Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The present work describes a methodology of controlled synthesis of block copolymers by one-pot reactions involving simultaneous RAFT and ROP processes mediated by a bifunctional compound which acts as a chain transfer agent (CTA) for the RAFT process and co-initiator of the ROP process. Reactions involving the RAFT of Styrene (St) and the ROP of ε-Caprolactone (ε-CL) were performed to obtain PS-b-PCL diblock copolymers. The catalysts Sn(Oct)2 and diphenyl phosphate (DPP) were evaluated in the ROP process. Diphenyl phosphate is the most appropriate for this kind of reaction, since Sn(Oct)2 proved to be avid when interacted with CTA, interfering antagonistically in the radical equilibrium of the RAFT process. The reactions were always controlled when DPP was used as a ROP catalyst, wherein copolymers with narrow molar mass distribution were obtained in the end. This methodology was employed in the synthesis of other linear and graft amphiphilic block copolymers, proving to be an excellent alternative for this purpose. Thermoresponsive copolymers based on Poly(oligo(ethylene glycol)methyl ether methacrylate) (POEGMA) and pH responsive based on Poly(acrylic acid) (PAA) were obtained. The physicochemical properties of the copolymers were investigated in solid state as well as in solution, and the results are in total agreement with values reported in the literature. / Este trabalho descreve uma metodologia de síntese controlada de copolímeros em bloco por reações one-pot envolvendo processos RAFT e ROP simultâneos, mediados por um composto bifuncional que atua como agente de transferência de cadeia (CTA) para o processo RAFT e co-iniciador do processo ROP. Reações envolvendo a RAFT do estireno (St) e a ROP da ε-Caprolactona (ε-CL) foram realizadas para obter copolímeros dibloco PS-b-PCL. Os catalisadores Sn(Oct)2 e difenil fosfato (DPP) foram avaliados, sendo o último o mais apropriado para este tipo de reação, uma vez que Sn(Oct)2 mostrou-se ávido por interações com o CTA, interferindo antagonicamente no equilíbrio de radicais do processo RAFT. As reações mantiveram o caráter controlado quando DPP foi usado como catalisador ROP, sendo que ao final, copolímeros com estreita distribuição de massa molar foram obtidos. Esta metodologia foi empregada na síntese de outros copolímeros em bloco anfifílicos lineares e enxertados, se mostrando uma excelente alternativa para este propósito. Copolímeros termoresponsivos à base de Poli(metacrilato de poli(etilenoglicol)metil éter) (POEGMA) e pH responsivos à base de Poli(ácido acrílico) (PAA) foram obtidos. As propriedades físico-químicas dos copolímeros foram investigadas em estado sólido e em solução, e os resultados estão em plena concordância com valores relatados na literatura.

[EN] Different strategies were used to improve physical properties of corn starch based films, with glycerol (30%) as plasticizer, based on increasing their hydrophobic character in order to reduce the materials' water sensitivity. Starch was blended with different components (surfactants and more hydrophobic polymers), with and without compatibilizers, to obtain blend films through different processing techniques (casting, melt blending, compression molding and extrusion). Bilayer film formation by compression molding with starch and poly(e-caprolactone) (PCL) was also studied. The addition of surfactants to starch films obtained by casting gave rise to a decrease in water vapor permeability (WVP), but an increase in the film fragility was observed. Surfactants with lower hydrophilic-lipophilic balance (HLB), solid at room temperature, promoted a fine microstructure in the matrix with smaller lipid particle, which enhanced water vapor barrier properties. Thermo-processing was used to obtain the other films due to its broader industrial application. Starch blends with hydroxypropyl methylcellulose (HPMC) showed an HPMC dispersed phase in the starch matrix and better water barrier properties, but they were more permeable to oxygen, especially when they contained citric acid (CA) as compatibilizer. CA induced cross-linking in the polymeric matrix, thus slightly increasing film hardness, but decreasing its extensibility. The incorporation of PCL in different ratios to starch films obtained by compression molding gave rise to polymer phase separation, although a small PCL miscibility in the starch rich phase was detected, which reduced the glass transition temperature of the starch phase. The structural heterogeneity and lack of interfacial adhesion between polymers gave rise to fragile films. Nevertheless, small amounts of PCL (10%) reinforced the matrix (increase in the elastic modulus). When the PCL ratio increased, WVP was reduced but oxygen permeability increased. The incorporation of CA as compatibilizer of these blends provoked an increase in the water solubility of the films, by hydrolysis, and improved the mechanical properties of the films when PCL ratio was low (10%), but it did not affect the film barrier properties. The incorporation of polyethylene glycol (PEG 4000) to the blends with a low proportion of PCL did not imply an improvement in the film properties, since it promoted phase separation. Starch-PCL blends with 1:0.05 mass ratio, without compatibilizer, were quite homogenous and exhibited good mechanical properties and stability. In order to incorporate greater amounts of PCL, thus improving film hydrophobicity and stability, PCL was chemically modified by grafting glycidyl methacrylate or glycidyl methacrylate and maleic anhydride (PCL-g), to be used as compatibilizers. Films with 20 % PCL and 2.5 or 5 % of PCL-g showed very good mechanical and barrier properties and stability, inhibiting starch retrogradation. Their barrier properties met the food packaging requirements for a wide number of food products. Bilayer films obtained by compression molding of starch (or starch with 5% PCL) and PCL layers showed very low WVP and oxygen permeability and adequate mechanical properties. The adhesion of bilayers was greatly improved by the application of ascorbic acid and, especially, potassium sorbate, as aqueous solutions, at the interface before compression molding. These compounds, in turn, imparted antioxidant and antimicrobial properties, respectively, to the films, thus improving their potential use as active packaging material for food uses. / [ES] Se han utilizado diversas estrategias para mejorar las propiedades físicas de films a base de almidón de maíz, con glicerol (30 %) como plastificante, basadas en el incremento de su carácter hidrofóbico, para reducir su sensibilidad al agua. El almidón se mezcló con diferentes compuestos (surfactantes y polímeros más hidrofóbicos), con y sin compatilizadores, para la obtención de films mixtos por diferentes técnicas de procesado (casting, mezclado en fundido, moldeo por compresión y extrusión). Se estudió también la formación de films bicapa almidón-poli-e-caprolactona (PCL) mediante moldeo por compresión. La adición de surfactantes a los films de almidón elaborados por casting dio lugar a una disminución de su permeabilidad al vapor de agua (WVP), pero aumentó su fragilidad. Los surfactantes con menor balance hidrófilo-lipófilo (HLB), y sólidos a temperatura ambiente, proporcionaron una microestructura de los films con menor tamaño de partícula, que potenció las propiedades barrera al vapor de agua. Por su mayor aplicabilidad industrial, se emplearon técnicas de termo-procesado para la obtención del resto de films estudiados. Los obtenidos por mezcla con hidroxipropil metilcelulosa (HPMC) presentaron una fase dispersa de HPMC en la matriz de almidón y mejores propiedades barrera al vapor de agua, pero fueron algo más permeables al oxígeno, sobre todo cuando se incorporó ácido cítrico (CA) como compatibilizador. Este provocó entrecruzamiento en la matriz polimérica, incrementado ligeramente su dureza y reduciendo su extensibilidad. La incorporación de PCL en diferentes proporciones a los films de almidón obtenidos por termo-compresión, dio lugar a la separación de fases polímericas, detectándose una pequeña miscibilidad de la PCL en la fase rica en almidón que redujo la temperatura de transición vítrea de la fase amilácea. La heterogeneidad de su estructura y la falta de adhesión entre fases dio lugar a films demasiado frágiles, aunque en pequeña proporción (10%), la PCL reforzó la matriz (aumentó el módulo de elasticidad). Al aumentar la proporción de PCL, disminuyó la WVP de los films, pero aumentó la permeabilidad al oxígeno. La incorporación de CA como compatibilizador de estas mezclas aumentó la solubilidad en agua de los films por efecto de hidrólisis y supuso una mejora en las propiedades mecánicas de los films con baja proporción de PCL (10 %), pero no afectó a sus propiedades barrera. La incorporación de polietilenglicol (PEG 4000) a las mezclas con baja proporción de PCL no mejoró las propiedades de los films, potenciando la separación de fases. Las mezclas almidón:PCL con proporción másica 1:0.05, sin compatibilizador, fueron bastante homogéneas y exhibieron buen comportamiento mecánico y estabilidad. Para incorporar una mayor proporción de PCL, y mejorar la hidrofobicidad y estabilidad de los films, se modificó la PCL por reacción con glicidil metacrilato o anhídrido maleico y glicidil metacrilato (PCL-g), para su uso como compatibilizadores. Los films con 20% de PCL y 2.5 y 5 % de los PCL-g presentaron muy buenas propiedades mecánicas y de barrera al vapor de agua y a los gases y buena estabilidad al inhibir la retrogradación del almidón. Sus propiedades de barrera cumplieron con los requisitos de envasado de un número importante de productos alimentarios. La obtención de films bicapa por termo-compresión a partir de almidón (o almidón con 5% PCL) y PCL proporcionó un material con muy baja permeabilidad al vapor de agua y al oxígeno y buenas propiedades mecánicas. La adhesión entre las capas mejoró en gran medida con la incorporación de ácido ascórbico, y sobre todo de sorbato potásico, en la interfase en forma de disolución acuosa antes de la termo-compresión. Estos compuestos impartieron, a su vez, propiedades antioxidantes y antimicrobianas, respectivamente, a los films, mejorando su uso potencial para el envasad / [CAT] S'han utilitzat diverses estratègies per a millorar les propietats físiques de films a base de midó de dacsa, amb glicerol (30 %) com plastificant, basades en l'increment del seu caràcter hidrofòbic, per a reduir la seua sensibilitat a l'aigüa. El midó es va mesclar amb diferents compostos (surfactants i polímers més hidrofòbics), amb i sense compatibilitzadors, per l'obtenció de films mixtos mitjançant diferents tècniques de processat (càsting, mesclat en fos, modelatge per compressió i extrusió). Es va estudiar també la formació de films bicapa midó-poli-e-caprolactona (PCL) mitjançant modelatge per compressió. L'addició de surfactants als films de midó elaborats per càsting va donar lloc a una disminució de la seua permeabilitat al vapor d'aigüa (WVP), però va augmentar la seua fragilitat. Els surfactants amb menor balanç hidròfil-lipòfil (HLB), i sòlids a temperatura ambient, varen proporcionar una microestructura dels films amb menor grandària de partícula, que varen potenciar les propietats barrera al vapor d'aigüa. Per la seua major aplicabilitat industrial, es van emprar tècniques de termo-processat per l'obtenció de la resta de films estudiats. Aquells obtinguts per mescla amb hidroxipropil-metilcellulosa (HPMC) varen presentar una fase dispersa de HPMC en la matriu de midó i millors propietats barrera al vapor d'aigüa, però varen ser un poc més permeables a l'oxigen, sobretot quan es va incorporar àcid cítric (CA) com compatibilitzador. Aquest va provocar entrecreuament en la matriu polimérica, incrementant lleugerament la seua duresa i reduïnt la seua extensibilitat. La incorporació de PCL en diferents proporcions als films de midó obtinguts per termo-compressió, va donar lloc a la separació de fases polimèriques, detectant-se una xicoteta miscibilitat de la PCL en la fase rica en midó que va reduir la temperatura de transició vítria de la fase amilàcea. L'heterogeneïtat de la seua estructura i la falta d'adhesió entre fases va donar lloc a films massa fràgils, encara que en xicoteta proporció (10%), la PCL va reforçar la matriu (augmentant el mòdul d'elasticitat). Al augmentar la proporció de PCL, va disminuir la WVP dels films, però va augmentar la permeabilitat a l'oxigen. La incorporació de CA com compatibilitzador d'aquestes mescles va augmentar la solubilitat en aigüa dels films per efecte d'hidròlisi i va suposar una millora en les propietats mecàniques dels films amb baixa proporció de PCL (10 %), però no va afectar les propietats barrera. La incorporació de polietilenglicol (PEG 4000) a les mescles amb baixa proporció de PCL no va millorar les propietats dels films, potenciant la separació de fases. Les mescles midó:PCL amb proporció màssica 1:0.05, sense compatibilitzador, varen ser prou homogènies i varen exhibir un bon comportament mecànic i una bona estabilitat. Per a incorporar una major proporció de PCL i millorar l'hidrofobicitat i estabilitat dels films, es va modificar la PCL per reacció amb glicidil metacrilat o anhídrid maleic i glicidil metacrilat (PCL-g), per al seu ús com compatibilitzadors. Els films amb 20% de PCL i 2.5 i 5 % dels PCL-g varen presentar molt bones propietats mecàniques i de barrera al vapor d'aigüa i als gasos i bona estabilitat al inhibir la retrogradació del midó. Les seues propietats de barrera varen complir amb els requisits d'envasament d'un nombre important de productes alimentaris. L'obtenció de films bicapa per termo-compressió a partir de midó (o midó amb 5% PCL) i PCL va proporcionar un material amb molt baixa permeabilitat al vapor d'aigüa i al oxigen i bones propietats mecàniques. L'adhesió entre les capes va millorar en gran mesura amb l'incorporació d'àcid ascòrbic, i sobretot de sorbat de potassi, en la interfase en forma de dissolució aquosa abans de la termocompressió. Aquestos compostos varen impartir, a la vegada, propietats antioxidants i antimicrobianes, respec / Ortega Toro, R. (2015). DESARROLLO Y CARACTERIZACION DE PELÍCULAS DE ALMIDÓN DE MAÍZ POR MEZCLADO CON COMPUESTOS MÁS HIDROFÓBICOS [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/52521 / TESIS

The design and selection of a biomaterial will depend on its specific application and the required properties for that application, both mechanical physicochemical properties. Biomaterials can be extremely helpful in order to treat and help the human body to heal and repair faster any kind of fracture produced in bones. Calcium phosphate scaffolds produced by sol-gel procedures have been used for this purpose with a great success regarding mechanical properties and biocompatibility. This is the reason why new techniques needs to be developed to be able to produce scaffolds in a faster way and to reach a personalized treatment to each patient. By using 3D printing techniques, a new and promising scope is open for bone tissue engineering due to the possibility of printing scaffolds with any shape and complexity through CAD design and modelling. In this project 3D printed scaffolds with a matrix combination of polymers and calcium phosphate will be produced and studied for bone tissue regeneration. Self-setting alpha tricalcium phosphate (α-TCP) based cement inks combined with polycaprolactone (PCL) were optimized, and 3D printed structure scaffolds were successfully generated by direct ink writing. Afterwards, the scaffolds were subjected to different hardening processes in order to obtain different hydroxyapatite microstructure morphologies and were characterised by different methodologies. It was demonstrated the important effect of obtaining a complete transformation from the α-TCP into hydroxyapatite in the mechanical properties. An improvement in the mechanical properties at compression was achieved with the addition of PCL within the scaffold ́s structure and a different fracture mode of the scaffolds was observed.

To investigate and assess bone regeneration in sheep in combination with new implant materials classical histological staining methods as well as immunohistochemistry may provide additional information to standard radiographs or computer tomography. Available published data of bone defect regenerations in sheep often present none or sparely labeled histological images. Repeatedly, the exact location of the sample remains unclear, detail enlargements are missing and the labeling of different tissues or cells is absent. The aim of this article is to present an overview of sample preparation, staining methods and their benefits as well as a detailed histological description of bone regeneration in the sheep tibia. General histological staining methods like hematoxylin and eosin, Masson-Goldner trichrome, Movat’s pentachrome and alcian blue were used to define new bone formation within a sheep tibia critical size defect containing a polycaprolactone-co-lactide (PCL) scaffold implanted for 3 months (n = 4). Special attention was drawn to describe the bone healing patterns down to cell level. Additionally one histological quantification method and immunohistochemical staining methods are described.

Les maladies cardiovasculaires continuent à être parmi les principales sources de morbidité et de mortalité dans le monde [1, 2]. Malgré les avancées importantes dans le traitement médical et endovasculaire de ces pathologies, le besoin en revascularisations artérielles par pontage ne cesse de prendre de l’ampleur. Les conduits vasculaires synthétiques actuels performent bien lorsqu’utilisés pour des vaisseaux de calibre moyen, mais ceux de petit diamètre (< 6 mm) démontrent encore à ce jour des taux de perméabilité beaucoup trop bas [3-11]. Deux hypothèses pouvant expliquer ce phénomène sont le manque d’endothélialisation et de compliance des conduits synthétiques actuels [12-18]. Le but de cette étude était de créer et d’évaluer la performance d’un nouveau conduit de petit diamètre avec un potentiel d’endothélialisation supérieur et une compliance similaire aux vaisseaux natifs. Cette étude présente deux aspects distincts : l’élaboration et l’évaluation in vitro d’un conduit électrofilé de petit diamètre (5 mm) composé d’une structure de polyuréthane/polycaprolactone (PU/PCL) et d’un revêtement bioactif de sulfate de chondroïtine (CS) par une équipe spécialisée en biomatériaux, puis l’élaboration et l’évaluation d’un essai in vivo mettant à l’épreuve la performance du néo-conduit dans un modèle de grand animal par une seconde équipe. Les conduits à l’étude (eVG-CS) ont démontré une compliance 10 fois supérieure à celle des conduits de polytétrafluoroéthylène expansé (ePTFE) actuellement utilisés en clinique, ainsi qu’une bonne stabilité au vieillissement in vitro. L’évaluation in vivo, sous forme de pontages carotidiens bilatéraux chez le mouton, a par contre démontré l’infériorité des conduits à l’étude comparativement aux contrôles en ePTFE en termes de perméabilité et de par l’absence d’endothélialisation significative des greffons à l’étude. L’infériorité in vivo de ces nouveaux pontage électrofilés bioactifs par rapport aux résultats favorables in vitro fut attribuée principalement à la trop faible porosité des greffons à l’étude ainsi qu’à l’incapacité du revêtement de CS à favoriser un processus d’endothélialisation rapide. L’établissement d’un greffon plus poreux avec un revêtement bioactif différent représente une piste d’amélioration future de cette structure prometteuse de PU/PCL. / Cardiovascular diseases present a growing burden of morbidity and mortality worldwide [1, 2]. Despite significant advances in medical and endovascular treatments of these pathologies, the need of revascularization by arterial bypass is increasing. Actual synthetic vascular conduits perform well when used on large-diameter arteries, but small-diameter conduits (<6 mm) still show unacceptably low medium- and long-term permeability rates [3-11]. Two hypotheses can explain this phenomenon – the inability of synthetic bypasses to create a neo-endothelium and compliance mismatch between the graft and the native artery [12-18]. The goal of this study was to create and evaluate the performance of a novel small-diameter vascular conduit with superior endothelialization properties and a compliance similar to native vessels. This study presents two distinct aspects : the in vitro elaboration and evaluation of an electrospun, small-diameter (5 mm) vascular conduit made up of a scaffold of polyurethane/polycaprolactone (PU/PCL) combined with a chondroitin sulfate (CS) bioactive coating by a team specialized in biomaterials, and the elaboration and evaluation of an in vivo trial testing the performance of the novel vascular graft in a large animal model by a second team. The experimental conduits (eVG-CS) showed an in vitro compliance 10-times superior to their commercially-available expanded polytetrafluoroethylene (ePTFE) counterparts, while remaining stable after aging trials. However, in vivo evaluation, as bilateral interposition carotid bypasses in sheep, showed the novel bypasses to be inferior to ePTFE controls in terms of permeability and by the absence of significant endothelialization. The in vivo inferiority of these novel bioactive electrospun grafts despite favorable in vitro results was attributed to the low porosity of the grafts and to the inability of the CS coating to promote the endothelialization process. Establishment of a more porous graft with a different bioactive coating represents the future of the evaluation of this promising PU/PCL structure.

Mechanochromic polymers respond to external force by changing their color. This can be achieved by the incorporation of a molecular switch such as spiropyran (SP) into polymers. SPs can be isomerized by mechanical force from their colorless form into colored merocyanines. Main chain copolymerization of spiropyrans allows investigation of their mechanochromic behavior and potential use as force sensors. So far, several covalent polymer matrices have been used to investigate the mechanochromic response of SPs, among them poly(ε caprolactone) (PCL). Less investigated is how the mechanochromic response can be fine-tuned by substituent effects. First, PCL with differently substituted spiropyrans at the chain’s midpoint were used in order to investigate the effect of different substituents and their regiochemistry on the isomerization behavior of SPs under mechanical stress. A low activation barrier was observed for NO2 substitution of “ortho”-spiropyrans compared to no substitution (R = H). In order to investigate phenyl-substituted “para,para” spiropyrans, a newly developed kinked polyarylene was employed as covalent matrix material. This new polyarylene (PmmpP) has a meta,meta,para connection in its backbone and exhibits excellent mechanical properties. Its high strength allows the isomerization of this molecular switch with a large activation barrier. The phenyl-substituted “para,para” spiropyran showed transient mechanochromism and was switched 25 times in force-and-release cycles. The synthesis of PmmpP was carried out by a Suzuki polycondensation in three steps from commercial starting materials. To further capitalize on the simplicity and properties of PmmpP, a two step synthesis of a semifluorinated kinked polyarylene was demonstrated by direct arylation polycondensation with tetrafluorobenzene (F4). This partially fluorinated PmmpF4 was synthesized with a variety of side-chains. Resulting polymers exhibited a large range of glass transition temperatures, allowing for the production of tailor-made smart materials.

Předkládaná disertační práce se zabývá přípravou a charakterizací nových biokompatibilních nanovláken s potenciální aplikací v medicíně. V této práci byl výběr jednotlivých složek pro přípravu nanovlákenného materiálu zvolen tak, aby vyhovoval nárokům tkáňového inženýrství. Literární rešerše shrnuje poznatky o elektrostatickém zvlákňování a o jeho parametrech. Dále se věnuje možnostem elektrostatického zvlákňování proteinů kolagenu a želatiny a jejich směsmi se syntetickými polymery a biopolymery a anorganickými plnivy. Teoretická část řeší také různé postupy síťování nanovláken vedoucí ke zlepšení jejich hydrolytické stability a mechanických vlastností. Poslední část je zaměřena na anorganické nanotrubky halloysitu (HNT), které získaly svou pozornost díky svým vynikajícím fyzikálním a biologickým vlastnostem. V experimentální části byly zpracovány dvě případové studie, z nichž každá se zabývá přípravou nanovlákenných biomateriálů s potenciální aplikací v medicíně. První studie je zaměřena na přípravu a charakterizaci nových hydrolyticky stabilních antibakteriálních želatinových nanovláken modifikovaných pomocí oxidované celulózy. Unikátní inhibiční účinky nanovláken byly testovány na kmenu bakterie Escherichia coli pomocí metody chemické bioluminiscence. Kultivované buňky lidského papilárního adenokacinomu plic prokázaly dobrou adhezi a proliferaci k povrchu nanovláken. Druhá část popisuje vliv zdroje a množství anorganických halloysitových nanotrubek na strukturu a vlastnosti amfifilních nanovláken ze směsi želatiny a syntetického polykaprolaktonu. Přídavek HNT zlepšil tepelnou stabilitu, mechanické vlastnosti (jak tuhost, tak prodloužení) a snížil krystalinitu nanovláken. HNT z různých zdrojů neměl vliv na chování buněk, ale mírně ovlivnil proliferaci a životaschopnost buněk na povrchu nanovláken.

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