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Synthesis and characterization of Alendronate functionalized Poly (l-lactide) polymers for engineering bone tumor targeting nanoparticlesSriadibhatla, Soma Sekhar January 1900 (has links)
Master of Science / Department of Chemistry / Santosh Aryal / Nanomedicine-based therapeutics have exhibited clear benefits when compared to unmodified drugs, which include improved pharmacokinetics, drug retention, targeting efficiency, and minimizes toxicity. Every year thousands of bone cancer cases are diagnosed in the United States. Moreover, development of bone metastasis occurs in over 80% to 90% of various cancers that metastasize and signals the entry of the disease into an incurable phase. Cancer in bones can cause pain, fractures, hypercalcemia, and compression of the spinal cord, due to deposits that can erode into the bone using bone-absorbing cells. Bisphosphonates are drugs that reduce the activity of bone-absorbing cells and targets overexpressed calcium. They are characterized pharmacologically to inhibit bone resorption, skeletal distribution, and renal elimination. In addition, they can target bone microenvironment and bind strongly with calcium. The goal of this thesis is to engineer targeted nanomedicine drug with the ability to spatiotemporally control therapeutics delivery to the bone.
Herein we synthesized biopolymers with functional end group moieties as alendronate (a molecular member of bisphosphate), which can target overexpressed calcium ions at the vicinity of the bone lesion where bone resorption takes place. In order to achieve our goal, a ring opening polymerization of cyclic L-lactide initiated by ALE in the presence of catalytic amount of stannous octoate was conducted in an inert environment. Thus, formed polymers are characterized for their chemistry and physicochemical properties using various analytical tools. These polymers were characterized by nuclear magnetic resonance (¹H-NMR) and Fourier Transfer Infrared Spectrometer (FT-IR), which shows monomer conversion and the presence of amide and phosphate moiety.
Thereafter we engineered bone-homing polymeric nanoparticles of 80nm diameter by nanoprecipitation for controlled delivery of Dox, a first line anticancer drug used in clinics. The in-vitro results show that the nanoparticles have the ability to accumulate and internalized into the bone cancer cells, deliver drugs efficiently, and are least toxic. Therefore, innovative and efficient bisphosphonate functionalized Poly-l-lactide polymers were synthesized to target bone microenvironment.
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Synthesis, characterisation and invitro evaluation of PLLA-co-succinic anhydride networksGeorge, Karina Anne January 2006 (has links)
The biocompatibility and the in vivo degradation of poly(L-lactide), (PLLA)- based materials has prompted much interest in the development of these materials into scaffolds for tissue engineering applications. PLLA-based polymers have been available for use in craniomaxillofacial surgery since 1991. Usually, a plate or sheet of the polymer is placed in or over a defect in the bone. Ideally the bone will use the polymer as a support to repair the defect and as the polymer degrades, the bone will continually remodel, so that the loss of mass and mechanical strength of the polymer correlates with the increase in the mass and strength of the new bone. However, this is an ideal situation, and is not always observed in practice. The aim of this work is to develop PLLA-based materials that should encourage bone growth onto the material and allow control over the rate of degradation. PLLA-co-succinic anhydride networks were synthesised and the mineralisation and degradation of these materials were evaluated in vitro. The synthesis of these networks, involved the polymerisation of 4-arm star PLLA polymers, which were coupled through their end groups with succinic anhydride. The low molecular weight star PLLA polymers were synthesised using calcium hydride and pentaerythritol as initiator and co-initiator respectively. Calcium hydride was preferred to stannous octoate in this study as there is concern over the release of tin-containing when the polymer is implanted. As only very limited studies have been directed into the polymerisation and resulting polymers formed using calcium hydride, this was a major focus of the study. The identification of hydrogen in the reaction tubes was evidence that calcium alkoxide, formed from the reaction of pentaerythritol and calcium hydride, is the actual initiating species for the ring opening polymerisation. In situ FT-Raman spectroscopy was used as a tool to monitor the reaction process and was found to be a convenient and reliable method for obtaining information about the polymerisation kinetics. Analysis of the FTRaman kinetic curves, along with analysis of products by GPC, polarimetry and NMR spectroscopy showed that the polymerisation was 'quasi-living' depending on the ratio of pentaerythritol and calcium hydride in the system. Furthermore, both the degree of transesterification and racemisation of polymers synthesised in optimised reactions were low. The PLLA-co-succinic anhydride networks were synthesised by coupling of hydroxyl-terminated PLLA star polymers with succinic anhydride (one-pot reaction) and by coupling hydroxyl-terminated PLLA stars with succinic anhydride-terminated PLLA star polymers (two-pot reaction), using a carbodiimide, EDC to mediate the esterification. The one-pot reaction produced polymers with high gel fractions and high conversion of functional groups in the gel, whereas the gel fraction and conversion of functional groups was lower in the two-pot reaction. For the networks synthesised in the one-pot reaction, the molecular weight between crosslinks was controlled by the length of the PLLA polymer arms. The networks synthesised were characterised by FTIR-ATR spectroscopy, SEM, contact angle and by swelling. The extent of mineralisation of the PLLA-co-succinic anhydride networks in simulated body fluid (SBF) after 14 days was greater than the mineral deposition on the high molecular weight PLLA reference polymer. The degradation of the networks was carried out under accelerated conditions in 0.1 M NaOH at 37 degrees Celsius. All networks degraded much more slowly than the high molecular weight linear PLLA reference sample. The rate of degradation was found to be dependent on the crystallinity of the polymer chains, with the more crystalline networks degrading at a faster rate, while the location of the degradation, surface or bulk, was controlled by the crosslink density, showing that the degradation is 'tuneable'.
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Fabrication of Micro and Nanoparticles of Paclitaxel-loaded Poly L Lactide for Controlled Release using Supercritical Antisolvent Method: Effects of Thermodynamics and HydrodynamicsLee, Lai Yeng, Smith, Kenneth A., Wang, Chi-Hwa 01 1900 (has links)
This paper presents the fabrication of controlled release devices for anticancer drug paclitaxel using supercritical antisolvent method. The thermodynamic and hydrodynamic effects during supercritical antisolvent process on the particle properties obtained were investigated. Scanning electron microscopy was employed to study particle sizes and morphologies achieved. It was observed that increasing supercritical pressure improves the surface morphology of particles obtained, and increasing the flow rate of the organic solution jet reduces the particle sizes obtained. A modified Supercritical Antisolvent with Enhanced Mass transfer setup was developed to produce monodispersed nanoparticles with high recovery yield. High performance liquid chromatography was used to determine the encapsulation efficiency and in vitro release profiles of paclitaxel loaded particles obtained. The encapsulation efficiencies of particles obtained using the modified SASEM process were high and up to 83.5%, and sustained release of paclitaxel from the polymer matrix was observed over 36 days release. The thermogram properties of the particles were also analyzed using differential scanning calorimetry to determine the crystalline state of polymer and drug. / Singapore-MIT Alliance (SMA)
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Elaboration de copolymères biorésorbables pour endoprothèse / Design of bioabsorbable copolymers for endoprosthesisDuval, Charlotte 29 March 2011 (has links)
L’objectif de ce travail était d’élaborer un copolymère biodégradable dans le but de développer une endoprothèse biorésorbable. Ainsi, des copolymères de lactide et de glycolide ont été synthétisés par copolymérisation par ouverture de cycle, dans des conditions permettant le contrôle de leurs paramètres macromoléculaires. Après plastification et mise en forme des copolymères par extrusion, l’étude des propriétés mécaniques, à l’état sec et après immersion en milieu aqueux, a été réalisée. Les essais de traction ont permis de vérifier l’importance de la vitesse de sollicitation et d’accéder à certaines grandeurs caractéristiques du matériau. L’étude de la dégradation des copolymères, sous forme de jonc, a mis en évidence un mécanisme de dégradation hétérogène sur une durée en accord avec l’application visée. La plastification par des molécules acides a permis d’accélérer la vitesse d’hydrolyse des copolymères. En conclusion, les propriétés mécaniques et de dégradation des copolymères PDLGA synthétisés sont donc en adéquation avec le cahier des charges de l’application biomédicale. / This work describes the synthesis of biodegradable copolymer to design a bioabsorbable endoprosthesis. Lactide and glycolide-based copolymers were synthesized by ring opening polymerization. Experimental conditions were chosen to produce controlled structures. The study of mechanical properties was performed in dry and wet states. During the tensile experiments, the effect of strain rate was noticed and some characteristics parameters were determined. Hydrolytic degradation of materials was fast and revealed a heterogeneous mechanism. Addition of acidic molecules for plasticizing increased the degradation rate of the copolymers.Mechanical properties and degradation of the PDLGA copolymers are indeed in good agreement with the specifications of this biomedical application.
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Development And Characterization Of Cortisone Derivative Drugcarrying Polymeric MicrospheresOcal, Yigit 01 February 2011 (has links) (PDF)
In this study, it is aimed to develop an injectable controlled release system
of PCL and P(L,DL)LA microspheres loaded with TA and/or Ral for local treatment
of rheumatoid arthritis which will avoid from systemic side effects of traditional
administration and eliminate problems caused by direct local injections.
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder that
most commonly causes inflammation and tissue damage in joints and tendon
sheaths. Current strategies for the disease are mainly towards relieving
symptoms and increasing mobility. The microsphere form drug delivery systems
were developed to enhance the treatment success of rheumatic diseases by
providing these agents alone or together for long terms without causing systemic
or local site effects upon injection to the RA joints. Microspheres were prepared
with s/o/w solvent evaporation technique and optimized to achieve a suitable size for joint application, to sustain the delivery of the drug(s), to provide
required amount of the agent with feasible amount of microsphere. In order to
manage these, microspheres prepared with different combinations of polymers
and drugs were examined for particle size analysis, surface and structural
characterizations, time related drug release properties, and drug loading
capacities. In vitro cytotoxicity tests using 3T3 fibroblast cells were done to
evaluate the biocompatibility of drug loaded PCL microspheres. The degradation
of polymers were conducted and evaluated by GPC analysis.
In PCL:TA microspheres, as polymer:drug ratio decreased (from 10:1
towards 10:4), namely as the drug partition increased, it was seen that
encapsulation efficiency and loading percentages increased. Meanwhile, percent
release of the drug decreased, indicating more prolonged release. Among all
microspheres, PCL:TA 10:4 and PCL:Ral 10:2 were found to be the most
appropriate for dual release in terms of release values (ca 21% and 0.09%,
respectively), loadings (ca 27% and ca 13%, respectively) and mean particle size
values (ca 100 &mu / m and ca 95 &mu / m, respectively). After release studies,
microspheres preserved their sphericity. These selected polymer:drug groups
also represented no cytotoxic effect. The microspheres for dual drug study
(PCL:TA:Ral 10:4:2) released app. 55% of its TA and 0.29% of Ral at the end of
4 weeks. Drug loading capacities of these microspheres were found to be ca
14% for TA and 8% for Ral. Furthermore, with dual loading case, smallest mean
particle size (68 &mu / m) could be obtained among all studied groups.
P(L,DL)LA microspheres caused high viscosity problems during
microsphere preparation steps and resulted in the slowest release, which was
unfavorable for the aim of the study. To our knowledge there is no microsphere
study reported with P(L,DL)LA in literature. The TA and Ral delivery systems with PCL and P(L,DL)LA were developed
and studied for the first time in literature and they were optimized for RA
treatment purposes. The potential of these systems, should be further tested in
experimental animal models of RA.
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Synthèse de nouveaux polyesters “verts” issus de ressources oléagineuses : application au renfort au choc du poly(L-lactide) / Synthesis of novel “green” polyesters from plant oils : application to the rubber-toughening of poly(L-lactide)Lebarbe, Thomas 06 December 2013 (has links)
Dans cette étude, plusieurs voies ont été explorées dans l’objectif d’utiliser des polyesters aliphatiques issus de ressources oléagineuses comme additifs pour le renfort au choc du poly(L-lactide) (PLLA). Dans un premier temps, des poly(ester-amide)s (PEAs) ont été synthétisés à partir de dérivés de l’huile de ricin. La relation structure-propriétés des PEAs obtenus a été clairement établie. La dispersion des PEAs (à différents taux) par extrusion à l’état fondu dans une matrice de PLLA a ensuite été effectuée, démontrant un accroissement de la résilience de ces mélanges en comparaison au PLLA seul. Une étude systématique reliant la structure d’une large gamme de polyesters aux propriétés des mélanges polyesters/PLLA, a ensuite été réalisée. Une forte dépendance de la résilience des mélanges polyesters/PLLA avec la cristallinité de l’additif polyester a été observée et quantifiée.Une amélioration des propriétés mécaniques du PLLA a également été obtenue par polymérisation par ouverture de cycle du lactide amorcée par un poly(acide ricinoléique) di-hydroxy téléchélique. Les copolymères triblocs ainsi formés ont été caractérisés d’un point de vue morphologique et mécanique.Enfin, un travail exploratoire utilisant l’ADMET comme méthode de polymérisation a été conduit, permettant la synthèse de nouveaux polymères prometteurs pour le renfort au choc du PLLA. Notamment, la copolymérisation de α,ω-diènes bio-sourcés a permis de mimer le polyéthylène basse densité linéaire, couramment employé pour le renfort au choc du PLLA. / The objective of this thesis work, is to promote the use of fatty acid-based aliphatic polyesters as impact modifiers for poly(L-lactide) (PLLA).Firstly, poly(ester-amide)s (PEAs) have been synthesized from castor oil derivatives. The structure-properties relationship of the PEAs so-formed was clearly established. The PEAs were then melt-blended with PLLA by extrusion, yielding blends with improved impact strength compared to neat PLLA.A series of polyesters covering a wide range of thermo-mechanical properties was then employed to evaluate the influence of the polyester morphology on the properties of the blends with PLLA. A strong dependence of the impact strength of the blends was noticed with the crystallinity degree of the polyester additive.An improvement of the mechanical properties of PLLA was also obtained by ring-opening polymerization of lactide initiated by a di-hydroxy telechelic poly(ricinoleic acid). The so-formed triblock copolymers were fully characterized in terms of morphology and mechanical properties.Finally, an exploratory investigation related to the synthesis of PLLA impact modifiers by ADMET was carried out. Particularly, the copolymerization of two bio-based α,ω-dienes yielded a series of “LLDPE like” polyesters, LLDPE being a commonly used impact modifier for PLLA.
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Eletrofiação de nanocompósito de poli(L-ácido lático) com hidroxiapatita para regeneração óssea / Electrospinning of nanocomposites of poly (L-lactic acid) with hydroxyapatite for bone regenerationRodríguez Perea, Geraldine Nancy, 1986- 19 August 2018 (has links)
Orientadores: Cecília Amélia de Carvalho Zavaglia, Marcos Akira d'Ávila / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Mecânica / Made available in DSpace on 2018-08-19T00:23:40Z (GMT). No. of bitstreams: 1
RodriguezPerea_GeraldineNancy_M.pdf: 1196408 bytes, checksum: 1a7f7c5e1320ddfd713867dbc7a1d5b6 (MD5)
Previous issue date: 2011 / Resumo: Este trabalho consiste na obtenção pelo método de eletrofiação, de microfibras poliméricas e microfibras reforçadas com nanopartículas de hidroxiapatita. Este método foi utilizado, pois propicia a produção de membranas microporosas que possuem um grande potencial de aplicação na área de engenharia tecidual, especificamente em aplicações para regeneração óssea. Este trabalho teve como objetivo principal produzir fibras poliméricas com a intenção de comparar suas características com o nanocompósito de fibras poliméricas e nanopartículas de hidroxiapatita como reforço. Trabalhou-se com o poli(L-ácido lático) (PLLA) e nanopartículas de hidroxiapatita (HA) produzidas pelo processo sol-gel. As fibras e os nanocompósitos foram caracterizados pelos seguintes métodos: microscopia eletrônica de varredura (MEV), análise termogravimétrica (TGA), calorimetria exploratória diferencial (DSC) e espectroscopia na região do infravermelho por transformada de Fourier (FTIR). As fibras obtidas apresentaram diâmetros na faixa de 1 a 10 micrômetros. O objetivo de produzir membranas a partir de soluções de PLLA e nanocompósito PLLA/HA por eletrofiação foi atingido / Abstract: This work consists in obtaining polymeric microfibers and microfibers reinforced with nanoparticles of hydroxyapatite by the method of electrospinning. This method was used because it allows the production of microporous membranes that have great potential like application in tissue engineering, specifically in applications for bone regeneration. This work aimed to produce polymer fibers with the intention to compare their characteristics with the nanocomposite fibers with hydroxyapatite nanoparticles as reinforcement. The polymer used was poly (L-lactic acid) (PLLA) and nanoparticles of hydroxyapatite (HA) produced by the sol-gel process. The fibers and nanocomposites were characterized by the following methods: scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), spectroscopy in the region of Fourier transform infrared (FTIR). The fibers obtained presented diameters in the range 1 to 10 micrometers. The goal of producing membranes from solutions of PLLA and nanocomposite PLLA / HA by electrospinning was reached / Mestrado / Materiais e Processos de Fabricação / Mestre em Engenharia Mecânica
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Implantable composite devices of unsintered hydroxyapatite and poly-L-lactide with dispersive marbling morphology to enhance in vivo bioactivity and bioresorbability / 相補的な三次元分散形態をもつ非焼結ハイドロキシアパタイトとL‐ポリ乳酸からなる骨接合材は、高い生体活性と生体吸収性を有するMorizane, Kazuaki 25 March 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21682号 / 医博第4488号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妻木 範行, 教授 大森 孝一, 教授 別所 和久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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An “off-the shelf” Synthetic Membrane to Simplify Regeneration of Damaged CorneasSefat, Farshid, Ortega, Í., McKean, R., Deshpande, P., Ramachandran, C., Hill, C.J., Tzokov, S.B., Claeyssens, F., Sangwan, V.S., Ryan, A.J., MacNeil, S. January 2014 (has links)
Yes / Our overall aim is to develop a synthetic off-the-shelf alternative to human amniotic membrane which is currently used for delivering cultured limbal stem cells to the cornea in patients who suffer scarring of the cornea because of the loss of limbal stem cells. We have recently reported that both cultured cells and limbal explants grow well on electrospun Poly(D,L-lactide-co-glycolide) (PLGA) (44 kg/mol) with a 50:50 ratio of lactide and glycolide and sterilized with γ-irradiation. Prior to undertaking a clinical study our immediate aim now is to achieve long term storage of the membranes in convenient to use packaging. Membranes were electrospun from Poly(D,L-lactide-co-glycolide) (44 kg/mol) with a 50:50 ratio of lactide and glycolide and sterilized with γ-irradiation and then stored dry (with desiccant) for several months at -80°C and -20°C , Room temperature (UK and India), 37°C and 50°C. We explored the contribution of vacuum sealing and the use of a medical grade bag (PET/Foil/LDPE) to achieve a longer shelf life. Confirmation of membranes being suitable for clinical use was obtained by culturing tissue explants on membranes post storage. When scaffolds were stored dry the rate of breakdown was both temperature and time dependent. At -20°C and -80°C there was no change in fiber diameter over 18 months of storage, and membranes were stable for 12 months at 4°C while at 50°C (above the transition temperature for PLGA) scaffolds lost integrity after several weeks. The use of vacuum packaging and a medical grade bag both improved the storage shelf-life of the scaffolds. The impact of temperature on storage is summarized beneath. We report that this synthetic membrane can be used as an off-the-shelf or-out-of-the freezer alternative to the amniotic membrane for corneal regeneration.
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Linear block copolymers of L–lactide and 2–dimethylaminoethyl methacrylate : synthesis and propertiesKryuchkov, Maksym 02 1900 (has links)
Part of the research described in this thesis is conducted in collaboration with Centre d' étude et de Recherche sur les Macromolécules (CERM), Université de Liège, Sart-Tilman, Belgium / Les copolymères séquencés amphiphiles sont très prometteurs pour des applications de technologie de pointe en raison de leur capacité à s'auto-assembler dans des structures bien organisées à l'échelle du micro– et du nanométre, et de leur sensibilité à des stimulations de différentes natures. La formation des nanomotifs bien ordonnés dans les films et/ou en masse fournit un substitut à la nanolithographie et est utile pour le design et l'ingénierie de nanomembranes et de matériaux nanoporeux. L'auto–assemblage dans des solvants sélectifs, en incluant la sensibilité au pH et à la température, peut être ajusté pour correspondre aux besoins de différentes applications biomédicales, telles que l’encapsulation et/ou relargage de médicaments, l'ingénierie de tissus, etc. Dans ce contexte, des copolymères séquencés de type L–lactide (LLA) et méthacrylate 2–diméthylaminoéthyl (DMAEMA) sont d’un grand intérêt.
Comme le contrôle sur l'auto–assemblage des copolymères séquencés est permis au niveau moléculaire, il est très important de préparer des copolymères bien définis avec des longueurs de bloc prévisibles et de faible polydispersité. Ainsi, une partie de cette étude a été consacrée au développement de procédures synthétiques optimales et à la caractérisation détaillée de copolymères di– et triblocs de LLA et de PDMAEMA. Un outil simple pour déterminer la présence d'homo–PLLA résiduel a été développée; cela a permis de déterminer et d'expliquer plusieurs voies de synthèse indésirables. La dernière inclut la participation possible de l'amorceur bifonctionnel utilisé, et nous avons alors proposé un système alternatif d'amorceur bifonctionnel/catalyseur. La racémisation du LLA par les unités amine de (P)DMAEMA a été observée pendant la polymérisation, limitant ainsi l'utilisation première du bloc PDMAEMA pour la préparation des copolymères PLLA–b–PDMAEMA. Les études thermiques et de cristallisation, en incluant les copolymères séquencés partiellement quaternisés, ont révélé un retard significatif de la vitesse de cristallisation, en présence du bloc de PDMAEMA. Nous avons constaté que les blocs sont miscibles pour de faibles masses molaires et que la miscibilité partielle est maintenue après quaternisation. Selon la longueur et le taux de quaternisation du bloc PDMAEMA, la cristallisation du PLLA a été étudiée dans un environnement restreint et confiné, faiblement ou fortement. La torsion des lamelles cristallines observée pour certains copolymères biséquencés a été accentuée dans les copolymères triséquencés, où la formation de sphérolites annelés a été observée dans toutes les conditions thermiques utilisées. / Multi–functional amphiphilic block copolymers have much promise for various high technology applications thanks to the controlled stimuli–responsive self–assembly into well–organized structures on the micro– and nanometer scales. The formation of well–ordered nanopatterns in films and/or in bulk provides a competitive substitute to nanolithography and is useful in the design and engineering of nanomembranes and nanoporous materials. Solution self–assembly in selective solvents, including pH and temperature sensitivity, can be tuned to match the needs of different biomedical applications, such as drug encapsulation/delivery, tissue engineering, etc. In this context, block copolymers of L–lactide (LLA) and 2–dimethylaminoethyl methacrylate (DMAEMA) are of great interest.
Since the control over self–assembly of block copolymer systems is enabled on a molecular level, it is of great importance to prepare well–defined block copolymers with predictable block lengths and low polydispersity. Thus, a major part of the research in this study was devoted to developing optimal synthetic procedures with detailed characterization of linear di– and triblock copolymers of LLA and PDMAEMA. A simple tool to determine homo–PLLA impurity was developed, which helped to determine and explain several undesired routes. The latter includes possible involvement of the bifunctional initiator used, and an alternative bifunctional initiator/catalyst system was proposed. Racemization of LLA by (P)DMAEMA moieties was observed during LLA polymerization thus limiting the utilization of PDMAEMA–first approach for the preparation of PLLA–b–PDMAEMA. Thermal and crystallization studies, including on quaternized block copolymers, revealed a significant retardation effect of the PDMAEMA block on the crystallization kinetics. The blocks were found to be miscible in the melt at low molecular weights, and maintained partial miscibility after quaternization. Depending on the length and the quaternization degree of PDMAEMA, PLLA crystallization was studied in a templated, soft or hard confinement environment. Crystalline lamellae twisting observed in certain diblock copolymers was facilitated in triblock copolymers, where the formation of banded spherulites was observed in all thermal conditions used.
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