abstract: Electronic devices based on various stimuli responsive polymers are anticipated to have great potential for applications in innovative electronics due to their inherent intelligence and flexibility. However, the electronic properties of these soft materials are poor and the applications have been limited due to their weak compatibility with functional materials. Therefore, the integration of stimuli responsive polymers with other functional materials like Silicon is strongly demanded. Here, we present successful strategies to integrate environmentally sensitive hydrogels with Silicon, a typical high-performance electronic material, and demonstrate the intelligent and stretchable capability of this system. The goal of this project is to develop integrated smart devices comprising of soft stimuli responsive polymeric-substrates with conventional semiconductor materials such as Silicon, which can respond to various external stimuli like pH, temperature, light etc. Specifically, these devices combine the merits of high quality crystalline semiconductor materials and the mechanical flexibility/stretchability of polymers. Our innovative system consists of ultra-thin Silicon ribbons bonded to an intelligently stretchable substrate which is intended to interpret and exert environmental signals and provide the desired stress relief. As one of the specific examples, we chose as a substrate the standard thermo-sensitive poly(N-isopropylacrylamide) (PNIPAAm) hydrogel with fast response and large deformation. In order to make the surface of the hydrogel waterproof and smooth for high-quality Silicon transfer, we introduced an intermediate layer of poly(dimethylsiloxane) (PDMS) between the substrate and the Silicon ribbons. The optical microscope results have shown that the system enables stiff Silicon ribbons to become adaptive and drivable by the soft environmentally sensitive substrate. Furthermore, we pioneered the development of complex geometries with two different methods: one is using stereolithography to electronically control the patterns and build up their profiles layer by layer; the other is integrating different multifunctional polymers. In this report, we have designed a bilayer structure comprising of a PNIPAAm hydrogel and a hybrid hydrogel of N-isopropylacrylamide (NIPAAm) and acrylic acid (AA). Typical variable curvatures can be obtained by the hydrogels with different dimensional expansion. These structures hold interesting possibilities in the design of electronic devices with tunable curvature. / Dissertation/Thesis / M.S. Chemical Engineering 2012

L’originalité de ce projet consiste au développement et à l’étude de nouvelles structures hybrides à base de nanocelluloses et de polymères stimulables. En particulier, c’est le design d’hydrogels aux propriétés thermosensibles qui est visé. Les nanocelluloses - nanoparticules issues de la cellulose - sont de deux types : les nanocristaux de cellulose (CNCs) et les nanofibrilles de cellulose (CNFs) et possèdent des propriétés bien particulières. Cette étude s’est concentrée sur l’élaboration d’hydrogels de CNCs. Plusieurs polymères thermosensibles ont été utilisés pour leur biocompatibilité et leur température de solution critique (LCST) aux abords de la température du corps humain. Ce travail a consisté en (i) la préparation des systèmes sur les principes de la chimie verte, (ii) l’étude rhéologique de ces gels thermosensibles et (iii) l’élaboration d’applications à forte valeur ajoutée pour ces biomatériaux uniques. A travers l’utilisation de grands équipements (SANS, SAXS), les interactions physico-chimiques CNCs/polymères ont été étudiées. L’utilisation de block copolymères a permis l’obtention de suspension de CNCs aux propriétés rhéologiques spécifiques : de liquide a température ambiante à gel viscoélastique à température du corps. D’un point vue applicatif, les hydrogels ainsi réalisés ont permis le déploiement de systèmes injectables pour le biomédical ainsi que des surfaces thermosensibles.Mots clés : nanocristaux de cellulose, hydrogel, thermosensible, stimulable / This project consists to develop and study new hybrid structures based on nanocelluloses and stimuli-responsive polymers, in particular, thermo-responsive polymers. Nanocelluloses - nanoparticles extracted from cellulose - exist in two forms: cellulose nanocrystals (CNCs) and cellulose nanofibrils (CNFs). This study focused on the design of CNCs hydrogels with stimuli-responsive polymers. Several thermo-responsive polymers have been used for their biocompatibility and lower critical solution temperature (LCST) close to body temperature. This work consisted of (i) preparation of systems using the principles of green chemistry, (ii) the rheological study of these thermo-sensitive hydrogels, and (iii) the development of smart applications for these unique biomaterials. Through the use of state of the art technologies (SANS, SAXS), physicochemical interactions between the polymers and CNCs have been studied. The use of block copolymers made it possible to create CNCs-based hydrogels with specific rheological properties: liquid at ambient temperature to viscoelastic gel at body temperature. These hydrogels can be used in the creation of injectable systems for biomedical applications, as well as thermosensitive surfaces.Key-words: Cellulose nanocrystals, hydrogel, thermo-responsive, stimuli-responsive

Pour pallier le problème d’efficacité de la plupart des médicaments disponibles sur le marché aujourd’hui, lié à des manques de spécificité et de solubilité, notamment dans le cadre du traitement du cancer, la nanomédecine, via les nanoparticules présente une alternative de grande importance. Dans ce domaine, les nanoparticules de silice ont récemment attiré une énorme attention de la part des scientifiques. Cependant, des problèmes d’élimination liés à la solidité du matériau entravent aujourd’hui sa traduction clinique. Afin d’élucider cette problématique, nous présentons, dans cette thèse, l’utilisation de nanoparticules de silice hybrides dont l’une est mésoporeuse et l’autre sous forme de nanocapsule dépourvue de porosité. Les particules qui sont sphériques ont été préparées en incorporant un groupement imine dans leur charpente afin de les rendre sensibles au pH bas, sachant que les tissus cancéreux présentent une certaine acidité par comparaison aux tissus sains. Les matériaux préparés se montrent particulièrement sensibles aux milieux acides similaires aux conditions dans les milieux cancéreux. Dans le même temps, ces particules exposent une bonne stabilité en milieu à pH neutre similaire aux conditions physiologiques. Des études in vitro réalisées avec la particule mésoporeuse sur une lignée de cellule cancéreuse issue du sein humain démontrent une bonne et rapide internalisation. De plus, lorsque le matériau est chargé avec un médicament hydrophobe très puissant utilisé dans le traitement du cancer du sein, le système en résultant indique une efficacité de grande ampleur en tuant une forte majorité des cellules cancéreuses, contrairement au système basé sur la particule non cassable et au médicament isolé. Parallèlement, les nanocapsules chargées avec un autre agent anticancéreux se montrent particulièrement cytotoxiques vis-à-vis de cellules cancéreuses très communes et qui l’internalisent de manière très rapide. / To overcome the limitations of most of the drugs avaible nowadays on the market due to their lack of solubility and specifity in cancer treatment for instance, nanomedicine plays an emerging role as an alternative. In that field, nanoparticles are endowed with several advantages, leading them to be highly considered for drug delivery systems preparation. In this respect, silica nanoparticles have recently a great deal of attention from the scientists. Nevertheless, some issues related to the in vivo elimination of silica materials represent the main obstacle impeding their clinical translation. To elucidate this problematic, we report, in this thesis, the use of breakable hybrid organosilica nanoparticles where one is mesoporous and the other one consists in a nanocapsule without porosity. Such materials have been prepared by incorporating an imine-based linker in the particles framework in order to make them pH-responsive. The advantage of the pH sensitivity relies on the fact that cancerous media present certain acidity as compared to those healthy. The particles exhibit a high pH sensitivity where, at low pH, they fully break down, while a good stability is observed in physiological conditions. Furthermore, in vitro studies performed with a drug delivery system based on the mesoporous particle and a highly hydrophobic drug show a remarkable efficiency towards a cancer cell line from human breast, which moreover, rapidly internalises the material. The nanocapsule loaded with a hydrophilic drug also demonstrates a fast internalisation towards a commonly used cancer line which does not resist to the system and thus dies by a very high rate.

Stimuli-responsive polymers and self-assembling peptides represent two classes of materials with interesting properties and great potential to be used as biomaterials. The conjugation of polymer with peptide offers a way to combine the controlled chemical, mechanical, and thermal properties of polymer with the functionality of designed bioactive group. Pure hybrid materials with the characteristics of individual components or systems containing hybrid materials became attractive for applications in drug delivery and tissue engineering. This work focused on systems where the thermo-responsive properties of a polymer were combined with the gelling properties of two different ionic-complementary peptides via conjugation. The prototypical thermo-responsive polymer poly(N-isopropylacrylamide) (PNIPAAm) was chosen due to its lower critical solution temperature (LCST) ~32°C being close to body temperature. Ionic-complementary oligo-peptides, containing the alternating hydrophobic/hydrophilic and charged/uncharged amino acids, phenylalanine (F), glutamic acid (E) and lysine (K), were selected as they are known to form β-sheet rich fibrillar networks at low concentrations. Two peptide sequences with different charge distribution were chosen: FEFEFKFK and FEFKFEFK which form self-supporting gels at ~17 and 10 mg ml-1 respectively. Polymer-peptide conjugates were used to confer self-assembling and thermo-responsive behaviour to the system.Thermo-responsive PNIPAAm-rich hydrogels were obtained by targeting different degrees of functionalisation of PNIPAAm with the self-assembling peptides. Two series of such systems were prepared by using either a thiol-modified FEFEFKFK or a thiol-modified FEFKFEFK peptide as the chain-transfer agent in the free radical polymerisation of NIPAAm. The resulting polymer/conjugate mixtures were studied by proton nuclear magnetic resonance (1H NMR). The polymer/conjugate ratios were calculated and showed that the conjugate fraction in the mixtures increased with increasing concentration of peptide used for the polymerisation. Static light scattering (SLS) and viscometry showed the aggregation of the polymer/conjugate mixtures presumably due to the presence of peptide. The values from gel permeation chromatography (GPC), which were mostly attributed to the unconjugated polymers, were higher than those obtained from 1H NMR and centrifugation for the conjugates. The polymer/conjugate mixtures formed self-supporting gels where the critical gelation concentration decreased with increasing conjugate content. Oscillatory rheology experiments confirmed gels had formed and revealed that their elastic modulus, G' varied from ~ 10 to 400 Pa depending on the sample. TEM and AFM studies proved the formation of β-sheet fibres of ~ 4.5 ± 1.5 nm in diameter. The PNIPAAm-rich hydrogels were also characterised by micro DSC to reveal their thermo-responsiveness and phase separation and showed the LCST at ~ 30°C. The results of the study showed that varying the peptide sequence did not have an effect on thermal, mechanical or morphological properties of the hydrogels. By exploiting the self-assembly of the ionic-complementary peptides, it was possible to create PNIPAAm-rich, thermo-responsive hydrogels with controllable properties.Further in the study pure PNIPAAm-FEFEFKFK conjugate was incorporated into the FEFEFKFK peptide matrix to create peptide-rich thermo-responsive composite gels. Two series of the composite gels were prepared by varying separately the peptide matrix and polymer-peptide conjugate concentration. Micro DSC measurements revealed an endothermic peak at ~ 30ºC characteristic of the LCST of PNIPAAm. Oscillatory rheology studies showed that the composite gels became stronger with increasing conjugate concentration (G' ~ 20 - 200 Pa). Network morphology was studied by SANS. Using contrast variation and contrast matching techniques it was possible to distinguish between the peptide fibres and the PNIPAAm chains. Below and above the LCST the scattering curves showed a q-1 behaviour which is typical of rod-like objects. TEM and AFM also proved the formation of fibres of ~4.0 ± 0.8 nm and ~4.5 ± 1 nm respectively. AFM studies showed that the fibres of the composite gels were decorated with polymer chains. The thermo-responsiveness and the gelation properties of these conjugate-based scaffolds have potential for use as drug delivery vehicles or tissue engineering scaffolds.

Les polymersomes sont des vésicules dont la membrane est formée d'une bicouche de polymères amphiphiles. Les polymersomes dits stimulables sont particulièrement étudiés de nos jours pour leurs propriétés de relargage contrôlé. Ces propriétés peuvent être ajustées simplement en variant la nature chimique du polymère constituant la membrane vésiculaire.Dans le cadre de ce travail de thèse, nous nous sommes intéressés à des polymersomes originaux, assemblés à partir de copolymères cristaux liquides. Ces copolymères comprennent un bloc cristal liquide hydrophobe et un bloc poly(ethylene glycol) (PEG) hydrophile. Les cristaux liquides sont des entités particulièrement intéressantes pour leur capacité d'auto-assemblage et leurs réponses aux stimuli physiques tels la température, les champs magnétiques et la lumière.Plusieurs types de polymersomes basés sur des copolymères cristaux liquides ont été étudiés en température et en champ magnétique. L'effet thermique est drastique, perturbant totalement la morphologie vésiculaire au dessus d’une température critique. Différents hybrides de nanoparticules d’oxyde de fer et de polymères cristaux liquides ont aussi été examinés dans le but d’induire un chauffage local par hyperthermie magnétique.Enfin, nous décrivons la synthèse de copolymères amphiphiles cristaux liquides biodégradables incluant des motifs cholesterol. L'auto-assemblage de ces molécules en milieu aqueux a permis la formation de nanoparticules bien définies et prometteuses pour des applications de relargage en milieu biologique. / Polymersomes are vesicles whose bilayer is made of amphiphilic polymers. Stimuli responsive polymersomes are nowadays increasingly studied for their encapsulation properties and ability to release their content upon stimulation. Such smart polymersomes can be designed by using appropriate responsive building blocks.In the present study, we were interested in studying thermoresponsive and biodegradable polymersomes made of liquid crystalline (LC) amphiphilic copolymers. LC polymers represent here the hydrophobic block while the hydrophilic block consists in poly(ethylene glycol) (PEG). LC polymers are very good self-assocative building blocks and are intrinsically responsive to physical stimuli such as temperature, light and magnetic fields.We report here the investigation of temperature effects on liquid crystalline and non liquid crystalline polymersomes. Temperature was shown to alter dramatically LC polymersomes morphology above a critical thermal threshold. Hybrid colloids made of iron oxide nanoparticles and amphiphilic liquid crystalline copolymers were also studied with the aim of applying a magnetically induced local heating.Finally, we designed biodegradable liquid crystalline copolymers based on cholesterol. Their self assembly in water gave access to very well defined nanoparticles that could be promising for bioapplications.

abstract: As experiencing hot months and thermal stresses is becoming more common, chemically protective fabrics must adapt and provide protections while reducing the heat stress to the body. These concerns affect first responders, warfighters, and workers regularly surrounded by hazardous chemical agents. While adapting traditional garments with cooling devices provides one route to mitigate this issue, these cooling methods add bulk, are time limited, and may not be applicable in locations without logistical support. Here I take inspiration from nature to guide the development of smart fabrics that have high breathability, but self-seal on exposure to target chemical(s), providing a better balance between cooling and protection. Natural barrier materials were explored as a guide, focusing specifically on prickly pear cacti. These cacti have a natural waxy barrier that provides protection from dehydration and physically changes shape to modify surface wettability and water vapor transport. The results of this study provided a basis for a shape changing polymer to be used to respond directly to hazardous chemicals, swelling to contain the agent. To create a stimuli responsive material, a novel superabsorbent polymer was synthesized, based on acrylamide chemistry. The polymer was tested for swelling properties in a wide range of organic liquids and found to highly swell in moderately polar organic liquids. To help predict swelling in untested liquids, the swelling of multiple test liquids were compared with their thermodynamic properties to observe trends. As the smart fabric needs to remain breathable to allow evaporative cooling, while retaining functionality when soaked with sweat, absorption of water, as well as that of an absorbing liquid in the presence of water were tested. Micron sized particles of the developed polymer were deposited on a plastic mesh with pore size and open area similar to common clothing fabric to establish the proof of concept of using a breathable barrier to provide chemical protection. The polymer coated mesh showed minimal additional resistance to water vapor transport, relative to the mesh alone, but blocked more than 99% of a xylene aerosol from penetrating the barrier. / Dissertation/Thesis / Doctoral Dissertation Chemical Engineering 2020

Autophagy is a critical cellular maintenance machinery in cells, and prevents the accumulation of toxic protein aggregates, organelles or lipid droplets through degradation via the lysosome. In macro-autophagy, autophagosome first engulfs around aggregates or cellular debris and subsequently fuses with a lysosome that is sufficiently acidic (pH 4.5–5.5), where the contents are then degraded via lysosomal enzymes. Autophagy inhibition as a result of lysosomal acidification dysfunction (pH > 5.5) have been reported to play a major role in various diseases pathogenesis. Hence, there is a pressing need to target lysosomal pH to rescue autophagy. Nanoparticles are attractive materials which has been shown to be efficiently uptaken into cellular organelles and can serve as an agent to specifically localize into lysosomes and modulate its pH. Lipotoxicity, induced by chronic exposure to free fatty acids, and exposure to neurotoxins (e.g. MPP+), elevates lysosomal pH in pancreatic beta cells (Type II Diabetes, T2D) and hepatocytes (Non-alcoholic fatty liver disease, NAFLD), and PC-12 cells (Parkinson’s Disease), respectively. We first tested the lysosome acidification capability of photo-activable nanoparticles (paNPs) and poly (lactic-co-glycolic) acid nanoparticles (PLGA NPs) in a T2D model. Both NPs lowered lysosomal pH in pancreatic beta cells under lipotoxicity and improved insulin secretion function. However, paNPs only release acids upon UV trigger, limiting its applicability in vivo, while PLGA NPs degrade upon lysosome localization. We further showed that PLGA NPs are able to rescue MPP+ induced cell death in a PD model, though it has a slow degradation rate. To attain the most efficacious nanoparticle with a fast degradation and acidification rate, we synthesized acidic nanoparticles (acNPs) based on tetrafluorosuccinic and succinic acids to form optimized nanoparticles. The acNPs showed faster rescue of cellular function compared to PLGA NPs in the PD model. Finally, we tested the acNPs in NAFLD model, and where lysosomal pH reduction by acNPs restored autophagy, reduced lipid accumulation, and improved mitochondria function in high-fat diet mice. In sum, nanoparticles are of potential therapeutic interest for pathologies associated with lysosomal acidity impairment. Future studies include testing the acNPs in NASH disease model and clinical studies. / 2022-05-18T00:00:00Z

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22471号 / 工博第4732号 / 新制||工||1739(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 秋吉 一成, 教授 大内 誠, 准教授 松岡 秀樹 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Polymer nanoparticles (PNPs) that exhibit selective stimuli-responsive degradation and drug release at tumor sites are promising candidates in the development of smart nanomedicines. In this thesis, we demonstrate a microfluidic approach to manufacturing biological stimuli-responsive PNPs with flow-tunable physicochemical and pharmacological properties. The investigated PNPs contain cleavable disulfide linkages in two different locations (core and interface, DualM PNPs) exhibiting responsivity to elevated levels of glutathione (GSH), such as those found within cancerous cells. First, we conduct a mechanistic study on the microfluidic formation of DualM PNPs without encapsulated drug. We show that physicochemical properties, including size, morphology, and internal structure, of DualM PNPs are tunable with manufacturing flow rate. Microfluidic formation of DualM PNPs is explained by the interplay of shear-induced coalescence, shear-induced breakup, and intraparticle chain rearrangements. In addition, we demonstrate that rates of GSH-triggered changes in size and internal structure are linearly correlated with initial PNP sizes and internal structures, respectively. Next, we expand our study to focus on microfluidic control of pharmacological properties of DualM PNPs containing either an anticancer drug (paclitaxel, PAX-PNPs) or a fluorescent drug surrogate (DiI-PNPs). Microfluidic PAX-PNPs and DiI-PNPs show similar sizes and morphologies with their non-drug-loaded counterparts under the same flow conditions. We then show that pharmacological properties of DualM PNPs, including encapsulation efficiency, GSH-triggered release rate, cell uptake, cytotoxicity against MCF-7 (cancerous) and HaCaT (healthy), and relative difference in MCF-7 and HaCaT cytotoxicity, all increase linearly as flow-directed PNP size decreases, providing remarkably simple process-structure-property relationships. In addition, we show that microfluidic manufacturing improves encapsulation homogeneities within PNPs relative to bulk nanoprecipitation. These results highlight the potential of flow-directed shear processing in microfluidics for providing controlled manufacturing routes to biological stimuli-responsive nanomedicines optimized for specific therapeutic applications. Finally, we summarize various design strategies of biological stimuli-responsive PNPs. We show that the location and density of disulfide linkages within PNPs determines stimulus-triggered degradation mechanism and kinetics. In addition, we show various bottom-up approaches to tune PNP responsivities that involves chemical processing, including formulation chemistry and intramolecular forces. Along with the top-down microfluidic approach that we demonstrate experimentally, this chapter provides a more comprehensive understanding of process-structure-property relations opening up vast possibilities for manufacturing smarter nanomedicines. / Graduate

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