Dans ce travail, nous avons étudié la relation entre la viscosité et la dynamique microscopique (caractérisée par le temps de relaxation structurale) d'une suspension colloïdale en fonction de la fraction volumique. Nous avons mis au point une expérience originale nous permettant de mesurer la viscosité et le temps de relaxation simultanément sur le même échantillon. La dynamique microscopique est mesurée à l'aide de techniques conventionnelles de diffusion dynamique de la lumière "multi-speckles" ; la viscosité est quant à elle obtenue en mesurant la vitesse de sédimentation de particules-sondes micrométriques. Ces mesures nous ont permis d'étendre d'au moins deux décades la gamme de viscosités à taux de cisaillement nul préalablement explorée. Nous montrons que la viscosité et le temps de relaxation structurale mesuré au pic du facteur de structure statique, sont couplés jusqu'à des fractions volumiques situées bien au-delà de la transition vers un régime surfondu. Par ailleurs, nous avons constaté que le fort accroissement du temps de relaxation à l'approche de la transition vitreuse était bien décrit par une divergence exponentielle, plutôt que par une loi de puissance critique prévue par la Théorie de Couplage des Modes (MCT). / In this work, we have investigated the relation between the viscosity and the microscopic dynamics (structural relaxation time) of colloidal suspensions, as a function of volume fraction. We have designed and implemented an original setup which allows us to measure the viscosity and the relaxation time simultaneously on the very same sample. The dynamics are measured by conventional multispeckle dynamic light scattering, while the viscosity is obtained by measuring the sedimentation velocity of micron-sized tracer particles. Our measurements extend the range of previous measurements of the zero-shear viscosity by two decades. We find that the viscosity and the relaxation time measured at the peak of the static structure factor are coupled up to deep in the supercooled regime, thereby extending previous observations that were limited to the onset of supercooling. Furthermore, we show that the steep growth of the relaxation time on approaching the glass transition is well described by an exponential divergence, rather than by a critical power law as predicted by Mode Coupling Theory (MCT).

Monodispersed nanoparticles of poly-N-isopropylacrylamide-co-allylamine (PNIPAM-co-allylamine) and PNIPAM-co-acrylic acid (AA) have been synthesized and used as building blocks for creating three-dimensional networks. The close-packed PNIPAM-co-allylamine and PNIPAM-co-AA nanoparticles were stabilized by covalently bonding neighboring particles at room temperature and at neutral pH; factors which make these networks amicable for drug loading and release. Controlled release studies have been performed on the networks using dextran markers of various molecular weights as model macromolecular drugs. Drug release was quantified under various physical conditions including a range of temperature and molecular weight. These nanoparticle networks have several advantages over the conventional bulk gels for controlling the release of biomolecules with large molecular weights. Monodispersed nanoparticles of poly-N-isopropylacrylamide-co-allylamine (PNIPAM-co-allylamine) can self-assemble into crystals with a lattice spacing on the order of the wavelength of visible light. By initiating the crystallization process near the colloidal crystal melting temperature, while subsequently bonding the PNIPAM-co-allylamine particles below the glass transition temperature, a nanostructured hydrogel has been created. The crystalline hydrogels exhibit iridescent patterns that are tunable by the change of temperature, pH value or even protein concentration. This kind of soft and wet hydrogel with periodic structures may lead to new sensors, devices, and displays operating in aqueous solutions, where most biological and biomedical systems reside. The volume-transition equilibrium and the interaction potential between neutral PINPAM particles dispersed in pure water were investigated by using static and dynamic light-scattering experiments. From the temperature-dependent size and energy parameters, the Sutherland-like potential provides a reasonable representation of the inter-particle potential for PNIPAM particles in swollen and in collapsed phases. An aqueous dispersion of PNIPAM particles can freeze at both high and low temperatures. At low temperatures, the freezing occurs at a large particle volume fraction, similar to that in a hard-sphere system; while at high temperature, the freezing occurs at low particle concentrations, driven by the strong van der Waals attraction due to the collapsed microgel particles. The calculated phase diagram has been confirmed semi-quantitatively by experiments.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Doxorubicin (DOX) and Pluronic-PAA interaction was investigated using isothermal titration calorimetry (ITC). DOX/polymer interaction is governed primarily by electrostatic interaction. The uptake of DOX results in the formation of insoluble polymer/DOX complex. Addition of salt weakens the interaction of drug and polymer by charge shielding effect between positive ionized amino group on DOX and oppositely charged polymer chains. However high drug-loading capacity in high salt condition implied that self-association property of DOX also play a role in the drug loading process. / Singapore-MIT Alliance (SMA)

This dissertation focuses on utilization of poly(N-isopropylacylamide) (pNIPAm) based mirogels for regulated macromolecule drug delivery applications. There is particular emphasis on incorporation of stimuli responsive materials into multi-layer thin film constructs with the main goal being fabrication of highly functional materials with tunable release characteristics. Chapter 1 gives a broad overview of hydrogel and microgel materials focusing on fundamental properties of pNIPAm derived materials. Chapter 2 illustrates the progression of controlled macromolecule release from hydrogel and microgel materials and sets up the scope of this thesis work. Chapter 3 details studies on thermally modulated insulin release from microgel thin films where extended pulsatile release capabilities are shown. Chapters 4 and 5 focus on more fundamental synthesis and characterization studies of PEG and acrylic acid modified pNIPAm microgels that could ultimately lead to the design of protein loaded microgel films with tunable release characteristics. Chapter 6 illustrates fundamental macromolecule loading strategies, which could also prove useful in future protein drug delivery design using stimuli responsive networks. Chapter 7 concentrates on direct insulin release studies that probe the interaction between entrapped and freely diffusing protein and microgels. These model experiments could prove useful in design of tunable macromolecule drug release from functionally modified microgels and could aid in the tailored design of peptide-loaded microgel thin films. Chapter 8 discusses the future outlook of controlled macromolecule release from microgel based materials.

Hydrogel materials have become a heavily studied as materials for interfacing with biology both for laboratory investigations and the development of devices for biomedical applications. These polymers are water swellable and can be made responsive to many different stimuli by choice of monomers, co-monomers, and cross-linkers or functionalization with pendent ligands, substrates, or charged groups. The high water content, low moduli and potential responsively of these polymers make good candidates for biomaterials. A specific type of hydrogel called a microgel or a hydrogel micro/nanoparticle has similar properties to bulk hydrogel materials. Many of the interesting results and utility of the microgels in bioapplications are due to their inherent softness of the material. Here, the softness, flexibility, and conformability of these water swollen particles is used to create an interesting sensor platform, studied in the context of a microgel passing through a pore, and used as an emulsifier to create a drug delivery platform. The unifying theme of this dissertation is the softness of microgels which is critical for all of these experiments. However, the study of individual microgel softness is challenging and complex, since the softness is composed of two different components. The first is that the microgel is a swollen polymer which can be deswollen by an external stimuli or force. The second is that the microgel is a volume conserving elastic colloid which can deform without deswelling under the certain conditions. Throughout, this dissertation will discuss the ramifications of the complex softness of microgels in each experimental result and potential application.

Microgels are lightly cross-linked hydrogel particles in the sub-micrometer to micrometer size range with a capacity to drastically change their volume in response to changes in the external environment. Microgels have an ability to bind and store substances such as biomacromolecular drugs, notably proteins and peptides, and release them upon stimuli, making them potential candidates as drug delivery vehicles and functional biomaterials. This thesis aims at clarifying important factors affecting peptide-microgel interactions. These interactions were studied by micromanipulator-assisted light and fluorescence microscopy focusing on microgel deswelling in response to peptide binding, as well as re-swelling in response to peptide release or enzymatic degradation. To evaluate peptide uptake in microgels, solution depletion measurements were used whereas the peptide secondary structure was investigated by circular dichroism. In addition, the peptide and enzyme distribution within microgels was analyzed with confocal microscopy. Results presented in this thesis demonstrate that peptide incorporation into microgels, as well as peptide-induced microgel deswelling, increases with peptide length and charge density. In addition, results demonstrate that the peptide charge (length) rather than peptide charge density determines microgels deswelling. End-to-end cyclization is shown to not noticeably influence peptide-microgel interactions, suggesting that peptide cyclization can be used in combination with oppositely charged microgel carriers to improve the proteolytic and chemical stability of the peptide compared to the corresponding linear variant. Peptide secondary structure is found to drastically affect peptide incorporation into, and release from, oppositely charged microgels. Furthermore, it is shown that microgel charge density, peptide molecular weight, and enzyme concentration all greatly influence microgel bound peptide degradation. Of importance for applications, protective effects of microgels against proteolytic peptide degradation are observed only at sufficiently high microgel charge densities. Enzyme-mediated microgel degradation is shown to increase with increasing enzyme concentration, while an increased peptide loading in microgels causes a concentration-dependent decrease in microgel degradation. Taken together, results obtained in this work have provided some insight into factors of importance for rational use of microgels as delivery systems for protein or peptide drugs, but also in a host of other biomedical applications using weakly cross-linked polymer systems.

This thesis presents a study of the preparation and characterisation of microgels (MGs) and microgel-based systems which contain a high proportion of primaryamine groups. This is carried out with the aim of being used as the precursor materials for the development of an enzyme responsive system. The particle preparations discussed in this thesis begin with a particle dispersion prepared by a polymer-polymer interaction between partially oxidised dextran (Dexox) and poly(allylamine)(PA) or poly(vinylamine) (PVAM). The particle dispersions did show good tunability of properties by altering certain variables, such as extent of oxidation which resulted in the largest  -potential change with pH. However, these particles were not viable for further work as the largest swelling ratio by volume, Q value measured was only around 1.25, not sufficient for a pH responsive property swelling change (e.g. fluid-to-gel transition or drug delivery). MG particles were prepared using a non-aqueous dispersion polymerisation of Nvinylformamide (NVF), glycidylmethacrylate (GMA) and a crosslinker, 2-(Nvinylformamido)ethyl ether (NVEE). The PNVFx-GMAy-NVEEz particles were then hydrolysed to expose the primary amine groups in the resulting PVAMx-GMAy-BEVAMEz core-shell MGs. The shell, made up of GMA and NVF prevented hydrolysis taking place on the inside of the MGs, resulting in a PVAM rich shell. These hydrolysed MGs were cationic at low pH and were shown to have polyampholyte behaviour, caused by hydrolysis of some of the GMA groups. The inclusion of the NVEE crosslinker led to increased integration of the GMA and NVF into one homogenous phase in the shell and prevented hydrolytic fragmentation. The final system studied here concerns the macroscopic gel formation between the amine-rich MGs, poly(vinylamine-co-bis(ethyl vinylamine)ether) (PVAMBEVAME)and Dexox. These mixed dispersion gels were prepared and characterised. The MGs were externally crosslinked with the Dexox in order to form an elastically effective network. This was done by forming imine bonds by reaction between the primary amine groups present on the MGs and the aldehyde groups of the Dexox. These networks displayed high storage modulus (G’) and yield strains(*) of up to 140% and the G’ values for the MG-Dexox gels increased with mass ratio (MR) of Dexox to MG. The yield strains determined from rheology remained high (~125%) with increased MR. As the imine bonds formed were not reduced, they became unstable at low pH. This was exploited in order to investigate pH-triggered gel disruption of the network. This work demonstrates that new MG/aldehyde mixtures form ductile and versatile colloidal gels and our new method provides a route to increasing ductility of hydrogels containing MG particles. This research has led to the formation of amine rich MGs, as well as an injectable gel system. These materials are well placed to be developed for enzyme responsive materials in the future.

This dissertation studies the thermodynamic and structural properties of aqueous dispersions of ionic microgels ? soft colloidal particles composed of cross-linked polymer gels that swell in a good solvent. Starting from a coarse-grained model of microgel particles, we perform computer simulations and theoretical calculations using two complementary implementations of Poisson- Boltzmann (PB) theory. Within the framework of a cell model, the nonlinear PB equation is exactly solved and used to compute counterion distributions and osmotic pressures. By varying the free energy with respect to microgel size, we obtain exact statistical mechanical relations for the electrostatic component of the single-particle osmotic pressure. Explicit results are presented for equilibrium swelling ratios of charged microcapsules and of charged cylindrical and spherical microgels with fixed charge uniformly distributed over the surface or volume of the particle. Molecular dynamics simulations validate the theoretical findings. In the second method, within a one-component model framework, based on a linear-response approximation for effective electro- static interactions, we develop Monte Carlo (MC) simulations to compute the equilibrium swelling ratio, bulk osmotic pressure, radial distribution function, and static structure factor. Results presented in this dissertation demonstrate that swelling of ionic microgels increases with increasing microgel charge and decreases with increasing concentration of salt and microgels. In addition, results demonstrate that the microion distributions and osmotic pressure determine equilibrium swelling of microgels. Cell model predictions for bulk osmotic pressure agree well with data from MC simulations of the one-component model. The MC simulations also provide access to structural properties and to swelling behavior of microgels in highly concentrated suspensions. Taken together, results obtained in this work provide insight into factors of importance for practical use of microgels as drug delivery systems, in tissue engineering, and for other biomedical applications.

<p>Membrane filtration is widely used to biomedical and analytical applications. Compared to other techniques available membrane filtration provides fast processing time, easy availability, robust performance and relatively low cost. These advantages make ultrafiltration and microfiltration well integrated into bioseparation, purification of biomedical materials and downstream polishing. Apart from the advatanges, there are certain drawbacks with microfiltration and ultrafiltration. While perceived negative in many scenarios, the effects does not necessarily counteract the purpose of the process and could find some useful applications if treated from a different perspective.</p> <p>By the virtue of fast processing of membrane filtrations, applications were made in processing biomedical materials and developing analytical methods. Poly(<em>N</em>-isopropylacrylamide) microgels are of potential in many biomedical applications. Microfiltration and ultrafiltration of such microgels for fast purification were explored. Meanwhile, the environmental responsive behaviours of such microgels bring about opportunity and challenge. Investigations were made on the salt-responsive transmission behaviours of microgels in microfiltrations. A hypothesis was raised and verified. Implications of applications <em>in vivo</em> were drawn based on experimental results. Many techniques for analysis of protein-drug binding have been under development. A new alternative utilizing pulsed tangential flow ultrafiltration was developed in this study and used to obtain binding data between aspirin and BSA under different conditions. The performance of the systems was assessed under different parameter settings. Possibility of further automation was discussed. On account of the fouling and concentration polarization, a new perspective was taken with the effort of developing such effects into potential applications. Patterned fouling was introduced and the fouled membrane was used to filter coloured feed to reveal the patterns transferred. Concentration polarization in ultrafiltrations with different levels of fixation of membranes was visualized by dyed particles. The possible flow modes under these conditions were suggested. A hypothesis was attempted from a fluidics point of view.</p> / Master of Applied Science (MASc)