abstract: Severe cases of congenital heart defect (CHD) require surgeries to fix the structural problem, in which artificial grafts are often used. Although outcome of surgeries has improved over the past decades, there remains to be patients who require re-operations due to graft-related complications and the growth of patients which results in a mismatch in size between the patient’s anatomy and the implanted graft. A graft in which cells of the patient could infiltrate, facilitating transformation of the graft to a native-like tissue, and allow the graft to grow with the patient heart would be ideal. Cardiac tissue engineering (CTE) technologies, including extracellular matrix (ECM)-based hydrogels has emerged as a promising approach for the repair of cardiac damage. However, most of the previous studies have mainly focused on treatments for ischemic heart disease and related heart failure in adults, therefore the potential of CTE for CHD treatment is underexplored. In this study, a hybrid hydrogel was developed by combining the ECM derived from cardiac tissue of pediatric CHD patients and gelatin methacrylate (GelMA). In addition, the influence of incorporating gold nanorods (GNRs) within the hybrid hydrogels was studied. The functionalities of the ECM-GelMA-GNR hydrogels as a CTE scaffold were assessed by culturing neonatal rat cardiomyocytes on the hydrogel. After 8 days of cell culture, highly organized sarcomeric alpha-actinin structures and connexin 43 expression were evident in ECM- and GNR-incorporated hydrogels compared to pristine GelMA hydrogel, indicating cell maturation and formation of cardiac tissue. The findings of this study indicate the promising potential of ECM-GelMA-GNR hybrid hydrogels as a CTE approach for CHD treatment. As another approach to improve CHD treatment, this study sought the possibility of performing a proteomic analysis on cardiac ECM of pediatric CHD patient tissue. As the ECM play important roles in regulating cell signaling, there is an increasing interest in studying the ECM proteome and the influences caused by diseases. Proteomics on ECM is challenging due to the insoluble nature of ECM proteins which makes protein extraction and digestion difficult. In this study, as a first step to perform proteomics, optimization on sample preparation procedure was attempted. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2018

Orientador: Keizo Yukimitu / Resumo: Com a crescente populacional a demanda pelos polímeros aumentou significativamente, levando assim a pesquisas cientificas visando adequar materiais as nossas necessidades. O PMMA ou acrílico é muito utilizado em nosso cotidiano, sendo um material muito versátil com aplicabilidade em diversos setores. O intuito deste trabalho foi realizar a produção de um filme de acrílico [Poli(metil-metacrilato)] isento de bolhas e transparente, a qual tivesse uma repetibilidade. Foi realizada a dopagem com terras raras, sendo o Óxido de Érbio e o Óxido de Itérbio escolhidos como dopantes em diferentes concentrações de gramas/mol por gramas/mol (0 % referência, 5 %, 10%, 15% e 20 %). Logo após foi feita a caracterização dos filmes, determinando o índice de refração das amostras utilizando o Interferomêtro de Michelson com laser He-Ne (vermelho) de comprimento de onda de 632,8 nm. Notamos que o índice de refração do PMMA na amostra de referência aumentou gradativamente com as dopagens, o laser diodo na cor verde de comprimento de onda de 532 nm também foi utilizado e os resultados demostraram comportamentos similares. A Espectroscopia no Infravermelho por Transformada de Fourier (FTIR) foi realizada, observando o aparecimento de picos característicos dos elementos dopantes nas amostras e que esses picos aumentavam conforme a concentração de dopagem aumentava. A Difração de Raios-X (DRX) nos mostrou a incidência picos de cristalinidade referentes aos elementos dopantes em contraste com o espec... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: With the growing population demand for polymers has increased significantly, leading to scientific research aimed at adapting materials to our needs. PMMA or acrylic is widely used in our daily lives, being a very versatile material with applicability in several sectors. The purpose of this work was to produce an acrylic film [Poly (methyl-methacrylate)] which had a repeatability. Rare earth doping was performed, with Erbium Oxide and Ytterbium Oxide chosen as dopants in different concentrations of grams / mole per gram / mole (0% reference, 5%, 10%, 15% and 20%). After the characterization of the films, determining the refractive index of the samples using the Michelson Interferometer with He-Ne (red) laser of wavelength of 632.8 nm, we noticed that the refractive index of the PMMA in the sample of reference period increased gradually with doping, the green diode laser wavelength of 532 nm was also used and the results demonstrated similar behaviors. Fourier Transform Infrared Spectroscopy (FTIR) was performed, observing the appearance of characteristic peaks of the dopant elements in the samples and that these peaks increased as the doping concentration increased. X-ray Diffraction (XRD) showed us the incidence of crystallinity peaks relative to the dopant elements in contrast to the normal PMMA spectrum demonstrating the insertion of the rare earths into the matrix structure. / Mestre

La thèse présente l'étude des polymères biocompatibles dans le domaine de la libération contrôlée de médicaments. Les principes de la libération contrôlée sont soulignés et les applications des polymères sont décrites. Séries de copolymères de HEMA ont été synthétisées par polymérisation en suspension-dispersion, polymérisation précipitante et en masse. La fonctionnalisation a été donnée par l'introduction de monomères comme : methacryloxyethyl phospahte, guanidino-propyl methacrylate, diethylaminoethyl methacrylate, diallyldimethyl ammonium chloride, methacryloyloxyethyl acetoacetate, methacryloyloxyethyl trimethylammonium chloride, glycidyl methacrylate, tetrahydrofurfuryl methacrylate. Les polymères ont été caractérisés physico-chimiquement et biologiquement. Les rapports de réactivité des monomères dans les systèmes : MMA-TIPA, HEMA-AA, AA-dDMA, HEMA-dDMA-AA ont été étudiés. Une autre direction a été l'étude du comportement de ces copolymères avec des colorants fluorescents, et d'un copolymère contenant du MMA et un monomère iodé, pour la détection biologique. Pour l'obtention de systèmes actifs de libération, on aa utilisé deux méthodes : liaison physique en cas de thalidomide et liaison chimique pour le nafcilline. La liaison polymère-médicament a été analysée par FT-IR et UV, et a été confirmée par MEB et EDX. On a effectué des études in vitro pour vérifier les interactions entre les polymères chargés avec médicaments et les cellules, en utilisant comme méthode d'analyse le FOM, dans le cas du thalidomide, et l'UV-VIS, pour le nafcilline. Les résultats obtenus donnent une vraie option pour une future utilisation dans le domaine de l'anti-angiogenèse des tumeurs.

Facile, one-step synthesis of self-assembling, cationic block copolymers of poly(2-N-(dimethylaminoethyl) methacrylate) (pDMAEMA) and PEO-PPO-PEO (Pluronic®) is developed. The copolymers are obtained via free-radical polymerization of DMAEMA initiated by Pluronic-radicals generated by cerium (IV). The copolymers possess surface activity, are polycationic at pH<7.1, and self-assemble into micelle-like aggregates when neutralized. Potential applications of the novel copolymers for DNA transfection in gene therapy are discussed. / Singapore-MIT Alliance (SMA)

The phenomenon of depropagation or reverse polymerization for multicomponent polymerizations has been studied in detail. The monomer Alpha-Methyl Styrene (AMS) has been copolymerized with Methyl Methacrylate (MMA) and Butyl Acrylate (BA) at temperatures ranging from 60oC to 140oC and the kinetics have been studied in the form of propagation/cross propagation and depropagation parameters. There have been multiple attempts with varying amounts of success in the past to determine the kinetic parameters for depropagating systems including work by Lowry and Wittmer as well as other modelling methodologies that are not as mechanistic. The most recent development of the mechanistic terminal model is that of the Kruger model. The model is robust and can take into account all special cases as well as all reactions being reversible. The kinetic parameters have been estimated for each of the three binary systems using the Kruger model (MMA/AMS, MMA/BA, BA/AMS). The Alfrey-Goldfinger model is inadequate to describe depropagating terpolymer systems and in order to study them, a new model was developed based upon the binary Kruger model. This new model takes into account a fully depropagating terpolymer system leading to a total of 15 parameters to be estimated. These 15 parameters have the same definitions as those estimated from the binary Kruger model, thus making accurate analysis of the binary systems crucial since these will be used as first estimates for the terpolymer system. Extensive experimental data (composition, conversion and molecular weights) was collected and analysed for the MMA/AMS and BA/AMS systems. For the BA/AMS system both the bulk and solution copolymerizations were studied in detail with the results from the Kruger model not showing a significant difference in the reactivity ratios between the two types of polymerization. For the MMA/AMS system, a bulk study only was done which revealed an interesting phenomenon that points toward a break down of the long chain approximations used for all of the models being studied. For both of these systems, extensive ¹H NMR analysis was done to determine the copolymer composition. Data collected in previous research for the MMA/BA system was reanalysed using the Kruger model and it was found that the parameter estimates did not differ significantly from the published values. Extensive benchmarking was done with the newly developed terpolymer model on non-depropagating systems using data from the literature to ensure it worked for the simplest cases. It was found that the model matched the parameter estimates from the literature and in some cases improving upon them to fit the data better. Along with the benchmarking a sensitivity analysis was done which revealed some interesting information. For the MMA/BA/AMS terpolymer system a set of experiments (based upon practical considerations) were performed and the composition of the polymer was determined using ¹³C NMR instead of the usual ¹H NMR due to the difficulty of peak separation for the complex terpolymer. Using the depropagating terpolymer composition data in conjunction with the parameter estimates from the three binary systems allowed for estimation of the 15 kinetic parameters, which showed only minor variation from the binary estimates.

The phenomenon of depropagation or reverse polymerization for multicomponent polymerizations has been studied in detail. The monomer Alpha-Methyl Styrene (AMS) has been copolymerized with Methyl Methacrylate (MMA) and Butyl Acrylate (BA) at temperatures ranging from 60oC to 140oC and the kinetics have been studied in the form of propagation/cross propagation and depropagation parameters. There have been multiple attempts with varying amounts of success in the past to determine the kinetic parameters for depropagating systems including work by Lowry and Wittmer as well as other modelling methodologies that are not as mechanistic. The most recent development of the mechanistic terminal model is that of the Kruger model. The model is robust and can take into account all special cases as well as all reactions being reversible. The kinetic parameters have been estimated for each of the three binary systems using the Kruger model (MMA/AMS, MMA/BA, BA/AMS). The Alfrey-Goldfinger model is inadequate to describe depropagating terpolymer systems and in order to study them, a new model was developed based upon the binary Kruger model. This new model takes into account a fully depropagating terpolymer system leading to a total of 15 parameters to be estimated. These 15 parameters have the same definitions as those estimated from the binary Kruger model, thus making accurate analysis of the binary systems crucial since these will be used as first estimates for the terpolymer system. Extensive experimental data (composition, conversion and molecular weights) was collected and analysed for the MMA/AMS and BA/AMS systems. For the BA/AMS system both the bulk and solution copolymerizations were studied in detail with the results from the Kruger model not showing a significant difference in the reactivity ratios between the two types of polymerization. For the MMA/AMS system, a bulk study only was done which revealed an interesting phenomenon that points toward a break down of the long chain approximations used for all of the models being studied. For both of these systems, extensive ¹H NMR analysis was done to determine the copolymer composition. Data collected in previous research for the MMA/BA system was reanalysed using the Kruger model and it was found that the parameter estimates did not differ significantly from the published values. Extensive benchmarking was done with the newly developed terpolymer model on non-depropagating systems using data from the literature to ensure it worked for the simplest cases. It was found that the model matched the parameter estimates from the literature and in some cases improving upon them to fit the data better. Along with the benchmarking a sensitivity analysis was done which revealed some interesting information. For the MMA/BA/AMS terpolymer system a set of experiments (based upon practical considerations) were performed and the composition of the polymer was determined using ¹³C NMR instead of the usual ¹H NMR due to the difficulty of peak separation for the complex terpolymer. Using the depropagating terpolymer composition data in conjunction with the parameter estimates from the three binary systems allowed for estimation of the 15 kinetic parameters, which showed only minor variation from the binary estimates.

Hydrophilic poly(2-hydroxyethyl methacrylate), PHEMA, and hydrophobic poly(dimethyl siloxane), PDMS, segments containing copolymers have been widely used as a biomaterial. These amphiphilic copolymers also used as an emulsifying agent in polymer solutions and compatibilizer in polymer blends. In this case, solution polymerizations of HEMA by radiation, ATRP and RAFT methods were studied. The thermal degradation mechanism of PHEMA, which was prepared in aqueous solution by gamma radiation technique, was studied in detail. The DSC, TGA and Mass Spectroscopy analyses revealed that the degradation is linkage and depolymerization with a combination of monomer fragmentation. The ATRP of HEMA was performed with ethyl-2-bromoisobutyrate (EBriB) initiator and CuCl/bipyridine catalyst in MEK/1-propanol solvent mixture. Cu(II) complexes and PHEMA obtained via ATRP were characterized by UV-vis, FTIR and 1H-NMR analysis. The RAFT polymerization of HEMA with different [RAFT]/[AIBN] ratios were also investigated in three solvents (methyl ethylketone, ethyl acetate and toluene). The controlled polymerization of HEMA with the ratio of [RAFT]/ [AIBN]=18 at 80 oC in MEK and ethyl acetate, shows the first-order kinetic up to the nearly 40 % conversion Macroazoinitiator PDMS-MAI was synthesized from bifunctional PDMS and then copolymerized with MMA, EMA, HEMA and TMS-HEMA monomers Different characterization methods such as FTIR, 1H-NMR, solid state NMR, GPC, XPS, SEM, DSC, etc. have been used for the characterization of block copolymers. P(DMS-b-TMSHEMA) was converted to the P(DMS-b-HEMA) block copolymer by deprotection of TMS groups. The phase separated morphology was observed for the P(DMS-b-HEMA) copolymer, which was different from P(DMS-b-MMA) and P(DMS-b-EMA) copolymers.

Acrylamide based hydrogels were synthesized through copolymerization reaction of allyl methacrylate with acrylamide. Copolymerization reactions were carried out with solution polymerization in tetrahydrofuran by using &alpha / -&alpha / -azoisobutyronitrile as an initiator at 60 0 C. Three copolymer compositions were studied having 5, 15, 25 molar percentage of allyl methacrylate as feed concentrations. The synthesized copolymers were characterized by FTIR, NMR, DSC, TGA and GPC. 1H-NMR spectra were used to confirm the chemical structures of the copolymers and to determine the comonomer compositions of the copolymers. DSC and TGA analysis were conducted to determine the thermal properties of the copolymers and TGA results showed that copolymers have two step degradation behavior. Molecular weights of the copolymers were determined by GPC. Swelling capacities of the obtained hydrogels were investigated and swelling capacity of the gels reached to 77% as maximum value.

Acrylic resins, synthesized from a mixture of monomers selected from the methacrylate, acrylate and styrene families, are the base polymer components for many automotive coatings due to their excellent chemical and mechanical properties. The low molecular weight polymers with reactive functionalities are made via high-temperature starved-feed free-radical solution semibatch terpolymerization, operating conditions that greatly promote the importance of secondary reactions, such as methacrylate depropagation, and acrylate backbiting, chain scission and macromonomer propagation. In this work, a generalized model for styrene/methacrylate/acrylate terpolymerization has been developed and formulated in the PREDICI software package and poorly understood high temperature mechanisms have been studied. Unknown rate coefficients for methacrylate depropagation, reactivity of acrylate macromonomer and penultimate copolymerization kinetics were determined via separate kinetic experiments. The generality of the terpolymerization mechanistic model was verified against data obtained under a range of polymerization conditions, and provides an exclusive insight into the kinetic complexity of methacrylate/styrene/acrylate terpolymerization at high temperatures. / Thesis (Ph.D, Chemical Engineering) -- Queen's University, 2010-04-28 19:56:36.906

The viscoelastic relaxation dynamics of a series of poly(methyl methacrylate) [PMMA] based nanocomposites filled with carbon nanotubes have been studied using dynamic mechanical analysis and broadband dielectric spectroscopy. The networks were prepared using four methods: (i) melt mixing, (ii) solution processing, (iii) in-situ polymerization, and (iv) polymer grafting. Nanotube modifications included surface oxidation via acid exposure and surface functionalization for polymer grafting. The effect of variations in processing method and nanotube modification on glass transition temperature (Tg) and relaxation dynamics was investigated. The relaxation behavior of the nanocomposites was sensitive to processing method and nanotube functionalization. Nanotube loading (to 5 wt%) led to a progressive increase in rubbery modulus, with the increase more pronounced in the solution-processed samples owing to enhanced nanotube dispersion. In the case of the oxidized nanotubes, loading led to an increase in modulus, but also a systematic decrease in Tg of ~ 15°C with 3 wt% nanotubes. For in-situ polymerized (PMMA/MWNT-ox) nanocomposites, there was no readily discernable trend in Tg. Composites prepared via in-situ polymerization in the presence of methyl methacrylate functionalized tubes (i.e., polymer grafting) displayed a positive shift in Tg of nearly 20°C at 1 wt% loading. Investigation of the dielectric relaxation of the PMMA/MWNT composites indicated a percolation threshold between 0.3 and 0.4 wt% MWNT.