Viktorovich Kirill

Ekaterina Kovtunov
email: kovtunov@tomo.nsc.ru

Oleg Pokochueva

Samuel Salnikov

Dennis Cousin

Basile Kurzbach

Sami Vuichoud

Eduard Jannin

Boyd Chekmenev

Danila Goodson

Barskiy

Dr Kirill V Kovtunov

Ekaterina V Pokochueva

Prof. I Oleg G V Salnikov

Dr Samuel Cousin

Dr Dennis Kurzbach

Dr Basile Vuichoud

Sami Jannin

Eduard Y Chekmenev

Boyd M Goodson

] Danila

A Barskiy

Igor V Koptyug

Koptyug

Prof. S Jannin

Prof E Y Chekmenev

Prof. B M Goodson

Dr D A Barskiy

Prof Eduard Y Chekmenev

Richard J Wittebort

Prof P Daniel

Weitekamp

Dr Brian D Ross

) In

Hyperpolarized NMR: d-DNP, PHIP, and SABRE

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

Dissolution dynamic nuclear polarization

Since its invention in 2003 by Ardenkjaer-Larsen and colleagues, [1] dissolution dynamic nuclear polarization (d-DNP) has enabled exceptional sensitivity enhancements in the field of magnetic resonance (frequently greater than 10 000) and turned out to be a real game-changer for various applications includingamong many others -in-vivo cancer detection, treatmentresponse monitoring, [2,3] in-cell NMR [4] , drug development, [5,6] and biomolecular analysis. [7] d-DNP still undergoes significant developments and improvements. The aim of this review is to provide an overview of recent critical developments (Figure 1).

The general principle behind d-DNP

A d-DNP experiment starts with a specific sample preparation that in general uses a solution of one or several chemical compounds that are to be hyperpolarized doped with 10-80 mM of a polarizing agent (PA), generally a free radical molecule. The d-DNP solution is typically vitrified at low temperatures either in-situ within a dedicated DNP apparatus or prior to insertion into the latter. DNP setups provide i) a suitable magnetic field (typ. BDNP = 3.35 -7 T), with ii) low temperatures (typ. TDNP= 1.2 -4.2 K) to ensure a large electron spin polarization of the PAs, and iii) a possibility to irradiate a sample with a microwave (typ. fμw = 94 GHz -188 GHz and Pμw ~ 100 mW) resulting in the desired transfer of polarization from the PA to the nuclear spins of the target molecules, i.e., in dynamic nuclear polarization. The hyperpolarized sample is subsequently dissolved and rapidly transferred either to an MRI or NMR detection device to perform d-DNP enhanced experiments. [1,8]

d-DNP sample formulation

The choice of PA is crucial for a successful d-DNP experiment (a list of popular PAs can be found in references [9][10][11][12] ). The PA solubility, stability, and electron paramagnetic resonance (EPR) parameters are of great importance in DNP. Indeed, the EPR line shape, electronic relaxation rates, and electron spin spectral diffusion rates [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] determine the efficiency of a given DNP mechanism such as the solid effect, the cross effect, or thermal mixing. The efficiency of a given mechanism often depends on the magnetic field and temperature. Different recent approaches towards a better understanding can be found in the works of Wenckebach, [START_REF] Wenckebach | [END_REF] Vega [15] and co-workers or Rosso and others [16] . Two families of PAs are intensively used in d-DNP, namely nitroxide and tri-aryl-methyl (trityl) radicals, the former being especially effective for the polarization of nuclei with large gyromagnetic ratio ( 1 H), , and the latter for low- ( 13 C 15 N, 31 P, 6 Li, 129 Xe, etc.) nuclei.

A high hyperpolarization uniformly distributed over the entire sample is generally achieved on efficiently vitrified samples capturing the spatial distribution of the PAs at the glass transition temperature Tg. Vitrification is typically achieved via the addition of a glassing agent such as glycerol. Recently it was found that such preparations can yet undergo ripening processes on the order of minutes that may influence the efficiency of DNP. [17] The PA concentration often needs to be finely optimized to maximize the hyperpolarization efficiency. However, one must beware of the fact that a too high PA concentration can have important effects on relaxation properties of a sample, especially after dissolution (vide infra) leading to exacerbated polarization losses. Nitroxide-based PAs can in principle be scavenged with vitamin C [18] and trityl can be filtered through precipitation. More recently, alternative sample formulations involving in-situ UV-generated PAs [19] or silica-and polymer-based hybrid polarizing solids (HYPSO [20] and FLAP [21] ) have offered a way to solve this problem.

Polarization, dissolution and transfer

The polarization transfer from the PA's electron spins to nuclear spins of interest is in general induced by monochromatic or frequency modulated [22] polarization to the latter. Polarization levels up to P( 13 C) ≈ 70% in ca. 20 min [23,24] have been achieved. In d-DNP conditions, suspending (gating) the microwave irradiation during the CP contact can improve the efficiency. [25] Sample detection subsequent to hyperpolarization at low temperatures is achieved by dissolution with superheated (sometimes heavy) water and transfer to the NMR or MRI apparatus. Two points need to be considered with respect to the survival of the hyperpolarized spin state during this procedure: i) dissolution and transfer need to be quicker than the involved nuclear relaxation processes, and ii) dilution of the PAs reduces the influence of paramagnetic relaxation enhancements (PREs).

Though dilution of PAs is beneficial to the persistence of hyperpolarization, it does not always suffice to preserve the polarization during transfer. Instead, complete removal of the PAs is desirable. Depending on the sample formulation, this can be achieved by precipitation followed by filtration, [26] phase separation, [27,28] or a dilution-free freeze-melt approach. [29] Additionally, passages through low-or zero-field need to be avoided. To this end, a magnetic tunnel (sustaining a field of ca. 0.9 T) can be used [30] which has, e.g., recently been used for efficient transfer of hyperpolarized water over distances > 5 m. [31] Very recently, it has been demonstrated by Hilty and co-workers how the dissolution and transfer process can be coupled to electroporation of cell suspensions to enable in-cell d-DNP of arbitrary targets. [32]

Samuel

Robustness and repeatability

Though hyperpolarization can provide dramatic sensitivity enhancements exceeding 10 000, it can be of very limited use if robustness and repeatability are not guaranteed. This is in part due to the fact that several steps in the d-DNP process are manual (sample preparation, loading, dissolution) which are potential sources of variability. Nevertheless, a repeatability with a variation coefficient of 3.6% has been demonstrated recently on a home-built instrument, [33] which potentially opens the way to applications of dissolution DNP in fields such as quantitative metabolomics.

Toward transport to remote locations

As d-DNP experiments are quite complex, expert operators are often necessary. In this respect, it has been recently proposed that hyperpolarized substrates could be produced off-site and subsequently transported and dissolved directly on-site. In the liquid-state prolongation of hyperpolarization lifetimes can be achieved by, e.g., the conversion of hyperpolarization into longlived states (LLS). [34,35] Another route towards long-lived hyperpolarization in the solid-state consists in suppressing paramagnetic relaxation by the PAs by using non-persistent lightinduced unpaired electrons. [19] Alternatively, a heterogeneous sample formulation can be employed combined with spin diffusion relayed CP enhanced DNP. [36] Hyperpolarization lifetimes as long as 37 h have been achieved via the latter strategy for [1- [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C]sodium pyruvate.

d-DNP has become one of the most important hyperpolarization methods. It is still constantly transforming and improving with new methodological developments, enabling new applications in many areas of research. Yet, d-DNP experiments are often very expensive and remain restricted to a few groups world-wide, the most recent developments may pave the way to a more widespread applicability of d-DNP in the near future.

Homogeneous Parahydrogen-Induced Polarization

When parahydrogen-H2 in its singlet state-is added in a pairwise manner to asymmetric unsaturated chemical compounds, the symmetry of the nascent hydrogen sites is broken, and it manifests itself as significantly enhanced nuclear spin polarization (also termed hyperpolarization). This effect was first demonstrated by Bowers and Weitekamp in the 1980s, [37][38][39] and the acronym of parahydrogen induced polarization (PHIP) [40,41] was later coined to describe the entire area of experiments when the resulting hyperpolarized (HP) state is produced by employing chemical transformation of parahydrogen (pH2) gas. While PHIP was utilized for studies of chemical reactions in the first 15 years after its invention, [41][42][43] it was not until the 2000s, when the teams of Goldman, [44][45][46][47] Golman, [48] and others [49][50][51] pioneered approaches for intramolecular polarization transfer via spin-spin couplings from nascent parahydrogen protons to significantly longer-lived hyperpolarized [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C carboxyl sites (Figure 2a). Moreover, because the [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C in vivo background signal is low, HP [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C compounds were very quickly shown to be useful in vivo contrast agents in 2001. [48,[52][53][54] Homogeneous PHIP was also utilized for hyperpolarization of non-natural amino acids. [55][56][57] In the context of biomedical imaging applications, it is important that the resulting HP compound is injected as part of an aqueous medium. Two groups of approaches were developed over the years. In the first approach, the reaction of pH2 pairwise addition is performed in the aqueous medium, which is facilitated by a water-soluble Rh-based catalyst. [51,58] The catalyst has a low toxicity profile, [START_REF] Chan | Proc. 17th Sci. Meet. Int. Soc. Magn. Reson. Med[END_REF] and the resulting HP solutions are suitable for studies in animal models. [START_REF] Hövener | [END_REF]61] Future clinical translation would require an additional step of solution purification and removal of such metal-based catalysts. In the second approach, hydrogenation and polarization transfer is first accomplished in an organic solvent, and the HP compound is then extracted into an aqueous medium. [62] The advantage of this approach is the production of pure (catalyst-free) solutions of HP compounds. Typical 13 C T1 of these HP contrast agents in vivo is in the range of 40-60 s. [63] A number of biomedically relevant [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C HP contrast agents were developed. [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C HP 2-hydroxyethyl 1-[ 13 C]-propionate (HEP) was shown to be a useful perfusion imaging agent. [49] 13 C HP 1-[ 13 C]-succinate (SUC) and diethyl 1-[ 13 C]-succinate (DES) were shown to be useful for probing TCA cycle metabolism. [64][65][66][67] 13 C HP tetrafluoropropyl 1-[ 13 C]-propionate (TFPP) [68] has been shown to be useful for probing vulnerable atherosclerotic plaques. [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C HP 1-[ 13 C]-phospholactate [69,70] (which metabolizes into 1-[ 13 C]-lactate in blood [71] ) can be potentially useful for lactate imaging of cancer and heart diseases. In 2015, Reineri and coworkers pioneered PHIP by side arm hydrogenation (SAH), [72,73] where pH2 pairwise addition is accomplished into an ester side arm attached to a carboxyl 13 C moiety. This approach significantly relieves the molecular requirements for unsaturated PHIP precursors. PHIP-SAH enabled hyperpolarization of key metabolites such as 1-[ 13 C]-acetate, [74] 1-[ 13 C]-pyruvate, [75] and 1-[ 13 C]-lactate, [76] and potentially will enable PHIP hyperpolarization of many other [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C-labeled metabolites. HP 1-[ 13 C]-pyruvate is already at the stage of clinical trials using d-DNP. [26] PHIP-SAH is of significantly lower cost (by approximately one order of magnitude) and is a significantly faster (by approximately one order of magnitude) [START_REF] Goodson | EMagRes[END_REF][START_REF] Nikolaou | [END_REF] alternative compared to d-DNP. [1] The key limitation of conventional PHIP is the requirement for a pairwise pH2 addition to an unsaturated substrate. In 2009, Duckett and co-workers pioneered a non-hydrogenative Signal Amplification by Reversible Exchange (SABRE) technique. [91][92][93] In this approach, parahydrogen and a to-be-hyperpolarized substrate molecule undergo simultaneous chemical exchange on a metal (typically Ir [94] ) complex. Spin order is transferred from pH2 protons to a nucleus of the substrate via spin-spin couplings during the temporary formation of the complex shown in Figure 2b. Spontaneous polarization transfer occurs at a wide range of static magnetic fields. For example, the proton nuclei of a substrate are best polarized at magnetic fields of a few millitesla, when the magnetic field is matched to a combination of spin-spin couplings. On the other hand, Theis and co-workers have shown that microtesla magnetic fields provide matching conditions for polarization transfer to heteronuclei such as 15 N and [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C. [95][96][97] The list of amenable nuclei has been expanded to 31 P, [98] 29 Si, 19 F [99] and others. [100] Spontaneous polarization transfer may also occur at high (Tesla) magnetic fields. [101,102] Alternatively, radio frequency irradiation can be used to create level anti-crossings (LAC) [103][104][105] for polarization transfer from parahydrogen to the tobe-hyperpolarized nuclei. [106] Most SABRE experiments to date have been performed in organic solvents, although strategies for SABRE hyperpolarization in aqueous media have been demonstrated, [107][108][109][110][111][112][113] which can potentially become suitable for in vivo experimentations. The latter would require Ir-based catalyst removal, e.g., by filtration. [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C and 15 N sites are arguably the most interesting in the context of biomedical applications due to the ubiquitous occurrence of nitrogen and carbon atoms in biomolecules. 15 N T1 values on the order of 3 minutes [114,115] have been routinely demonstrated. Moreover, SABRE hyperpolarization is especially useful for preparation of HP long-lived spin states (LLSS), [116,117] which have been shown to have relaxation constants up to 23 minutes [116] making the decay rate comparable to that of some radioactive-based contrast agents, e.g. the 11 C isotope. Polarization values of up to 50% have been demonstrated to date, with the entire hyperpolarization procedure requiring approximately 1 minute. [118,119] No fully automated hyperpolarization equipment has been reported so far, although many setups have been described to date. [120] A wide range of nitrogen-based heterocycles, [96,114,[121][122][123] diazirines, [116] sulfur heterocyclic compounds [124] and drugs [125] have been hyperpolarized by SABRE technique, which can potentially become suitable molecular probes of hypoxia, [115,118,126] pH sensing, [127] and other processes [128,129] in vivo, although no in vivo application has been demonstrated yetlargely because SABRE has been widely adopted only during the past few years. [63]

Heterogeneous SABRE

One limitation of SABRE is the requirement of the catalyst to achieve the transfer of spin order from pH2 to the target substrate. For many envisioned applications (including biomedical imaging), contamination of the hyperpolarized agent by the catalyst is prohibitive, necessitating some way to remove the catalyst while still enabling the agent to remain hyperpolarized for immediate use. Recent work with Ir-based heterogeneous catalysts-where the catalyst moieties are covalently linked to solid supports-have demonstrated the feasibility of SABRE hyperpolarization under heterogeneous conditions ("HET-SABRE"). First, Shi et al. observed SABRE enhancements of 1 H spins of pyridine with a variant of the Ir-IMes catalyst immobilized on microscale polymer supports functionalized with 4-dimethylaminopyridine. [130] Although the initial enhancements were modest (~5-fold at 9.4 T), the heterogeneous origin of the SABRE effect was demonstrated. With the idea of improving SABRE efficiency by increasing the surface-area-to-volume ratio, the same group reported nanoscale catalysts with Ir moieties immobilized on TiO2/PMAA (poly(methacrylic acid)) and PVP (polyvinylpyridine) supports with core-shell and "comb" morphologies. [131] These catalysts gave improved results, yielding ~7 and ~40-fold 1 H NMR enhancements at 9.4 T using PVP-based and TiO2/PMAA-based catalysts, respectively. This work also demonstrated successful separation and re-use of heterogeneous catalysts. Very recently, Kovtunov et al. demonstrated an alternative synthesis to attach the Ir catalytic complexes to polymer-functionalized SiO2 microbeads, and used these particles to show SABRE enhancement of heteronuclei under heterogeneous conditions. [132] After administering pH2 gas under SABRE-SHEATH conditions (i.e., within a magnetic shield), enhancements of roughly ~100-fold were observed in the 15 N NMR spectra of 15 N-pyridine at 9.4 T (figure 3). 15 N NMR of the 15 N-pyridine substrate; bubbling was performed inside a magnetic shield (i.e. SABRE-SHEATH conditions). Adapted by permission from John Wiley and Sons, [120].

As an alternative approach for separating SABRE catalysts from HP substrates, Iali et al. recently achieved ~300-3000-fold enhancements using phase-transfer catalysis. [133] In this method, a homogeneous SABRE catalyst is still used in an organic solvent. However, after the hyperpolarization step, the HP substrate is partitioned away from the catalyst into an immiscible aqueous phase.

Heterogeneous PHIP

The commonly used catalysts for heterogeneous hydrogenation and hydrogenolysis processes are nano-sized metal particles dispersed on porous oxide or carbon supports. It is widely accepted that dissociative hydrogen chemisorption takes place on such catalysts, [START_REF] Bond | Metal-Catalysed Reactions of Hydrocarbons[END_REF] and hydrogenation of unsaturated compounds occurs as a successive addition of two hydrogen atoms with intermediate formation of surface alkyl species. [START_REF] Cremer | [END_REF][136][137][138][139] It is also known that adsorbed hydrogen atoms can rapidly move over the surface of metal nanoparticles, [140] embed into the crystal lattice of the metal, [141][142][143] and migrate onto the support (also known as the spillover phenomenon). [144] Therefore, a probability of pairwise addition of two hydrogen atoms from the same H2 molecule to a substrate molecule should be extremely low. Furthermore, after dissociative chemisorption of H2 molecule the adsorbed H atoms become magnetically inequivalent, leading to rapid loss of spin correlation between them. [145] As a result, for a long time it was accepted that PHIP effects could not be observed in hydrogenation reactions over heterogeneous metal catalysts.

However, after successful demonstration of PHIP effects in hydrogenations catalyzed by immobilized metal complexes, [146] it was found that PHIP can also be generated over supported metal catalysts. It was demonstrated that hyperpolarized propane is formed in the gas-phase hydrogenation of propene over Pt/Al2O3 and Pd/Al2O3. [147] This observation indicates that the pairwise addition of hydrogen to unsaturated substrates over supported metal catalysts is possible. However, it should be noted that pairwise addition is not the main route of hydrogenation reactions over supported metal catalysts. For example, in the study mentioned above [147] the contribution of the pairwise hydrogen addition route was found to be ca. 3%, although the actual value can be higher due to the partial loss of hyperpolarization as a result of relaxation process.

For a better understanding of factors affecting the pairwise addition over metal catalysts, systematic investigations were conducted. Zhivonitko et al. [148] studied propene hydrogenation over platinum catalysts, supported on Al2O3, SiO2, ZrO2, and TiO2. It was found that in the case of Pt/TiO2 utilization the percentage of the pairwise addition was considerably higher and reached ca. 2.4%, while for other catalysts it was less than 1%. Such an increase was tentatively explained to be a result of lowtemperature strong metal-support interactions (SMSI), which usually occur after high-temperature reduction of the metal catalysts on reducible supports, e.g. TiO2, Nb2O5, CeO2, and others. [149,150] Later, an analogous study of palladium catalysts supported on the same oxides was performed. [151] The catalysts were tested in gas-phase hydrogenation of propyne and propene with parahydrogen. When Pd/Al2O3, Pd/SiO2, or Pd/ZrO2 were used in propyne hydrogenation, PHIP effects were observed only for the semihydrogenation product propene whereas propane protons did not exhibit hyperpolarization. At the same time, when Pd/TiO2 was used in propyne hydrogenation, enhanced signals were observed for both propene and propane. Similar results were obtained in propene hydrogenation over Pd catalysts where only a Pd/TiO2 catalyst was able to produce PHIP effects for propane.

The next step was the systematic study of the performance of Pt and Pd catalysts supported on Al2O3, SiO2, ZrO2, or TiO2 in hydrogenation of unsaturated C4 hydrocarbons -1,3-butadiene and 1-butyne. [145] It was found that hydrogenation of both substrates results in formation of three products: 1-butene, 2butene (its cis-trans isomers could not be distinguished by gas phase 1 H NMR due to nearly the same values of chemical shifts), and butane. In case of 1,3-butadiene and 1-butyne hydrogenation over Pt/Al2O3, Pt/SiO2, Pt/ZrO2, Pt/TiO2, and Pd/TiO2, PHIP effects were observed for all 1 H NMR signals of each reaction product (Figures 4 and5). Hyperpolarization of 1-butene protons labeled as 3 and 4 (Figure 4) and butane protons in 1,3-butadiene hydrogenation and 1-butene protons labeled as 1 and 2 (Figure 5) and butane protons in 1-butyne hydrogenation can be easily explained by pairwise addition of hydrogen to the corresponding unsaturated bonds. At the same time, observation of PHIP effects for other protons of 1-butene and 2-butene clearly indicates the occurrence of isomerization processes. Another interesting fact was the lack of hyperpolarization for 2-butene and butane in the case of 1,3butadiene hydrogenation over Pd/Al2O3, Pd/SiO2, and Pd/ZrO2, whereas 1-butene exhibited PASADENA [38] signals. At the same time PHIP effects were observed for all products of 1-butyne hydrogenation over these catalysts. Therefore, it can be concluded that the mechanism of hydrogenation reactions is strongly affected by the nature of both the active metal and the support, as well as by the nature of substrate.

Another interesting substrate for heterogeneous hydrogenation with parahydrogen is acetylene. The product of this reaction is ethylene, which in case of pairwise pH2 addition is enriched with certain spin isomers. [152] Such enrichment cannot be detected by NMR spectroscopy due to magnetic equivalence of hydrogen atoms in ethylene; however, if magnetic equivalence is broken, a direct NMR detection becomes possible. Zhivonitko et al. showed that it is possible to obtain a hyperpolarized adduct with distinctive antiphase signals in NMR spectra by addition of perfluoro(para-tolylsulfenyl)chloride to ethylene, which was produced by hydrogenation of acetylene with parahydrogen over Pd/TiO2. [152] It was found that acetylene hydrogenation over palladium nanoparticles of different morphology (cubes, octahedra, cuboctahedra) can also yield C4-oligomeric products (1,3-butadiene, 1-butene, and 2-butene). Such oligomers exhibit high levels of polarization (up to 1.7%). [153] The range of substrates for producing PHIP effects is not limited to unsaturated hydrocarbons only. A successful hydrogenation of α,β-unsaturated carbonyl compounds over various supported catalysts, [154] C6 cyclic compounds, [155] and furan derivatives [156] over Rh/TiO2, Pd/TiO2, Pt/TiO2, and thiophene hydrodesulfurization over MoS2/γ-Al2O3 and Pt/TiO2 [157] with parahydrogen was performed. Such experiments can provide very useful mechanistic information about hydrogenation processes.

A promising class of heterogeneous catalysts for production of hyperpolarized compounds by PHIP are metal oxides, because the mobility of hydrogen atoms on the surface of oxides is significantly lower than on the metal surfaces-increasing the likelihood of pairwise H2 addition. Indeed, in 2014 it was shown that pairwise addition of H2 to unsaturated hydrocarbons (1,3butadiene,1-butyne, propyne) is possible over several oxide catalysts (CaO, Cr2O3, CeO2, PtO2, PdO, and Pt(OH)2). However, the contribution of pairwise hydrogen addition route on such catalysts was comparable with the values for supported metal catalysts. [158] In 2015-2016 Bowers et al. studied propene and propyne hydrogenation over CeO2 nanocrystals of different shape (nanocubes, nano-octahedra, and nanorods). [159] In the case of propene hydrogenation, the percentage of pairwise hydrogen addition was 2.4% for all catalysts, i.e. no dependence on the nanocrystals shape was found. In contrast, in propyne hydrogenation strong influence of crystal shape was observed: for rods the percentage of the pairwise addition was 8.1%, whereas for octahedra it was only 1.6%. [160] Supported metal catalysts may produce PHIP effects not only in gas-phase, but also in liquid-phase hydrogenation. The first examples were hydrogenation of methyl propiolate over Pt/SiO2, Pd/SiO2, Pt/Al-MCM-48, Pt/Al-SBA-15, Rh/C, and hydrogenation of styrene and 1-phenyl-1-propyne over Pt/SiO2. [161] In these experiments organic solvents were used (CD3OD and CDCl3). Later, PHIP effects were demonstrated in the aqueous phase hydrogenation of acrylamide over Rh/TiO2 [162] yielding [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] Chyperpolarized ethyl acetate with the achieved conversion of ca. 90% [163] , and in the liquid-phase hydrogenation of propene performed by bubbling the propene-parahydrogen mixture through the Rh/TiO2 or Rh/Al2O3 catalyst suspension in organic solvent (toluene-d8 or acetone-d6). [162]

Heterogeneous MRI

The main advantage of the use of heterogeneous catalysts in the production of PHIP-hyperpolarized compounds is the possibility to easily separate the reaction product from the catalyst-just as with the case for SABRE, as mentioned in Section 4. Importantly, PHIP allows one to obtain a continuous flow of hyperpolarized gas, which can be used for MRI experiments. One of the most convenient gases is propane, because it is non-toxic (so it can be used for biomedical purposes) and can be easily produced in a hyperpolarized state by hydrogenation of propene with parahydrogen. [164] The first experiments of this kind were performed with the use of Wilkinson's catalyst immobilized on modified silica gel. It was demonstrated that hyperpolarized propane, produced by propene hydrogenation over heterogenized catalyst, could be successfully used for MR visualization of model objects (Figure 6) [165] or catalytic microreactors in situ (Figure 7). [166] However, such catalysts were found to be unstable under reaction conditions and the intensity of hyperpolarized signals was low due to the low catalytic activity. [167,168] Reproduced by permission from The American Association for the Advancement of Science, [154].

In order to get a high-quality MR image, it is necessary to achieve a significant signal enhancement of the hyperpolarized product. Therefore, it is reasonable to use catalysts that provide both high percentage of pairwise addition of molecular hydrogen and high conversion of the reagents. In the study by Kovtunov et al. [164] it was shown that among all metal catalysts supported on titanium dioxide, the best polarization levels are obtained with the use of Rh/TiO2 catalyst with 1.6 nm particles. Despite the fact that maximum achieved percentage of polarization was 1.3%, such an enhancement was enough to perform 3D MRI of hyperpolarized propane (Figure 8). The challenge in utilization of PHIP-hyperpolarized propane gas is the short lifetime of hyperpolarization (~0.6 s at Earth's magnetic field and within high-field MRI scanners). The possible solution is utilization of low magnetic fields in between these limits, e.g. 0.05 T, wherein the hyperpolarized propane relaxation time is ~4.7 s. [169] The challenges of NMR and MRI detection of hyperpolarized propane at such magnetic fields may be overcome by the use of spin-lock induced crossing (SLIC) pulse sequence, [170] which allows one to convert the long-lived pseudosinglet state of hyperpolarized propane into observable magnetization. [169] Further increase in propane hyperpolarization lifetime can be gained by utilization of the deuterated substrate propene-d6. For propane-d6 produced by heterogeneous hydrogenation of propene-d6 over Rh/TiO2, ~6 s relaxation time at 0.05 T magnetic field was reported. [171] The resultant gas can be successfully imaged at low magnetic field. Another promising approach for increasing hyperpolarized propane lifetime is the use of higher pressures. For example, at 7.6 atm hyperpolarized propane relaxation time is ~4.5 s at 9.4 T [172] and ~13 s at 0.05 T. [173] An interesting approach is production of hyperpolarized propene from propyne, which would require the use of a selective catalyst. One of the suitable catalysts is the single-site catalyst. [174] This catalyst demonstrated high selectivity to propene (up to 98%), as well as significant signal enhancement (ca. 3400-fold for CH-group of propene, corresponding to 9.4% polarization), while the conversion of propyne reached 18%. It allowed to acquire 1 H MRI of hyperpolarized propene (shown in Figure 9), which can be used in the future for development of MRI techniques for the in situ visualization of selective catalytic hydrogenations.

Therefore, heterogeneous PHIP can produce catalyst-free hyperpolarized molecules suitable for visualization via conventional MRI which, without doubt, opens up completely new areas of MRI applications in both the biomedical and the material science research areas.

Analytical vision of SABRE and PHIP

Introduction

While major theoretical aspects of PHIP and SABRE (i.e., magnetic field dependence and the efficiency of polarization transfer from 1 H to heteronuclei) are well understood, the polarization dependence on the chemical system parameters (such as reagents/products concentrations, reaction rate constants, etc.) still remain the subject of further study. Complete physicochemical models of the pH2-based hyperpolarization processes could significantly improve the polarization levels and yield of hyperpolarized contrast agents.

In principle, PHIP and SABRE allow transferring 100% of the spin order of pH2 to a variety of heteronuclei in various chemical motifs. [37,39] However, in practice the efficiency of the process is generally much lower than 100% and polarization levels on different substrates rarely achieves 20%. [70,81,118] The net efficiency of the process is limited by several factors including reaction kinetics (i.e., deviation of hydrogenation from the pairwise addition route), equilibration of ortho/para spin isomers of H2 in the presence of metal complexes, low polarization efficiency (from 1 H to heteronuclei) and relaxation/decoherence during the polarization build-up process. [175,176] Here we briefly describe simple models which one to analyze factors that have the most dramatic effect on the final polarization levels in PHIP and SABRE processes. For the sake of brevity, we will mainly focus on homogeneous processes, while heterogeneous (HET) processes can be described similarly.

PHIP Modeling

PHIP is based on a hydrogenation reaction, i.e., an addition of a hydrogen molecule (H2) to a molecular precursor (R), a process that requires the presence of a catalyst. Homogeneous hydrogenation catalysts are typically platinum-group metal complexes in solution. While the detailed mechanism of homogeneous hydrogenation can be quite complex and may involve multiple short-lived intermediates, the end result is straightforward: formation of the reaction product (P).

It can be convenient to describe pH2-based polarization process by introducing concentrations of the so-called "hyperpolarized species". [177] Concentrations of these "fictitious" species are defined as an imbalance between concentrations of molecules in the corresponding spin states. For example, a useful quantity is [H 2 * ] , an imbalance between para-and ortho-H2 [START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C. [74] Given these definitions, it is possible to write down the polarization build-up process in PHIP as the following chemical kinetic scheme:



The first process is the formation of hyperpolarized product P * via pairwise hydrogenation of R by pH2. The second step describes how longitudinal relaxation leads to the disappearance of the hyperpolarized product. One should note that concentration of hyperpolarized species [P * ] decays to zero if thermal polarization is neglected. Hydrogenation reaction kinetics is governed by a kinetic rate constant kH2. However, the polarization process also includes a quantity 𝜆, the polarization transfer efficiency factor. This coefficient may include the magnetic field dependence of polarization transfer and the efficiency of pairwise hydrogen addition. Solving the above kinetic scheme by assuming firstorder hydrogenation kinetics, one can obtain:

  0 2 2 1 2 [] 20 / 1 0 [] 41 [ *]( ) 3 1/ [ ] H k R t H p tT H kH P t e e T k R           
Here, [R] 0 and [H 2 ] 0 are the initial concentrations of the precursor and hydrogen in solution, respectively (here we assume that [R] 0 ≫ [H 2 ] 0 , which is readily achievable in closed vessels such as NMR tubes. Since the NMR signal of hyperpolarized species is enhanced by the factor 𝜂 (defined as the maximal theoretical enhancement) compared to thermally polarized species, the attainable enhancement factor 𝜀 is derived as a ratio of concentrations of hyperpolarized species and thermally polarized species at any given moment in time: PASADENA conditions, and analyzed the results using the equations derived above. [178] This analysis allowed them to accurately measure polarization transfer efficiency (𝜆) for a variety of hydrogenation catalysts at different magnetic fields. Surprisingly, not only concentration of reagents, but also ligand structure, e.g., BINAP (2,2'-bis(diphenylphosphino)-1,1'binaphthyl) vs. DPPB (1,4-bis(diphenylphosphino)butane) had a dramatic effect on 𝜆 . While 𝜆 for both catalysts [Rh(COD)BINAP]BF4 and [Rh(COD)DPPB]BF4 (COD=cyclooctadiene) was the same at the beginning of the hydrogenation reaction, 𝜆 in the case of DPPB started to decline after approximately 350 s, whereas the efficiency of BINAP continued to grow asymptotically toward reaching 0.4. The magnetic field of detection also affected the hyperpolarization process. When hydrogenation was performed at 14 T, the polarization transfer efficiency was 0.3 whereas 𝜆 measured at 7 T was only ~0.05. This observation clearly demonstrates that relaxation and ortho/para-H2 equilibration in the intermediates prior to chemical reaction constitutes a highly relevant loss pathway. Overall, by modeling PHIP one can gain insights into reaction losses and optimize parameters to obtain higher polarization levels for the desired product.

SABRE Modeling

Modeling of the SABRE process can be realized in a manner similar to PHIP. However, the polarization build-up process is more complex and includes additional steps: ⁄ (stage V). The parameter 𝜆 has a similar meaning as in PHIP, i.e., the efficiency of the polarization transfer process. In SABRE, this quantity depends on the NMR parameters of the system and the magnetic field in which the polarization process takes place. Analytical for 𝜆 can be derived for both the high-field SABRE effect based on cross-relaxation [101] and for conventional low-field SABRE (including SABRE-SHEATH) [114] based on coherent redistribution of polarization in the complex. [179] Solving the set of equations corresponding to the kinetic scheme written above, Barskiy et al. showed that the enhancement factor achievable in SABRE experiments can be written as follows: This simple formula allows one to predict the dependence of SABRE enhancement on system parameters such as relaxation rates, reaction rate constants, J-couplings, etc. Remarkably, the formula not only correctly explains the trends observed in other studies (i.e., lower signal enhancements for higher substrate concentrations, linear dependence on the hydrogen supply rate, enhancement "saturation" with the increased catalyst concentration), but also it allows one to predict the optimal substrate dissociation rate which results in the maximal enhancement (given the known J-coupling topology of the polarization transfer complex). The analytical expression also shows that the key parameters of the system that should be optimized are the relaxation rates (especially, 𝑅 c ) and not the dissociation rate constants. Partial deuteration of ligands and substrate molecules is a promising strategy to decrease 𝑅 c and 𝑅 s , particularly for maximizing 1 H SABRE enhancements. Results presented by Rayner et al. confirm this statement by demonstrating several-fold NMR signal enhancement for partially deuterated substrates compared to non-deuterated analogues. [119]

Modeling HET-PHIP/SABRE

Heterogeneous (HET) PHIP and SABRE processes can be described in a similar manner. For example, reaction of gaseous propylene with pH2 over heterogeneous catalysts was characterized using a packed-bed reactor model at continuous flow at a fixed rate of flow. [180] A combined analysis of spin dynamics and reaction kinetics allowed the authors to quantitatively explain the flow rate dependence of NMR signals of hyperpolarized propane in the ALTADENA (Adiabatic Longitudinal Transport After Dissociation Engenders Net Alignment) [181] experiment. Remarkably, the main source of signal reduction in HET-PHIP is relaxation during the free flow in the gas phase and not relaxation of the hyperpolarized propane within the catalyst bed. Nonadiabaticity of the transfer (i.e., too high flow rates) can also reduce the observable signal. Therefore, optimal conditions exist in which a compensation between relaxation losses, adiabaticity of the gas flow, and reaction kinetics allow one to achieve maximal polarization on the molecules in the gas phase.

Therefore, attempts to provide theoretical descriptions of PHIP and SABRE phenomena are accompanied by difficulties of describing both nuclear spin dynamics and chemical kinetics (i.e., combination of coherent and incoherent processes). However, under certain conditions such descriptions are feasible and they can provide valuable information about mechanisms of polarization build-up processes that can be exploited to achieve improved results. Indeed, physicochemical modeling of pH2based hyperpolarization is necessary for optimizing production capability and performance of contrast agentsthe final goal that will enable these hyperpolarization techniques to become valuable tools in biomedicine.

Figure 1 .

 1 Figure 1. Schematic point of view of several key improvements implemented in d-DNP.

  low-power microwave irradiation close to the central EPR transition. Cross-polarization (CP) pulse sequences have recently been coupled to d-DNP to boost performances in DNP of low- nuclei such as 13 C or 15 N by transferring the often higher and faster building 1 H Basile Vuichoud was born in Lausanne (Switzerland) in 1988. He graduated from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in 2013 with a Master in Molecular and Biological Chemistry and in 2017 with a PhD in Sciences, specialized in Nuclear Magnetic Resonance with Prof. Geoffrey Bodenhausen. He is currently working as a Post-doc in the group of Hyperpolarized Magnetic Resonance with Sami Jannin at the University of Claude Bernard Lyon 1 in France. His current researches are focused on various applications for dissolution Dynamic Nuclear Polarization coupled to NMR. Sami Jannin received his PhD in Physics from the EPFL in Switzerland in 2009. Since then, his field of expertise has been centered around dissolution-DNP enhanced NMR. During 7 years he developed this research theme in the group of Geoffrey Bodenhausen, successively as a PostDoc and Bruker staff. In 2016, he was appointed full Professor at the Lyon University in France. His research interests are spanning from the development of new d-DNP methods and instrumentation, to the exploration of various d-DNP enhanced NMR applications in diverse fields such as analytical chemistry, drug discovery, or metabolomics

  F. Cousin graduated from University of Paris (UPMC) and Ecole Normale Superieure (ENS) in 2013 with a Master of Chemistry degree. He did his PhD under the supervision of Fabien Ferrage (ENS, France), and a first postdoc with Lucio Frydman (Weizmann Institute of Science, Israel). He is currently working as a postdoc in Sami Jannin laboratory (CRMN, Lyon). Dennis Kurzbach received his PhD in chemistry at the Max Planck Institute for Polymer Research in 2013 focusing on EPR methods for the characterization of complex soft matter. Subsequently he moved to the University of Vienna developing integrative EPR and NMR approaches for intrinsically disordered proteins. Since 2015 he is coordinating the d-DNP team at the Ecole Normale Supérieure in Paris in the group of Geoffrey Bodenhausen investigating fundamental aspects and developing applications of the method to complex materials such as proteins as well as to multi-dimensional.

Figure 2 .

 2 Figure 2. a) Schematic of the parahydrogen-induced polarization (PHIP)process. Note the symmetry breaking of the pH2 singlet state in the first step of pairwise pH2 addition. Spin-spin couplings (denoted as J) are employed for polarization transfer from nascent parahydrogen nuclear spins to an X nucleus (typically[START_REF] Wenckebach | Essentials of Dynamic Nuclear Polarization[END_REF] C or 15 N). b) Schematic of the signal amplification by reversible exchange (SABRE) process. Note the simultaneous chemical exchange of pH2 and the to-be-hyperpolarized substrate. Spin-spin couplings (denoted as J) enable polarization transfer.

  After graduating from Princeton (1995), Boyd Goodson earned his Ph.D. in 1999 with Alex Pines at UC Berkeley. Following a postdoc with Caltech's Ahmed Zewail, in 2002 Goodson joined SIU Carbondale, and was promoted to full professor in 2014. Recognitions include an NSF CAREER Award. His research concerns MR & optical spectroscopies and NMR/MRI sensitivity enhancement via hyperpolarization.

Figure 3 .

 3 Figure 3. Bubbling pH2 into a solution containing a heterogeneous SABRE catalyst (immobilized on silica supports) yielded ~100-fold enhancement of15 N NMR of the 15 N-pyridine substrate; bubbling was performed inside a magnetic shield (i.e. SABRE-SHEATH conditions). Adapted by permission from John Wiley and Sons,[120].

  photochemistry group of Professor N. J. Turro (Columbia University, New York). He earned his Dr. Sci. (Habilitation) degree in catalysis in 2003 and a title of Professor in 2006; currently, he is the deputy director of International Tomography Center, Siberian Branch of the Russian Academy of Sciences, Novosibirsk. His research interests include signal enhancement in NMR and applications of NMR and MRI in catalysis.

Figure 4 .Figure 5 .

 45 Figure 4. a) Reaction scheme of 1,3-butadiene hydrogenation. (b-c) 1 H NMR spectra acquired in hydrogenation of 1,3-butadiene over Pt/Al2O3 catalyst with b) parahydrogen and c) normal hydrogen. Adapted by permission from Springer Nature: Springer, Top. Curr. Chem. [133] © (2012).

Figure 6 .

 6 Figure 6. a) High-resolution 1 H MRI of a cross-shaped phantom filled with water. b) 1 H MRI of the same phantom filled with thermally polarized propene acquired by selective excitation of the protons of CH2 group of propene. c) 1 H MRI of the same phantom filled with hyperpolarized propane acquired by selective excitation of the protons of CH3 group of propane. Reproduced by permission from John Wiley and Sons, [153].

Figure 7 .

 7 Figure 7. a) MRI of a tightly packed catalytic bed, filled with thermally polarized propene. b) MRI of the same area, filled with hyperpolarized propane.Reproduced by permission from The American Association for the Advancement of Science,[154].

Figure 8 .

 8 Figure 8. a) 3D gradient echo imaging of flowing hyperpolarized propane in a spiral phantom. b) Corresponding image of the same phantom filled with water. Reproduced by permission from John Wiley and Sons, [157].

Figure 9 .

 9 Figure 9. a) 1 H MRI of a 10 mm NMR tube filled with hyperpolarized propene acquired by selective excitation of the protons of CH-(Ieft), CH2-(middle), and CH3-(right) groups of propene. b) Same as a, but with 1 H MRI obtained with thermally polarized propene corresponding protons. All images were acquired under gas-flow conditions. Matrix size and spatial resolution were 64 ˟ 64 and 0.8 ˟ 0.8 mm 2 /pixel respectively. Reproduced by permission from John Wiley and Sons, [162].

  the concentration [P] is determined by the following equation: [P](𝑡) = [H 2 ] 0 (1 -𝑒 -𝑘 H 2 [R] 0 •𝑡 ) . Emondts et al. conducted separate measurements of the reaction conversion, relaxation, and intensities of hyperpolarized signals under

  Dr. Danila A.Barskiy studied Chemistry in Novosibirsk State University where he obtained a Ph.D. degree in 2015 (supervisor Dr. Kirill V. Kovtunov). He then joined the group of Prof. Eduard Chekmenev at the Vanderbilt University Institute of Imaging Science. Currently he is pursuing his research interests at UC Berkeley (Prof. Alex Pines). His research interests include the development of hyperpolarization techniques, the interplay between nuclear spin dynamics and chemical kinetics, and applications of NMR spectroscopy and imaging to study biomedical and industrial processes.

  The polarization build-up starts with the formation of hyperpolarized species C * (i.e. the metal complex and parahydrogen; stage I), whose polarization decays with the relaxation rate constant 𝑅 c = 1 𝑇 1 c ⁄ (stage II). This species takes part in the exchange process with the substrate governed by the substrate dissociation rate constant 𝑘 s d (stage III) and substrate association rate constant 𝑘 s a (stage IV). The hyperpolarized substrate concentration [S * ] decays with a rate constant 𝑅 s = 1 𝑇 1 s

  ] , described as the imbalance in concentration of product molecules in |𝛽⟩ and |𝛼⟩ states: [P * ] = [P |𝛽⟩ ] -[P |𝛼⟩ ] . Here |𝛼⟩ and |𝛽⟩ are Zeeman states of the target to-be-polarized spin-1/2 nucleus in the product molecule, for example,

	concentrations, [H 2 * ] = [H 2 ](4𝑥 𝑝 -1)/3 , where [H 2 ] is a total
	hydrogen concentration in solution and 𝑥 𝑝 is the pH2 fraction. It
	can be shown that, in principle, one mole of [H 2 * ] can be
	completely converted into one mole of the hyperpolarized species
	[P

*

((Author Portrait)) ((Author Portrait)) ((Author Portrait))

((Author Portrait))

Acknowledgements

O.G.S., E.V.P., and K.V.K. thank the Russian Science Foundation (grant 17-73-20030) for the support to NMR studies of ((Author Portrait)) hyperpolarized molecules production in heterogeneous hydrogenation. I.V.K. thanks the Federal Agency for Scientific Organizations (project #0333-2017-0002) for the support to studies of H2 activation. The US team thanks the following funding sources for the support of PHIP and SABRE experiments: NSF CHE-1416268, and CHE-1416432, NIH 1U01CA202229, 1R21EB020323, and R21CA220137, DOD CDMRP BRP W81XWH-12-1-0159/BC112431, DOD PRMRP awards W81XWH-15-1-0271 and W81XWH-15-1-0272, and RFBR (17-54-33037-OHKO_a). S.f.C, B.V and S.J would like to thanks the support of the European Research Council under the European Unions's Horizon 2020 Research and Innovation Programme (ERC Grant Agreement No. 714519/HP4all), the ENS-Lyon, the French CNRS, Lyon 1 University. Keywords: parahydrogen • hyperpolarization • DNP • PHIP • SABRE

Title(s), Initial(s), Surname(s) of Author(s)


Antoine Costes

Fabien Danieau

Argelaguet Ferran

Anatole Sanz

Philippe Lécuyer

Guillotel

Ferran Argelaguet

Anatole Lécuyer

Philippe Guillotel

A Holistic Approach for Haptic Texture Mapping

Keywords: texture, compliance, roughness, friction, temperature, haptic material

come

Introduction

3D scanning techniques have flourished in the last decade, giving the possibility of digitizing real-life objects in a photo-realistic way. How could and should such virtual objects be enhanced with haptic properties in a touch-realistic way? Which features are to be considered, and how to store them in a standard format?

As for today, there is no obvious, generalized way to provide haptic properties to a virtual object, and most haptic rendering setups rely on custom and specific data formats. Even "holistic" systems [START_REF] Kammermeier | Display of holistic haptic sensations by combined tactile and kinesthetic feedback[END_REF][15] [START_REF] Drif | Design of a Multilevel Haptic Display[END_REF], aiming at an exhaustive combination of haptic actuators, did not clearly address the question of holistic haptic data. This lack of standard representation impedes the whole computer haptics pipeline, from acquisition to rendering. A common, standardized way of storing haptic data would help to unify the approaches, simplify the processes, to facilitate setups' compatibility, and to spread haptic databases.

If the CHAI3D project 3 is an example of unifying achievement regarding force feedback, its extension to other technologies like pin arrays, vibrators and thermal displays remains to be done, and stresses the need for a generic format addressing multi-cues rendering. Such a format would ideally comprise sufficient information for the rendering of any perceptually meaningful feature, and rely on standard metrics.

Haptic perception of surfaces is commonly divided in four main components: compliance, surface geometry, friction and warmth [START_REF] Tiest | Tactual perception of material properties[END_REF]. In order to express these properties, haptic devices produce four types of physical cues: kinesthetic, cutaneous, vibratory or thermal. Holistic haptic data should take into account all combinations between those percepts and cues, but most of them have been addressed separately, and they were never combined in a single format so far.

Texture mapping refers to a set of techniques to efficiently display fine the details of a 3D model in a realistic way without the need of a high-resolution mesh [START_REF] Heckbert | Survey of Texture Mapping[END_REF]. Originally developed in computer graphics, this approach has been advantageously applied to haptic rendering [START_REF] Kim | A haptic-rendering technique based on hybrid surface representation[END_REF], but mostly in a hardware-specific way, with a limited range of haptic features. Following this approach, virtual objects can be seamlessly enhanced with additional haptic properties distributed on their surfaces, that are easy to edit and to visualize. Furthermore, the use of separated layers is appropriate to merge heterogeneous data.

In this paper, we propose the notion of "haptic material" as a reference to the similar notion of "materials" in computer graphics. In computer graphics, materials are handy packages with all the data required for the visual rendering of a virtual object. As an analogy, the haptic material should provide all the necessary elements for haptic rendering. Our format takes in account ten different spatially distributed haptic features, which we extract from previous literature in order to cover the possible combinations of four haptic percepts and four rendering cues. The ten haptic features are stored in haptic maps, which provide an intuitive way to visualize them and facilitates many tasks related to haptic design. We provide therefore two contributions:

an analysis of the literature on haptic surface perception, according to both psychophysical quantities and rendering cues, leading to ten elementary haptic features a new haptic material format, which extends the texture mapping approach to these ten complementary features, so to be compatible with a large variety of hardware

In the next section, we show from previous experimental findings that ten elementary haptic features can be used in a complementary way for the rendering of haptic surfaces. Then, we present a new format that extends texture mapping to these ten features, storing them spatially in ten dedicated haptic maps. We provide a detailed example of a texture and the ten associated maps, as well as a general-case specification table.

Ten relevant features for haptic surfaces

Decades of research on touch perception showed that pressure forces, vibrations, friction forces and temperature are perceived in a complementary way, resulting in four distinct percepts (for review see [START_REF] Tiest | Tactual perception of material properties[END_REF] and [START_REF] Okamoto | Psychophysical dimensions of tactile perception of textures[END_REF]):

-compliance refers to the perception of deformation modalities, -surface geometry refers to shape, reliefs and asperities, -friction refers to sliding-related sensations, -warmth refers to perceived temperature differences. These perceptual dimensions, or percepts, arise from the reception of different types of cues by various body receptors:

-cutaneous cues, relating to contact area and skin deformation, are mainly sensed by SA-I, SA-II and FA-I in the region of contact, -vibratory cues, relating to rapid deformation, propagate trough the limbs and are mainly sensed by FA-II receptors in deep tissues and joints, -kinesthetic cues, relating to limb movements and efforts, are mainly sensed by proprioceptors located in muscles and joints, -thermal cues, relating to the heat flux transmitted by contact, are sensed by thermoreceptors in the region of contact.

Despite a tempting correspondence, these four types of cues do not match directly the four perceptual dimensions of texture perception. Indeed, finger pad deformations, contact vibrations and constrained motion are not specific to a given property, but can rather arise from compliance, geometry or friction attributes. For instance, the compliance of an object can be felt and judged either by the vibrations occurring on contact, by the fingertip deformation under pressure, by the movement due to object indentation, or by any combination of those. Thus, the compliance percept arises from three distinct stimuli, depending on the context. Therefore, the three mechanical dimensions can be decomposed according to the three possible mechanical cues, leading to nine haptic mechanical features. The thermal cues, in contrast, appear to match the dimension of warmth.

In the next subsections, we detail these ten elementary haptic features and show how previous studies stated their specific complementary contributions to haptic perception. For each of them, we identify the corresponding perceptual metric proposed by the literature when there is one, or suggest one according to the results and terms of previous research, as summarized in Table 1.

Compliance features

Although compliance has been traditionally assimilated to stiffness (force/displacement ratio, independent of damping), the "spring force" approach has been found to have both realism and technical stability limitations [START_REF] Van Beek | The effect of damping on the perception of hardness[END_REF]. A variety of approaches intended to replace it with better representative quantities.

Kinesthetic cues:

Considering the gestual aspect of compliance that is felt through proprioception, the "rate-hardness" metric has been proposed to better match the psychophysical quantity that is actually perceived [START_REF] Lawrence | Ratehardness: A new performance metric for haptic interfaces[END_REF]. Ratehardness is defined as the initial rate of change of force over the penetration velocity, and is used to simulate both stiffness and damping behaviors with better stability. Kinesthetic Rate-hardness [START_REF] Lawrence | Ratehardness: A new performance metric for haptic interfaces[END_REF] Local surface orientation [START_REF] Dostmohamed | Trajectory of contact region on the fingerpad gives the illusion of haptic shape[END_REF] Kinetic friction [START_REF] Mullenbach | ActivePaD surface haptic device[END_REF] /

Cutaneous

Contact area spread rate [START_REF] Bicchi | Haptic discrimination of softness in teleoperation: the role of the contact area spread rate[END_REF] Local indentation [START_REF] Shimojo | Human shape recognition performance for 3D tactile display[END_REF] Static friction [START_REF] Provancher | Fingerpad skin stretch increases the perception of virtual friction[END_REF] / Vibratory Dynamic stiffness [START_REF] Higashi | Hardness perception by tapping: Effect of dynamic stiffness of objects[END_REF] Stroke spectral response [START_REF] Kuchenbecker | Improving contact realism through event-based haptic feedback[END_REF] Stick-slip [START_REF] Konyo | Alternative display of friction represented by tactile stimulation without tangential force[END_REF] / Thermal / / / Thermal profile [START_REF] Tiest | Tactile perception of thermal diffusivity[END_REF] Cutaneous cues: Pressing an object does not only bend its surface, but also flattens the fingertip, producing a change in contact area that is very precisely detected by receptors in the skin. Somewhat counter-intuitively, these cutaneous cues have been found to be much more important than kinesthetic cues in the perception of compliance [START_REF] Bergmann Tiest | Cues for haptic perception of compliance[END_REF]. Rather than force or pressure distribution, the change in contact area seems to be the decisive element for softness judgments, leading to interesting illusion cases [START_REF] Moscatelli | A change in the fingertip contact area induces an illusory displacement of the finger[END_REF]. The "contact area spread rate" (CASR) has been proposed as a metric [START_REF] Bicchi | Haptic discrimination of softness in teleoperation: the role of the contact area spread rate[END_REF]. It is defined as the rate by which the contact area spreads over the finger surface as the finger presses a surface.

Vibratory cues:

Examining the compliance of a specimen can also be achieved with a probe with similar performances [START_REF] Friedman | Magnitude estimation of softness[END_REF]. The transient vibrations produced by tapping are known to be important hardness cues, improving rendering both realism [START_REF] Kuchenbecker | Improving contact realism through event-based haptic feedback[END_REF] and manipulation performances [START_REF] Kontarinis | A tactile shape sensing and display system for teleoperated manipulation[END_REF]. Their capture and modeling has been extensively studied in the form of a single-frequency decaying sinusoid [START_REF] Hwang | Toward event-based haptics: rendering contact using open-loop force pulses[END_REF]. However this approach oversimplifies the richness of real tapping transients, as realism is improved when larger spectral characteristics are taken into account [START_REF] Higashi | Hardness perception by tapping: Effect of dynamic stiffness of objects[END_REF]. Moreover, the relationship between the fundamental frequency of the transient and the physical properties of the material are unclear [START_REF] Higashi | Effects of mechanical parameters on hardness experienced by damped natural vibration stimulation[END_REF]. Thus, Higashi et al. proposed to use spectral impulse response profiles, which they called "dynamic stiffness", to characterize compliant virtual objects. It is typically modeled by an autoregressive filter with a few dozen of coefficients.

Surface geometry features

Surface geometry comprises relief patterns from large-scale curvature, or shape, to small-scale asperities, or texture. Texture is usually split into two categories: "fine" roughness refers to asperities below 0.1mm and is felt through stroke vibrations, while "coarse" or "macro" roughness refers to reliefs at the millimeter scale that can be well perceived with static cutaneous contact [START_REF] Hollins | Evidence for the duplex theory of tactile texture perception[END_REF] [START_REF] Okamoto | Psychophysical dimensions of tactile perception of textures[END_REF]. On the other hand, the two devices of [START_REF] Benko | Normaltouch and texturetouch: High-fidelity 3d haptic shape rendering on handheld virtual reality controllers[END_REF] exemplify the difference between local and and global shape rendering.

Vibratory cues: The perception of fine roughness have been extensively studied with respect to various geometrical parameters (see [START_REF] Tiest | Tactual perception of material properties[END_REF] for a review), but was also shown to correlate with different physical measurements, depending on the subject [START_REF] Tiest | Haptic and visual perception of roughness[END_REF]. To circumvent this issue, more recent approaches focus on the quality of the spectral restitution of vibrations measurements from real materials thanks to autoregressive filter modeling [START_REF] Mcmahan | High frequency acceleration feedback significantly increases the realism of haptically rendered textured surfaces[END_REF] [START_REF] Culbertson | Refined methods for creating realistic haptic virtual textures from tool-mediated contact acceleration data[END_REF]. Doing so, the wide spectral response to stroke is saved in a compressed format, from which stroke vibrations can be reproduced with a high fidelity.

Cutaneous cues: Asperities at the millimeter scale indent the fingertip on simple contact. Haptic research has a rich history of pin array devices (see [START_REF] Benko | Normaltouch and texturetouch: High-fidelity 3d haptic shape rendering on handheld virtual reality controllers[END_REF] for a review) reproducing these local indentations at fingertip receptors resolution.

Kinesthetic cues: Relief patterns with a curvature higher than the one of the finger require an active exploration to be felt. Thus, they involve proprioceptive information in addition to fingertip contact sensations. Several studies demonstrated that local surface orientation (integrated with tangential trajectory) is the dominant source of information for shape, rather than vertical displacement for example [START_REF] Dostmohamed | Trajectory of contact region on the fingerpad gives the illusion of haptic shape[END_REF] [25].

Friction features

Friction refers to the variety of contact interactions refraining the relative movement between two touching bodies. Friction modeling is a complicated topic (for a review, see [START_REF] Armstrong-Helouvry | Survey of models, analysis tools and compensation methods for the control of machines with friction[END_REF]), and even the most sophisticated models remain based on simplistic empirical laws. They generally match the different regimes observed experimentally by conditionally switching between several different relationships [START_REF] Kikuuwe | Fixed-step friction simulation: from classical Coulomb model to modern continuous models[END_REF]. Although some refined models involve additional parameters, we will only consider here the very few common fundamentals of most approaches. The most essential distinction is made between sliding and stiction, that is when the two object are respectively resting or moving relative to each other. In both cases, friction is traditionally described through the ratio between the resistive tangential force and the normal force on contact, also called friction coefficient.

Cutaneous and Kinesthetic cues: When a finger starts stroking a sticky surface, if the tangential/normal force ratio is low, the finger pad deforms without sliding until a certain limit, defined by the static friction coefficient. Overcoming this threshold and actually stroking the surface leads to experience a dynamic resistance to movement, that is given by kinetic friction coefficient (assuming no lubricant) [START_REF] Kikuuwe | Fixed-step friction simulation: from classical Coulomb model to modern continuous models[END_REF]. We believe it is reasonable to state that the friction cues are mainly cutaneous under stiction, and mainly kinesthetic under sliding.

Vibratory cues:

The vibratory phenomenon that is eventually observed on the transition between stiction and sliding is called stick-slip. There is little consensus on the very description of the stick-slip phenomenon. If some approaches consider it as the implicit result of the stiction-sliding transition [START_REF] Drif | Design of a Multilevel Haptic Display[END_REF], it can be more explicitly treated with a dedicated vibrator [START_REF] Konyo | Alternative display of friction represented by tactile stimulation without tangential force[END_REF]. We will consider here a vibratory modelling similar to the one of fine roughness, that is a spectral response to stroke, as it is both explicit and extensive.

Thermal features

Temperature is a crucial parameter for material discrimination, but humans are much more sensitive to temperature differences rather than absolute temperatures [START_REF] Jones | Material discrimination and thermal perception[END_REF]. Psychophysical judgments of thermal features mainly rely on both target temperature and initial heat extraction rate, that is proportional to thermal diffusivity [START_REF] Tiest | Tactile perception of thermal diffusivity[END_REF]. From these two parameters, a thermal display can elaborate realistic cooling or warming profiles simulating the behavior of real materials. We will thus consider here exponential decay profiles, defined using heat extraction rate as tangent at origin, and target temperature as end value.

Discussion

To sum up, we propose to characterize haptic surfaces with ten elementary features, given by the possible combinations of physical cues and psychophysical percepts. Taken together, experimental results indicate that the more features are rendered, the more realistic the virtual material is. However, this has to be put in balance with technical limitations, as most actuators are specialized in a given stimulus. For instance, several studies stated that cutaneous cues dominated kinesthetic cues for compliance discrimination [START_REF] Bergmann Tiest | Cues for haptic perception of compliance[END_REF], but one should note that CASR displays do not have the popularity and technical accessibility that force-feedback devices have. Table 2 provides a summary of the technical solutions that are typically used to provide these ten different types of stimuli.

Yet, very little is known about the relative importance of each cues for a given percept. For instance, in the case of compliance, the relative importance of vibratory cues is unknown. The systematic study of cues relative importance for compliance, surface geometry and friction perception is needed to determine an optimal combination of stimuli for a given haptic experience to be realistic.

It should be kept in mind that the proposed conceptual distinction between cues is not tight and comprises some overlap. The most clear case is certainly the one of surface geometry. The well-documented "duplex theory" states that vibratory cues are necessary to perceive reliefs below 0.1mm, and that coarser asperities are correctly perceived with static contact only, however vibratory cues contribute to coarse roughness perception through dynamic contact [START_REF] Hollins | Evidence for the duplex theory of tactile texture perception[END_REF]. Also, it can be argued that the cutaneous and kinesthetic perceptions are hardly separable, as both local indentation and surface orientation integrate finger pad deformation with trajectory to form a spatially distributed percept. Nevertheless, the display of haptic shape at different scale involve different stimuli [START_REF] Hayward | Display of haptic shape at different scales[END_REF], and it seems reasonable to consider three different orders of magnitude relatively to the size of a finger, insofar the finger is clearly affected in three different ways, namely vibrations, indentation and compression.

Table 2: Typical rendering devices used to render each of the ten percept/cue combinations.

Compliance

Geometry Friction Warmth Kinesthetic Normal force feedback [START_REF] Lawrence | Ratehardness: A new performance metric for haptic interfaces[END_REF] Parallel platform [START_REF] Dostmohamed | Trajectory of contact region on the fingerpad gives the illusion of haptic shape[END_REF] Variable friction display [START_REF] Bau | TeslaTouch: electrovibration for touch surfaces[END_REF] NA Cutaneous CASR display [START_REF] Bicchi | Haptic discrimination of softness in teleoperation: the role of the contact area spread rate[END_REF] Micro-pin array [START_REF] Shimojo | Human shape recognition performance for 3D tactile display[END_REF] Tangential force feedback [START_REF] Drif | Design of a Multilevel Haptic Display[END_REF] NA

Vibratory

Vibrator (tapping transients) [START_REF] Higashi | Hardness perception by tapping: Effect of dynamic stiffness of objects[END_REF] Vibrator (stroking response) [START_REF] Kuchenbecker | Improving contact realism through event-based haptic feedback[END_REF] Vibrator (stroking transients) [START_REF] Konyo | Alternative display of friction represented by tactile stimulation without tangential force[END_REF] NA

Thermal NA NA NA Peltier module [9]
Finally, the vibrations conveying either roughness or friction information are hardly separable in practice, whether for acquisition or rendering, as they both arise from the rubbing of the surface. One can hypothesize that they match different spectral or temporal patterns: for instance the friction information being mainly characterize by abrupt changes and transient dynamics while the roughness information would be expressed by stable patterns for a given speed and force. However this hypothesis remains hard to evaluate experimentally.

Holistic haptic texture mapping

In this section, we present a new haptic material format suited for multi-cues haptic rendering without prior knowledge on display hardware. Based on the ten complementary haptic features identified in the previous section, our format associate a texture (or image) with ten dedicated haptic maps. Our haptic material can be associated to the 3D mesh of a virtual object to provide all the necessary information for haptic rendering at any point of the surface, similarly to a virtual material for visual rendering.

Related work in haptic texture mapping

If texture mapping has been extensively used for haptic rendering of small-scale geometry (see [START_REF] Theoktisto Colmenares | A hybrid rugosity mesostructure (HRM) for rendering fine haptic detail[END_REF] for a review), only a few authors extended the method to other haptic features. Kim et al. used a single "material map" containing both stiffness and friction values [START_REF] Kim | A haptic-rendering technique based on hybrid surface representation[END_REF], while Wakita et al. stored them sperately in two gray-scaled maps [START_REF] Wakita | A texturebased haptic model design with 3D brush[END_REF]. Kamuro et al. used three different gray-scaled maps for stiffness, friction and vibrotactile features [START_REF] Kamuro | Haptic editor[END_REF]. In addition, each one of these three papers also described a "paint-like" interactive interface for local editing of haptic properties in an intuitive manner. Finally, Kim et al. proposed a method to embed diffuse, depth, stiffness and damping maps in a single 24-bit image [START_REF] Kim | Haptic annotation for an interactive image[END_REF]. They also suggested an audio-vibrotactile rendering as an alternative to force-feedback, but did not mention other types of rendering. Although these different works had very similar approaches, each of them involved a custom format for haptic data that is not directly compatible with the other setups.

The holistic image format

By extending texture mapping to a variety of features, our holistic image format benefits from its intuitive visualization and rapid editing possibilities. The ten haptic maps can be elaborated either from real-world measurements and/or perceptual models, but can also be sketched manually.

In our illustrative example, a wooden texture image (see Fig 1a), taken from a high quality scan-based texture package [START_REF]Mura Vision[END_REF], is augmented with ten haptic maps. For sake of simplicity our haptic maps are all defined either as regular grayscale or RGB images. In addition, we will assume that vibratory features are defined in the form of regression models [START_REF] Culbertson | Refined methods for creating realistic haptic virtual textures from tool-mediated contact acceleration data[END_REF] [START_REF] Higashi | Hardness perception by tapping: Effect of dynamic stiffness of objects[END_REF], defined in specific files stored together with the haptic image. Therefore, the vibratory maps store only the references to vibration models, similarly to [START_REF] Kamuro | Haptic editor[END_REF]. 2e) contains the vertical coordinates of the surface with respect to the 3D mesh. Both are defined as it commonly is in computer graphics, and were provided within the texture package. In the absence of measurement from the real material, all other maps were visually sketched from the texture visuals. The rate-hardness, CASR, static friction and kinectic friction maps (respectively Figure 2a, 2d, 2c, and2f) store eponymous values in 8-bit maps. Finally, the dynamic stiffness, stroke spectral response and stick-slip maps provide references to their respective models stored in separate files.

The thermal map (Fig 1b) is a 24-bit RGB image. The R and G channels are respectively used to store the local values for relative temperature and the thermal diffusivity (B channel is not used). The local temperature values are defined relatively to ambient temperature (which is defined assigned to the whole virtual object, like mass). As detailed on (Fig 1b), the color shades arise from a uniform dark green value expressing the uniform low thermal diffusivity of wood, and uneven local temperatures due to an potentially invisible heat source. Fig. 2: Examples of the ten haptic maps of the holistic haptic image format, organized along perceptual dimensions and physical cues.

Format specification table

Our haptic format benefits from texture mapping's technical maturity: when using haptic materials, user can seamlessly make use of tiling or unwrapping.

Texture mapping techniques also addressed extensively the trade-off problem between resolution and performance, leading to various tricks like anti-aliasing and mipmapping. When applying this approach to haptics however, the question remains delicate as the different haptic maps address different physical quantities, matching different perceptual thresholds that might not have been directly address in previous literature. As an example, it is not trivial to decide which range and resolution should be required for a static friction coefficient.

Therefore, we propose a general-case specification table to define the format, range and resolution for haptic maps content. In specific contexts requiring other ranges or enhanced precision, custom specifications could be used to interpret the maps in the appropriate way. Table 3 summarizes the units, range and resolutions for each metric. In this paper, we presented a new format for haptic texturing taking into account ten different haptic features, which are complementary both from a technical and a perceptual point of view. This format provides a generic description of haptic materials without prior knowledge on display hardware. The possibility to edit haptic properties directly on volumetric objects through a haptic interface opens the way to fast-prototyping haptic design, providing means of quick experimental iterations to sensory designers in the production of multi-sensory experiences.

Besides, this format especially suited for the constitution of haptic databases, which are meant to be shared between haptic researchers using various devices. Yet, the optimal complementarity between the ten features remains to be ensured by the systematic study of pyschophysical thresholds and relative importance of each cues, which represents a consequent body for future research. An unified rendering software solution remains also a challenging following. Finally, the topic of haptic material acquisition is still an open research question, as both real-world measurements and synthesis models have strengths and limitations.

Fig. 1 :

 1 Fig. 1: Example of a visual image and thermal map revealing a hidden piping system.

  (a) The visual image. (b) The thermal map and its two channels.

Figure 2

 2 Figure 2 presents an example of the ten haptics maps. The normal map (Figure 2b) stores the orientation of the surface for any point on the image. The height map (Figure2e) contains the vertical coordinates of the surface with respect to the 3D mesh. Both are defined as it commonly is in computer graphics, and were provided within the texture package. In the absence of measurement from the real material, all other maps were visually sketched from the texture visuals. The rate-hardness, CASR, static friction and kinectic friction maps (respectively Figure2a, 2d, 2c, and 2f) store eponymous values in 8-bit maps. Finally, the dynamic stiffness, stroke spectral response and stick-slip maps provide references to their respective models stored in separate files.The thermal map (Fig1b) is a 24-bit RGB image. The R and G channels are respectively used to store the local values for relative temperature and the thermal diffusivity (B channel is not used). The local temperature values are defined relatively to ambient temperature (which is defined assigned to the whole virtual object, like mass). As detailed on (Fig1b), the color shades arise from a uniform dark green value expressing the uniform low thermal diffusivity of wood, and uneven local temperatures due to an potentially invisible heat source.

Table 1 :

 1 Representative quantities for the ten haptic percept/cue combinations.

	Percepts → Cue Types ↓	Compliance	Geometry	Friction	Warmth

Table 3 :

 3 General specification table for the features stored in the haptic maps. Vibratory maps are not considered as they store only references.

	Haptic feature	Format	Range	Resolution
	Rate-hardness	8-bit	0-10000 N.s -1 /m.s -1	40 N.s -1 /m.s -1
	Contact area spread rate	8-bit	0-25.6 N/cm 2	0.1 N/cm 2
	Local surface orientation 3x8-bit	2 x 0-180 •	0.002 •
	Local indentation	8-bit	±5mm	0.04mm
	Kinetic friction	8-bit	±5	0.04
	Static friction	8-bit	±5	0.04
	Relative temperature	8-bit	±25.4 •	0.2 •
	Temperature slope	8-bit	0-5.0 • /s	0.02 • /s
	4 Conclusion and future work

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