The aim of this thesis is the investigation of modeling and optimization particularities of tubular polymerization reactors. The original work is divided in two sections, the first treating a modeling and optimization study of tubular reactors for methyl methacrylate polymerization in solution, and the second, an experimental and theoretical study of L-lactide reactive extrusion. In the first section, reactor simulations in similar operating conditions were performed in order to select a representative kinetic model among the published kinetic models for MMA solution polymerization. Two widely used numerical algorithms, one based on Pontryagin's Minimum Principle and the other a Genetic Algorithm, were compared for an average-complexity optimization problem. The results showed a superior robustness of the Genetic Algorithm for this category of problems. The second part of the thesis deals with the modeling and optimization of L-lactide reactive extrusion. A kinetic model is proposed and its parameters estimated using nonlinear estimation numerical procedures based on experimentally measured data. Reactive extrusion experiments were performed in representative operating conditions. The Llactide/ polylactide flow in the extruder was characterized by simulation using the commercial software LUDOVIC®. The simulated residence time distributions characteristics are used to model the reactive extrusion process of two approaches, an axial dispersion model and a compartment model, based on compartments whose characteristics are deduced from the simulations using LUDOVIC®. The modeling results are in good agreement with the measured data in the same operating conditions.

Atualmente, existe uma grande necessidade médica por enxertos vasculares de pequeno calibre (< 6 mm), que possam ser utilizados em cirurgias de reconstrução vascular. Nesse trabalho, dois tipos de biomateriais vasculares foram desenvolvidos pela técnica de electrospinning: biomateriais de policaprolactona (PCL) e biomateriais de poli(carbonato de trimetileno – co – ácido lático) (PTMCLLA). Os biomateriais de PCL foram funcionalizados com heparina e com VEGF (PCL/Hep/VEGF). Os biomateriais de PTMCLLA foram desenvolvidos a partir de três razões de carbonato de trimetileno/ ácido lático: 20/80, 30/70 e 40/60. Os biomateriais de PCL apresentaram taxa de degradação lenta e alta elasticidade. A funcionalização dos biomateriais preveniu a coagulação do sangue e também favoreceu o crescimento de células-tronco mesenquimais (CTMs) e de células progenitoras endoteliais (CPEs) nessas estruturas. A análise de PCR demonstrou que o VEGF adsorvido aos biomateriais não foi suficiente para diferenciar as CTMs em células endoteliais. O cultivo das CPEs sobre os biomateriais aumentou a expressão de VE-caderina e a presença de VEGF nas estruturas manteve o nível de expressão de CD31 e CD34 nessas células. Após essas análises, os biomateriais de PCL/Hep/VEGF foram fabricados em formato tubular. As CPEs foram semeadas no lúmen do biomaterial, através de biorreatores de parede rotatória (BPR), e mantidas em cultivo, por biorreatores de perfusão (BP). O BPR favoreceu a distribuição homogênea das CPEs na parede luminal dos biomateriais enquanto que o BP estimulou seu crescimento e otimizou seu metabolismo energético. Os biomateriais produzidos a partir dos copolímeros de PTMCLLA 30/70 e 40/60 exibiram uma alta flexibilidade. Porém, os biomateriais de PTMCLLA 40/60 tiveram um grande enrugamento. Os biomateriais de PTMCLLA 30/70 suportaram a adesão e o crescimento de CTMs, de CPEs e de células musculares lisas. Os resultados obtidos no presente estudo demonstram que biomateriais de PCL/Hep/VEGF apresentam características físico-químicas compatíveis para o uso vascular. Ainda, previnem a formação de trombos em sua superfície e propiciam o desenvolvimento da camada endotelial em seu lúmen. Os biomateriais de PTMCLLA 30/70 exibem alta flexibilidade e suportam o desenvolvimento de células vasculares e de células-tronco mesenquimais. De acordo com esses resultados, é possível concluir que biomateriais de PCL/Hep/VEGF e de PTMCLLA 30/70 são candidatos promissores para aplicação como enxertos vasculares. / Currently, there is a great medical need for small caliber vascular grafts (<6 mm), which can be used in vascular replacement surgeries. In this work, two types of vascular biomaterials were developed by the electrospinning technique: biomaterials of polycaprolactone (PCL) and biomaterials of poly(trimethylene carbonate-co-L-lactide) (PTMCLLA). PCL biomaterials were functionalized with heparin and VEGF (PCL / Hep/VEGF). The PTMCLLA biomaterials were developed from three ratios of trimethylene carbonate/lactide: 20/80, 30/70 and 40/60. The PCL biomaterials presented a slow degradation rate and high elasticity. The functionalization of the biomaterials prevented the blood from clotting and also favored the growth of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) in these structures. PCR analysis demonstrated that VEGF adsorbed by the biomaterials was not sufficient to differentiate the MSCs into endothelial cells. The cultivation of CPEs on the biomaterials increased their expression of VE-cadherin and the presence of VEGF in the structures maintained the cell expression of CD34 and CD31. After these analyzes, the PCL/Hep/VEGF biomaterials were produced in a tubular geometrical form. The CPEs were seeded into their lumen by rotating bioreactors (RB) and maintained in culture by perfusion bioreactors (PB). The RB favored the homogeneous distribution of the CPEs in the luminal wall of the biomaterials while the BP stimulated their growth and optimized their energetic metabolism. The biomaterials produced from the PTMCLLA 30/70 and 40/60 copolymers exhibited high flexibility. However, the PTMCLLA 40/60 biomaterials exhibited substantial wrinkling. The PTMCLLA 30/70 biomaterials supported the adhesion and growth of MSCs, CPEs and smooth muscle cells. This study has demonstrated that PCL/Hep/VEGF biomaterials have physicochemical characteristics compatible with vascular use. Furthermore, they prevent thrombus formation on their surfaces and promote the development of the endothelial layer in their lumen. Biomaterials of PTMCLLA 30/70 exhibit high flexibility and support the development of vascular and mesenchymal stem cells. According to these results, it can be concluded that PCL/Hep/VEGF and PTMCLLA 30/70 biomaterials are promising candidates for use as vascular grafts.

Atualmente, existe uma grande necessidade médica por enxertos vasculares de pequeno calibre (< 6 mm), que possam ser utilizados em cirurgias de reconstrução vascular. Nesse trabalho, dois tipos de biomateriais vasculares foram desenvolvidos pela técnica de electrospinning: biomateriais de policaprolactona (PCL) e biomateriais de poli(carbonato de trimetileno – co – ácido lático) (PTMCLLA). Os biomateriais de PCL foram funcionalizados com heparina e com VEGF (PCL/Hep/VEGF). Os biomateriais de PTMCLLA foram desenvolvidos a partir de três razões de carbonato de trimetileno/ ácido lático: 20/80, 30/70 e 40/60. Os biomateriais de PCL apresentaram taxa de degradação lenta e alta elasticidade. A funcionalização dos biomateriais preveniu a coagulação do sangue e também favoreceu o crescimento de células-tronco mesenquimais (CTMs) e de células progenitoras endoteliais (CPEs) nessas estruturas. A análise de PCR demonstrou que o VEGF adsorvido aos biomateriais não foi suficiente para diferenciar as CTMs em células endoteliais. O cultivo das CPEs sobre os biomateriais aumentou a expressão de VE-caderina e a presença de VEGF nas estruturas manteve o nível de expressão de CD31 e CD34 nessas células. Após essas análises, os biomateriais de PCL/Hep/VEGF foram fabricados em formato tubular. As CPEs foram semeadas no lúmen do biomaterial, através de biorreatores de parede rotatória (BPR), e mantidas em cultivo, por biorreatores de perfusão (BP). O BPR favoreceu a distribuição homogênea das CPEs na parede luminal dos biomateriais enquanto que o BP estimulou seu crescimento e otimizou seu metabolismo energético. Os biomateriais produzidos a partir dos copolímeros de PTMCLLA 30/70 e 40/60 exibiram uma alta flexibilidade. Porém, os biomateriais de PTMCLLA 40/60 tiveram um grande enrugamento. Os biomateriais de PTMCLLA 30/70 suportaram a adesão e o crescimento de CTMs, de CPEs e de células musculares lisas. Os resultados obtidos no presente estudo demonstram que biomateriais de PCL/Hep/VEGF apresentam características físico-químicas compatíveis para o uso vascular. Ainda, previnem a formação de trombos em sua superfície e propiciam o desenvolvimento da camada endotelial em seu lúmen. Os biomateriais de PTMCLLA 30/70 exibem alta flexibilidade e suportam o desenvolvimento de células vasculares e de células-tronco mesenquimais. De acordo com esses resultados, é possível concluir que biomateriais de PCL/Hep/VEGF e de PTMCLLA 30/70 são candidatos promissores para aplicação como enxertos vasculares. / Currently, there is a great medical need for small caliber vascular grafts (<6 mm), which can be used in vascular replacement surgeries. In this work, two types of vascular biomaterials were developed by the electrospinning technique: biomaterials of polycaprolactone (PCL) and biomaterials of poly(trimethylene carbonate-co-L-lactide) (PTMCLLA). PCL biomaterials were functionalized with heparin and VEGF (PCL / Hep/VEGF). The PTMCLLA biomaterials were developed from three ratios of trimethylene carbonate/lactide: 20/80, 30/70 and 40/60. The PCL biomaterials presented a slow degradation rate and high elasticity. The functionalization of the biomaterials prevented the blood from clotting and also favored the growth of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) in these structures. PCR analysis demonstrated that VEGF adsorbed by the biomaterials was not sufficient to differentiate the MSCs into endothelial cells. The cultivation of CPEs on the biomaterials increased their expression of VE-cadherin and the presence of VEGF in the structures maintained the cell expression of CD34 and CD31. After these analyzes, the PCL/Hep/VEGF biomaterials were produced in a tubular geometrical form. The CPEs were seeded into their lumen by rotating bioreactors (RB) and maintained in culture by perfusion bioreactors (PB). The RB favored the homogeneous distribution of the CPEs in the luminal wall of the biomaterials while the BP stimulated their growth and optimized their energetic metabolism. The biomaterials produced from the PTMCLLA 30/70 and 40/60 copolymers exhibited high flexibility. However, the PTMCLLA 40/60 biomaterials exhibited substantial wrinkling. The PTMCLLA 30/70 biomaterials supported the adhesion and growth of MSCs, CPEs and smooth muscle cells. This study has demonstrated that PCL/Hep/VEGF biomaterials have physicochemical characteristics compatible with vascular use. Furthermore, they prevent thrombus formation on their surfaces and promote the development of the endothelial layer in their lumen. Biomaterials of PTMCLLA 30/70 exhibit high flexibility and support the development of vascular and mesenchymal stem cells. According to these results, it can be concluded that PCL/Hep/VEGF and PTMCLLA 30/70 biomaterials are promising candidates for use as vascular grafts.

<p>Degradable polymers have gained an increased attention in the field of biomedical applications over the past decades, for example in tissue engineering. One way of improving the biocompatibility of these polymers is by chemical surface modification, however the risk of degradation during the modification procedure is a limiting factor. In some biomedical applications, for example in nerve guides, a patterned surface is desired to improve the cell attachment and proliferation.</p><p>In this thesis a new non-destructive, single-step, and solvent free method for surface modification of degradable polymers is described. Poly(L-lactide) (PLLA) substrates have been functionalized with one of the following vinyl monomers; N-vinylpyrrolidone (VP), acrylamide (AAm), or maleic anhydride (MAH) grafts. The substrates were subjected to a vapor phase atmosphere constituted of a mixture of a vinyl monomer and a photoinitiator (benzophenone) in a closed chamber at very low pressure and under UV irradiation. Poly(ε-caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), and poly(trimethylene carbonate) (PTMC) have been surface modified with VP using the same procedure to show the versatility of the method. The wettability of all of the four substrates increased after grafting. The surface compositions were confirmed by ATR-FTIR and XPS. The VP grafted PLLA, PTMC and PLGA substrates have been shown to be good substrates for the normal human cells i.e. keratinocytes and fibroblasts, to adhere and proliferate on. The topography of substrates with well defined nano patterns was preserved during grafting, since the grafted layer is very thin. We have also shown that the method is useful for a simultaneous chemical and topographical modification of substrates by masked vapor phase grafting. The surface topography was determined with SEM and AFM.</p> / <p>Intresset för användningen av nedbrytbara polymerer till biomedicinska applikationer som till exempel vävnads rekonstruktion har ökat avsevärt de senaste decennierna. Ett sätt att öka biokompatibiliteten hos dessa polymerer är genom kemisk ytmodifiering, men risken för nedbrytning under själva modifieringen är en begränsande faktor. I vissa biomedicinska applikationer, till exempel nervguider, är det önskvärt att ha en väldefinierad ytstruktur för att öka vidhäftningen och tillväxten av celler.</p><p>I den här avhandlingen presenteras en ny ickeförstörande, lösningsmedelsfri enstegsprocess för ytmodifiering av nedbrytbara polymerer. Substrat av poly(L-laktid) (PLLA) har ytfunktionaliserats med var och en av följande vinylmonomerer, N-vinylpyrrolidon (VP), akrylamid (AAm) eller maleinsyraanhydrid (MAH). Substraten har exponerats för en gasfasatmosfär av en blandning av en vinylmonomer och en fotoinitiator (bensofenon) i en tillsluten reaktor vid mycket lågt tryck och under UV-strålning. Metodens mångsidighet har även påvisats genom att ytmodifiera substrat av poly(ε-kaprolakton) (PCL), poly(laktid-co-glykolid) (PLGA) och poly(trimetylen karbonat) (PTMC) med VP. Vätbarheten ökade för alla fyra materialen efter ympning med en vinylmonomer. Ytsammansättningen fastställdes med ATR-FTIR och XPS. De VP ympade filmerna av PLLA, PLGA och PTMC visade sig vara bra substrat för mänskliga celler, i detta fall keratinocyter och fibroblaster, att vidhäfta och växa på. Yttopografin hos filmer med väldefinierade nanomönstrade ytor kunde bevaras efter ympning, tack vare att det ympade lagret är så tunt. Gasfas metoden har också visat sig användbar för att simultant ytmodifiera både kemiskt och topografiskt genom maskad gasfasympning. Yttopografin bestämdes med SEM och AFM.</p>

Degradable polymers have gained an increased attention in the field of biomedical applications over the past decades, for example in tissue engineering. One way of improving the biocompatibility of these polymers is by chemical surface modification, however the risk of degradation during the modification procedure is a limiting factor. In some biomedical applications, for example in nerve guides, a patterned surface is desired to improve the cell attachment and proliferation. In this thesis a new non-destructive, single-step, and solvent free method for surface modification of degradable polymers is described. Poly(L-lactide) (PLLA) substrates have been functionalized with one of the following vinyl monomers; N-vinylpyrrolidone (VP), acrylamide (AAm), or maleic anhydride (MAH) grafts. The substrates were subjected to a vapor phase atmosphere constituted of a mixture of a vinyl monomer and a photoinitiator (benzophenone) in a closed chamber at very low pressure and under UV irradiation. Poly(ε-caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), and poly(trimethylene carbonate) (PTMC) have been surface modified with VP using the same procedure to show the versatility of the method. The wettability of all of the four substrates increased after grafting. The surface compositions were confirmed by ATR-FTIR and XPS. The VP grafted PLLA, PTMC and PLGA substrates have been shown to be good substrates for the normal human cells i.e. keratinocytes and fibroblasts, to adhere and proliferate on. The topography of substrates with well defined nano patterns was preserved during grafting, since the grafted layer is very thin. We have also shown that the method is useful for a simultaneous chemical and topographical modification of substrates by masked vapor phase grafting. The surface topography was determined with SEM and AFM. / Intresset för användningen av nedbrytbara polymerer till biomedicinska applikationer som till exempel vävnads rekonstruktion har ökat avsevärt de senaste decennierna. Ett sätt att öka biokompatibiliteten hos dessa polymerer är genom kemisk ytmodifiering, men risken för nedbrytning under själva modifieringen är en begränsande faktor. I vissa biomedicinska applikationer, till exempel nervguider, är det önskvärt att ha en väldefinierad ytstruktur för att öka vidhäftningen och tillväxten av celler. I den här avhandlingen presenteras en ny ickeförstörande, lösningsmedelsfri enstegsprocess för ytmodifiering av nedbrytbara polymerer. Substrat av poly(L-laktid) (PLLA) har ytfunktionaliserats med var och en av följande vinylmonomerer, N-vinylpyrrolidon (VP), akrylamid (AAm) eller maleinsyraanhydrid (MAH). Substraten har exponerats för en gasfasatmosfär av en blandning av en vinylmonomer och en fotoinitiator (bensofenon) i en tillsluten reaktor vid mycket lågt tryck och under UV-strålning. Metodens mångsidighet har även påvisats genom att ytmodifiera substrat av poly(ε-kaprolakton) (PCL), poly(laktid-co-glykolid) (PLGA) och poly(trimetylen karbonat) (PTMC) med VP. Vätbarheten ökade för alla fyra materialen efter ympning med en vinylmonomer. Ytsammansättningen fastställdes med ATR-FTIR och XPS. De VP ympade filmerna av PLLA, PLGA och PTMC visade sig vara bra substrat för mänskliga celler, i detta fall keratinocyter och fibroblaster, att vidhäfta och växa på. Yttopografin hos filmer med väldefinierade nanomönstrade ytor kunde bevaras efter ympning, tack vare att det ympade lagret är så tunt. Gasfas metoden har också visat sig användbar för att simultant ytmodifiera både kemiskt och topografiskt genom maskad gasfasympning. Yttopografin bestämdes med SEM och AFM. / QC 20101014