Water molecules play a significant role in biological process and are directly involved with bio-molecules and organic compounds and ions. Recent research has focused on the thermal dynamics and kinetics of water molecules in solution, including experimental (infrared spectroscopy and Raman spectroscopy) and computational (Quantum Mechanics and Molecular Dynamics) approaches. The reason that water molecules are so unique, why they have such a profound influence on bio-activity, why water molecules show some anomalies compared to other small molecules, and where and how water molecules exert their influence on solutes are some of the areas under study. We studied some properties of hydrogen bond networks, and the relationship of these properties with solutes in water. Molecular dynamics simulation, followed by an analysis of “water bridges”, which represent protein-water interaction have been carried out on folded and unfolded proteins. Results suggest that the formation of transient water bridges within a certain distance helps to consolidate the protein, possibly in transition states, and may help further guide the correct folding of proteins from these transition states. This is supporting evidence that a hydrophilic interaction is the driving force of protein folding. Biological membranes are complex structures formed mostly by lipids and proteins. For this reason the lipid bilayer has received much attention, through computation and experimental studies in recent years. In this dissertation, we report results of a newly designed pH sensitive lipid MORC16, through all-atom and coarse-grained models. The results did not yield a MORC16 amphiphile which flips its conformation in response to protonation. This may be due to imperfect force field parameters for this lipid, an imperfect protonation definition, or formation of hydrogen bond does not responsible for conformation flip in our models. Despite this, some insights for future work were obtained.

Background: In the last decade, flow diversion (FD) has been established as hemodynamic treatment for cerebral aneurysms arising from proximal and distal cerebral arteries. However, two significant limitations remain—the need for 0.027” microcatheters required for delivery of most flow diverting stents (FDS), and long-term dual anti-platelet therapy (DAPT) in order to prevent FDS-associated thromboembolism, at the cost of increasing the risk for hemorrhage. This study reports the experience of three neurovascular centers with the p64MW-HPC, a FDS with anti-thrombotic coating that is implantable via a 0.021” microcatheter. Materials and methods: Three neurovascular centers contributed to this retrospective analysis of patients that had been treated with the p64MW-HPC between March 2020 and March 2021. Clinical data, aneurysm characteristics, and follow-up results, including procedural and post-procedural complications, were recorded. The hemodynamic effect was assessed using the O’Kelly–Marotta Scale (OKM). Results: Thirty-two patients (22 female, mean age 57.1 years) with 33 aneurysms (27 anterior circulation and six posterior circulation) were successfully treated with the p64MW-HPC. In 30/32 patients (93.75%), aneurysmal perfusion was significantly reduced immediately post implantation. Follow-up imaging was available for 23 aneurysms. Delayed aneurysm perfusion (OKM A3: 8.7%), reduction in aneurysm size (OKM B1-3: 26.1%), or sufficient separation from the parent vessel (OKM C1-3 and D1: 65.2%) was demonstrated at the last available follow-up after a mean of 5.9 months. In two cases, device thrombosis after early discontinuation of DAPT occurred. One delayed rupture caused a caroticocavernous fistula. The complications were treated sufficiently and all patients recovered without permanent significant morbidity. Conclusion: Treatment with the p64MW-HPC is safe and feasible and achieves good early aneurysm occlusion rates in the proximal intracranial circulation, which are comparable to those of well-established FDS. Sudden interruption of DAPT in the early post-interventional phase can cause in-stent thrombosis despite the HPC surface modification. Deliverability via the 0.021” microcatheter facilitates treatment in challenging vascular anatomies.

No description available.

No description available.

No description available.

Proton exchange membrane fuel cells (PEMFCs) have been extensively studied as clean, sustainable and efficient power sources for electric vehicles, and portable and residential power sources. As one of the key components in PEMFC system, proton exchange membranes (PEMs) act as the electrolyte that transfers protons from the anode to the cathode. The state-of-art commercial PEM materials are typically based on perfluorinated sulfonic acid containing ionomers (PFSAs), represented by DuPont's Nafion®. Despite their good chemical stability and proton conductivity at high relative humidity (RH) and low temperature, several major drawbacks have been observed on PFSAs, such as high cost, high fuel permeability, insufficient thermo-mechanical properties above 80°C, and low proton conductivity at low RH levels. Therefore the challenge lies in developing alternative PEMs which feature associated ionic domains at low hydration levels. Nanophase separated hydrophilic-hydrophobic block copolymer ionomers are believed to be desirable for this purpose Three series of hydrophobic/hydrophillic, partially fluorinated/sulfonated multiblock copolymers were synthesized and characterized in this thesis. The hydrophilic blocks were based upon the nucleophilic step polymerization of 3, 3′-disulfonated, 4, 4′-dichlorodiphenyl sulfone (SDCDPS) with an excess 4, 4′-biphenol (BP) to afford phenoxide endgroups. The partially fluorinated hydrophobic blocks were largely based on 4, 4′-hexafluoroisopropylidenediphenol (6F-BPA) and various difluoro monomers (excess). These copolymers were obtained through moderate temperature (~130-150°C) coupling reactions, which minimize the ether-ether interchanges between hydrophobic and hydrophilic telechelic oligomers via a nucleophilic aromatic substitution mechanism. The copolymers were obtained in high molecular weights and were solvent cast into tough membranes, which had nanophase separated hydrophilic and hydrophobic regions. The performance and structure-property relationships of these materials were studied and compared to random copolymer systems. NMR results supported that the multiblock sequence had been achieved. They displayed superior proton conductivity, due to ionic, proton conducting channels formed through the self-assembly of the sulfonated blocks. The nano-phase separated morphologies of the copolymer membranes were studied and confirmed by transmission electron microscopy (TEM) and small angle X-ray scattering (SAXS). Through control of a variety of parameters, including ion exchange capacity and sequence lengths, performances as high, or even higher than those of the state-of-the-art PEM, Nafion®, were achieved. Another series of semi-crystalline hydrophobic poly(ether ether ketone)-hydrophilic sulfonated poly(arylene ether sulfone) (PEEK-BPSH100) multiblock copolymers was first synthesized and characterized. However due to their semi-crystalline structure, PEEK blocks are insoluble in most organic solvents at relatively low reaction temperatures, which prevents the coupling reaction between PEEK and BPS100. In order to facilitate the synthesis and processing, removable bulky ketimine was introduced to synthesize amorphous pre-oligomers poly(ether ether ketimine) (PEEKt). The synthetic procedure first involves the synthesis of hydrophobic poly(ether ether ketimine)-hydrophilic sulfonated poly(arylene ether sulfone) (PEEKt-BPS100) multiblock pre-copolymers via coupling reactions between phenoxide terminated hydrophilic BPS100 and fluorine terminated hydrophobic PEEKt blocks. The membranes cast from PEEKt-BPS100 were boiled in 0.5M sulfuric acid water solution to hydrolyze the amorphous PEEKt blocks to semi-crystalline PEEK blocks and acidify BPS100 blocks to BPSH100 blocks simultaneously. FT-IR spectra clearly showed the successful hydrolysis and acidification. The proton conductivity, water uptake and other membrane properties of the acidified semi-crystalline PEEK-BPSH100 membranes were then evaluated and compared with those of the state-of-the-art PEM, Nafion®. / Ph. D.

Dans ce travail, nous avons cherché à mettre en évidence l'influence de la méthode de préparation de films minces de polymère pour la biofonctionnalisation de surfaces planes. Dans un premier temps, un polymère réactif, le poly(méthacrylate de glycidyle) p(GMA) a été choisi et sa capacité de fixation vis-à-vis d'une biomolécule modèle l'albumine de sérum bovin a été étudiée. Deux stratégies principales de préparation du film polymère ont été utilisées : la technique du grafting onto et celle du grafting from avec deux voies de synthèse : la polymérisation radicalaire classique (PRC) avec l'amorceur en solution et la polymérisation initiée à partir de la surface avec un amorceur photochimique. Il a été montré que la méthode du « grafting from » permettait l'obtention de films d'épaisseur plus élevées que la technique du « grafting onto » avec une meilleure capacité de fixation de biomolécules de BSA. Ces films de p(GMA) se sont révélés relativement hydrophobes, ce qui nous incités à analyser l'influence de la balance hydrophobe/hydrophile des interfaces sur leurs propriétés, dans un second temps. Par la préparation de films copolymères poly(GMA-co-acrylamide) et poly(GMA-co-méthacrylate de glycérol) et la modification des films de poly(GMA) par de l'éthanolamine, l'influence de l'hydrophilie du film sur la capacité de fixation en molécules de BSA et l'activité de reconnaissance moléculaire de celles-ci ont été évaluées. Il a été démontré que par un choix judicieux de la méthode d'hydrophilisation du film polymère, il est possible de réduire considérablement l'adsorption non-spécifique de biomolécules d'où l'obtention de films polymères bioinertes. De plus, les résultats préliminaires ont montré qu'il est possible d'améliorer sensiblement la capacité de reconnaissance moléculaire entre la BSA et son anticorps l'anti-BSA / It is now well accepted that polymeric spacers permit to attach proteins to surfaces efficiently as they carry several binding sites. Moreover, direct attachment of proteins to surfaces might result in the decrease of bioactivity which is critical in the case of the development of biosensors. In this context, we modified gold substrates by polymer grafts via the so-called (i) grafting onto and (ii) grafting from strategies. In (i) preformed polymer chains were attached to the surface, whilst in (ii) surface-confined photopolymerization was performed on either acrylic monomer- or initiator-functionalized gold substrates. The polymer grafts were further biofunctionalized by covalent immobilization of an active protein (bovine serum albumin, BSA). Given the protein-polymer and polymer-gold covalent bonds, the gold/polymer/BSA hybrids permitted to design robust optical biosensors. The modified gold substrates were characterized in terms of chemical composition (X-ray photoelectron spectroscopy), hydrophobicity (contact angle measurements), and polymer coating thickness (surface plasmon resonance, SPR). SPR was also used to monitor in real time the interaction between the grafted antigen to the specific antibody (aBSA). Using unique reactive monomer, glycidyl methacrylate (GMA) in the present case, the implementation of these three methods is assumed to provide polymer films of similar chemical composition but varied interfacial chains conformation. In this respect, influence of polymer chains mobility on the performance of the immunosensing reaction was evaluated. In a further step, hydrophobic/hydrophilic balance of the polymer films was modulated through copolymerization of GMA with acrylamide, and with glycerol methacrylate. It was demonstrated that control over the surface chemical composition of the polymer grafts allows preparing bioinert films, i.e. resistant to non specific adsorption, with enhanced biospecific activity

L'objectif de ce travail a été l'utilisation d'une méthodologie de formulation des formes à libération prolongée. Le choix de «matrices hydrophiles» a été fait en raison de l'intérêt et de l'importance des travaux qui lui sont consacrés, mais surtout en raison de la possibilité d'utilisation de la technologie simple de fabrication des comprimés par compression directe.Le principe actif choisi est le diclofenac de sodium, un anti-inflammatoire largement utilisé dont la molécule est tombée dans le domaine public. Utilisé  à raison de 100 mg par comprimé. La première partie bibliographique résume l'intérêt des formes à libération prolongée, décrit les différentes formes galéniques existantes pour la voie orale et fait le point sur les formules et les propriétés des agents matriciels hydrophiles parmi les plus utilisés, notamment les éthers de celluloses, hydroxypropymethylcellulose (METOLOSES®) (1). Dans la partie expérimentale, nous avons réalisé les différentes étapes nécessaires au développement d'une forme à libération prolongée qui correspondant aux étapes classiques  de pré-formulation, formulation et optimisation. Dans une première étape d'essais préliminaires  nous avons étudiés le comportement d'un point de vue pharmacotechnique des matières premières utilisés seuls et en mélange. Ce qui a permis de faire des orientations en ce qui concerne les différents types de METOLOSES, la nature du diluant, et leurs concentrations. Dans une deuxième étape, nous avons réalisé un premier plan d'expériences de criblage des facteurs, qui permet de déterminer le poids de chacun et leurs éventuelles interactions. Ce qui nous a permis de conclure sur l'effet des différents facteurs en formulation. Dans une troisième étape, nous avons réalisé un deuxième plan d'expériences d'optimisation de la formulation  en utilisant un plan composite centré constitué de 9 expériences ce qui a permis de sélectionner une zone de formules optimales. Enfin, la réalisation d'une formule optimale nous a permis de confirmer les résultats obtenus dans les travaux de développement et dont l'objectif été une libération sur 12 heures. / The objective of this work was the use of a formulation methodology of prolonged release dosage forms. The choice of “hydrophilic matrices” was done because of the interest and the numbered works which is devoted to it, but also for the use of a simple manufacture technology by direct compression. The selected active pharmaceutical ingredient is one of the most largely used nonsteroidial anti-inflammatory drug, the sodium diclofenac which is out of patent and used at 100 Mg per tablet. The first bibliographical part summarizes the interest of the prolonged release dosage forms, described the existing oral dosage forms and gives a progress report on the formulas and the properties of hydrophilic matrices agents among most used, in particular the cellulose ethers, hydroxypropymethylcellulose (METOLOSES®) (1). In the experimental part, we carried out the various steps necessary to the development of a prolonged release dosage form which correspond to the traditional steps of pre-formulation, formulation and optimization. In a first step of pharmaceutics preliminary tests we studied the behavior of raw materials used alone and in mixture. What made orientations with regard to the various types of METOLOSES, the nature of diluents, and their concentrations. In a second step, we carried out a first screening factors experimental design, which enabled us to conclude on the effect of the various factors in formulation. In a third step, we carried out a second optimization experimental design using a centered composite plan consisted of 9 experiments which lead us to define a space design of optimal formulas. Lastly, the manufacture of a formula from the design space enabled us to confirm the results to development work and for which the objective was a sustained release over 12 hours.

Les micelles complexes de polyions, ou « micelles PIC », formées par interaction électrostatique entre un copolymère à blocs double hydrophile neutre-ionique (DHBC) et un homopolyélectrolyte de charge opposée au DHBC possèdent des propriétés particulièrement intéressantes : solubilité des polyélectrolytes dans l'eau, stabilité des micelles, contrôle de l'association/dissociation micellaire par divers stimuli (pH, force ionique, irradiation lumineuse…). Dans cette thèse, les propriétés physico-chimiques des micelles PIC de type DHBC neutre-cationique/homopolymère anionique et DHBC neutre-anionique/homopolyélectrolyte cationique ont été étudiées en solution aqueuse en vue de leur utilisation comme agent structurant des matériaux siliciques organisés à l'échelle nanométrique. La gamme de pH de formation des micelles PIC, la concentration micellaire critique et le nombre d'agrégation des micelles ont été déterminés pour chacun des systèmes étudiés. Nous avons montré que la formation des micelles suit un mécanisme coopératif qui dépend de la taille de l'homopolymère. Par ailleurs, nous avons proposé une voie originale de formation des micelles PIC photoinduite, basée sur une modification du pH suite à l'irradiation d'une molécule photochrome. Les études concernant l'utilisation des micelles PIC comme agent structurant des matériaux nous ont permis de montrer que la morphologie (nanoparticulaire, massif) et la structure des matériaux (lamellaire, vermiculaire) peuvent être contrôlés par divers paramètres, tels que la concentration en masse du système DHBC/homopolyélectrolyte/précurseur de silice, la teneur en précurseur de silice et le rapport entre les fonctions cationique et anionique des polyélectrolytes. Le lavage des matériaux sous des conditions douces (à l'eau) permet de récupérer l'agent structurant. / Polyion complex micelles, or "PIC micelles", formed by electrostatic interaction between a neutral-ionic double hydrophilic block copolymer (DHBC) and an oppositely charged homopolyelectrolyte possess interesting properties: solubility of the polyelectrolytes in water, stability of micelles, control of the micellar association / dissociation by various stimuli (pH, ionic strength, light irradiation ...). In this thesis, the physico-chemical properties of PIC micelles of neutral-cationic DHBC/ anionic homopolymer and neutral-anionic DHBC/cationic homopolymer were studied in aqueous solution for use as structuring agents of silica-based organized nanomaterials. The pH range of PIC micelle formation, the critical micelle concentration and aggregation number of micelles were determined for each studied system. We have shown that the formation of micelles follows a cooperative mechanism which depends on the size of the homopolymer. Furthermore, we proposed an original way of photoinduced PIC micelle formation, based on a pH change after irradiation of a photochromic molecule. The studies on the PIC micelles as structuring agents of materials have shown that the morphology (nanoparticular, bulk) and the material structure (lamellar, vermicular) can be controlled by various parameters, such as the mass concentration of the DHBC / homopolyelectrolyte / silica precursor system, the content of the silica precursor and the ratio between the functions of the cationic and anionic polyelectrolytes. Finally, the template was removed by washing the hybrid materials under soft conditions in water.

This thesis deals with (i) complex nanoaggregates of cationic perfluorinated surfactant N-(1,1,2,2- tetrahydroperfluorodecyl)pyridinium chloride and of double hydrophilic block polyanions poly(ethylene oxide)-b-poly(methacrylate) and poly(ethylene oxide)-b-poly((2-sulfamate-3- carboxylate)isoprene), and with (ii) mixed micelles of amphiphilic copolymer poly(ethylene oxide)- b-poly(e-caprolactone) and nonionic perfluorinated fluorosurfactant Zonyl FSN-100. The study was aimed at the characterization of the association behavior of the block copolymer-fluorosurfactant systems in aqueous solutions depending on the amount of the added surfactant, pH of the solvent and the structure of the copolymers.