanisms, organic and inorganic free excitons and self trapped excitons. From the study of the temperature dependence of PL spectra of this OIH material, we deduced an exciton activation energy 𝐸 𝑎 =6 meV and detected the presence of singularities around 50 and 180K on the behaviors of the thermal dependence integrated intensity, the FWHM, and the position of the PL peaks.

These singularities were also tracked from the study of the thermal dependences of the PL spectra of the associated ammonium salt, and are attributed to structural phase transitions, often observed in OIH perovskites materials.

Considering the low cost character of the present new WL material, its room-temperature facile synthesis and excellent optical properties, this new perovskite phosphor which enriches the restricted list of WL OIH materials, represents a highly promising alternative to replace conventional inorganic rare-earth-based phosphors and quantum dot-based phosphors that currently dominate the field of optically pumped WLEDs.

Supporting Information: Crystallographic data, relevant structural parameters, crystal and molecular structures descriptions and Raman spectrum.

  photoluminescence quantum efficiency (PLQE) have been observed in many low-dimensional

Figure 1 .Figure 2

 12 Figure 1. (Left) Crystal structure of the (TAE)2[Pb2Cl10](Cl)2 HOI material projected along the crystallographic b-axis. (Right) Two [Pb2Cl10] 6-individual bi-octahedra showing different distortions values (T=300 K).

Figure2.

  Figure2. (Left) (a,b) Optical absorption spectrum (solid blue line) and the PL emission spectrum (solid red line) of the OIH material (TAE)2[Pb2Cl10](Cl)2. (c,d) Optical absorption spectrum (dashed blue line) and the PL emission spectrum (dashed red line) of the ammonium salt TAE.HCl. (e) PLE spectrum (solid black line) of the (TAE)2[Pb2Cl10](Cl)2 material. (Right) PL emission spectra of (TAE)2[Pb2Cl10](Cl)2 excited with (black) 3.30 eV, (red) 3.81 eV and (blue) 4.66 eV, (T=300 K).White-Light Emission

Figure3.

  Figure3. (Left) CIE Chromaticity coordinates of (TAE)2[Pb2Cl10](Cl)2 emission excited by 4.66 eV.(Right) Photographsshowing the samemicrocrystal before and during photoluminescence under 3.30 eV irradiation (T=300 K).

Figure 4 .

 4 Figure 4. (Left) Variation of the emission spectra at 4.66 eV with different excitation intensities (13.75-25 mW/cm 2 ). (Right) Linear dependence of emission intensity on excitation density and a linear fit, (T=300 K).

  mode coupled to the electronic transition, E b represents the average binding energy of emissive defect states, and the constants Γ LO and Γ inh give the relative contributions of electron-phonon coupling and inhomogeneous broadening to the emission line width. The best fit of the data (Figure 5c) gives E LO = 6±1 meV, E b = 12±3 meV, Γ 0 = 193 ± 8 meV, Γ LO = 170 ± 6 meV and Γ inh = 93 ± 7 meV.

  of a strong exciton-phonon coupling in (TAE)2[Pb2Cl10](Cl)2 material. (ii) The LO phonon energy (E LO =6 ± 1 meV) obtained from this fitting of Eq. (2), agrees well with the activation energy (E a =6 ± 1 meV) deduced from the Arrhenius fitting of the integrated intensity of S1 peak. In addition, this LO phonon energy along with the Eb energy can be coincided with the frequencies of 67 cm -1 (8.3 meV) and 90 cm -1 (11.2 meV), evidenced by Raman spectroscopy (FigureS5) and so well align well within the range of PbCl stretching frequencies. In the same context, we observed an intense Raman scattering of our material at room temperature, further confirming the existence of an electron-phonon coupling in a strongly deformable lattice. (iii) We can then attribute the exciton self-trapping process in the current material to originate primarily from the inorganic lattice like concluded by Hu et al. for (N-MEDA)[PbBr4] material.[START_REF] Hu | Mechanism for Broadband White-Light Emission from Two-Dimensional (110) Hybrid Perovskites[END_REF] On the other hand, the temperature dependence of the FWHM of S2 peak shows three different regimes for each temperature range which suggests, once again, the possible presence of structural changes as a function of temperature. Concerning the thermal behavior of S1 and S2 PL position, they keep almost the same position as a function of temperature, with the presence of singularity around 180 K, for the position of S2 peak (Figure5d).

Figure5.

  Figure5. (a) 3D plot of the temperature dependence of the PL spectra of (TAE)2[Pb2Cl10](Cl)2 single crystals, in 10-300 K temperature range, under 3.816 eV excitation. Plot of temperature dependence of (b) the integrated intensity, (c) FWHM, and (d) the peak position of both S1 and S2 PL peaks. Inset of Figure5b shows the ratio between intensities of S1 and S2 as a function of temperature.

Figure 6a ,

 6a Figure 6a, shows the temperature dependence of the PL spectra of the ammonium salt

Figure 6 .

 6 Figure 6. (a) Temperature dependence of the PL spectra of TAE.HCl ammonium salt. Plot of the temperature dependence of (b) the integrated intensity (c) the FWHM and (d) the position of the PL peak.

Table S2

 S2

, the average values of Pb1-Cl and Pb2-Cl bond lengths are 2.9012 and 2.9035 Å, leading to an octahedral elongation λ oct of 1.0011 and 1.0008, respectively. Furthermore, the corresponding octahedral angle variance,σ oct 2 , are evaluated as 28.4 and 48.2 °2, respectively. Such values are very large when compared with reported ones (5.98 °2 for (CyBMA)[PbBr4] 54 , 8.28 °2 for (C4N2H14)[PbCl4] 63 and 14.2 °2 for (EDBE)[PbI4]

Table of Contents Use Only

White light emission from a zero-dimensional lead-chloridehybrid material

Slim Elleuch, * Alain Lusson, Sebastien Pillet, Kamel Boukheddaden, and Younes Abid


Florence Poizeau

Sandrine Kerbrat

André Happe

Caroline Rault

Erwan Drezen

Frédéric Balusson

Philippe Tuppin

Bernard Guillot

Anne Thuret

Lise Boussemart

Monica Dinulescu

Marc Pracht

Thierry Lesimple

Catherine Droitcourt

Emmanuel Oger

MD Alain Dupuy
email: alain.dupuy@chu-rennes.fr.

Patients with metastatic melanoma receiving anticancer drugs: changes in overall survival, 2010-2017

Keywords: revision ICI, immune checkpoint inhibitors OS, overall survival PD-1, programmed cell death 1 RCT, randomized controlled

come

INTRODUCTION

Metastatic melanoma has been at the forefront of the recent changes in oncology. For almost 40 years, cytotoxic chemotherapy used in metastatic melanoma had been associated with a median survival of less than 12 months [START_REF] Balch | Final Version of 2009 AJCC Melanoma Staging and Classification[END_REF]. The emergence of new anticancer drugs over the last 10 years has profoundly changed treatment strategies, since each new treatment has demonstrated gains in survival over reference therapy in randomized controlled trials (RCTs) [START_REF] Eggermont | New drugs in melanoma: It's a whole new world[END_REF][START_REF] Ugurel | Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017[END_REF]. Novel therapeutic approaches have included immune checkpoint inhibitors (ICIs) and targeted therapies. A first wave of new anticancer drugs started in 2011 with the anti-CTLA-4 drug ipilimumab and BRAF inhibitors. Since 2015, agents targeting programmed cell death 1 (PD-1), and BRAF combined with MEK inhibitors have become the new standards.

The extent to which these changes have translated into an improvement in survival in the real world remains to be further investigated. We used the French insurance database to identify all patients who received a systemic treatment for metastatic cutaneous melanoma between 2010 and 2017 in France. Our objectives were to describe changes in anticancer drug use and to analyze the impact on overall survival over the study period.

J o u r n a l P r e -p r o o f

RESULTS

Anticancer drugs used for metastatic melanoma: 2010-2017

Every patient beginning a first-line treatment in France for metastatic cutaneous melanoma was included. The numbers of new patients per trimester between January 2010 and December 2017 are presented in Figure 1. The number of patients initiating an anticancer drug for melanoma more than doubled over the study period, from 910 in 2010 to 1890 patients in 2017.

Drastic changes in therapeutic modalities were observed whenever a novel drug became available (Figure 1), leading to very distinct profiles for our 4 cohorts. Cytotoxic chemotherapy was the only therapeutic option in cohort 1, and this was almost entirely replaced by novel therapies in the following cohorts. Vemurafenib, a BRAF inhibitor, became available from the starting date of cohort 2. Cohort 3 had access to ipilimumab as a first-line additional option. The hallmarks of cohort 4 were the availability of anti-PD-1 antibodies as first-line treatment and the combination of MEK and BRAF inhibitors for targeted therapies.

Therefore, the 4 cohorts reflected time periods with very distinct categories of first-line treatment options (Figure 1c). Age, sex and comorbidities among the advanced melanoma patients were fairly stable across the cohorts (Table 1).

Changes over time in patient care trajectories

For each cohort, a visual representation of vital status and treatment lines at 6 and 12 months after a first anticancer drug had been initiated is presented in Figure 2. This descriptive data show how the variety of available drugs impacts care trajectories, not only for first-line treatments but also for subsequent treatment lines.

J o u r n a l P r e -p r o o f

Changes over time in overall survival for metastatic melanoma patients Overall survival in cohorts 2, 3, and 4 was compared to cohort 1. Crude hazard ratios (HR) and 95% confidence intervals (95%CI) were 0.93 [0.87-1.00], 0.69 [0.64-0.74], and 0.54 [0.50-0.57] respectively. After adjustment on age, sex, comorbidities (congestive heart failure, cerebrovascular disease, chronic pulmonary disease, renal disease), number and location of metastatic sites (lymph node, lung, liver, brain, bone), surgical resection of distant metastases and radiotherapy in the 12 months before initiation of the first-line treatment, HR [95%CI] were 0.92 [0.85-0.98], 0.72 [0.67-0.77] and 0.56 [0.52-0.60]. Median, 1-year and 2-year overall survival results in each cohort are provided in Table 2, and survival curves are presented in Figure 3. The estimated effects of patient characteristics, number and location of metastatic sites, prior surgical resection and radiotherapy on overall survival are shown in Supplementary Table S1.

Overall survival according to the first-line treatment received

Overall survival was estimated for the two most widely prescribed first-line treatment categories within each cohort (Figure 4, Supplementary Table S2). The best survival was obtained for patients from cohort 4 treated with anti-PD-1 antibodies as first-line treatment (n=2605; median overall survival: 22.5 months, , 24-month overall survival: 48.4%, 95%CI [45.7%-51.1%]). Patients from cohort 3 receiving ipilimumab as a first-line treatment (n=832) had a median overall survival of 16. 3 months,], and a 24-month overall survival of 42.2%, 95%CI [38.8%-45.5%]. Targeted therapies (which shifted over time from BRAF inhibitor monotherapy to a combination of BRAF and MEK inhibitors) provided increasingly better results according to the time period (median overall survival from 10.6 months [9.5-11.8] in cohort 2 to 15.9 months [14.9-17.7] in cohort 4; 24month overall survival from 24. 4% [21.2-27.5] to 39.6% [36.4-42.8]).

J o u r n a l P r e -p r o o f DISCUSSION From a large overview at French nationwide level, we report an improvement in overall survival among patients with metastatic cutaneous melanoma treated with anticancer drugs over the 2010-2017 period. Two-year overall survival rose from 21 to 44%.

The use of routinely collected data has the potential to provide important information in a public health perspective [START_REF] Booth | Real-world data: towards achieving the achievable in cancer care[END_REF]. The French national health insurance system covers 98.8% of the population living in France and registers all deaths [START_REF] Bezin | The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology[END_REF][START_REF] Tuppin | Value of a national administrative database to guide public decisions: From the système national d'information interrégimes de l'Assurance Maladie (SNIIRAM) to the système national des données de santé (SNDS) in France[END_REF]. It enabled us to identify and follow all French patients with metastatic melanoma without attrition bias. Due to the characteristics of the French health insurance system and the homogeneous public and private hospital coding rules, we can confidently say that every patient treated with systemic anticancer drugs for metastatic melanoma was identified. Patients for whom the metastatic disease was left untreated or was treated exclusively with surgery or radiotherapy were outside the scope of this study (Supplementary Table S3).

Other real-world approaches in melanoma have been developed in France: MelBase is a multicentre bioclinical cohort following more than 1300 patients with advanced melanoma since 2013 [START_REF] Kandel | Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort[END_REF][START_REF] Tétu | Impact of radiotherapy administered simultaneously with systemic treatment in patients with melanoma brain metastases within MelBase, a French multicentric prospective cohort[END_REF]; the RIC-Mel registry includes all-stage melanomas, with a minority of metastatic patients [START_REF] Bocquet-Tremoureux | Efficacy and safety of nivolumab in metastatic melanoma: real-world practice[END_REF]. A vast amount of real-world data from other countries provided information about the effectiveness and safety of novel therapies in different populations [START_REF] Cowey | Real-world treatment patterns and clinical outcomes among patients with advanced melanoma[END_REF][START_REF] Forschner | Improvement of overall survival in stage IV melanoma patients during 2011-2014: analysis of real-world data in 441 patients of the German Central Malignant Melanoma Registry (CMMR)[END_REF][START_REF] Luke | Targeted agents or immunooncology therapies as first-line therapy for BRAF-mutated metastatic melanoma: a real-world study[END_REF][START_REF] Mangana | Multicenter, reallife experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland[END_REF][START_REF] Moser | Comparative-effectiveness of pembrolizumab vs. nivolumab for patients with metastatic melanoma[END_REF][START_REF] Polkowska | Survival of melanoma patients treated with novel drugs: retrospective analysis of real-world data[END_REF][START_REF] Tarhini | Treatment patterns and outcomes for patients with unresectable stage III and metastatic melanoma in the USA[END_REF][START_REF] Whitman | Treatment patterns and outcomes J o u r n a l P r e -p r o o f for patients with advanced melanoma in US oncology clinical practices[END_REF]. However, these studies explore selected population, and therefore have limited generalizability. Little exhaustive data from nationwide population-based registries or databases are available [START_REF] Donia | The real-world impact of modern treatments on the survival of patients with metastatic melanoma[END_REF][START_REF] Jochems | Dutch Melanoma Treatment Registry: Quality assurance in the care of patients with metastatic melanoma in the Netherlands[END_REF].

Registries in the Netherlands and Denmark have addressed several questions on metastatic J o u r n a l P r e -p r o o f melanoma management and provided survival results close to ours [START_REF] Donia | The real-world impact of modern treatments on the survival of patients with metastatic melanoma[END_REF][START_REF] Jochems | Dutch Melanoma Treatment Registry: Quality assurance in the care of patients with metastatic melanoma in the Netherlands[END_REF]. Studies by the Dutch registry focused on a limited time frame, from 2012 to 2015, and on two novel therapied of that period: vemurafenib and ipilimumab [START_REF] Jochems | Realworld use, safety, and survival of ipilimumab in metastatic cutaneous melanoma in The Netherlands[END_REF][START_REF] Schouwenburg | Vemurafenib in BRAF-mutant metastatic melanoma patients in real-world clinical practice[END_REF]. The Danish database enabled patients, treatments and outcomes to be described in 2012 (n=83), 2014 (n=129) and2016 (n=115) [START_REF] Donia | The real-world impact of modern treatments on the survival of patients with metastatic melanoma[END_REF]. Data from a larger population, and over the whole 2010-2017 period, were thus required to study all available immunotherapies and targeted therapies. We here provide this large overview of therapeutic changes and their impact on overall survival, according to the period and the first-line treatment received.

The number of patients starting a first-line anticancer drug for metastatic melanoma over the study period increased twofold between 2010 and 2017. The incidence of melanoma has been steadily increasing by 2.4 and 3.4% a year in men and women respectively over the past decade (Defossez G, Le Guyader-Peyrou S, Uhry Z, Grosclaude P, Colonna M, Dantony E).

Under the hypothesis that this increase fuels the metastatic stage in the same proportion, this increase in incidence explains 22% of the observed increase in newly-treated metastatic melanoma patients. Our data on comorbidities and metastasis profiles do not argue for a reservoir of patients who today would be treated with systemic anticancer drugs whereas they would have been left untreated in the years 2010-2011. Over the study period, we observed an increase in the proportion of patients starting a systemic anticancer drug within one year after a lymphadenectomy. This suggests that patients are now treated earlier in the metastatic course. Roughly, the availability of efficacious treatments could lead to their use for asymptomatic patients presenting radiological evidence of metastasis, while in earlier periods, when only underperforming chemotherapy was available, the treatment was not initiated until the metastases had become symptomatic.

J o u r n a l P r e -p r o o f

A comparison of overall survival across our 4 cohorts evidenced a striking improvement over the study period. This improvement runs parallel to the availability of more and more efficacious anticancer drugs, for which clinical benefits have been demonstrated in many published RCTs [START_REF] Ugurel | Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017[END_REF]. Our data on drug use and therapeutic sequences evidence the dramatic changes that any clinician treating patients with metastatic melanoma has experienced over recent years. It is important to recall, however, that observational studies are prone to biases, most importantly selection and indication bias (D'Agostino and D 'Agostino 2007). Most of the changes in therapeutic management are direct consequences of better therapeutic efficacy (and often better tolerance) of new drugs. But, because the decision to treat or not to treat a patient could differ according to the therapies available, and since we compared survival across treated patients, the improved survival across the cohorts is not only attributable to the improved effectiveness of novel therapies. Concrete examples of clinical situations are presented in the Box. In a situation of such rapid and drastic changes in treatment strategies, propensity score would be of little help [START_REF] Stukel | Analysis of Observational Studies in the Presence of Treatment Selection Bias[END_REF]). We can rather consider that the period is the best global proxy for known and unknown confounders, and we used the period as a relevant and meaningful factor to compare the strategies. In another study involving 837 Danish patients, the same approach of comparing periods demonstrated a similar improvement in survival [START_REF] Donia | The real-world impact of modern treatments on the survival of patients with metastatic melanoma[END_REF].

We report survival according to treatment category within each cohort. As expected, for most treatments, real-world survival in our study was lower than its counterparts reported in RCTs [START_REF] Ugurel | Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017[END_REF]). Excluding patients with brain metastases or severe comorbidities from most RCTs leads to a lack of comparability between trial participants and non-participants [START_REF] Donia | The real-world impact of modern treatments on the survival of patients with metastatic melanoma[END_REF][START_REF] Elting | Generalizability of cancer clinical trial results: Prognostic differences between participants and nonparticipants[END_REF][START_REF] Sanoff | Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma[END_REF]). In addition, the higher toxicity of treatments in a real-world setting alters drug regimens and could lead to reduced effectiveness [START_REF] Fraser | Are patients in clinical trials representative of the general population? Dose intensity and toxicities associated with FE100C-D chemotherapy in a non-trial population of node positive breast cancer patients compared with PACS-01 trial group[END_REF][START_REF] Prasad | Oral Anticancer Drugs: How Limited Dosing Options and Dose Reductions May Affect Outcomes in Comparative Trials and Efficacy in Patients[END_REF]. Only patients treated with first-line ipilimumab in our J o u r n a l P r e -p r o o f study exhibited better survival than those reported in RCTs [START_REF] Ugurel | Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017[END_REF]. Anti-PD-1 antibodies as a second-line therapy (34.7% of patients in our study), which were not available for earlier ipilimumab users, could explain these differences. Among patients treated with targeted therapy as the first line, improved survival across cohorts 2 to 4 was observed, a phenomenon probably due to the availability of different second-line treatments, and also to the arrival of MEK inhibitors combined with BRAF inhibitors, this combination being more efficacious and better tolerated than monotherapy with BRAF inhibitors [START_REF] J O U R N A L P R E -P R O O F Flaherty | Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations[END_REF][START_REF] Larkin | Combined vemurafenib and cobimetinib in BRAF-mutated melanoma[END_REF][START_REF] Long | Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma[END_REF][START_REF] Robert | Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib[END_REF]. We did not directly compare survival rates of patients receiving ICIs vs. targeted therapy, since the latter is only offered to patients with BRAF-mutated melanoma, which could in itself entail a poorer prognosis [START_REF] Bucheit | Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma[END_REF][START_REF] Long | Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma[END_REF][START_REF] Thomas | Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma[END_REF]. Interestingly, distinct shapes of survival curves were observed between patients receiving a targeted therapy (BRAF-mutated melanoma) or an ICI (mostly wild-type melanoma) as first-line treatment. The survival curves crossed at 8 and 9 months for cohorts 3 and 4 respectively. This crossing point had already been identified in RCTs [START_REF] Ugurel | Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017[END_REF]. This suggests a more rapid effect of targeted therapy, and then longer remissions obtained with ICIs and/or an intrinsically poorer prognosis for BRAFmutated melanoma [START_REF] Luke | Targeted agents or immunooncology therapies as first-line therapy for BRAF-mutated metastatic melanoma: a real-world study[END_REF][START_REF] Moser | Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab[END_REF][START_REF] Schilling | First-line therapy-stratified survival in BRAF-mutant melanoma: a retrospective multicenter analysis[END_REF].

Exhaustiveness at nationwide level and the absence of attrition bias are among the strengths of our study, as is the quality of the information enabling the reconstruction of individual care trajectories. Beyond the limitations inherent in observational studies mentioned above, some potential weaknesses should be discussed. First, the identification of chemotherapy is based on ICD-10 Z51.1 coding and we cannot exclude the possibility that a small minority of miscoded Z51.1 hospitalisations were contemporaneous to participation in a clinical trial. Some first-line treatments referred to as "chemotherapy" in cohort 4 were dispensed by investigative centres where cytotoxic chemotherapy as the first-line approach had been J o u r n a l P r e -p r o o f abandoned. This is why the Z51.1-based category has been labeled "chemotherapy & other".

Although we have no means to estimate the magnitude of this potential misclassification, the coding rules and the evolution of the category over the study period argue for a very large majority of true cytotoxic chemotherapies. Second, with the exception for the abovementioned situation, participation in a clinical trial implies no billing to the National Health Insurance, this time period being invisible in our study. Therefore, some so-called first-line treatments may have actually been second-line treatments following participation in a clinical trial. Third, we had no individual clinical data outside the discharge codes, and important information such as the BRAF genotype was not available. According to a report from the French genotyping platforms (INCa 2013), BRAF mutation is presently identified in 37.5% of melanomas, a proportion close to the 33.0% of patients receiving a targeted therapy as the first-line treatment in cohorts 2 to 4.

We here provide an overview of the treatment of metastatic melanoma within a key timeframe that covered major changes in the therapeutic landscape. Real-world studies are complementary to randomized controlled trials for medical evidence. We believe that realworld overviews are helpful for clinicians and patients when considering long-term prognoses and treatment decisions, especially for patients who are under-represented in clinical trials.

They are also useful for clinicians to evaluate their practice at population level and for health authorities in an economic perspective. Despite the achievements in improving survival for metastatic melanoma patients, a majority of patients still die in the short term. In our study, even for cohort 4, 56% of patients died within 24 months after the initiation of an anticancer drug for metastatic melanoma. Further progress towards curing melanoma is clearly needed.

Current hope lies in adjuvant therapy for resected stage III melanoma. Both ICIs and the combination of BRAF and MEK inhibitors have proven efficacy for recurrence-free survival in large RCTs [START_REF] Eggermont | Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma[END_REF][START_REF] Eggermont | Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy[END_REF][START_REF] Hauschild | Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma[END_REF]Long et J o u r n a l P r e -p r o o f al. 2017; [START_REF] Weber | Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma[END_REF]. Large-scale real-world data will be especially insightful in an adjuvant setting. Future research should also implement RCTs in real-world settings, using linkage of electronic health records to administrative databases [START_REF] Booth | Real-world data: towards achieving the achievable in cancer care[END_REF].

J o u r n a l P r e -p r o o f

MATERIALS AND METHODS

Data source

The French national health insurance database (SNDS, Système National des Données de Santé, formerly SNIIRAM, Système national d'information inter-régimes de l'Assurance maladie) covers 98.8% of the entire population living in France (around 66 million inhabitants) and contains exhaustive data on all reimbursements for health-related expenditures, including dispensed drugs with date of dispensation, as well as individual anonymous data on sociodemographic characteristics (e.g. age, sex, area of residence, date of death). Information about all hospitalisations in a public or private hospital is also provided: dates of hospital admission and hospital discharge, diagnoses (using ICD-10 codes, international classification of diseases 10 th revision) and expensive drugs prescribed during hospital stays. Long-term disease status entitling the patient to full health expenditure coverage, including cancers, is also recorded, with diagnoses encoded according to ICD-10.

No biological information is available, notably BRAF mutational status [START_REF] Bezin | The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology[END_REF][START_REF] Tuppin | Value of a national administrative database to guide public decisions: From the système national d'information interrégimes de l'Assurance Maladie (SNIIRAM) to the système national des données de santé (SNDS) in France[END_REF].

Access authorizations

The study protocol was approved and authorized in March 2017 by the French Drug Regulatory Agency (ANSM, Agence Nationale de Sécurité du Médicament). Direct access to the SNDS database was granted by ANSM to our research consortium.

Population selection

We reconstructed a national cohort including every new patient receiving a systemic treatment in France for metastatic melanoma between January 2010 and December 2017. All patients had at least one mention of an ICD-10 code indicating cutaneous melanoma (D03, J o u r n a l P r e -p r o o f C43) and either a mention of chemotherapy (Z51.1 code) or reimbursement for one of the anticancer drugs among the following: vemurafenib, cobimetinib, dabrafenib, trametinib, nivolumab, pembrolizumab, ipilimumab, temozolomide, fotemustine (nota: because of different billing rules, among the classic chemotherapy drugs, the last two could be specifically mentioned, while dacarbazine and other less commonly used drugs came under the Z51.1 code with no specific tracking details). We excluded patients with evidence of another contemporaneous cancer. We excluded patients who had received a systemic treatment for melanoma during the year 2009, so as to retain only newly-treated metastatic melanoma patients between 2010 and 2017 (n=10,936). The detailed selection process is presented in Supplementary Table S4.

Cohort constitution

The 10,936 patients were divided into 4 successive cohorts, according to when their first treatment line was initiated. Dates for availability (including early access programs) of new drug categories were used to define the cut-offs between cohorts (Figure 1). Thus, cohort 1 included patients for whom a first-line treatment was initiated for metastatic melanoma from January 1, 2010 to December 31, 2011. Cohort 2 included patients starting their first systemic treatment after BRAF inhibitors had been available for BRAF-mutated melanomas (i.e.

between January 1, 2012 and October 31, 2013). Cohort 3 included patients beginning their first line of treatment just after the approval of ipilimumab as a first-line treatment (i.e.

between November 1, 2013 andMay 31, 2015). Cohort 4 started with the combination of MEK and BRAF inhibitors for BRAF-mutated melanomas, and anti-PD-1 antibodies, irrespective of BRAF mutational status (i.e. from June 1, 2015 to December 31, 2017).

J o u r n a l P r e -p r o o f

Treatment lines and care trajectories A treatment line was defined as a series of consecutive dispensations of the same drug category. The date of initiation of the treatment line was the date of the first dispensation. The treatment line was considered as discontinued when another treatment line was initiated. If no subsequent treatment was initiated within 3 months after the last recorded dispensation for a given drug category, the treatment line was modelled to end 3 months after the last recorded dispensation. Since ipilimumab is delivered as a fixed series of 4 infusions, patients were considered as receiving it until initiation of subsequent therapy, if any. Otherwise, ipilimumab was modelled to end 3 months after the last infusion. Treatments were defined according to drug categories: targeted therapy, ipilimumab, anti-PD-1 antibodies, combination of ipilimumab and anti-PD-1 antibodies, and chemotherapy. Targeted therapies included BRAF inhibitors (vemurafenib, dabrafenib) and combinations of BRAF and MEK inhibitors (vemurafenib and cobimetinib, dabrafenib and trametinib). Chemotherapy lines included all cytotoxic chemotherapies under the Z51.1 code. Two drugs -temozolomide and fotemustine -were also identified by way of a specific tracking system. A small proportion of Z51.1coded treatment lines could have related to the participation in a clinical trial rather than a sequence of chemotherapy infusions. This is the reason why we labeled the corresponding treatment category as "chemotherapy & other".

Care trajectories from the first treatment dispensation for metastatic melanoma were analyzed using Sankey diagrams. The status of the patient (which treatment does the patient receive? is he/she still being treated? is he/she dead?) 6 and 12 months after the beginning of the first treatment line was determined. The Sankey diagrams show each cohort separately, with cohort 4 restricted to patients beginning their first-line treatment before December 31, 2016, so that every patient had a minimum of 12 months follow-up.

J o u r n a l P r e -p r o o f

Survival analysis

Survival was estimated from the initiation of the first treatment line to the date of death, or until censoring on December 31, 2017. The 12-month, 24-month and median overall survival were estimated using the Kaplan-Meier method for each of the 4 cohorts. Overall survival was also estimated for the two most commonly prescribed first-line drugs in each cohort. As there was no lost to follow-up, each patient from cohorts 1 to 3 had respectively at least 72, 50 and 310 months of follow-up, except in case of death. Overall survival across the 4 cohorts was first compared using a univariate Cox proportional hazards model. To further take into account potential confounders, age, sex, number and location of metastatic sites, prior surgical resection or radiotherapy, and comorbidities were tested for independence using a multivariate backward stepwise Cox regression analysis. Proportional hazards were assessed by plotting log(-log(survival)) versus log of survival time for categorical covariates, and scaled Schönfeld residuals versus survival time for continuous covariates. HR resulting from a follow-up time limited to 31 months for each cohort provided similar results.

Statistical analyses were performed using SAS Enterprise Guide Software (SAS Institute, Inc., USA, version 9.4).

This study followed the REporting of studies Conducted using Observational Routinelycollected health Data (RECORD) guideline.

J o u r n a l P r e -p r o o f

Table 1. Demographic characteristics of metastatic melanoma patients.

Patients beginning a systemic treatment for metastatic melanoma in France between 2010 and 2017 broken down into 4 successive cohorts, according to the time period in which they began the first-line treatment. Patient status was provided 6 and 12 months after the beginning of the first-line treatment. Each Sankey diagram shows the healthcare trajectory of patients belonging to a cohort (cohorts 1 to 4 respectively on panels a to d). Cohort 4 was limited to patients beginning their first-line treatment between June 2015 and December 2016, so that they have a minimum follow-up of 12 months.

Figure 1 .

 1 Figure 1. First-line treatment for metastatic melanoma in France. Evolution over the 2010-2017 period.a. Timeline of novel therapy approvals for metastatic melanoma in France. b. Number of patients beginning a first-line treatment for metastatic melanoma, per trimester and per drug, in France. c. Distribution of first-line treatment for metastatic melanoma, per trimester, in France. Segmentation of 4 successive cohorts according to major changes in first-line treatment used. Anti-PD-1 antibodies include pembrolizumab and nivolumab. Targeted therapies include dabrafenib, vemurafenib, used alone or in combination with trametinib and cobimetinib respectively. Chemotherapy & other include temozolomide, fotemustine, cytotoxic chemotherapies that are not individually identifiable including dacarbazine, and some nonvisible drug dispensations during clinical trials.

Figure 2 .

 2 Figure 2. Changes over time in the healthcare trajectory (2010-2017).

Figure 3 .

 3 Figure 3. Comparative overall survival across the 4 cohorts of advanced melanoma patients in France (2010-2017). Kaplan-Meier curves for overall survival are shown per cohort. Cohorts 1 to 4 correspond to patients receiving a first-line systemic treatment for metastatic melanoma between Jan 2010 to Dec 2011, Jan 2012 to Oct 2013, Nov 2013 to May 2015, Jun 2015 to Dec 1017, respectively.As there was no loss-to-follow-up, all censored patients were individuals who were still alive on December 31, 2017. Two-year overall survival was computed for each cohort.

Figure 4 .

 4 Figure 4. Comparative overall survival (OS) for metastatic melanoma patients within cohorts, according to the treatment received as first-line therapy.

Table 2 .

 2 Comparative overall survival (OS) across the 4 cohorts of metastatic melanoma patients in France. : confidence interval. OS: overall survival.

	Overall survival	Cohort 1	Cohort 2	Cohort 3	Cohort 4
		Jan 2010 -Dec	Jan 2012 -Oct	Nov 2013 -May	Jun 2015 -Dec
		2011	2013	2015	2017
		N=1808	N=2069	N=2334	N=4725
	median OS
	months [95%CI]

CI

ACKNOWLEDGEMENTS

We would like to thank Prof Céleste Lebbé and Prof Jean-Jacques Grob for their critical review of an earlier version of the manuscript. We thank Ms Angela Verdier and Ms Sarah Leyshon for the English language revision.

FUNDING

This work was supported by a grant from the French National Agency for the safety of Medicines and Health Products (Agence Nationale de Sécurité du Médicament -ANSM), France.

ROLE OF THE FUNDING SOURCE

The funding source revised the protocol and critically appraised the internal study report. The funding source had no role in drafting the manuscript.

DATA AVAILABILITY

The protocol and the statistical code are is available on justified request. Under French law and regulations, databases extracted from the SNDS cannot be made available.

DATA ACCESS AND CLEANING METHODS

The authors (FP, SK, AH, EO and AD) had full access to all the data (extracted from the SNDS database) that was used to generate the study population. The database extracted was stored locally in a dedicated and secure data centre: extraction was performed by CNAMTS; csv data files were imported into the MySql database with a physical model consistent with the original SNDS database design; the investigators had no direct access to SNDS.

Different metrics and visual tools were used to check data completeness and fit to expected data extraction: the metrics included the number of patients extracted (compared to the expected number) and the stability of reimbursement frequencies over time in order to validate data completeness at population level.

CONFLICTS OF INTEREST

Dr Boussemart reports personal fees from BMS, grants and personal fees from Roche, personal fees from Pierre Fabre, grants and personal fees from Novartis, grants from MSD outside the submitted work. Dr Lesimple reports grants from Roche, personal fees from MSD, personal fees from Pierre Fabre, personal fees from Novartis outside the submitted work. Prof Oger reports grants from ANSM (French Health Product Agency) during the conduct of the study. Other authors have nothing to disclose.

J o u r n a l P r e -p r o o f


Lucian Florin

Constantin

F L Constantin

Multifrequency terahertz-wave emission and detection with the photomixing approach: theory and experiments

Keywords: low-temperature-grown GaAs photomixer, optical frequency down-conversion, THz frequency comb, THzwave modulation, THz-wave direct detection, THz-wave heterodyne detection

INTRODUCTION

The terahertz-waves are interesting for several applications including high-speed communications, spectroscopy, metrology and medical research [START_REF] Dhillon | The 2017 terahertz science and technology roadmap[END_REF] . Research in THz photonics has been driven by THz time-domain spectroscopy approach (THz-TDS) [START_REF] Mittleman | Sensing with THz Radiation[END_REF] . This approach has a problem of spectral resolution and requires massive femtosecond laser oscillators leading to a high system cost. The optical frequency conversion with a photomixer was developed for compact and cost-effective continuous-wave (cw) THz generation [START_REF] Brown | Photomixing up to 3.8 THz in low-temperaturegrown GaAs[END_REF] . Two cw lasers emitting at frequencies f 1 and f 2 are mixed in an ultrafast photodetector with quadratic response to the optical fields. The photocurrent, oscillating at the frequency of the optical beat f THz =|f 1 -f 2 | in the terahertz domain, drives an antenna to generate monochromatic THz waves. The approach has the advantage to provide narrow spectral linewidth, wide frequency tunability, high dynamic range and high signal-to-noise ratio. The photomixer has been used as transmission element for high-speed communications that reached data rates higher than 100 Gbit/s [START_REF] Yu | 160 Gbit/s photonics wireless transmission in the 300-500 GHz band[END_REF] . In addition, the photomixing approach may provide system integration in compact setups using the silicon photonics technology [START_REF] Harter | Silicon-plasmonic integrated circuits for terahertz signal generation and coherent detection[END_REF] . This contribution addresses the generation and the detection of terahertz frequency combs with a photomixer based on low-temperature-grown GaAs photoconductor coupled to a planar antenna and driven by the optical beat of two continuous-wave lasers. A photomixing signal is generated by applying on the photoconductor an alternative electric field superposed on a bias electric field. The current density in the photomixer, driven by the optical beat, is expressed with carrier lifetimes and velocities that depend nonlinearily on the electric field applied to the photoconductor. A theoretical framework based on unidimensional carrier transport is developed to calculate the amplitudes and the phases of different spectral components of the current density. Bifrequency optoelectronic signal generation is addressed with a photomixer operated with an alternative voltage around zero-bias. Conversely, the photomixer is exploited as a detector for an electric field induced in the photoconductor by THz-waves. The resultant THz electric field is applied on the optically-driven nonlinear photoconductance, leading to rectification and THz-to-MW conversion that are theoretically and experimentally addressed [START_REF] Constantin | Phase-coherent heterodyne detection in the terahertz regime with a photomixer[END_REF] . In addition, THz waveforms are generated by modulation of a microwave synthesizer that drives a frequency multiplier. The heterodyne detection enables phase-sensitive detection of waveforms generated by frequency modulation. *fl.constantin@univ-lille1.fr

PHOTOMIXING SIGNAL THEORY

Frequency mixing is addressed here with a model of unidimensional uniform carrier transport driven by various electric fields applied on the photoconductor. The continuity equations allow to express the total current density :

( ) ( ) ( ) ( ) ( ) ( ) ( ) ⎥ ⎥ ⎦ ⎤ ⎢ ⎢ ⎣ ⎡ ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ωτ + ω + ω ωτ + τ + ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ωτ + ω + ω ωτ + τ ϖ η = 2 2 1 1 1 1 2 p p p p n n n n t cos t sin v t cos t sin v Ad P e t j h (1)
where two laser beams with power P, energy , are used to make an optical beat at the angular frequency ϖ h ω focused on a photoconductive area A with an absorption depth d with a quantum efficiency η. The carrier lifetimes τ n,p have a nonlinear dependence with the electric field [START_REF] Zamdmer | Increase in response time of low-temperature-grown GaAs photoconductive switches at high voltage bias[END_REF] . The last term adds small dependence on the electric field, and here a linear dependence on the total electric field E is considered:

( ) ( ) [ ] T k eE E B p , n p , n 2 λ 3 1 τ τ 0 0 + ≈ (2)
where k B is the Boltzmann constant, e electron charge, T=300 K is the room temperature, τ 0n,0p are the low-field carrier lifetimes and λ is the distance between Coulomb barriers in LTG-GaAs. The carrier drift velocities have a nonlinear dependence on the electrical field [START_REF] Brown | A photoconductive model for superior GaAs THz photomixer[END_REF] , which is expressed as :

( ) ( ) [ ] E v v E v p , n sp , sn sp , sn p , n 0 0 µ 1+ = ( 3 )
where v sn,sp are the saturation velocities and µ 0n,0p are the low-field mobilities for electrons and holes. An oscillating electric field can be applied to the photoconductor by coupling a radiofrequency (amplitude V RF , angular frequency ω RF ) to the electrodes of the antenna. Alternatively, focusing a THz-wave on the antenna induces an equivalent Thévenin voltage on electrodes of the antenna which is expressed in the parallel-plate approximation in terms of the incident THz-electric field (amplitude , angular frequency ω THz , phase ϕ THz ), the effective vector length

inc THz Ε r eff l r
of the antenna and the width of the photoconductive gap r. The total electric field inside the photoconductor can be expressed generally as alternative electric fields superposed to a bias electric field E 0 :

( ) ( ) ( ) ( ) ( THz THz eff inc THz RF RF t cos r l t cos r V E t E ϕ + ω × ⋅ Ε + ω × + = ) r r 0 (4)
The nonlinear electrical response of the photoconductor, arising from the slow electric field dependences of v n,p (E) and τ n,p (E), leads to frequency components of the current density oscillating at angular frequencies ω±nω THz ±mω RF , with m, n integers. This mechanism can be exploited for multifrequency THz-wave generation or detection. The electrical response of the photoconductor is analytically calculated here by expressing the carrier densities and the current density as a power series expansion in terms of the amplitude of the oscillating field at a given bias electric field E 0 .

Let's consider first the case of multifrequency generation with a photomixer operated with an optical beat in the THz domain, a radiofrequency electric field and no bias field. The amplitudes and phases of the spectral components of the current density in the photoconductor are calculated using numerical values from Table 1 and the results are displayed in Fig. 1.(a). The plot shows equidistant spectral components with slightly different phases. Two intense spectral components are situated, as expected, at angular frequencies ω±ω RF . The phases and the amplitudes of the spectral components at ω+nω RF and ω-nω RF are the same. The dependences of the amplitudes and the phases of the spectral components with the amplitude of the oscillating electric field applied to the photoconductor are plotted in Fig. 1.(b). For fields up to a few 10 5 V/m, supralinear increases of the amplitudes are associated with stable values of the phases. Next, the photomixer operated with no bias field is used to detect a monochromatic THz-wave with an optical beat in the THz domain. The detuning between the optical beat and the THz-wave is in the microwave range. The spectral components of the current density are calculated using numerical values from Table 1 and the results are displayed in Fig. 2.(a). The plot displays a dc current density, which corresponds to the rectified signal. There is a microwave spectral component at δω=|ω-ω THz | that correspond to the heterodyne detection signal. In addition, there are spectral components at angular frequencies of the THz-wave, optical beat and at mixing frequencies in the THz domain. Fig. 2.(b) displays a linear dependence of the phase of each alternative spectral component on the relative phase between the THz-wave and the optical beat.

EXPRIMENTAL RESULTS

The experimental setup (Fig. 3) is based on two extended cavity laser diodes emitting at 820 nm. Laser beams with the same power and linear polarisation are spatially superposed with a beamsplitter and focused with an aspheric lens on the photomixer active area. The photomixer is a 2 µm thick LTG-GaAs epitaxial layer grown on a semi-insulating GaAs substrate with a low-field electron recombination lifetime of 1.2 ps. A self-complementary log-spiral antenna with an outer radius of 1.5 mm drives the active area of 8 µm × 8 µm defined with interdigitated electrodes (1.8 µm gap, 0.2 µm width). The extremities of the antenna are connected with wire bonds to a semirigid 50-Ω microwave line addressed with a bias-T. On the DC port is coupled the bias voltage through a choke and, capacitively, the modulation signal from a low-frequency synthesizer (LF). The THz source is an active frequency multiplier (Militech AMC-10-R0000) driven by a microwave (MW) synthesizer. The output has mW-level power in the 75-110 GHz frequency range. The MW synthesizer can be additionally modulated with a radiofrequency synthesizer (RF). The optical beat can be modulated electrically by direct current modulation of a diode laser using a signal provided by RF LO synthesizer. The photomixing signal is recorded with a microwave spectrum analyser with 50 Ω input impedance coupled on the AC port of the bias-T. The synthesizers and the spectrum analyser have an internal impedance of 50 Ω and are phase-referenced to the signal provided by a GPS-driven quartz oscillator with 10 -12 level frequency accuracy. Bifrequency operation of the photomixer driven by an optical beat in the microwave domain is observed by applying a low-frequency modulation signal. Fig. 4.(a) displays the spectrum of the photomixing signal. The spectral components with the highest amplitudes are at ~(1176±2) MHz with similar amplitudes. In addition, less intense spectral components at ~(1176±2×n) MHz for odd n are detected. The amplitudes of all spectral components are calculated with the numerical values from Table 1 and multiplied with a common factor in order to match the measured amplitudes of the two most intense spectral components. The calculated and experimental amplitudes of the spectral components at ~(1176±4) MHz agree. The model predicts also spectral components spaced by an even multiple of the modulation which are not experimentally detected.

DL 1 MW

A THz waveform is generated by frequency modulation of the MW synthesizer with a signal provided by the RF synthesizer. The spectrum of the THz waveform displays frequency components at f c ±nf mod , centered on the carrier frequency f c where n is an integer and f mod is the modulation frequency, with amplitudes proportional to Bessel function J n (β) of the modulation index β. This approach allows to generate a phase-coherent frequency comb in the THz domain with broadband tuning of the carrier frequency and of the modulation frequency by phase-referencing both synthesizers to a clock. A THz-wave at 89.52 GHz is down-converted in the microwave domain using the heterodyne detection and the recorded signal is shown in

CONCLUSION

The generation and the detection of multifrequency THz-waves with a LTG-GaAs photomixer driven with the optical beat of two continuous-wave lasers are theoretically and experimentally demonstrated. The spectral components of the current density in the photoconductor are calculated in the case of the photomixing driven by an alternative electric field superposed to a bias electric field. Nonlinear electrical conduction mechanism is exploited for multifrequency generation in the microwave regime. THz waveforms are generated with a frequency multiplier driven by a microwave synthesizer that is modulated in the radiofrequency range. The optical beat, exploited as a local oscillator, provides down-conversion of the THz-waves to the microwave domain with the photomixer. This contribution demonstrates that the photomixing approach may be reconfigured easily for THz signal processing and may allow integration of local oscillator and mixer functions in a single photonic device.

Figure 1 .

 1 Figure1. (a) Amplitude and phases of spectral components generated with an optical beat at ω=2π×2 THz and a radiofrequency modulation with amplitude E RF =10[START_REF] Harter | Silicon-plasmonic integrated circuits for terahertz signal generation and coherent detection[END_REF] V/m at ω RF =2π×1 MHz. The other parameters used for the calculations are taken from Table1. (b) Dependences of amplitudes and phases in multifrequency generation in the photomixer with an alternative electric field.

Figure 2 .

 2 Figure2.(a) Spectral components of the current density in the photomixer driven with an optical beat at ω=2π×1 THz and a THz-wave that induces an electric field with amplitude E THz =10[START_REF] Harter | Silicon-plasmonic integrated circuits for terahertz signal generation and coherent detection[END_REF] V/m at ω+δω=2π×1.001 THz. The other parameters used for the calculations are taken from Table1. (b) Dependences of the phases of the alternative components of the current density in the photomixer with the relative phase between the THz-wave and the optical beat.

Figure 3 .

 3 Figure 3. Experimental setup. DL1, DL2 diode lasers, SA spectrum analyzer, THzFM frequency multiplier. LF, RF, RF LO , MW synthesizers referenced to a GPS-disciplined Quartz. Inset: equivalent model for the photomixer. Z A antenna impedance, C electrodes capacitance, G d optically-driven nonlinear photoconductance, V THz antenna-induced Thévenin voltage, V DC,RF alternative voltage superposed on a continuous voltage.

Fig. 4 .Figure 4 .

 44 Figure 4.(a) Bifrequency operation of the photomixer in the microwave regime. Optical beat at ω=2π×1176 MHz, modulation at ω m =2π×2 MHz, bias 4 mV, modulation amplitude 5 V at frequency 2 MHz. Combined optical power 2×20 mW. RBW 300 kHz, sweep time 4 ms, 16 video averages. The calculated amplitudes of the spectral components are plotted with red bars. (b.1) Heterodyne detection of a monochromatic THz-wave at 89.52 GHz. (b.2) Heterodyne detection signal for frequency modulation of the THz-wave. (b.3) Heterodyne detection signal for direct current modulation of a laser diode with an adjusted amplitude of RF LO . The amplitudes of the spectral components, proportional with J n (β), are plotted with red bars. Frequency modulation at 2.5 MHz, modulation index β=2.4, combined optical beat power 2×20 mW. RBW=1 MHz, sweep time 5 ms, 10 video averages.

Table 1 .

 1 Experimental parameters for a LTG-GaAs photomixer

	Photoconductor absorption depth d	2 μm	Low-field hole lifetime 8 τ 0n	0.4 ps
	Photoconductor width r	2 μm	Low-field electron mobility 8 µ 0n	400 cm 2 /Vs
	Laser power P	10 mW	Low-field hole mobility 9 µ 0p	100 cm 2 /Vs
	Photoconductive area A	12.56 µm 2	Optical phonon mean free path 7 λ	7 nm
	Laser frequency ν	365.85 THz Distance between Coulomb barriers 7 a	2 nm
	Electron saturation velocity 8 v sn	40000 m/s	Dielectric constant ε	12.8
	Hole saturation velocity 8 v sp	10000 m/s	Antenna resistance R A	72 Ω
	Low-field electron lifetime 8 τ 0n	0.1 ps	Photomixer capacitance C	0.5 fF