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ABSTRACT CORNEA ENGINEERING ON BIODEGRADABLE POLYESTERS Zorlutuna, Pinar M. Sc., Department of Biotechnology Supervisor: Prof. Vasif Hasirci Co-Supervisor: Asst. Prof. AySen Tezcaner January 2005, 66 pages Cornea is the outermost layer of the eye and has an important role in vision. Damage of cornea due to injuries or infections could lead to blindness lowering the quality of life of the patient severely. In such cases, transplantation or artificial corneas have been used for treatment but both had drawbacks. The novel approach for corneal replacements is the tissue engineering of the cornea, a promising method which would be free of these drawbacks, if successful. In this study, carriers for tissue engineering of the cornea were designed and tested in vitro. Blends of biodegradable and biocompatible polyesters of natural (PHBV8) and synthetic (PLLA) origin were used to construct these carriers. For the epithelial layer of the cornea, PLLA-PHBV8 micropatterned films were prepared with solvent casting and seeded with D407 (retinal pigment epithelial) cells. In order to achieve proper cell growth, the films were coated with fibronectin. For the stromal layer of the cornea, highly porous foams of PLLA-PHBV8 were prepared by lyophilization and seeded with 3T3 cells (fibroblasts). A new approach was developed to create a combination of the film and the foam to obtain a surface patterned, 3 dimensional cell carrier. These carriers were seeded with Saos-2 cells (osteosarcoma cells) in the preliminary optimization studies and with D407 and 3T3 cells in further studies. The cell numbers on the carriers were quantified by using MTS assay (non-radioactive cell proliferation assay) and the cell proliferation on polymeric carriers was significantly higher than that of control (Tissue culture polystyrene) by the day 14. Characterization of these cells and the carrier was done using a variety of microscopic methods. The micrographs showed that the foam had a highly porous structure and the pores were interconnected. 3T3 cells were found to be distributed quite homogeneously at the seeding site, but due to the high thickness of the foam, the cells could not sufficiently populate the core (central parts of the foam) during the given incubation time. The micropatterned film allowed multilayer formation of D407 cells. The functionality of the cells seeded on the carriers was examined by immunohistochemistry. These analyses proved that the cells retained their phenotype during culturing. D407 cells formed tight junctions characteristic of epithelial cells, and 3T3 cells deposited collagen type I into the foams. Based on the results, it can be concluded that the 3-D PLLA-PHBV8 construct with surface patterns have a serious potential for use as a tissue engineering carrier for the reconstruction of the cornea. Key words: Tissue engineering, cornea, polymeric carrier, biodegradable, polyester.

Le poly(butylène succinate) (PBS) est un polyester aliphatique biodégradable dont les propriétés en font un bon candidat pour le remplacement des polyoléfines. De plus, ses deux monomères, l'acide succinique et le butane-1,4-diol, peuvent être issus de la biomasse via un procédé de fermentation de sucres. L'étude réalisée ici a été séparée en deux grandes parties : le PBS linéaire d'une part et le PBS branché d'autre part. La première partie montre que la cinétique de synthèse du PBS suit bien le modèle d'estérification établi par Flory. Par la suite, l'étude des propriétés physico-chimiques du PBS a permis de remonter à des paramètres comme la masse molaire critique d'enchevêtrement, le module du plateau caoutchoutique, l'énergie d'activation du PBS fondu ou encore les paramètres de l'équation Mark-Houwink-Sakurada. Une étude sur ses propriétés thermiques a permis de décrire l'évolution de son comportement en fonction de sa masse molaire. Enfin, le profil d'énergie potentielle de l'estérification entre l'acide succinique et le butane-1,4-diol a été tracé en utilisant un outil de chimie quantique. La seconde partie traite de l'étude de PBS branchés obtenus en employant des agents de branchement (polyols) pouvant être issus de la biomasse comme l'huile de ricin, le glycérol et le polyglycérol. La stratégie adoptée a été le couplage entre un oligomère PBS fonctionnalisé acide carboxylique et les agents de branchement. L'étude en présence d'huile de ricin a mis en avant les relations entre la structure, déterminée en SEC-Triple Détection, et les propriétés physico-chimiques du PBS branché. L'optimisation de la synthèse en présence de glycérol ou de polyglycérol a été abordée à partir de la méthode des plans d'expériences. Comparé à la méthode « un facteur à la fois », des résultats prometteurs et semblables à ce qui est rapporté dans la littérature ont été obtenus pour l'étude du PBS branché en présence de glycérol. / Poly(butylene succinate) (PBS) is a biodegradable aliphatic polyester whose properties make it a promising polymer for the replacement of polyolefins. Moreover, its two monomers, succinic acid and 1,4-butanediol, can be produced via a fermentation process of sugars. This study has been separated into two great parts: linear PBS on the one hand and branched PBS on the other hand. In the first part, kinetics of the PBS synthesis showed a good agreement with the esterification model of Flory. We determined some fundamental parameters of PBS like critical molecular weight of entanglement, the rubbery plateau modulus, the energy of activation of melt PBS and parameters of the Mark-Houwink-Sakurada relationship. We have also realized a study on the influence of the molecular weight on the thermal properties of PBS. Finally, we constructed the potential energy profile of the esterification between succinic acid and 1,4-butanediol through a quantum chemistry study. The second part dealt with the study of branched PBS in the presence of biosourced polyols like castor oil, glycerol and polyglycerol. These syntheses were realized between an acid-functionalized PBS oligomer and the branching agents. We put forward the relationships between the structure, determined by SEC-Triple Detection, and the physicochemical properties of branched PBS in presence of castor oil. Syntheses of branched PBS in presence of glycerol or polyglycerol were optimized with design of experiments technique. Promising and similar results from the literature were obtained in the case of branched PBS in presence of glycerol compared to the method of “one parameter at a time”.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Os materiais poliméricos tem sido uma das causas dos problemas ambientais discutidos em todo mundo nos últimos tempos. Como uma das soluções para esse problema, estão os polímeros biodegradáveis que são materiais que se degradam pela ação de microorganismos. Uma Indústria sediada no Brasil lançou recentemente um poliéster biodegradável que surge boa alternativa para o crescimento no mercado dos polímeros biodegradáveis, principalmente por possuir em sua composição matéria prima de fonte renovável. Neste trabalho foram preparados compósitos com matriz de poliéster biodegradável e fibra de coco verde com e sem modificação química por acetilação em misturador interno Haake. Foi estudada a biodegradabilidade em solo simulado do polímero puro e de seus compósitos e foram avaliadas as propriedades térmicas, morfológicas e mecânicas do polímero puro e de alguns de seus compósitos. O teste de biodegradabilidade foi feito pelo enterro das amostras em solo simulado por períodos distintos, variando de duas a dezessete semanas, seguindo a Norma ASTM G 160 03. Após cada período de teste, as amostras foram retiradas do solo e analisadas por microscopia ótica (MO), microscopia eletrônica de varredura (MEV), análise termogravimétrica (TGA), calorimetria diferencial de varredura (DSC), espectroscopia na região do infravermelho (FTIR) e análise mecânica de tração. Os resultados obtidos indicaram que tanto o polímero puro quanto os seus compósitos sofreram biodegradação, a presença da fibra apenas atrasa o processo de biodegradação, as fibras de coco tiveram uma boa afinidade com a matriz polimérica, a incorporação de 5% fibra de coco na matriz torna o compósito mais rígido e a incorporação da fibra e o processo de biodegradação alteram as características da fase cristalina no material polimérico. / The final disposal of the polymer materials have been one of the causes of environmental problems discussed around the world in recent times. As one of the solutions to this problem comes the biodegradable polymers, which are materials that are degraded by microorganisms. An industry based in Brazil recently lauched a biodegradable polyester that comes good alternative for growth in the market for biodegradable polymer, mainly by having in its composition raw material from renewable resources. In this work, composites were prepared with biodegradable polyester matrix and green coconut fiber with and without chemical modification acetylation internal mixer Haake. The degradation of pure polymer and their composites in simulated soil were evaluated and also the morphology, thermal and mechanical properties of the polymer and some of its composites. The biodegradability test was carried out by burying the samples in simulated soil for different periods ranging from two to seventeen weeks, following the ASTM G 160-03. After each test, samples were removed from the soil and analyzed by optical microscopy (OM), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectroscopy (FTIR) and analysis of stress strength. The results indicated that both the polymer pure as their composites suffered biodegradation, the presence of the fiber only delays the process of biodegradation. The coconut fibers had affinity with the polymer matrix and the incorporation of 5% coconut fiber in the matrix polyester made it became stiffer. Besides, the incorporation of the fiber and the biodegradation process changes the characteristics of the polymer crystalline phase.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Os materiais poliméricos tem sido uma das causas dos problemas ambientais discutidos em todo mundo nos últimos tempos. Como uma das soluções para esse problema, estão os polímeros biodegradáveis que são materiais que se degradam pela ação de microorganismos. Uma Indústria sediada no Brasil lançou recentemente um poliéster biodegradável que surge boa alternativa para o crescimento no mercado dos polímeros biodegradáveis, principalmente por possuir em sua composição matéria prima de fonte renovável. Neste trabalho foram preparados compósitos com matriz de poliéster biodegradável e fibra de coco verde com e sem modificação química por acetilação em misturador interno Haake. Foi estudada a biodegradabilidade em solo simulado do polímero puro e de seus compósitos e foram avaliadas as propriedades térmicas, morfológicas e mecânicas do polímero puro e de alguns de seus compósitos. O teste de biodegradabilidade foi feito pelo enterro das amostras em solo simulado por períodos distintos, variando de duas a dezessete semanas, seguindo a Norma ASTM G 160 03. Após cada período de teste, as amostras foram retiradas do solo e analisadas por microscopia ótica (MO), microscopia eletrônica de varredura (MEV), análise termogravimétrica (TGA), calorimetria diferencial de varredura (DSC), espectroscopia na região do infravermelho (FTIR) e análise mecânica de tração. Os resultados obtidos indicaram que tanto o polímero puro quanto os seus compósitos sofreram biodegradação, a presença da fibra apenas atrasa o processo de biodegradação, as fibras de coco tiveram uma boa afinidade com a matriz polimérica, a incorporação de 5% fibra de coco na matriz torna o compósito mais rígido e a incorporação da fibra e o processo de biodegradação alteram as características da fase cristalina no material polimérico. / The final disposal of the polymer materials have been one of the causes of environmental problems discussed around the world in recent times. As one of the solutions to this problem comes the biodegradable polymers, which are materials that are degraded by microorganisms. An industry based in Brazil recently lauched a biodegradable polyester that comes good alternative for growth in the market for biodegradable polymer, mainly by having in its composition raw material from renewable resources. In this work, composites were prepared with biodegradable polyester matrix and green coconut fiber with and without chemical modification acetylation internal mixer Haake. The degradation of pure polymer and their composites in simulated soil were evaluated and also the morphology, thermal and mechanical properties of the polymer and some of its composites. The biodegradability test was carried out by burying the samples in simulated soil for different periods ranging from two to seventeen weeks, following the ASTM G 160-03. After each test, samples were removed from the soil and analyzed by optical microscopy (OM), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectroscopy (FTIR) and analysis of stress strength. The results indicated that both the polymer pure as their composites suffered biodegradation, the presence of the fiber only delays the process of biodegradation. The coconut fibers had affinity with the polymer matrix and the incorporation of 5% coconut fiber in the matrix polyester made it became stiffer. Besides, the incorporation of the fiber and the biodegradation process changes the characteristics of the polymer crystalline phase.

Nanoparticles from biodegradable polymers are considered one of the most promising systems for biomedical application as drug delivery systems. Therefore, the synthesis and characterization of a new aliphatic biodegradable copolyester named PBS/PBDL (poly(butylene succinate-co- butylene dilinoleate)) intended to the application as drug delivery system is reported in the thesis. Surfactant-free biodegradable and narrowly distributed, nanosized spherical particles (RH < 60 nm) have been produced from the biodegradable material by applying a single-step nanoprecipitation protocol. The size of the generated polymer nanoparticles (PNPs) could be controlled by adjusting the polymer concentration, the choice of organic solvent, mixing different organic solvents or by changing temperature and ionic strength. By optimizing such parameters sub-100 nm uniform PNPs can be produced through this methodology including the advantage and ability to scale-up production. The nanoparticles structure was characterized in detail by employing a variety of scattering techniques and transmission electron microscopy (TEM). Combined static light scattering (SLS) and dynamic light scattering (DLS) measurements suggested that the nanoparticles comprise a porous core conferring them a non-compact characteristic. Their porosity...

<p>U ovom radu vr&scaron;ena su istraživanja u cilju razvoja novih postupaka sinteze za nekoliko vrsta polimernih mreža i hibridnih biopolimernih materijala za specijalne primene. Cilj je bio da se razvije novi postupak sinteze rotaksana na bazi poli(etilen glikola) i &beta;-ciklodekstrina kaoprekursora mreža. Dobijeni prekursori mreža iskori&scaron;ćeni su za sintezu topolo&scaron;kih gelova koji su umreženi preko hidroksilnih grupa ciklodekstrinskih prstena. Analiziran je i uticaj količine umreživača, odnosno gustine umreženja, na svojstva bubrenja. Proučavan je i uticaj nanopunila na svojstva modelnih epoksi mreža na bazi bisfenola A i poli(oksi propilen) diamina. Kao punila kori&scaron;ćene su nanočestice nemodifikovanog i povr&scaron;inski modifikovanog titanijum(IV)oksida (TiO₂). Dinamičko-mehaničkom analizom potvrđen je ojačavajući efekat punila. Razvijen je postupak sinteze poli(D,L-laktida) u mikrotalasnom polju, čime je drastično smanjeno vreme polimerizacije (sa 150 sati na 15 minuta) u odnosu na klasičnu termosintezu. Sintezom poli(laktida) kao i kopolimera poli(laktida) sa biorazgradivim monomerima (na osnovu obnovljivih sirovina) dobijeni su materijali izuzetnih ekolo&scaron;kih svojstava. Poli(laktid) se odlikuje veoma dobrim mehaničkim svojstvima i biorazgradivo&scaron;ću, dok je blok-kopolimerizacijom sa drugim biorazgradivim monomerima vr&scaron;ena sinteza termoplastičnih poliestara. Variranje dužine segmenata je ostvareno sintezom adekvatnih oligomera kao prekursora za kopolimerizaciju. Vr&scaron;eno je projektovanje sirovinskog sastava segmentiranih elastomera kod kojih postojanje mekih i tvrdih segmenata ima za posledicu mikrofaznu separaciju faza &scaron;to u toku eksploatacije utiče na mehanička svojstva i mogućnost III razgradnje. Na taj način dobijeni su elastomerni materijali željenih svojstava. Metodama FTIC i 1H NMR spektroskopijom potvrđena je pretpostavljena struktura segmenata i finalnih termoplastičnih poliestara. Analizom molskih masa poliestara metodama gel propusne hromatografije, viskozimetrije i osmometrije napona pare, potvrđena je izuzetna kontrola reakcija polimerizacije i uspe&scaron;nost primenjenih metoda sinteze. Analiza toplotnih svojstava blok poliestara diferencijalno skenirajućom kalorimetrijom je pokazala da zbog neme&scaron;ljivosti faza, tvrdih i mekih segmenata, finalni blok poliestri mogu da pokažu razlike u temperaturama faznih transformacija u zavisnosti od dužine i udela segmenata. Termogravimetrijskom analizom je potvrđen uticaj dužine segmenata i faznog razdvajanja na toplotna svojstva termoplastičnih poliestara. Očekuje se da će sintetisani materijali biti podesni za primene u inženjerstvu tkiva, a posebno kao materijali za kontrolisano otpu&scaron;tanje lekova.</p> / <p>The primary goal of the work described in this thesis was to develop new methods for the<br />synthesis of polymer networks and hybrid biopolymers for special applications. The purpose was a development of synthesis procedure for the preparation of rotaxane based on poly(ethylene glycol) and &beta;-cyclodextrin, as network precursors. These network precursors were then cross-linked through hydroxy groups on cyclodextrine rings. Polyrotaxanes are intermediary products in the synthesis of topological gels and they are formed by the insertion of the linear polymer chains of poly(ethylene oxide) into the &beta;-CD cavities. In this work polyrotaxanes from acetylated-&beta;-CD and poly(ethylene oxide) were synthesized. The influence of crosslinker contents, and crosslink density on swelling properties was investigated. The influence of synthesis parameters and filler modification on reactions and final properties of organic-inorganic hybrid materials based on epoxy resin and an organically modified titanium(IV)oxide (TiO2) was investigated. Dynamic-mechanical analysis was used to determine reinforcement effect of nanofiller on the epoxy resin properties. The aim of this work was the investigation of microwave irradiation on the polymerization of D,L-lactide. It was found that if heating is carried out in the microwave field polymerization time of D,Llactide rapidly decreases from 150 hours to 15 minutes. Environmentally friendly materials were obtained from poly(lactide) and copolymers of poly(lactide) and monomers based on renewable resources. Poly(lactide) is biocompatible and biodegradable polymer with high stretching and low extension capacities. It has been used for the production of orthopedic fraction fixators and sutures surgery. Poly(lactide) was used for thermoplastic polyester (TPE) synthesis. Most thermoplastic polyesters derive their properties from segmented or block structures which are achieved by alternating hard and soft segments. FT-IR and 1H NMR spectroscopy were confirmed the assumed structure of segments and final thermoplastic polyesters. Since the properties of these materials strongly depend on the degree of phase separation, the influence of the lenghts of soft and hard segment on final properties of obtained TPEs was studied. Analysis of molecular mass of these polyesters by gel permeation chromatography, vapor pressure osmometry and viscozimetric analysis confirmed that good control of polymerization was achieved and that synthesis methods were successful. Thermal properties were characterized by means of differential scanning calorimetry (DSC) and thermo-gravimetric analysis (TGA). Phase separation had strong influences on thermal properties of obtained TPEs. DCS measurements showed that due to poor mixability of hard and soft segments, final block polyesters could have different temperatures of phase transitions depending on the length of the segments. Thermal degradation and the influence of phase separation on thermal stability of segmented thermoplastic polyesters were confirmed by nonisothermal analysis, using thermogravimetric analysis. It is expected that synthesized materials will be suitable for tissue engineering and as drug carriers.</p>

Au cours des dernières décennies, l’utilisation de polymères biodégradables a connu un regain d’intérêt pour des applications agricoles. Dans cette étude, nous nous concentrons sur le développement de textiles biodégradables destinés à la protection anti-insecte des cultures. Actuellement, ces textiles doivent être collectés par des entreprises après la saison agricole et entraîne un coût non négligeable pour l’utilisateur. Une alternative serait d’avoir des agro-textiles qui pourraient être collectés par l’utilisateur et minéralisés après quelques mois. Les polymères biodégradables pourraient répondre à ces objectifs. Dans cette étude, nous nous sommes concentrés sur le poly(butylene succinate) un polymère biodégradable et biosourcé. Le PBS a été synthétisé sur un pilote de polycondensation. Néanmoins, le PBS issu de cette synthèse présente de faibles propriétés rhéologiques. La structure du PBS a donc été modifiée par l’incorporation de branchements ou d’allongeurs de chaines. Les propriétés mécaniques ont également été optimisées via la synthèse de systèmes PBS/PLA transréagits et de PBS nanocomposites. Ces PBS modifiés ont été testés au filage. Finalement un fil de PBS avec 0,5% de silice sphérique a été produit à plus grande échelle et un textile a été fabriqué. Le vieillissement de ces fils PBS a été étudié et la conservation des propriétés mécaniques durant l’utilisation du fil en extérieur a été validée. Enfin, une dernière approche plus exploratoire a été testée. Elle consiste en la modification du PBS par des interactions supramoléculaires réversibles en température. / In the last decade, biodegradable polymers have gained significant interest for agricultural applications. Here we focus on the development of biodegradable textiles for insect-proof nets. Currently these textiles must be collected by specialized companies after the growing season and generate disposal cost. An ideal agrotextile would be collected by the user at the end of the growing season, and undergo full mineralization within few months. These requirements can be achieved by using biodegradable polymers. In this study, poly(butylene succinate) (PBS), a biobased and biodegradable polymer was studied. PBS was synthesized by polycondensation on a pilot plant reactor. Because of low rheological properties of the synthesized polyester, the chemical structure of PBS was modified by several approaches like chain extension or branching. The mechanical properties were tuned with the synthesis of PBS/PLA transreacted systems and PBS nanocomposites. These modified PBS were tested upon fiber spinning. Finally a PBS yarn with 0,5% spherical silica was produced at higher scale and a textile was done. Ageing of the PBS yarns was also studied and the conservation of the mechanical properties during use of the textile was validated. Lastly a more exploratory approach was tested. It is synthesis of modified PBS by supramolecular interactions, which are reversible upon temperature.

Dans le domaine des plastiques biodégradables, les produits se doivent d’être de plus en plus compétitifs. Ces travaux, menés entre le laboratoire IMP@UJM et la société LCI ont eu pour objectif principal l’augmentation de la part en matières d’origines renouvelables dans le mélange de polymères biodégradable poly(butylène adipate-co-téréphtalate) (PBAT)/TPF (farine thermoplastique), sans diminuer ses propriétés mécaniques. Ce mélange est obtenu par extrusion en une seule étape, comprenant la plastification de la farine et le mélange avec le polyester. L’enjeu scientifique était donc en premier lieu de comprendre les relations entre la mise en oeuvre, l’établissement de la morphologie du mélange, la concentration en chacun des polymères et les propriétés mécaniques. Dans un second temps, ces résultats ont été exploités en vue de l’augmentation des propriétés mécaniques du mélange. L’influence de la concentration en TPF et du rapport de viscosité entre les phases a donc été mise en évidence sur toute la gamme de concentration, mettant en lumière l’importance de contrôler la tension interfaciale du mélange. Des mécanismes d’établissement de la morphologie et des interprétations quant à son effet sur les propriétés mécaniques du mélange sont proposés. L’étude d’une modification par extrusion réactive du PBAT est ensuite présentée. L’évolution de la structure du polyester est caractérisée par chromatographie d’exclusion stérique en fonction de différents paramètres, dont le temps de mélange. Enfin, différentes modifications du mélange PBAT/TPF sont testées. L’influence de la modification du PBAT, de la modification de la phase TPF ou de la modification de l’interface via des agents compatibilisants est étudiée sur les propriétés rhéologiques, morphologiques et mécaniques du mélange / Biodegradable plastics need to be more and more competitive. This work, conducted between IMP@UJM laboratory and LCI company had the main objective of increasing the content of renewable materials in the biodegradable blend of poly(butylene adipate-co-terephthalate) (PBAT)/ thermoplastic flour (TPF), without decreasing its mechanical properties. The blend was obtained by a single step extrusion, including flour thermoplastification and blending with the polyester. The scientific challenge was to understand the relationship between processing parameters, the morphology establishment, the concentration of each phase of the blend and its mechanical properties. Then, these results were exploited in order to increase the mechanical properties of the mixture. The influence of the concentration of TPF and the viscosity ratio between the phases was highlighted over the entire concentration range. This highlighted the importance of controlling the interfacial tension of the blend. Mechanisms of the morphology establishment were proposed, as well as interpretations about its effect on the mechanical properties of the blend. Then, a study of the PBAT modification by reactive extrusion was proposed. The evolution of the polyester structure was characterized by size exclusion chromatography, according to various parameters including the mixing time. Finally, various modifications of PBAT/TPF mixture were tested. Modifying the PBAT, the TPF phase or the interface via the compatibilizers were studied in order to tailor the rheological, morphological and mechanical properties