Tesis sobre el tema "Near-Alpha"

Thesis (Ph. D.) -- University of Maryland, College Park, 2004.
Thesis research directed by: Material Science and Engineering. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

The ambient temperature fatigue response of the near alpha titanium alloy Timetal 834 has been evaluated using specimens manufactured from two material sources:- hot-rolled barstock and an isothermally forged compressor disc. The effects of dwell periods imposed at peak stress and different R values were assessed. Significant differences were observed between the two alloy variants particularly with respect to their sensitivity to dwell loading. In particular it was found that dwell sensitivity is enhanced by high R values (R = 0.5) and longer dwell times but is reduced by compressive minimum loads (R = -0.5). Variations in microstructural morphology together with differences in localised texture were found to control the contrasting dwell performance in the two materials. Sub-surface fatigue crack initiation has been observed for both coarse grained Timetal 685 and the two Timetal 834 forms. With typical as received hydrogen concentrations of 40-60ppm these initiation sites are characterised by quasi-cleavage facetting. EBSD analysis has demonstrated that the facets are of a near basal orientation with respect to the hexagonal crystal lattice. At high hydrogen concentration in Timetal 685, fractographic and EBSD studies combined with mechanical data from a previous investigation, show that premature fatigue failures are associated with the operation of alternative failure mechanisms. These include strain induced alpha/beta interface cracking and the shear related separation of basal planes. Fatigue crack propagation in the disc material, under dwell and cyclic loading, was explored using three specimen designs: CC, DEN and TDEN. The CC and DEN geometries allowed the behaviour of part through cracks to be evaluated in a uniform stress field and within a plastically deformed stress gradient. The TDEN enabled through section crack behaviour to be quantified. Growth rates were dependent on R-ratio but unaffected by dwell periods at peak load. Increased growth rates at higher R values were attributed to the fact that a high mean stress encourages enhanced strain accumulation and facet formation. The lack of a dwell effect on crack propagation is due to stress relaxation at the crack tip. It could also be associated with compression in the crack tip plastic zone on unloading.

High precision uniaxial constant stress tests were carried out for the near-alpha titanium alloy IMI834. Testing was completed at 823, 848, 873, 898 and 923 K, and at stresses chosen to give rupture lives in the range of about one day to six months at each temperature. Over the entire range of testing conditions, predominantly tertiary normal creep curves were recorded. During creep an alpha-case developed at air exposed surfaces, whose depth varied according to a parabolic rate law with an activation energy of 208 kJmol^-1. For tests failing after about 1000 hours at 848, 873 and 898 K, and 100 hours at 923 K, failure occurred due to the propagation of circumferential surface cracks which developed in the alpha-case. In contrast, for all tests at 823 K, and for rupture lives of less than 100 hours at 923 K, and for tests lasting less than about 1000 hours at the remaining temperatures, failure occurred due to the link up of creep cavities formed predominantly at the alpha/transformed beta interfaces. A conventional power law analysis of the creep data proved capable of describing the stress and temperature variation of the minimum creep rates and rupture lives. However, this approach gave no information concerning the evolution of creep strain with time. Consequently, the theta-projection concept and the continuum damage mechanics (CDM) constitutive equations were also fitted to the experimental data. Isothermal and anisothermal forms of each model were developed. These proved capable of representing the stress and temperature variation of the experimental failure times, minimum creep rates and failure strains. However, whilst the theta-projection method described entire creep curves, the creep curves constructed using CDM contained almost no primary stage.

The premature failure of gas turbine disc components constructed from near alpha titanium alloys under low temperature dwell loading have been attributed to areas of aligned alpha platelets in the specified basketweave microstructure. Attempts at modelling crack initiation within these aligned microstructures has either overlooked the anisotropic nature of alpha titanium or has been restricted by the lack of information on the stress/strain response of individual grains in these engineering alloys. To rectify this situation, fatigue crack initiation and propagation response in a large grained aligned alpha microstructure was studied and supported by an evaluation of the crystallographic orientation adjacent to the crack path. Fatigue crack initiation is shown to be highly dependent on the crystallographic orientation of the colony in which it occurs. Extended fatigue lives occur where basal planes of the initiating colony lie parallel to the applied load. Conversely, basal inclinations of 45° produce short fatigue lives. Stage II fatigue cracks propagate preferentially through colonies with common basal planes. Colony/grain boundaries and alpha lath direction affect crack propagation kinetics. Life to failure is inversely dependent upon applied stress range in all geometries studied. This relationship applies irrespective of whether the alloy cyclically softens or hardens.

Small crack growth rates are assessed for the near alpha titanium alloy, IMI 829, with beta processed microstructures. Constant load amplitude tests were conducted using three test piece geometries which encompassed plain surfaces and stress concentrations. Two computerised crack length measurement techniques were used: A switched d.c. potential drop method and a photomicroscopic system. The p.d. system together with a clip gauge were used to assess crack closure. Crack growth is structure sensitive, characterised by crack path tortuosity, crack bifurcation and a faceted fracture surface. Colony and prior beta grain boundaries provide barriers to propagation which result in temporary arrest in many instances. Small crack growth rates were compared and contrasted with available long crack data for the same alloy and microstructure. A transition, ΔK_T, was observed for the small crack growth rate data. This transition is most marked for through thickness cracks at notches and least marked for part through cracks in plain surfaces. Small crack growth behaviour was observed for values of ΔK less than ΔK_T with growth rates up to a factor of 10 greater than long crack rates. For values of ΔK greater than ΔK_T the data merge, although in some instances rates for through thickness small cracks were slower. The transition from small to long crack behaviour occurs as the monotonic crack tip plastic zone approaches the widmanstatten alpha colony size. At low ΔK there was no evidence of a threshold even at 3.6 MNm^-3/2. Load ratio was not observed to affect growth rates. The results suggest that the significant difference between crack voltage signals during a load cycle, for ΔK above and below ΔK_T, could be due to crack tip plasticity rather than closure in this study. Crack closure was not evident from crack opening displacements obtained using the clip gauge.

The flow and beta recrystallization behaviour during thermomechanical processing of near-alpha titanium alloy IMI834 (Ti-5.8Al-4Sn-4Zr-1Nb-0.5Mo-0.35Si), with an initial bimodal alpha+beta microstructure, has been investigated. The effects of temperature and strain rate were characterized and modelled at beta and alpha+beta hot working temperatures near the beta to alpha+beta transition temperature (beta transus) to study the quantitative differences in one- and two-phase isothermal forging. The experimental work for characterization and modelling was based on compression testing of lab-scale specimens at temperatures of 975-1100°C, strain rates of 0.01-1s-1, and post-deformation annealing times of 5-420s. Supplementary interrupted compression testing was also performed at 975-1000°C to evaluate the applicability of fractional softening in the determination of static recrystallization kinetics. The stress-strain analysis, which employed corrections for friction and deformation heating, showed increasing stress at increasing strain rates and decreasing temperatures. The stress-temperature dependence increased below the beta transus due to the increasing alpha phase fraction with decreasing temperature. Microstructural observation through optical microscopy indicated dynamic recrystallization occurred, although complete grain refinement and homogeneity was only achieved following static recrystallization. Quantitative measurement via image analysis revealed static recrystallization kinetics increased with temperature for single phase beta pre-deformation microstructures (1060-1100°C). However, bimodal alpha+beta microstructures (1000-1025°C) displayed greater recrystallization rates with decreasing temperature. This behaviour was attributed to the associated increase in alpha phase fraction, which yielded a refinement in initial beta grain size and an increase in favourable nucleation sites. Interrupte
L'évolution de la contrainte d'écoulement et de la recristallisation de la phase beta (beta) de l'alliage de titane IMI834 (Ti-5.8Al-4Sn-4Zr-1Nb-0.5Mo-0.35Si), qui présente une microstructure bimodale, a été étudiée lors d'essais thermomécaniques. Des essais de compression ont été effectués à des températures comprises entre 975°C et 1100°C et à des vitesses de déformation allant de 0,01 à 1s-1. Les échantillons ont ensuite été maintenus à la température de déformation pendant 5 à 420 secondes. Ces essais ont permis de mieux comprendre l'influence de la température et de la vitesse de déformation sur le procédé de forgeage isothermique. Des essais de compression interrompus ont également été effectués pour évaluer l'effet de l'adoucissement sur la cinétique de la recristallisation statique. Un modèle mathématique a ainsi pu être déterminé pour permettre une meilleure compréhension du procédé de forgeage à des températures supérieures et inférieures à la température de transformation allotropique (beta transus). Les courbes de déformation, auxquelles un facteur de correction attribuable à la friction et à la transformation de l'énergie de déformation en chaleur a été appliqué, démontrent que la contrainte est proportionnelle au taux de déformation et inversement proportionnelle à la température de déformation. Lorsque la déformation s'opère à une température inférieure au beta transus, la relation contrainte-température devient plus importante. Dans ces conditions, la microscopie optique révèle la présence de grains recristallisés dynamiquement, bien qu'une microstructure complètement recristallisée ne puisse être atteinte que sous l'influence de la recristallisation statique. L'étude quantitative de la microstructure déformée au-dessus du beta transus, via un système d'analyse d'image, révèle que le taux de recristallisation

The effect of fatigue crack closure in IMI 829 has been addressed for cracks growing from plain surfaces and under the influence of a stress concentration. Several test-piece configurations were employed, incuding thick and thin section double edge notches and standard corner crack (CC) geometries. All types incorporated an ultra fine corner slit to bias the crack initiation site. A thin double edge notch (DEN) specimen with a through section starter slit was also tested. Crack closure loads were measured using direct current potential drop (PD) and replica techniques. The primary closure mechanism was found to be a plasticity induced closure. The results indicate the dominance of surface effects. They also permit near tip and wake related closure effects to be resolved. At the higher stresses, notch root plasticity in the thick DEN dominates closure. At lower stresses where elastic conditions prevail, the results were comparable to those found in the plain CC specimen. Much work was carried out to characterise closure of part-through and through thickness cracks in the thin section notch. The transition between the two crack types invoked a complex closure response. A secondary closure mechanism was also identified, for all specimen types. This was roughness induced closure. On the basis of the PD measurements, an effective ΔK was derived which improved correlation of data over the range of stress levels and R values tested. At room temperature, crack lengths were measured using the above PD system and an existing photomicroscopic arrangement. A study of crack shape morphology was carried out using optical and SEM techniques. The observed complex stress and crack length dependency of shape development in thick notch specimens at higher stresses, was explained on the basis of enhanced plasticity induced closure in the notch root. Other deviations from expected shape characteristics, could be rationalised in terms of microstructural interactions.

In this work we describe the effects of the relaxation of the muffin-tin (MT) potential approximation (and the consequent use of full potentials (FPs)) in the ab initio calculation of X-ray-absorption near-edge structure (XANES) by the multiple-scattered-wave (MSW) Xα method. In doing so we demonstrate the validity and computational feasibility of the extended FP-MSW theory due to Natoli et al. (1986). We describe certain refinements to this theory and the development of a practicable computational approach for its realization. With the results of the newly-developed computer programs for certain model systems we show that the FP-MSW method leads to much higher accuracies in both bound-state energy eigenvalues and in photoionization cross-sections near the threshold. Our FP-MSW XANES calculations for the chromium hexa-carbonyl (Cr(CO)6) system therefore demonstrate, because the results are still significantly different from the experimental spectrum (although closer than the MT case), that there remain other deficiencies in the physical model. Although beyond the scope of this work, we strongly suspect that the bulk of the remaining error would be accounted for by a better treatment of inelastic loss and (to a lesser extent) exchange-correlation. Our final conclusion is that the use of FPs is necessary (and now feasible) for the accurate calculation of XANES. We begin with an introduction to X-ray absorption spectroscopy (XAS) and then concentrate on XANES giving the motivation in terms of its structural significance and describing the necessity and difficulty of accurate ab initio calculations. The central part of XANES calculations is the solution of Schrödinger’s equation for the initial and final molecular states in the absorption process, and we summarize the approximations to the full many-body equation that make it tractable. This leads to a discussion of the MT approximation and an illustration of its deficiences. We review various remedies that have been proposed and concentrate on the FP-MSW theory of Natoli et al. (1986). We then give a detailed presentation of the theory and develop the necessary representation of the potential in terms of spherical harmonic expansions (SHXs). It is shown that, for symmetric molecules with up to two coordinating shells of atoms, five to ten partial waves per prototype atom serve to make the SHX representation from one to three orders of magnitude more accurate than the MT case. The development of the FP-SW bound-state eigenvalue program ENESHX is described and the program tested with the hydrogen molecular ion (H2+). By comparison with the MT results we find that the error is reduced to less than 12% in the worst case (the ground state) and less than 0.2% for the highest levels. Calculations for the Cr(CO)6 system do show changes of as much as -O.4 Ryd. for the valence levels (stemming mostly from the better treatment of the interstitial region). The successfully-tested ENESHX is then adapted to produce the FP-SW continuum photoionization cross-section program CNTSHX which is then tested with a Li2+ ion pseudo-cluster whose exact analytic cross-sections are known. Above about 1 Ryd. from threshold, the CNTSHX cross-sections are within 1% of the exact values, compared to 7% for the MT case. Below 1 Ryd. the CNTSHX error remains less than 5%. CNTSHX is then run for Cr(CO)6 with the results described above.

Briser la frontière observationnelle de l’Univers lointain suscite de nombreux axes de recherches dans la cosmologie moderne. Exigeantes par la sensibilité demandée, ces observations constituent aussi bien un défi technologique pour les prochaines générations d’instruments qu’une étape nécessaire à la compréhension des différentes étapes d’évolution de l’Univers. Une des étapes importantes est la réionisation du milieu intergalactique, époque charnière marquant la fin des “Âges Sombres”. Déterminer quand et comment ce processus s’est déroulé et quelles ont été les sources l’ayant déclenché et entretenu sont les principales questions motivant ces recherches. Les travaux présentés dans cette thèse participent à l’effort de la communauté scientifique internationale dans la caractérisation de l’histoire de l’époque de la réionisation en recherchant des galaxies à grand décalage spectral vers le rouge (redshift). Après un panorama complet des contraintes observationnelles actuelles sur l’époque de la réionisation, sont ensuite présentés les deux projets ayant fournis les données constituant la matière première de cette analyse. En utilisant une même technique d’imagerie en bande étroite dans le domaine de longueurs d’onde proche-infrarouge, des observations avec l’instrument WIRCAM (CFHT) et d’autres avec l’instrument HAWK-I (VLT) ont permis d’établir des contraintes robustes sur la fonction deluminosité des Emetteurs Lyman-α au redshift z = 7.7. A l’occasion de la présentation du second projet, la problématique de la stratégie observationnelle est abordée, notamment via l’utilisation des amas de galaxies comme lentilles gravitationnelles amplifiant le flux des sources d’arrière-plan. L’absence de confirmation spectroscopique des Emetteurs Lyman-– sélectionnés durant l’analyse des données WIRCAM et l’absence de candidats dans le sondage HAWK-I suggèrent une évolution de la fonction de luminosité des Emetteurs Lyman-– entre les redshifts z = 6.5, telle quedéterminée dans d’autres études, et z = 7.7. La tendance de cette évolution, en luminosité ou en densité de galaxies, ne peut pas encore être déterminée compte tenu de la variabilité des résultats obtenus à plus bas redshift. Si cette évolutions’effectuait en luminosité, ce pourrait être le signe d’une augmentation de l’opacité du milieu intergalactique au rayonnement Lyman-α causée par une plus importante fraction d’hydrogène neutre, ce qui est une signature attendue de la réionisation
Breaking through the observational frontier of the distant universe motivates numerous scientific cases in modern cosmology. Demanding by the required sensitivity, high-redshift observations provide both a technological challenge for next generation instruments and a necessary step toward the understanding of cosmic evolution. One critical epoch is the reionization of the intergalactic medium bringing to light the end of the so-called “Dark Ages”. Determine when and how this process took place and what were the sources that started and maintained the reionization are the mainquestions motivating this research. The work presented in this thesis contributes to the effort of the internationalscientific community in characterizing the reionization epoch history by searching for galaxies at high redshift. First, I describe the current observational constraints in a comprehensive chapter. Then the two datasets used in that work are presented. From narrow-band observations in the near-infrared with WIRCAM at the CFHT and HAWK-I at the VLT, I put strong constraints on the luminosity function of Lyman-α Emitters at z = 7.7. The best strategy for this type of survey is discussed, in particular with the use of massive galaxy clusters acting as gravitational lenses that amplify the flux from background sources. The lack of spectroscopic confirmation of candidates found with WIRCAM and the lack of candidates found with HAWK-I suggest an evolution of the luminosity function from z = 6.5. This evolution could be either in luminosity or in number density but somewhat discrepant results at lower redshift prevent any definitive answer to this question. If the evolution was mostly in luminosity, it could be interpreted as an increase in the opacity of the intergalactic medium caused by an increased fraction of neutral hydrogen, which is an expected signature of reionization

En raison de l’omniprésence des hétérocycles azotés et de leurs propriétés biologiques, une attention particulière est accordée au développement de méthodologie pour leur synthèse et leur fonctionnalisation. L’étude de la fonctionnalisation d’énamides constitue une thématique importante car ces motifs s’avèrent être des outils synthétiques polyvalents permettant d’accéder à des dérivés hétérocycliques complexes. Les réactions de couplage Pd-catalysées constituent une méthode de choix rapide et efficace pour la synthèse d'énamides, notamment à partir de phosphates d'énols issus de lactames, d’imides ou d’amides. Le premier chapitre de ce travail porte sur le couplage organopalladié C-P de phosphines boranes secondaires chirales ou achirales avec des phosphates d’énols. Ce couplage C-P original, réalisé dans des conditions douces, conduit aux énamido-phosphines boranes correspondantes et offre de nombreuses possibilités pour la constitution d’une librairie de phosphines originales. Parallèlement à ce travail, l’addition nucléophile d’anions phosphures sur divers ène-carbamates acycliques conduit à des acides alpha-aminés béta-phosphorés originaux, porteurs d’un carbone quaternaire en alpha de l’azote. Le deuxième chapitre de la thèse porte sur la préparation et la caractérisation de chromophores organiques originaux basés sur un noyau pyrazinique et qui sont susceptibles de présenter des propriétés de fluorescence. Ces composés sont conçus pour former des nouveaux systèmes sensibilisateurs de cations de lanthanides, et être utilisés comme sensibilisateurs organiques pour l'imagerie moléculaire dans le proche infrarouge
On account of the ubiquity of nitrogen heterocycles and their biological properties, the great attention is paid to developing methodologies of their synthesis and functionalization. For this purpose, the study of functionalization of enamides constitutes an important topic due to the utility of these motifs in the construction of complex heterocyclic derivatives. Palladium-catalyzed reactions of cross- coupling are rapid and efficient methods of choice for synthesis of enamides particularly starting from enol phosphates derived from lactams, imides or amides. The first chapter of the thesis evokes the original C-P coupling reaction of chiral and achiral secondary phosphine boranes with different enol phosphates in mild reaction conditions, leading to corresponding enamido-phosphine boranes. This methodology permits the construction of libraries of novels phosphines. Also, the reaction of nucleophilic addition of phosphide anions onto various enecarbamates acyclic was elaborated, giving an access to original beta-phosphino alpha-amino acids, bearing the quaternary carbon on alpha position to nitrogen. The second chapter is devoted to the preparation and characterization of organic chromophores based on the pyrazinic core, which are likely to exhibit the fluorescence properties. These compounds were designed to form new sensitizing systems for lanthanide cations and could be used as organic sensitizers for molecular imaging in near infrared

L'amélioration de la tenue en température des alliages de titane représente un défi de taille pour l'industrie aéronautique. En effet, dépasser la limite actuelle de 550°C dans les turbomoteurs requiert de trouver le meilleur compromis entre une bonne tenue à l'oxydation et de bonnes propriétés mécaniques en température. Les alliages dits quasi-alpha, constitués majoritairement de phase hexagonale compacte, sont ceux qui offrent les meilleures performances. Ils sont malheureusement sensibles à la fatigue/fluage à froid dit effet Dwell. Dans ce contexte, l'objectif de notre travail est double. D'une part, il s'agit de contribuer à la conception de nouveaux alliages quasi-alpha par apprentissage automatique grâce à une campagne extensive de caractérisation des propriétés mécaniques, à l'ambiante et à chaud. D'autre part, il s'agit de mieux comprendre l'impact de la composition chimique, notamment la teneur en silicium, sur la microstructure et le comportement mécanique. Pour cela, notre démarche a reposé sur la caractérisation de la microstructure de plusieurs alliages sélectionnés judicieusement, en croisant différentes techniques de microscopie. Nous avons ainsi examiné l'influence d'une variation de la teneur en silicium à différentes échelles, en combinant la microscopie électronique à balayage (MEB) et la microscopie électronique en transmission (MET). Nous avons mis en évidence la précipitation de siliciures au-delà d'une certaine teneur en Si, et entrepris de les caractériser de manière approfondie. En particulier, nous avons démontré les limitations d'une analyse en deux dimensions, et nous avons utilisé une technique alternative, combinant le découpage par faisceau d'ions (FIB) et l'observation par MEB pour reconstruire la microstructure en trois dimensions. Cette approche nous a permis d'observer en détail les formes, les tailles et les répartitions spatiales des siliciures. Enfin, nous avons mené des essais de traction à différentes vitesses de déformation ainsi que des essais de fluage dans diverses conditions, pour mieux comprendre le rôle bénéfique du silicium sur le comportement à froid et à chaud des alliages quasi-alpha
Improving the high-temperature resistance of titanium alloys is a major challenge for the aerospace industry. Exceeding the current limit of 550°C in aircraft engines requires finding the best compromise between good oxidation resistance and good mechanical properties. Near-alpha alloys consisting mainly of a compact hexagonal phase are the best candidates. Unfortunately, they are sensitive to cold creep-fatigue, known as the dwell effect. In this context, our work aims to achieve two main objectives. Firstly, to contribute to the design of new near-alpha alloys based on machine learning, supported by extensive mechanical testing, at both ambient and high temperatures. Secondly, to gain a better understanding of the effect of chemical composition, particularly silicon content, on the microstructure and mechanical behaviour. Our approach was based on multi-scale microstructure study of selected alloys using a combination of different microscopy techniques. We examined the influence of a variation in silicon content using a combination of scanning electron microscopy (SEM) and transmission electron microscopy (TEM). We showed that silicide precipitation occurs above a certain silicon content. We demonstrated the limitations of two-dimensional analysis, and used an alternative technique combining ion beam cutting (FIB) with SEM observation to reconstruct the 3D microstructure. This approach enabled us to analyze and quantify the shapes, sizes and spatial distributions of the silicides. Finally, we carried out tensile tests at different strain rates as well as creep tests under various conditions to better understand how silicon addition improves the behaviour of near-alpha alloys

Introduction : La thérapie ciblée des cancers des VADS nécessite la mise au point de nouveaux vecteurs spécifiques. Ces vecteurs servent à acheminer des substances thérapeutiques, mais aussi ils peuvent être couplés à des fluorophores afin de les utiliser dans la chirurgie guidée par l'imagerie de fluorescence proche infrarouge.Objectifs : L'objectif de notre travail est de tester de nouveaux vecteurs des cancers des VADS et d'étudier l'apport de l'imagerie de fluorescence proche infrarouge dans la chirurgie des cancers des VADS chez un modèle animal orthotopique que nous mettons au point.Matériel et méthodes : La lignée cellulaire des cancers des VADS CAL33 est caractérisée in vitro et in vivo. De nouveaux vecteurs qui ciblent un ou plusieurs récepteurs des cellules CAL33 comme l'intégrine alpha v beta 3, l'EGFR et la NRP1, sont testés in vitro. Parallèlement, un modèle animal orthotopique des cancers des VADS est développé par implantation de fragments tumoraux des cellules CAL33, au niveau de la cavité buccale de la souris nude. La résection des tumeurs orthotopiques est guidée par l'imagerie de fluorescence proche infrarouge, après injection systémique du peptide RAFT-c[RGD]4 couplé à un fluorophore. Ce peptide cible l'intégrine alpha v beta 3 et est préalablement testé in vivo sur les cellules CAL33.Résultats : Nos résultats préliminaires montrent que certaines molécules bispécifiques présentent une liaison accrue in vitro aux cellules CAL33. Par ailleurs, la chirurgie guidée par l'imagerie de fluorescence proche infrarouge ciblant l'intégrine alpha v beta 3, présente un impact positif sur la survie sans rechute dans notre modèle orthotopique, à travers la détection de reliquats tumoraux qui pourraient passer inaperçus si l'exérèse tumorale avait été réalisée exclusivement d'une façon macroscopique. Elle permet aussi de détecter les adénopathies métastatiques.Conclusion : L'imagerie de fluorescence proche infrarouge améliore la qualité de l'exérèse tumorale dans notre modèle orthotopqiue optimisé des cancers des VADS. Cette étape préclinique est indispensable avant de tester cette technique chez l'être humain
Introduction: Targeted therapy of head and neck squamous cell carcinoma (HNSCC) requires the development of novel specific vectors that can deliver therapeutic molecules. These vectors could also be coupled to fluorophores to be used in near infrared fluorescence imaging-guided surgery.Objectives: The aim of our work is to test new targeted vectors of HNSCC and to study the role of the near infrared fluorescence imaging-guided surgery in HNSCC resection in a novel orthotopic animal model that we develop.Materials and Methods: The HNSCC cell line CAL33 is characterized in vitro and in vivo. Novel vectors that target one or more receptors of this cell line such as alpha v beta 3 integrin, EGFR and NRP1, are tested in vitro. Meanwhile, an orthotopic animal model of HNSCC is developed by implanting tumor fragments of CAL33 cells, in the oral cavity of nude mice. Surgical resection of orthotopic tumors is guided by the near infrared fluorescence imaging after systemic injection of RAFT-c[RGD]4 peptide coupled with a fluorophore. This peptide targets alpha v beta 3 integrin and is previously tested in vitro.Results: Our preliminary results show that bispecific vectors would present an increased binding to CAL33 cells in vitro. On the other hand, near infrared fluorescence imaging-guided surgery has a positive impact on the recurrence-free survival rate in our orthotopic model, by detecting fluorescent cancer foci that could remain unidentified if resection was performed exclusively under visual guidance. Our results show also that near infrared fluorescence imaging can also help to detect metastatic lymph nodes.Conclusion: Near-infrared fluorescence imaging-guided surgery improves the quality of tumor resection in our optimized orthotopic animal model of HNSCC. This preclinical stage is essential before testing this novel technique in humans

Introduction : La thérapie ciblée des cancers des VADS nécessite la mise au point de nouveaux vecteurs spécifiques. Ces vecteurs servent à acheminer des substances thérapeutiques, mais aussi ils peuvent être couplés à des fluorophores afin de les utiliser dans la chirurgie guidée par l'imagerie de fluorescence proche infrarouge.Objectifs : L'objectif de notre travail est de tester de nouveaux vecteurs des cancers des VADS et d'étudier l'apport de l'imagerie de fluorescence proche infrarouge dans la chirurgie des cancers des VADS chez un modèle animal orthotopique que nous mettons au point.Matériel et méthodes : La lignée cellulaire des cancers des VADS CAL33 est caractérisée in vitro et in vivo. De nouveaux vecteurs qui ciblent un ou plusieurs récepteurs des cellules CAL33 comme l'intégrine alpha v beta 3, l'EGFR et la NRP1, sont testés in vitro. Parallèlement, un modèle animal orthotopique des cancers des VADS est développé par implantation de fragments tumoraux des cellules CAL33, au niveau de la cavité buccale de la souris nude. La résection des tumeurs orthotopiques est guidée par l'imagerie de fluorescence proche infrarouge, après injection systémique du peptide RAFT-c[RGD]4 couplé à un fluorophore. Ce peptide cible l'intégrine alpha v beta 3 et est préalablement testé in vivo sur les cellules CAL33.Résultats : Nos résultats préliminaires montrent que certaines molécules bispécifiques présentent une liaison accrue in vitro aux cellules CAL33. Par ailleurs, la chirurgie guidée par l'imagerie de fluorescence proche infrarouge ciblant l'intégrine alpha v beta 3, présente un impact positif sur la survie sans rechute dans notre modèle orthotopique, à travers la détection de reliquats tumoraux qui pourraient passer inaperçus si l'exérèse tumorale avait été réalisée exclusivement d'une façon macroscopique. Elle permet aussi de détecter les adénopathies métastatiques.Conclusion : L'imagerie de fluorescence proche infrarouge améliore la qualité de l'exérèse tumorale dans notre modèle orthotopqiue optimisé des cancers des VADS. Cette étape préclinique est indispensable avant de tester cette technique chez l'être humain
Introduction: Targeted therapy of head and neck squamous cell carcinoma (HNSCC) requires the development of novel specific vectors that can deliver therapeutic molecules. These vectors could also be coupled to fluorophores to be used in near infrared fluorescence imaging-guided surgery.Objectives: The aim of our work is to test new targeted vectors of HNSCC and to study the role of the near infrared fluorescence imaging-guided surgery in HNSCC resection in a novel orthotopic animal model that we develop.Materials and Methods: The HNSCC cell line CAL33 is characterized in vitro and in vivo. Novel vectors that target one or more receptors of this cell line such as alpha v beta 3 integrin, EGFR and NRP1, are tested in vitro. Meanwhile, an orthotopic animal model of HNSCC is developed by implanting tumor fragments of CAL33 cells, in the oral cavity of nude mice. Surgical resection of orthotopic tumors is guided by the near infrared fluorescence imaging after systemic injection of RAFT-c[RGD]4 peptide coupled with a fluorophore. This peptide targets alpha v beta 3 integrin and is previously tested in vitro.Results: Our preliminary results show that bispecific vectors would present an increased binding to CAL33 cells in vitro. On the other hand, near infrared fluorescence imaging-guided surgery has a positive impact on the recurrence-free survival rate in our orthotopic model, by detecting fluorescent cancer foci that could remain unidentified if resection was performed exclusively under visual guidance. Our results show also that near infrared fluorescence imaging can also help to detect metastatic lymph nodes.Conclusion: Near-infrared fluorescence imaging-guided surgery improves the quality of tumor resection in our optimized orthotopic animal model of HNSCC. This preclinical stage is essential before testing this novel technique in humans