abstract: Minimally invasive endovascular embolization procedures decrease surgery time, speed up recovery, and provide the possibility for more comprehensive treatment of aneurysms, arteriovenous malformations (AVMs), and hypervascular tumors. Liquid embolic agents (LEAs) are preferred over mechanical embolic agents, such as coils, because they achieve homogeneous filling of aneurysms and more complex angioarchitectures. The gold standard of commercially available LEAs is dissolved in dimethyl sulfoxide (DMSO), which has been associated with vasospasm and angiotoxicity. The aim of this study was to investigate amino acid substitution in an enzyme-degradable side group of an N-isopropylacrylamide (NIPAAm) copolymer for the development of a LEA that would be delivered in water and degrade at the rate that tissue is regenerated. NIPAAm copolymers have a lower critical solution temperature (LCST) due to their amphiphilic nature. This property enables them to be delivered as liquids through a microcatheter below their LCST and to solidify in situ above the LCST, which would result in the successful selective occlusion of blood vessels. Therefore, in this work, a series of poly(NIPAAm-co-peptide) copolymers with hydrophobic side groups containing the Ala-Pro-Gly-Leu collagenase substrate peptide sequence were synthesized as in situ forming, injectable copolymers.. The Gly-Leu peptide bond in these polypeptides is cleaved by collagenase, converting the side group into the more hydrophilic Gly-Ala-Pro-Gly-COOH (GAPG-COOH), thus increasing the LCST of the hydrogel after enzyme degradation. Enzyme degradation property and moderate mechanical stability convinces the use of these copolymers as liquid embolic agents. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2019

abstract: Current treatment methods for cerebral aneurysms are providing life-saving measures for patients suffering from these blood vessel wall protrusions; however, the drawbacks present unfortunate circumstances in the invasive procedure or with efficient occlusion of the aneurysms. With the advancement of medical devices, liquid-to-solid gelling materials that could be delivered endovascularly have gained interest. The development of these systems stems from the need to circumvent surgical methods and the requirement for improved occlusion of aneurysms to prevent recanalization and potential complications. The work presented herein reports on a liquid-to-solid gelling material, which undergoes gelation via dual mechanisms. Using a temperature-responsive polymer, poly(N-isopropylacrylamide) (poly(NIPAAm), the gelling system can transition from a solution at low temperatures to a gel at body temperature (physical gelation). Additionally, by conjugating reactive functional groups onto the polymers, covalent cross-links can be formed via chemical reaction between the two moieties (chemical gelation). The advantage of this gelling system comprises of its water-based properties as well as the ability of the physical and chemical gelation to occur within physiological conditions. By developing the polymer gelling system in a ground-up approach via synthesis, its added benefit is the capability of modifying the properties of the system as needed for particular applications, in this case for embolization of cerebral aneurysms. The studies provided in this doctoral work highlight the synthesis, characterization and testing of these polymer gelling systems for occlusion of aneurysms. Conducted experiments include thermal, mechanical, structural and chemical characterization, as well as analysis of swelling, degradation, kinetics, cytotoxicity, in vitro glass models and in vivo swine study. Data on thermoresponsive poly(NIPAAm) indicated that the phase transition it undertakes comes as a result of the polymer chains associating as temperature is increased. Poly(NIPAAm) was functionalized with thiols and vinyls to provide for added chemical cross-linking. By combining both modes of gelation, physical and chemical, a gel with reduced creep flow and increased strength was developed. Being waterborne, the gels demonstrated excellent biocompatibility and were easily delivered via catheters and injected within aneurysms, without undergoing degradation. The dual gelling polymer systems demonstrated potential in use as embolic agents for cerebral aneurysm embolization. / Dissertation/Thesis / Ph.D. Bioengineering 2012

[pt] O processo de tratamento de tumores por embolização vascular é sensível ao conjunto de partículas poliméricas empregado, ditos agentes embólicos, cujos fatores como tamanho e morfologia influenciam no sucesso do procedimento e podem ocasionar complicações quando mal dimensionados. Partículas esféricas de poli(acetato de vinila-co-metacrilato de metila) apresentam a maioria das características desejadas após tratamento por hidrólise alcalina. Este material é relativamente novo, o que significa que há uma lacuna de conhecimento em relação ao estudo dos fenômenos que regem sua cinética. Dessa forma, o presente trabalho investigou a cinética de copolimerização responsável pela sua produção. No desenvolvimento matemático, o método dos momentos foi utilizado assumindo estado quase-estacionário para as espécies radicalares. Além disso, o modelo considera difusão das moléculas no meio para contabilização dos efeitos viscosos, comumente determinados empiricamente. Constatou-se que as características físicas dos monômeros, assim como os parâmetros cinéticos da homopolimerização, puderam ser utilizados na copolimerização. Entretanto, como relatado na literatura para outros sistemas, os efeitos viscosos se comportam de forma consideravelmente diferente na copolimerização, sendo necessário a reestimação de alguns parâmetros relativos aos mesmos. Assim, foi possível reproduzir de forma adequada perfis de conversão, massas molares médias e composição do copolímero. Concluiu-se que o modelo proposto é capaz de representar a cinética da copolimerização em suspensão do poli(acetato de vinila-co-metacrilato de metila), possibilitando um melhor controle das características do copolímero aplicado ao procedimento de embolização vascular. Até onde se tem conhecimento, este é o primeiro trabalho que investiga e implementa com sucesso a modelagem cinética desse sistema. / [en] The treatment of vascularized tumors through vascular embolization is sensible to the polymeric particles used during procedure. These embolic agents have attributes, like size and morphology, which play a significant role on the success of this technique and can promote complications when not well dimensioned. Among the many options available, spherical particles of poly(vinyl acetate-co-methyl methacrylate) present most desired characteristics after alkalyne hydrolysis treatment. Being relatively new, the literature lack studies related to the kinetics of production of this material. Therefore, this research investigated the copolymerization kinetics of poly(vinyl acetate-co-methyl methacrylate) production. In the mathematical development, the method of moments was used assuming quasi-steady state for the free radical species. Additionally, the model includes the viscous effects through the diffusion of the involved molecules, which is usually accounted empirically. It was possible to use the physical properties of the monomers as well as the homopolymerization kinetic parameters in the copolymerization. However, as reported in the literature, some parameters are sensible to the system and some viscous effects affect the copolymerization differently. Therefore, some parameters were reestimated. It was possible to predict the conversion, average molecular weights and composition. Consequently, the model was capable of representing the kinetics of the suspension copolymerization of poly(vinyl acetate-co-methyl methacrylate), meaning it could be used to improve the production of this polymer as an embolic agent for vascular embolization procedure. As far as known by the author, this is the first study to successfully perform the kinetic modeling of this specific system.