Dissertations / Theses on the topic 'Multi-stimuli response'

Les molécules fluorescentes multiréactives peuvent ajuster leurs propriétés de fluorescence en réponse à des stimuli externes tels que des changements de température, de pression et d'environnement chimique. Cette capacité d'adaptation pourrait orienter efficacement le développement des technologies de capteurs, d'affichage et d'imagerie, offrant ainsi de nombreuses applications. Le mécanofluorochromisme (MFC) est une propriété fascinante des systèmes multiréactifs, où les matériaux subissent des changements fluorescents sous l'effet de contraintes mécaniques telles que la compression, le cisaillement et la friction. Les complexes difluorure de bore à ligand dicétone (DFB) attirent l'attention pour leurs caractéristiques photophysiques uniques, présentant non seulement un MFC mais aussi un polymorphisme et une fluorescence intense à l'état solide et en solution. Ce travail vise à explorer des méthodologies innovantes pour concevoir et synthétiser des matériaux DFB multi-réactifs et leurs composés précurseurs. L'accent est mis sur l'étude des caractéristiques photophysiques de ces matériaux et de leur réactivité à divers stimuli. En outre, les mécanismes sous-jacents du MFC sont étudiés. Tout d'abord, un nouveau DFB multiréactif et multicolore est discuté. La synthèse de l'amino-méthoxy-DFB (DFB-NH₂), impliquant l'introduction d'une amine primaire dans le cycle phényle par réarrangement de Curtius, a été entreprise. Grâce au groupe NH₂, la molécule présente un transfert de charge intramoléculaire (ICT) en solution et à l'état cristallin. Une structure de type quinoïde et une structure typique de dimère de type H tête-queue sont observées à l'état cristallin. Le cristal à faible émission rouge foncé présente une émission décalée vers le bleu après un frottement mécanique, ce qui constitue un comportement MFC original. Le composé déposé sur une feuille de papier présente également un MFC significatif. En outre, une réactivité acide/base caractéristique est observée en solution, dans les films polymères dopés et les échantillons de poudre. Deuxièmement, le système multiréactif est inséré dans une molécule symétrique en C₃. Un nouveau composé β-dicétone C₃-symétrique, BTA-D3, et son homologue monomère, D, ont été synthétisés avec succès. Notamment, l'émission induite par l'agrégation (AIE) est observée dans BTA-D3 contrairement à D. En outre, BTA-D3 présente des caractéristiques de fluorescence dépendantes du polymorphe, formant des fibres 1D avec une émission jaune dans le système THF/eau, tout en formant des feuilles 2D avec une émission bleue. En outre, les propriétés de transfert d'énergie intramoléculaire sont démontrées par BTA-D3, ce qui le distingue de D. Troisièmement, la migration d'énergie dans le gel, la formation d'assemblages, les effets mécaniques et la complexation du bore du BTA-D3 ont été explorés. Ces expériences ont permis de caractériser les propriétés de gélification et la fluorescence, révélant leur dépendance à la morphologie moléculaire. L'analyse de l'anisotropie dans le gel donne un aperçu de la migration de l'énergie à l'intérieur des molécules et entre elles, mettant en évidence des structures cruciales pour un auto-assemblage efficace. La structure unique contribue à diverses propriétés stimuli-réceptives, telles que l'induction chirale par des solvants chiraux et le MFC. Notamment, la boration de BTA-D3 donne une molécule très luminescente avec un déplacement marqué de la fluorescente vers le bleu par MFC. Ces résultats contribuent à une meilleure compréhension des molécules avec une symétrie C₃ et donnent un aperçu des stratégies de contrôle de l'assemblage moléculaire afin d'obtenir diverses colorations de fluorescence dans les matériaux moléculaires. L'ensemble de la thèse vise à fournir des lignes directrices pratiques et des idées pour le développement de nouveaux matériaux luminescents, contribuant ainsi à des avancées dans le domaine avec des applications potentielles
Multi-responsive fluorescent molecules can adjust their fluorescence properties in response to external stimuli such as changes in temperature, pressure, and chemical environment. This adaptability could efficiently direct the development of sensors, displays, and imaging technologies, providing various applications in the future. Mechanofluorochromism (MFC) is a fascinating property in multi-responsive systems, where materials undergo fluorescent changes under mechanical stress like compression, shear force, and friction. Difluoroboron β-diketonate (DFB) compounds draw attention for unique photophysical traits, featuring not only MFC but also polymorphism and intense fluorescence in both solid and solution. This research aims to explore innovative methodologies for designing and synthesizing multi-responsive DFB materials and their precursor compounds. Emphasis is placed on investigating these materials' photophysical characteristics and responsiveness to diverse stimuli. Additionally, the underlying mechanisms of MFC are studied. To achieve these objectives, a comprehensive approach is employed, integrating fluorescence spectroscopy, various microscopic techniques, anisotropic experiments, theoretical calculations, and other relevant methodologies.In the first topic of this thesis, a novel multi-responsive and multicolor DFB is discussed. The synthesis of amino-methoxy-DFB (DFB-NH₂), involving the introduction of a primary amine into the phenyl ring through Curtius rearrangement, was undertaken. Thanks to the NH₂ group, the molecule exhibits intramolecular charge transfer (ICT) in solution and in the crystalline phase. A quinoid-like structure and a typical head-to-tail H-type dimer structure are observed in the crystal state. The single crystal with dark-red weak emission demonstrates a blue-shifted emission after mechanical smearing, which constitutes an original MFC behavior. The drop-casted sample on a paper sheet also demonstrates significant MFC. Additionally, characteristic acid-/base-responsivity is observed in the solution phase, polymer-dispersed films, and powder samples.In the second topic of this thesis, the multi-responsive system is delved into a C₃-symmetrical molecule. A novel C₃-symmetrical β-diketone compound, BTA-D3, and its monomeric counterpart, D, are successfully synthesized. Notably, Aggregation-induced emission (AIE) is observed in BTA-D3 contrary to D. Additionally, BTA-D3 displays polymorph-dependent fluorescence characteristics, forming 1D fibers with yellow emission in the THF/water system, while forming 2D sheets with blue emission. In addition, intramolecular energy transfer properties are demonstrated by BTA-D3, distinguishing it from D.In the third topic of this thesis, energy migration in gel, assembly formations, mechanical effects, and boron complexation of BTA-D3 were explored. Through these experiments, the gelation properties and fluorescence are characterized, revealing their dependence on molecular morphology. Anisotropy analysis in gel offers insights into energy migration within and between molecules, highlighting crucial structures for efficient self-assembly. The unique structure contributes to diverse stimuli-responsive properties, such as chiral induction by chiral solvents and MFC. Notably, boronation of BTA-D3 results in a highly luminescent molecule with a distinctive blue-shift in MFC. These findings contribute to an enriched comprehension of C₃-symmetrical molecules and offer insights into strategies for controlling molecular alignment to achieve diverse fluorescence coloration in molecular materials. The whole thesis seeks to provide practical guidelines and insights for developing new luminescent materials, contributing to advancements in the field with potential applications

Artificial lipid bilayers formed on solid surface supports are widespread model systems to study physical, chemical, as well as biological aspects of cell membranes and fundamental interfacial interactions. The approach to use a thin polymer film representing a cushion for lipid bilayers prevents incorporated membrane proteins from pinning to the support and mimics the native environment of a lipid bilayer in certain aspects of the extracellular matrix and intracellular structures. A key component for cell anchorage to extracellular fibronectin is the transmembrane adhesion receptor alpha(5)beta(1) integrin. Its transport dynamics and clustering behavior plays a major role in the assembly of focal adhesions, which mediate mechanical forces and biochemical signals of cells with their surrounding. The system investigated herein is envisioned to use extrinsically controlled stimuli-responsive polymer cushions to tune the frictional drag between polymer cushion and mobile membranes with incorporated integrins to actively regulate lipid membrane characteristics. To attain this goal, a temperature- and pH-responsive polymer based on poly(N-isopropylacrylamide) copolymers containing varying amounts of carboxyl-group-terminated comonomers at different aliphatic spacer lengths (PNIPAAm-co-carboxyAAM) was surface-grafted to a poly(glycidyl methacrylate) anchorage layer. The swelling transitions were characterized using atomic force microscopy, ellipsometry and quartz crystal microbalance with dissipation monitoring (QCM-D) and found to be tunable over a wide range of temperature and pH. In agreement with the behavior of the polymers in solution, longer alkyl spacers decreased the phase transition temperature T(P) and higher contents of carboxylic acid terminated comonomers increased T(P) at alkaline conditions and decreased T(P) at acidic conditions. Remarkably, the point where the degree of carboxyl group deprotonation balances the T(P)-lowering effect of the alkyl spacer was distinctive for each alkyl spacer length. These findings illustrate how the local and global balance of hydrophilic and hydrophobic interactions along the copolymer chain allows to adjust the swelling transition to temperatures below, comparable, or above those observed for PNIPAAm homopolymers. Additionally, it could be shown that surface-grafting leads to a decrease in T(P) for PNIPAAm homopolymers (7°C) and copolymers (5°C - 10°C). The main reason is the increase in local polymer concentration of the swollen film constrained by dense surface anchorage in comparison to the behavior of dilute free chains in solution. In accordance with the Flory-Huggins theory, T(P) decreases with increasing concentration up to the critical concentration. Biological functionalization of the PNIPAAm-co-carboxyAAm thin films was demonstrated for the cell adhesion ligand peptide cRGD via carbodiimide chemistry to mimic extracellular binding sites for the cell adhesion receptors integrin. The outcome of QCM-D measurements of cRGD-functionalized surfaces showed a maintained stimuli-responsiveness with slight reduction in T(P). A drying/rehydration procedure of a 9:1 lipid mixture of the cationic lipid dioleoyl-trimethylammoniumpropane (DOTAP) and the zwitterionic dioleoyl-phosphatidylcholine (DOPC) was utilized to form lipid bilayer membranes on PNIPAAm-co-carboxyAAM cushions. Fluorescence recovery after photobleaching (FRAP) revealed that lipid mobility was distinctively higher (6.3 - 9.6) µm2 s-1 in comparison to solid glass support ((3.0 - 5.9) µm2 s-1). In contradiction to the initial expectations, modulation of temperature and pH led to poor variations in lipid mobility that did not correlate with the PNIPAAm cushion swelling state. The results suggested a weak coupling of the lipid bilayer with PNIPAAm polymer cushions that can be slightly tuned by electrostatic interactions. The transmembrane adhesion receptor alpha(5)beta(1) integrin was reconstituted into liposomes consisting of DOPC/sphingomyelin/cholesterol 2:2:1 for the formation of polymer cushioned bilayers. PNIPAAm- co-carboxyAAM and maleic acid (MA) copolymers were used as cushions, both with the option for cRGD functionalization. On the MA copolymer cushions, fusion of proteoliposomes resulted in supported bilayers with mobile lipids as confirmed by FRAP. However, incorporated integrins were immobile. In an attempt to explain this observation, the medium-sized cytoplasmic integrin domain was accounted to hamper the movement by steric interactions with the underlying polymer chains in conjunction with electrostatic interactions of the cationic cytoplasmic domain with the oppositely charged MA copolymer. On the PNIPAAm-co-carboxyAAM cushion only a drying/rehydration procedure lead to bilayer formation. However, again the integrins were immobile, presumably due to the harsh treatment during preparation. Nevertheless, the results of the investigated set of PNIPAAm copolymer films suggest their application as temperature- and pH-responsive switchable layers to control interfacial phenomena in bio-systems at different physiological conditions. The PNIPAAm-co-carboxyAAm cushioned bilayer system represents a promising step towards extrinsically controlled membrane – substrate interactions.

This thesis presents the development of two novel materials that undergo drastic changes when exposed to a certain trigger. One of them becomes harder and stiffer when exposed to visible light of a certain wavelength and one of them degrades when exposed to a certain enzyme. The properties of the materials were investigated thoroughly. The advanced 3D printing technique direct laser writing was used to fabricate microscopic structures from both materials. Such microstructures possessing highly adaptable properties could be used as scaffold materials for cells in order to study their development as a response to the triggered changes.

Grafting polymer brushes from surfaces is an effective method of surface modification. Importantly, such coatings are robust due to covalent bonding, establishing a chemically and mechanically stable interface not relying solely on weak physical bonding (e . g. van del' Waals forces) as alternative coating methods do. Polymer brushes have been shown to mediate effective lubrication, among other applications. In this work, stainless steel is the substrate of interest and a novel system of reagents specifically designed for this material has been applied to produce various polymer brush structures by surface initiated atom transfer radical polymerisation (SI-ATRP). For friction reduction in an aqueous environment, a multi-component hierarchical brush system, incorporating an underlying hydrophobic layer and a hydrophilic block on the outer periphery was proposed. The first layer of brushes, closest to the metals surface, was exploited as a barrier to drive water away from the solid interface, hence minimising corrosion of the metal, with the facile wetting of the second block giving a hydration layer at the interface to promote lubrication in the presence of water. Additionally, the hydrocarbon brush chosen as the outer layer in this system is known to be thermoresponsive, as chains collapse and become more hydrophobic at elevated temperatures. A co-polymer structure was employed and allowed the critical temperature of the brush to be tuned over a range of temperatures. This tuneable thermal response was intended to give switchable surface friction. Furthermore, use of an industrially relevant material in these investigations should potentially lead to a more straightforward utilisation in real world applications.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005.
Includes bibliographical references (leaves 35-36).
In normal-hearing ears, sound waves are amplified within the cochlea and a small fraction of the sound energy travels backward out into the ear canal, producing sounds known as "otoacoustic emissions" (OAE) that can be measured with a sensitive microphone. One class of OAE, called "stimulus-frequency-otoacoustic-emissions" (SFOAEs), has been hypothesized to be produced by a process known as "coherent reflection filtering" (CRF). The CRF theory provides a prediction between the SFOAE group delay and the group delays of tone responses on the basilar membrane within the cochlea. Using single and multiple-tone stimuli, we collected data from the firing patterns of single auditory-nerve-fibers (ANFs) from which basilar-membrane tone-response group delays can be calculated for both high and low best-frequency (BF) positions along the basilar membrane. These calculated basilar-membrane group delays were compared to published SFOAE group delays. Our results suggest that group delays calculated from the tip, the lower-frequency tail, or the above-BF region of ANF tuning curves do not match the CRF theory prediction. In obtaining the data to the test the CRF theory, we used two methods for obtaining ANF group delays at frequencies above BF: a previously published method and a simpler new method based on the same principle.
(cont.) Surprisingly, the two methods produced different results. Control measurements suggest that the previously published method does not do what it was expected to do.
by Holden Cheng.
S.M.

This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2020
Cataloged from student-submitted PDF of thesis.
Includes bibliographical references (pages 136-143).
Dynamic micro-optical components have revolutionized imaging, sensing, and display technologies. Multi-phase emulsions are micro-scale droplets formed from multiple immiscible material components suspended in a fluid medium. An interesting aspect of these droplets is that by tailoring the chemistry of the surrounding medium it is possible to control the droplet morphology or to render the droplets responsive to stimuli in the environment, including light, heat, specific molecules, or even bacteria. This thesis explores the optical characteristics of multi-phase droplets, including their refractive, emissive, and reflective properties. This work focuses predominantly on bi-phase droplets formed from two immiscible oils in water, which form double emulsions or Janus droplets. As tunable refractive components, these droplets form dynamic compound micro-lenses with adjustable focal length that is continuously variable from converging lenses to diverging lenses.
Macroscopically these refractive droplets can appear nearly transparent or strongly scattering, depending on their configurations. When a fluorescent dye is dispersed within the higher refractive index phase, a portion of the light emitted will undergo total internal reflection. This results in a strong morphology-dependent angular emission profile, which can be used in molecular sensing for chemicals or pathogens. In reflection, the droplets produce striking iridescent colors. This is due to the interference light being totally internally reflected at the internal interface along distinct optical paths, leading to color. These optical characteristics are analyzed both experimentally and theoretically. Finite Difference Time Domain simulations were used to model wave-optical effects and phenomena that could be treated using geometrical optics were calculated using a custom-built ray tracing algorithm.
Additionally, a theoretical model was developed to explain the iridescent colors, under a geometric approximation that takes into account interference effects. Experimentally the droplets were characterized using several different custom-built microscope setups. Beyond the optical characteristics, we used these setups to investigate the effects of thermal Marangoni flows within the droplets, which cause the droplets to re-orient towards a heat source. This work sets the foundation of understanding the refractive, reflective, and emissive properties of multi-phase droplets, which could form the basis of dynamically controllable or stimuli-responsive micro-scale optical components.
by Sara Nagelberg.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Mechanical Engineering

Ce mémoire de maîtrise porte sur la conception et la synthèse de monomères polymérisables en vue d’obtenir des macromolécules sensibles à plusieurs stimulations externes : 1) la lumière, 2) le pH (ou le CO[indice inférieur 2]) et 3) l’oxydo-réduction.

L'adsorption de protéine sur une surface artificielle solide est un phénomène fondamental qui détermine la réponse biologique d'un organisme vivant entrant dans n'importe quel matériel d'implant. Donc, l'adaptation de surfaces pour l'adsorption de protéine contrôlée est au coeur de beaucoup de champs de recherche d'aujourd'hui incluant la science de matériels et la biotechnologie. Dans ce contexte, les matériels sensibles de stimulus qui peuvent changer leurs propriétés comme une réponse à une petite monnaie dans leur environnement physicochimique attirent un grand intérêt comme ils permettent la création de surfaces avec des propriétés commutables pour le contrôle d'adsorption de protéine. Dans cette thèse, nous faisons un rapport sur la conception et l'élaboration de films minces sensibles de stimulus multi et de nanotubes. À cette fin, nous avons employé la couche-par-couche robuste et polyvalente…
Protein adsorption on a solid artificial surface is a fundamental phenomenon that determines the biological response of a living organism entering any implant material. Therefore, tailoring surfaces for controlled protein adsorption is at the heart of many of today's research fields including biotechnology and materials science. In this context, stimuli-responsive materials that are able to change their properties as a response to a small change in their physico-chemical environment are attracting a great interest as they allow the creation of surfaces with switchable properties for the control of protein adsorption. In this thesis, we report on the design and elaboration of multi stimuli-responsive thin films and nanotubes. For this purpose, we employed the robust and versatile layer-by-layer (LbL) assembly technique to incorporate block copolymers made of poly(acrylic acid) PAA and poly(N-isopropylacrylamide) PNIPAM with tunable and well-controlled block lengths. The combination of ellipsometry, quartz crystal microbalance with dissipation monitoring (QCM-D), surface plasmon resonance (SPR) and infrared data reveal the possibility to build up (PAH/PAA-b-PNIPAM)n multilayers. The stimuli-responsive properties of these LbL films were examined by monitoring the adsorption of proteins by means of QCM-D and fluorescence measurements, while varying (i) temperature, (ii) pH, (iii) ionic strength, or (iv) a combination of the above parameters. It appears that all these stimuli strongly influence the amount of adsorbed proteins. In short, these new PNIPAM block copolymer-based LbL coatings are easy to build on substrates of various nature and geometry (including nanoporous membranes)

L'adsorption de protéine sur une surface artificielle solide est un phénomène fondamental qui détermine la réponse biologique d'un organisme vivant entrant dans n'importe quel matériel d'implant. Donc, l'adaptation de surfaces pour l'adsorption de protéine contrôlée est au coeur de beaucoup de champs de recherche d'aujourd'hui incluant la science de matériels et la biotechnologie. Dans ce contexte, les matériels sensibles de stimulus qui peuvent changer leurs propriétés comme une réponse à une petite monnaie dans leur environnement physicochimique attirent un grand intérêt comme ils permettent la création de surfaces avec des propriétés commutables pour le contrôle d'adsorption de protéine. Dans cette thèse, nous faisons un rapport sur la conception et l'élaboration de films minces sensibles de stimulus multi et de nanotubes. À cette fin, nous avons employé la couche-par-couche robuste et polyvalente…
Protein adsorption on a solid artificial surface is a fundamental phenomenon that determines the biological response of a living organism entering any implant material. Therefore, tailoring surfaces for controlled protein adsorption is at the heart of many of today's research fields including biotechnology and materials science. In this context, stimuli-responsive materials that are able to change their properties as a response to a small change in their physico-chemical environment are attracting a great interest as they allow the creation of surfaces with switchable properties for the control of protein adsorption. In this thesis, we report on the design and elaboration of multi stimuli-responsive thin films and nanotubes. For this purpose, we employed the robust and versatile layer-by-layer (LbL) assembly technique to incorporate block copolymers made of poly(acrylic acid) PAA and poly(N-isopropylacrylamide) PNIPAM with tunable and well-controlled block lengths. The combination of ellipsometry, quartz crystal microbalance with dissipation monitoring (QCM-D), surface plasmon resonance (SPR) and infrared data reveal the possibility to build up (PAH/PAA-b-PNIPAM)n multilayers. The stimuli-responsive properties of these LbL films were examined by monitoring the adsorption of proteins by means of QCM-D and fluorescence measurements, while varying (i) temperature, (ii) pH, (iii) ionic strength, or (iv) a combination of the above parameters. It appears that all these stimuli strongly influence the amount of adsorbed proteins. In short, these new PNIPAM block copolymer-based LbL coatings are easy to build on substrates of various nature and geometry (including nanoporous membranes)

Ce travail de thèse porte sur l’élaboration de microgels biocompatibles et multi-stimulables à base de méthacrylate d’oligo(éthylène glycol) et de nanoparticules d’oxyde de fer. Des microgels sensibles au pH, à la température et au champ magnétique ont été élaborés au cours de cette étude via une stratégie multi-étape partant de : 1. la synthèse et la caractérisation de microgels pH- et thermosensibles à base d’oligo(éthylène glycol), 2. l'élaboration de microgels hybrides par imprégnation de nanoparticules magnétiques au sein des microgels d’oligo(éthylène glycol). L’étude de la synthèse des microgels et de leurs propriétés physico-chimiques a permis de mettre en avant l’effet important de la structure interne des microgels sur leurs propriétés de gonflement/contraction. La caractérisation des microgels hybrides a mis en évidence l’importance des fonctions acide carboxylique réparties de manière homogène au sein des microgels, le tout permettant d’encapsuler efficacement et de manière homogène des nanoparticules magnétiques tout en préservant les propriétés colloïdales et thermo-stimulables des microgels hybrides. Enfin des films structurés constitués de multicouches de microgels ont ainsi pu être élaborés via un procédé simple de séchage de dispersion aqueuse de microgels. Une étude prospective des propriétés optique et mécanoélectrique de films auto-assemblés de microgels d’oligo(éthylène glycol) hybride et non hybride par évaporation de solvant a permis de mettre en évidence le rôle positif des groupements ioniques issus des fonctions carboxylates sur le potentiel électrique induit lors de la compression des films
Smart polymer materials can provide wide range of options to induce advanced functional features and relevant surface properties in one material. This all-in-one concept is of great interest for applications that require several simultaneous treatments such as cosmetic application. Herein, we aim to develop oligo(ethylene glycol)-based biocompatible multiresponsive microgels that could both interact on the skin as smart drug delivery system (DDS) while fulfilling advanced properties such as surface protection, mechanical and optical properties. Specifically, aqueous dispersed microgels responsive to pH, temperature and magnetic field were synthesized via multi-step strategy: 1. The synthesis and characterization of pH- and thermo-responsive oligo(ethylene glycol)-based microgels by precipitation polymerization, 2. The encapsulation of pre-formed magnetic nanoparticles via adsorption of the nanoparticles into the multiresponsive microgels. The effect of the microgel microstructure on their pH- and thermo-responsive properties were highlighted thanks to a rational investigation of the crosslink density and acid-functional units distribution within the microgels. Oligo(ethylene glycol)-based microgels with homogeneous distribution of both acid-functional unit and crosslinker allowed the synthesis of highly pH-and thermo-responsive microgels. The hybrid microgels prepared by straightforward encapsulation of pre-formed magnetic nanoparticles were characterized. The homogeneous microstructure of the initial stimuli-responsive biocompatible microgels plays a crucial role for the design of unique well-defined ethylene glycol-based thermoresponsive hybrid microgels. Thus, robust monodisperse thermoresponsive magnetic microgels were produced, exhibiting both a constant value of the swelling-to-collapse transition temperature and good colloidal stability whatever the NPs content. These smart microgels can spontaneously form a transparent film with perfect arrangement of the microgels by simple solvent evaporation process. The characterization of the optical and mechanoelectrical properties of the self-assembled microgel films were performed. We highlighted that the presence of anionic charges inside the microgels emphasizes the mechanoelectrical effect of the films

In the last few decades, “smart”polymers have gained an increasing attention in the scientific community thanks to their large use in several applications, such as drug delivery, sensors, separation techniques and catalysts. The high versatility of smart materials comes from their tunable properties and their adaptability in response to external chemical and physical stimuli, such as temperature, light, pH and electron transfer. Currently, the research on the field of multi-stimuli-responsive polymers has been focused both on design of new polymer bearing two or more functionalities and on the development of novel responsive groups. In particular, hydrophilic multi-stimuli-responsive polymers are of special interest for their potential employments in aqueous solutions. In this context, oximes have been occasionally investigated as stimulus-responsive moieties, although they have a wide use in the field of macromolecules as, for example, photoinitiators for radical polymerization or reversible linker in crosslinked networks and bioconjugate polymers. The introduction of the oxime moiety can be realized applying the α-oximation of aldehydes via organo-somo catalysis developed, recently, in our group. A reaction which affords 2-(hydroxyimino)aldehydes (HIA) compounds from good to excellent yield. 2-(hydroxyimino)aldehyde (HIA) are molecules characterize by an aldehyde group adjacent to an oxime group, which endows them with some interesting properties, such as an unusually low pKa compared to simple oxime molecules and the existence of two configurational isomers E and Z that can be interchanged by light stimulus. Furthermore, the aldehyde group can bind bioactive molecules and the oximate ion can be oxidized reversibly in the range of 0.38 to 0.64 V vs. NHE. The aim of the present work has been the investigation of the possibilities offered by the highly versatile HIA group towards obtaining novel multi-stimuli responsive polymers. Copolymers of OEGMA with methacrylates bearing the 2-(hydroxyimino)aldehyde (HIA) group in the side chain have been prepared in order to combine the properties of the novel moiety HIA with the temperature responsiveness in aqueous solution of OEGMA. In the first part of the work a monomer encompassing the HIA group (HIABMA) was synthetized and characterized. In particular, CNO-H pKa and BDE, oxidation potential of oxime and oximate anion were assessed. Then, random copolymers of OEGMA with different content of HIABMA (from 10% to 50%) and a 1:1 diblock copolymer were prepared through RAFT method. All the obtained copolymers showed low dispersity (Ð less than 1.2), high conversion (up to 94%) and linear dependence of Mn vs. conversion during the reaction. In order to predict the photochemical response of HIA group in a polymer, the second part of the work was dedicated to the study of the photochemical behavior of several small HIAs bearing different substituents adjacent to the oxime group. Depending on HIA substituents, solvent and excitation wavelength (278 nm and 365 nm) two main photochemical phenomena were observed: the classical E/Z isomerization around oxime double bond and Norrish-Yang cyclization to cyclobutanol oxime. The photostimulation of P(HIABMA-co-OEGMA₅₀₀) 3:7 in DMSO-d₆ confirmed the occurrence of Norrish-Yang cyclobutanol formation, along with further photochemical processes that are currently under investigation. In the last part of the thesis, the investigation on thermal behavior of HIA bearing copolymers aqueous solutions was carried out through turbidimetry and DLS measurement. It was found that the presence and the percentage of HIA group in the side chain of the OEGMA copolymer strongly influences the Lower Critical Solution Temperature (LCST) behavior in aqueous solution. Specifically, an increasing amount of HIA moiety in the side chain of copolymers resulted in a progressive lower cloud point that goes from above 80°C for P(HIABMA-co-OEGMA₅₀₀) 1:9 to 47°C for P(HIABMA-co-OEGMA₅₀₀) 1:1. In addition, the photochemical stimulus also play an important role in the LCST behavior of the HIA bearing polymers. Irradiation of OEGMA₅₀₀ copolymer bearing 50% of HIA group leads to structural changes that result in a remarkable increase of Cloud Point in aqueous solution (up to 12-13°C). In conclusion, the research presented in this Thesis covered all aspects of the investigation on a novel stimuli-responsive polymer, from monomer and polymer synthesis and characterization to the effect of sequential application of multiple stimuli (temperature and light).Furthermore, this work constitutes the starting point for a better understanding of the effect of hydrogen bonding patterns provided by aldehydes, oximes and HIAs on polymer solution behavior.

Artificial lipid bilayers formed on solid surface supports are widespread model systems to study physical, chemical, as well as biological aspects of cell membranes and fundamental interfacial interactions. The approach to use a thin polymer film representing a cushion for lipid bilayers prevents incorporated membrane proteins from pinning to the support and mimics the native environment of a lipid bilayer in certain aspects of the extracellular matrix and intracellular structures. A key component for cell anchorage to extracellular fibronectin is the transmembrane adhesion receptor alpha(5)beta(1) integrin. Its transport dynamics and clustering behavior plays a major role in the assembly of focal adhesions, which mediate mechanical forces and biochemical signals of cells with their surrounding. The system investigated herein is envisioned to use extrinsically controlled stimuli-responsive polymer cushions to tune the frictional drag between polymer cushion and mobile membranes with incorporated integrins to actively regulate lipid membrane characteristics. To attain this goal, a temperature- and pH-responsive polymer based on poly(N-isopropylacrylamide) copolymers containing varying amounts of carboxyl-group-terminated comonomers at different aliphatic spacer lengths (PNIPAAm-co-carboxyAAM) was surface-grafted to a poly(glycidyl methacrylate) anchorage layer. The swelling transitions were characterized using atomic force microscopy, ellipsometry and quartz crystal microbalance with dissipation monitoring (QCM-D) and found to be tunable over a wide range of temperature and pH. In agreement with the behavior of the polymers in solution, longer alkyl spacers decreased the phase transition temperature T(P) and higher contents of carboxylic acid terminated comonomers increased T(P) at alkaline conditions and decreased T(P) at acidic conditions. Remarkably, the point where the degree of carboxyl group deprotonation balances the T(P)-lowering effect of the alkyl spacer was distinctive for each alkyl spacer length. These findings illustrate how the local and global balance of hydrophilic and hydrophobic interactions along the copolymer chain allows to adjust the swelling transition to temperatures below, comparable, or above those observed for PNIPAAm homopolymers. Additionally, it could be shown that surface-grafting leads to a decrease in T(P) for PNIPAAm homopolymers (7°C) and copolymers (5°C - 10°C). The main reason is the increase in local polymer concentration of the swollen film constrained by dense surface anchorage in comparison to the behavior of dilute free chains in solution. In accordance with the Flory-Huggins theory, T(P) decreases with increasing concentration up to the critical concentration. Biological functionalization of the PNIPAAm-co-carboxyAAm thin films was demonstrated for the cell adhesion ligand peptide cRGD via carbodiimide chemistry to mimic extracellular binding sites for the cell adhesion receptors integrin. The outcome of QCM-D measurements of cRGD-functionalized surfaces showed a maintained stimuli-responsiveness with slight reduction in T(P). A drying/rehydration procedure of a 9:1 lipid mixture of the cationic lipid dioleoyl-trimethylammoniumpropane (DOTAP) and the zwitterionic dioleoyl-phosphatidylcholine (DOPC) was utilized to form lipid bilayer membranes on PNIPAAm-co-carboxyAAM cushions. Fluorescence recovery after photobleaching (FRAP) revealed that lipid mobility was distinctively higher (6.3 - 9.6) µm2 s-1 in comparison to solid glass support ((3.0 - 5.9) µm2 s-1). In contradiction to the initial expectations, modulation of temperature and pH led to poor variations in lipid mobility that did not correlate with the PNIPAAm cushion swelling state. The results suggested a weak coupling of the lipid bilayer with PNIPAAm polymer cushions that can be slightly tuned by electrostatic interactions. The transmembrane adhesion receptor alpha(5)beta(1) integrin was reconstituted into liposomes consisting of DOPC/sphingomyelin/cholesterol 2:2:1 for the formation of polymer cushioned bilayers. PNIPAAm- co-carboxyAAM and maleic acid (MA) copolymers were used as cushions, both with the option for cRGD functionalization. On the MA copolymer cushions, fusion of proteoliposomes resulted in supported bilayers with mobile lipids as confirmed by FRAP. However, incorporated integrins were immobile. In an attempt to explain this observation, the medium-sized cytoplasmic integrin domain was accounted to hamper the movement by steric interactions with the underlying polymer chains in conjunction with electrostatic interactions of the cationic cytoplasmic domain with the oppositely charged MA copolymer. On the PNIPAAm-co-carboxyAAM cushion only a drying/rehydration procedure lead to bilayer formation. However, again the integrins were immobile, presumably due to the harsh treatment during preparation. Nevertheless, the results of the investigated set of PNIPAAm copolymer films suggest their application as temperature- and pH-responsive switchable layers to control interfacial phenomena in bio-systems at different physiological conditions. The PNIPAAm-co-carboxyAAm cushioned bilayer system represents a promising step towards extrinsically controlled membrane – substrate interactions.

碩士
國立交通大學
材料科學與工程學系所
106
In this master thesis, we presented a novel photochromic metallosupramolecular polymer synthesis scheme and properties characterization. The supramolecular polymer self-assembled by metal-ligand coordination and host-guest interactions of pseudorotaxane. The supramolecular polymer was self-assembled by molar ratio = 2:1:1 mixing complex of terpyridine functionalized dibenzo-24-crown-8 (DB24C8) derivatives (5), Zinc ion (Zn2+) and diarylethene-containing ammonium salt (10). Thanks to fluorescence resonance energy transferred from terpyridine to DAE salt, the polymer solution exhibited appreciable emission change either with UV/Vis irradiation or multi-chemical stimulation. The metal-ligand coordination and host-guest interactions can be reversible in the presence of Zn2+/cyclen and base/acid, respectively. Investigations on chemical multi-stimuli response of supramolecular polymer were monitored by UV-Vis, photoluminescence and 1H NMR spectrum. The formation of linear polymer is also evidenced by 1H NMR spectrum and viscosity measurement. This new supramolecular polymer utilized DAE photochromic behavior which changed the metal-terpyridinylmacrocycle fluorescence from deep blue to skyblue, including intensity enhancement and wavelength shift. Meanwhile, we have developed facile photochromic switchable supramolecular polymer that have potential for further applications such as metal, light or pH sensors.

The discovery of novel and efficient stimuli-responsive materials that change their properties according to external stimuli and therefore, adjust to our demands become an interesting research topic for several potential applications. The integration of the most promissory stimuli-responsive materials in devices for antiglare car mirrors, smart windows, sunglasses, sensors, among others has been applied. In this thesis, the development and application of stimuli-responsive materials containing ionic photochromic or electrochromic units have been explored. In general, it is possible to incorporate specific scaffolds possessing pH, temperature, and light or electron-transfer stimuli-responsive behaviour in the cation or anion structures. Also, ionic polymers based on these structures have been investigated. In this context, 4,4’-bipyridinium, diarylethenes and flavylium were selected as electrochromic and photochromic units, respectively. For the preparation of the selected organic salts including polymers, different synthetic routes and purification processes have been followed. Detailed characterization of all prepared salts by spectroscopic techniques in order to elucidate their structures and purities has been performed. Thermal, rheological, photochemical and electrochemical properties of some prepared salts were also studied. It is important to focus that the adequate selection of the counter-ions can be crucial to achieve ionic liquids as well as to tune their final properties. The most promissory electrochromic salts based on 4,4’-bipyridinium symmetrical and non-symmetrical di and tetra-cations as well as ionic polymers were tested in liquid, gel or solid electrochromic devices. The substituents from bipyridinium scaffold as well as counter-ions can significantly influence the electrochromic performance in particular its reversibility; stability; colour contrast and transition times. Photochromic Room Temperature Ionic Liquid based on the combination of diarylethene derivative anion with tri-octyl methylammonium ([ALIQUAT]) cation was developed and characterized. Additionally, a new thermal, pH and photo-stimuli responsive co-polymer containing N-isopropylacrylamide and flavylium derivative have been prepared. The chemical versatility of the prepared ionic photo- and electrochromic materials opens excellent perspectives for future applications as efficient and reversible multi stimuli-responsive materials.

碩士
國立交通大學
材料科學與工程學系所
104
A multi-stimuli responsive metallosupramolecular polymer network was constructed by the orthogonal assembly of metal-ligand interaction and conjugated terpyridine functionalized dibnzo-24-crown-8 (DB24C8) host and a tetraphenylethylene derivative as a guest with based aggregation-induced emission (AIE) property is fabricated successfully. Investigations on their AIE behaviors of metallosupramolecular polymer network their corresponding guests by using various glycerol fractions of DMSO and glycerol mixtures. Consecutively, quite different from usual supramolecular polymers constructed before, this novel supramolecular polymer of reversible fluorescence emission are realized by acid-base controllable and reversible supramolecular interactions. This strategy to design supramolecular polymers with switchable AIE property overcomes the common problem of aggregation-caused quenching (ACQ) in usual supramolecular polymers and provides a new concept to develop smart supramolecular polymeric materials.

博士
國立交通大學
材料科學與工程學系所
105
The pivotal objective of this dissertation is to design and construct novel fluorescent switchable mechanically interlocked molecular architectures with symmetric stopper and to study their molecular shuttling process under acid-base stimuli control along with their controllable high contrast fluorescence and impressively selective detection of anionic guest species. In the introduction of this doctoral thesis we have described brief early synthetic attempts to create mechanically interlocked molecules (MIMs) such as rotaxanes and catenanes as well as several chemosensing mechanism and aggregation induced emission (AIE). Moreover novel templating methodologies to build MIMs and some latest examples of fluorescence MIMs based molecular shuttles under different control stimuli were also introduced. Indeed, acid-based stimuli can drive the molecular shuttling between the two stations accompanied by changing the AIE behavior of AIE-active mechanically interlocked molecule investigated. Fairly, underplayed chemo sensing mechanisms in these systems were presented. Meanwhile, we have developed facile ratiometric sequential detection of copper and pyrophosphate based on rhodamine appended derivatives in this doctoral thesis as well. In chapter two, a novel multifunctional mechanically interlocked switchable [2]rotaxane R4 containing two molecular stations and rotaxane arms terminated with boron-dipyrromethene (BODIPY) fluorophores and its derivatives were synthesized for the first time by CuAAC click reaction. The shuttling motion of macrocycle between the dibenzylammonium and triazolium recognition sites and the distance dependent photoinduced electron transfer process of R4 is demonstrated by utilizing external chemical stimuli (acid/base). Interestingly, the reversible self-assembly process of R4 was recognized by the acid–base molecular switch strategy. Notably, two symmetrical triazolium groups acted as molecular stations, H2PO4– receptors, and H-bonded donors. Both [2]rotaxane R4 and thread R2 demonstrated excellent optical responses and high selectivity toward H2PO4– ion. The specific motion and guest–host interactions of mechanically interlocked machines (MIMs) were also further explored by quantum mechanical calculations. The thread R2 also demonstrated to enable the detection of H2PO4– in RAW 264.7 cells successfully. In chapter three, a novel near IR fluorescent switchable [2]rotaxane NIR4 composed of two different molecular stations and rotaxane arms terminated with near IR boron-dipyrromethene (BODIPY) fluorophores and its derivatives were synthesized for the first time by CuAAC click chemistry. The molecular shuttling motion could be addressed by the fluorescence signal transduction via distance dependent photo-induced electron transfer process of [2]rotaxane NIR4 triggered by external chemical stimuli (acid/base). The construction and efficient synthesis of [2]rotaxane NIR4 with high level of structural complexity designed always more challenging task of selective anion sensing. Conspicuously, the key to design involved encoding the flexible arms of [2]rotaxane NIR4 triazolium moiety acted as molecular stations and H-bonded donors, which exhibits impressive selectivity and sensitivity toward complementary anionic gust species. The specific mechanical molecular motion of [2]rotaxane NIR4, host-guest interactions of NIR2 and mechanically interlocked molecules (MIMs) were also further explored by quantum mechanical calculations. Importantly, the host of NIR2 and [2]rotaxane NIR4 could be applied for the vivo imaging and clarify the distribution of H2PO4- at subcellular levels. In chapter four, a novel AIE-active switchable [2]rotaxane TR2 incorporating two different molecular stations and rotaxane arms terminated with AIE-active TPE fluorophores and its derivatives were synthesized for the first time by click chemistry. The shuttling behavior of macrocycle component between the two molecular stations can be driven by external acid-base stimuli in solution, accompanied by NMR spectral changes. Investigation of their AIE fluorescence behavior changes showed that these analogous rotaxane are controlled by the molecular motion of the macrocycle component in the presence of external acid-base stimuli. The anion-templated construction of [2]rotaxane TR2 with high level of structural complexity designed always more challenging task. Evidently, the key to design involved encoding the flexible arms of both triazolium motif, is described which exhibit impressive selectivity and sensitivity toward complementary anionic gust species. The specific mechanical molecular motion and host-guest interactions of mechanically interlocked machines (MIMs) were also further explored by quantum mechanical calculations. Importantly, the AIE- active behaviors of [2]rotaxanes TR1, TR2 and TR3 were further investigated to study their potential bio-imaging application and specifically [2]rotaxane TR2 could be applied in vivo imaging with H2PO4- at subcellular levels. In chapter five, two rhodamine hydrazine derivatives Rh1 and Rh2 with catechol and ether functionalities have been synthesized and utilized towards sequential colorimetric detections of Cu(II) and pyrophosphate (PPi) ions in CH3CN–H2O (v/v = 9 : 1, 5 mM Tris–HCl, pH 7.4) semi-aqueous medium. Notably, Rh1 and Rh2 are the first example of colorimetric rhodamine-based probes for the sequential detections of Cu2+ ion and PPi anion. Based on the significant colorimetric responses (from colorless to pink) of Rh1 and Rh2 to Cu2+ ions, the detection limits were estimated as low as 1.22 × 10−8 M and 8.0 × 10−7 M, respectively, which signified the utilities of designed probes towards facile detections of Cu2+ ions. Furthermore, upon the successive addition of PPi ion to Rh1–Cu2+ and Rh2–Cu2+complexes, it has been altered and restored to its origin of Rh1 and Rh2 via re-coordination of PPi to Cu2+ ion, which was confirmed by color changes from pink to colorless. Moreover, computational DFT calculations provided more insights into HOMO–LUMO structures of rhodamine derivatives and their copper complexes. Additionally, the solid state strip-based colorimetric detections of Cu2+ ion were supplemented as a real time application. Thus in conclusion, novel fluorescence mechanically interlocked molecules designed to act as molecular switches have proceeded apace. Delightfully, the molecular shuttling to achieve by the addition of acid-base and studied on AIE behavior indicate that the molecular motion of macrocycle component could induce change the aggregation state of the AIE-active mechanically interlocked molecule. The remarkable stimulated responses towards dihydrogen phosphate (H2PO4-) were discussed. Furthermore, sequential detection of copper and pyrophosphate via ratiometric sensor based on rhodamine derivatives were presented in detail.

Σκοπός της παρούσας διδακτορικής διατριβής είναι η σύνθεση, ο χαρακτηρισμός και η βιολογική αξιολόγηση τροποποιημένων πολυλειτουργικών νανοπεριεκτών (ΠΝΠ) ως συστημάτων μεταφοράς φαρμάκων (ΣΜΦ), με άμεση εφαρμογή στη θεραπεία του καρκίνου του μαστού και του προστάτη. Με τον όρο νανοπεριέκτες (ΝΠ) εννοούμε τα σωματίδια τα οποία βρίσκονται στην κλίμακα του νανομέτρου και κυμαίνονται σε διαστάσεις από περίπου 1nm έως και 100 nm. Ο όρος πολυλειτουργικά αναφέρεται στις ιδιότητες αυτών των νανοδομών και πιο συγκεκριμένα στο πως μεταβάλλονται οι ιδιότητες αυτών όταν υπάρχει επίδραση εξωτερικών παραγόντων όπως θερμοκρασία, pH, όξειδο-αναγωγικό περιβάλλον και μεταβαλλόμενο μαγνητικό πεδίο. Για την παρασκευή των πολυμερικών νανοπεριεκτών χρησιμοποιήθηκαν διάφορα είδη πολυμερισμών όπως, πολυμερισμός γαλακτώματος μέσω ριζών, πολυμερισμός σπόρου (seed), πολυμερισμός μεταφοράς ατόμου με ρίζες, πολυμερισμός διασποράς και πολυμερισμός μέσω απόσταξης-καταβύθισης. Οι διάφορες ευαισθησίες στα ΝΣ προστέθηκαν μέσω συμπολυμερισμού διαφόρων μονομερών τα οποία παρουσιάζουν τις προαναφερθείσες ιδιότητες. Κάποια από τα μονομερή τα οποία χρησιμοποιήθηκαν, όπως το υδρόξυ προπυλικό μεθακρυλαμίδιο (HPMA) το οποίο παρουσιάζει ευαισθησία στη μεταβολή της θερμοκρασίας και το 3-Μεθυλ-N-(2-((2-(3-οξοβουταναμιδο)εθυλ) δισουλαφανυλ)εθυλ)βουτ-3-εναμίδιο (Disulfide) το οποίο παρουσιάζει ευαισθησία στις μεταβολές του όξειδο-αναγωγικού περιβάλλοντος συνετέθησαν στο εργαστήριο, ενώ τα υπόλοιπα ήταν εμπορικά διαθέσιμα. Το κύριο μονομερές το οποίο χρησιμοποιήθηκε στους πολυμερισμούς είναι ο Μεθακρυλικός Μεθυλεστέρας (MMA) το οποίο είναι μη τοξικό και κατά τον πολυμερισμό του δημιουργεί σφαιρικές δομές συγκεκριμένου μεγέθους (νανοσφαίρες). Με τη χρήση του συγκεκριμένου μονομερούς συνετέθησαν συμπολυμερή, τα οποία είναι ευαίσθητα στη θερμοκρασία, στο pH και στο όξειδο-αναγωγικό περιβάλλον ή σε συνδυασμό των παραγόντων αυτών. Οι πολυμερικές νανοσφαίρες-νανοπεριέκτες οι οποίες συνετέθησαν είναι κενές στο εσωτερικό τους, ή είναι της μορφής πυρήνας-κέλυφος, όπου το κέλυφος περιέχει τα μονομερή με τις επιθυμητές ευαισθησίες. Η κοιλότητα η οποία δημιουργείται στο εσωτερικό των νανοσφαιρών, σε ορισμένες περιπτώσεις, έχει ως σκοπό τον εγκλωβισμό φαρμακευτικών ουσιών. Τα φαρμακευτικά μόρια τα οποία χρησιμοποιούνται στην παρούσα διδακτορική διατριβή, είτε στο εσωτερικό των νανοσφαιρών είτε προσδεδεμένα στην επιφάνεια αυτών, είναι η Δοξορουβικίνη (Doxorubicin) και η Δαουνοροβικίνη (Daunorubicin). Η επαγωγή των μαγνητικών ιδιοτήτων στους νανοπεριέκτες πραγματοποιήθηκε με τη σύνθεση μαγνητικών νανοσωματιδίων (ΜΝΣ) τα οποία παρασκευάστηκαν πάνω στην επιφάνειά τους. Η χρήση ενός εναλλασσόμενου μαγνητικού πεδίου αυξάνει τοπικά τη θερμοκρασία με αποτέλεσμα, αφενός να διευκολύνεται η τοπική απελευθέρωση της εγκλωβισμένης φαρμακευτικής ουσίας και αφετέρου, εξαιτίας της υψηλής θερμοκρασίας που αναπτύσσεται τοπικά, να οδηγείται το καρκινικό κύτταρο σε απόπτωση (προγραμματισμένος κυτταρικός θάνατος). Για το χαρακτηρισμό των νανοπεριεκτών χρησιμοποιήθηκε μία πληθώρα τεχνικών. Για το μορφολογικό χαρακτηρισμό χρησιμοποιήθηκε η ηλεκτρονική μικροσκοπία σάρωσης και διέλευσης, Scanning Electron Microscopy (SEM) και Transmission Electron Microscopy (ΤΕΜ) αντίστοιχα, για το δομικό, η φασματοσκοπία υπερύθρου (FT-IR), η φασματοσκοπία Raman, η φασματοσκοπία πυρηνικού μαγνητικού συντονισμού (Nuclear Magnetic Resonance, NMR) και η τεχνική περίθλασης ακτίνων-Χ, ενώ για τη μελέτη των μαγνητικών ιδιοτήτων χρησιμοποιήθηκε η φασματοσκοπία δονούμενου δείγματος Vibrating Sample Magnetometry, VSM). Επίσης χρησιμοποιήθηκαν η τεχνική της δυναμικής σκέδασης φωτός (Dynamic Light Scattering, DLS) η οποία έδωσε πληροφορίες για τις ιδιότητες και τη συμπεριφορά των νανοπεριεκτών μέσα στο διάλυμα, καθώς επίσης και η φασματοσκοπία ορατού-υπεριώδους (Ultra Violet-Visible, UV-VIS), μέσω της οποίας έγινε μελέτη του εγκλωβισμού και της απελευθέρωσης των χρησιμοποιούμενων φαρμάκων από τις νανoσφαίρες. Τέλος, πραγματοποιήθηκαν μελέτες υπερθερμίας με τη βοήθεια ενός εξωτερικού εναλλασσόμενου μαγνητικού πεδίου.
The aim of this thesis is the synthesis, characterization and biological evaluation of modified multifunctional nanoparticles (MMNs) as drug delivery systems (DDS, with immediate effect in the treatment of breast and prostate cancer. The term nanoparticles (NPs) refer to the particles which are in the nanometer scale and range in size, from about 1nm to and 100 nm. The term multifunctional refers to the properties of these nanostructures and more particularly to the way that change their properties when external factors such as temperature, pH, redox environment and alternating magnetic field are applied. For the preparation of polymeric nanoparticles, different types of polymerizations were used such as, emulsion polymerization, seed polymerization, atom transfer radical polymerization, dispersion polymerization and polymerization through distillation-precipitation process. The different sensitivities were added via copolymerization of different monomers which exhibit the aforementioned properties. Some of the monomers used like, N-(-2-HydroxyPropyl) Methacrylamide (HPMA), which is sensitive to temperature changes and N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide) (Disulfide) which is sensitive to changes in the redox environment, were synthesized in the laboratory, while the rest, were commercially available. The primary monomer, used in the polymerizations, was Methyl Methacrylate (MMA) which is non-toxic and in through to its polymerization creates spherical structures of certain size (nanospheres). By using the specific monomer, copolymers, which are sensitive to temperature, pH and redox environment or a combination of these factors, were synthesized. The synthesized polymeric nanospheres-nanocontainers, are either hollow inside, or form core-shell structures, where the shell contains the monomers with the desired sensitivity. The cavity which is created inside the nanospheres, in some cases, is intended to entrap pharmaceutical substances. The drug molecules used in this thesis, either within or tethered to the surface of the nanospheres are, Doxorubicin (DOX) and Daunorubicin (DNR). The induction of the magnetic properties in nanocontainers was performed by the synthesis of magnetic nanoparticles (MNPs), prepared on their surface. The use of an alternating magnetic field increases the temperature locally resulting on one hand to facilitate local release of the entrapped drug, and on the other hand, because of the high temperatures developed locally, to lead the tumor cell to apoptosis (programmed cell death). For the characterization of nanoparticles a variety of techniques were used. For the morphological characterization, Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) were used while for the structural characterization, Fourier Transform Infrared Spectroscopy (FT-IR), Raman Spectroscopy, Nuclear Magnetic Resonance (NMR) and X-ray diffraction Spectroscopy were used. Magnetic properties were studied by Vibrating Sample Magnetometry (VSM). The Dynamic Light Scattering technique (DLS) was also used in order to get information about the properties and behavior of nanoparticles in solution and Ultra Violet-Visible Spectroscopy (UV-VIS), gave information about Loading and Release of the drugs used in nanocontainers. Hyperthermia measurements were carried out by using an external alternating magnetic field.

Tese no âmbito do doutoramento em Engenharia Química, apresentada ao Departamento de Engenharia Química da Faculdade de Ciências e Tecnologia da Universidade de Coimbra.
The main objective of the present thesis was the development and characterization of novel electroactive ionic liquid-based polycationic hydrogels. These materials were obtained by the functionalization of natural-origin and/or synthetic polymers with an ionic liquid-based vinyl monomer (functionalized at the cation) by two different approaches, namely by the formation of semi-interpenetrating polymer networks (s-IPNs) and by copolymerization with a non-charged comonomer. Through this doctoral work, three different multi-responsive systems were developed targeting a broad range of applications, such as, drug delivery devices, bioseparators, soft actuators, tissue engineering scaffolds, iontophoretic patches and wound dressings. The first approach was employed to obtain multi-responsive s-IPNs hybrid structures based on natural polymers (starch and chitosan) and homopolymers/copolymers of poly(1-butyl-3-vinylimidazolium chloride) (poly(BVImCl) and poly(2-hydroxyethyl methacrylate-co-1-butyl-3-vinylimidazolium chloride) (poly(HEMA-co-BVImCl)). In the case of the starch-based s-IPNs, results demonstrated that the sorption/release capacity of these hydrogels towards L-tryptophan (used as a model biomolecule) could be adjusted depending on the intensity of the applied DC voltage and/or sorption/release medium. It was also confirmed that the process employed to dry the hydrogels (oven and freeze-drying) has a major influence on the conductivity of the materials and that freeze-drying induced higher conductivity values. Furthermore, biological tests demonstrated that the prepared s-IPNs were able to guarantee fibroblasts viability. These newly obtained hybrid materials demonstrated to have potential to be employed for bio-separation processes and for the sustained delivery of specific charged-biomolecules. In the case of the chitosan-based s-IPNs it was demonstrated that the prepared hybrid hydrogels presented enhanced mechanical properties, water swelling capacities (at different pH and ionic strengths) and sorption capacities towards charged molecules when compared to pristine chitosan. Obtained s-IPN hydrogels also demonstrated to have modulated lidocaine hydrochloride permeation/delivery profiles at low current densities (0.56 mA/cm2) and as a function of their charge density. Moreover, biological tests showed that the prepared s-IPN hydrogels were non-hemolytic and presented potential hemostatic capability. These “smart” s-IPNs presented advantageous properties for the design of topical iontophoretic patches and/or hemostatic agents. The second approach was employed to obtain multi-responsive electro-actuating hydrogels based on poly(HEMA-co-BVImCl) copolymers. Studies were performed to evaluate the influence of surface properties on the actuating behavior of the hydrogels in different aqueous media, with different pH and ionic strength values. The different surface properties were obtained by simply employing different mold subtracts, with different hydrophobicities (namely Teflon® and glass) during the copolymer free radical polymerization in aqueous media. Obtained results demonstrated that hydrogels synthesized on Teflon® molds presented the highest electro-actuation capacity in aqueous media, with equivalent bending motion on both directions according to the polarization applied. Moreover, it was also noticed that hydrogels surface charge density and water swelling capacity could be modulated depending on the type of mold utilized during polymerization. Resulting soft stimuli-responsive materials can be regarded as “smart” platforms for the design of soft actuators and cell culture scaffolds for biomedical applications. Overall, this PhD thesis allows concluding that the functionalization of natural and/or synthetic polymers with ILs represents a viable and efficient strategy for the development of multi-responsive electroactive materials for applications in biomedicine, (bio)separation and electrochemistry.
O objetivo principal desta tese foi o desenvolvimento e caracterização de novos hidrogéis eletroativos policatiónicos à base de líquidos iónicos. Esses materiais foram obtidos pela funcionalização de polímeros de origem natural e/ou sintéticos com um monómero vinílico à base de líquidos iónico (funcionalizados no catião) por meio de duas diferentes abordagens, nomeadamente redes poliméricas semi-interpenetradas (s-IPNs) e copolimerização com um comonómero não carregado. Durante a realização do trabalho, foram desenvolvidos três sistemas multi-responsívos diferentes visando uma vasta gama de aplicações, por exemplo, dispositivos para a entrega de fármacos, bioseparadores, atuadores soft, scaffolds para engenharia de tecidos, pensos para iontoforese e para tratamento de feridas. A primeira abordagem consistiu na obtenção de s-IPNs híbridos multi-responsívos à base de polímeros naturais (amido e quitosano) e homopolímeros/copolímeros de poli(cloreto de 1-butil-3-vinilimidazólio) (poli(BVImCl) e poli(metacrilato de 2-hidroxietila-co-cloreto de 1-butil-3-vinilimidazólio) (poli(HEMA-co-BVImCl)). No caso dos hidrogéis s-IPNs à base de amido, os resultados demonstraram que a capacidade de sorção/entrega de L-triptofano, usado como biomolécula modelo, poderia ser otimizada consoante a diferença de potencial aplicada e/ou o tipo de meio utilizado na sorção/libertação. O processo de secagem utilizado nos hidrogéis (secagem em estufa e liofilização), provou ter uma influência significativa na condutividade dos materiais estudados, sendo que os foram sujeitos ao processo de liofilização apresentaram valores superiores de condutividade. Concomitantemente, a viabilidade de fibroblastos na presença dos s-IPNs foi comprovada com recurso a testes biológicos. Desta forma, os materiais híbridos e inovadores desenvolvidos nesta abordagem demonstraram potencial para serem utlizados em processos de biosseparação e para entrega contínua de biomoléculas carregadas específicas. No caso dos s-IPNs à base de quitosano, foi demonstrado que os hidrogéis híbridos desenvolvidos apresentaram melhores propriedades mecânicas, capacidades de entumecimento em água (em diferentes condições de pH e força iónica) e capacidades de sorção para moléculas carregadas, quando comparados com o quitosano puro. Os s-IPNs exibiram perfis modulares de permeação/entrega de lidocaína, a baixas intensidades de corrente (0.56 mA/cm2), em função da respetiva densidade de cargas. Além disso, após testes biológicos, os hidrogéis s-IPN provaram ser não-hemolíticos e hemostáticos. Estes s-IPNs “inteligentes” apresentaram propriedades vantajosas para a preparação de pensos tópicos para iontoforese e/ou pensos hemostáticos. A segunda abordagem estudada foi baseada na obtenção de copolímeros electroactuators híbridos multi-responsívos à base de hidrogéis de poli(HEMA-co-BVImCl). A influência das propriedades de superfícies no comportamento de atuação dos hidrogéis em diferentes meios aquosos (com diferentes valores de pH e força iónica), foi avaliada. Diferentes propriedades de superfície foram obtidas pela simples utilização de diferentes moldes com hidrofobicidade distintas, nomeadamente Teflon® e vidro, durante a copolimerização por polimerização radicalar livre, em meio aquoso. Os resultados demonstraram que os hidrogéis preparados em moldes de Teflon® apresentaram superior capacidade de eletroatuação em meio aquoso, com atuação mecânica equivalente em ambas direções, de acordo com a polaridade aplicada. Para além disso, foi também verificado que a densidade de carga na superfície dos hidrogéis e a capacidade de entumecimento em água pode ser modulada de acordo com o tipo de molde utilizado durante a polimerização. Os materiais responsivos a estímulos podem ser equiparados a plataformas “inteligentes” para a produção de atuadores soft e scaffolds para cultura celular em aplicações biomédicas. Em suma, a presente tese de doutoramento permitiu concluir que a funcionalização de polímeros naturais e/ou sintéticos, com ILs, representa uma estratégia viável e eficiente para o desenvolvimento de materiais eletroativos multi-responsívos para aplicações na biomedicina, biosseparação e eletroquímica.