Die vorliegende Dissertation beschäftigt sich mit nichtlinearen Reaktions-Transport-Systemen, die in zweidimensionalen Medien chemische Wellen und propagierende Fronten ausbilden können. Grundlage dieser Art von räumlichen Mustern sind sogenannte erregbare Systeme. Ein Themengebiet der Arbeit umfasst die Untersuchung von Spiralwellen in der Belousov-Zhabotinsky-Reaktion (BZ-Reaktion). Ein weiterer Teilabschnitt behandelt die Wechselwirkung zwischen Polymersystemen und nichtlinearen chemischen Reaktionen. In den untersuchten, räumlich ausgedehnten Systemen spielt die Kopplung nichtlinearer chemischer Reaktionen an Transportprozesse eine wichtige Rolle. Die generischen Typen von chemischen Mustern sind Pulswellen in einer Raumdimension, kreisförmige Wellen und Spiralen in einem zweidimensionalen System und kugelschalen- bzw. schraubenförmige Wellen in drei Raumdimensionen. Auf theoretischer Basis werden Effekte von Spiralwellen bei Änderung der Erregbarkeit des Reaktionsmediums dargestellt.In der vorliegenden Arbeit ist es erstmals gelungen, eine Methode zu entwickeln, die es erlaubt die Erregbarkeit in der BZ-Reaktion sowie in einer Vielzahl weiterer nichtlinearer Reaktionen zu beeinflussen. Ein weiteres Themengebiet dieser Dissertation ist die Untersuchung von pH-Systeme in Hydrogelen. Dies sind hydrophile Gele, die ihr Volumen in wässrigen Lösungen verändern können. In der vorliegenden Arbeit wurden Gele auf der Basis von Acrylamid und Methacrylat als Copolymer verwendet und an die oben beschriebenen pH-Oszillatoren angekoppelt. Durch Polymerisation von Acrylamid zusammen mit Natriummethacrylat konnte ein mit einem pH-Oszillator beladenes Gel hergestellt werden, das nach Start der Reaktion durch eine kleine Menge Säure mit einer deutlichen Volumenkontraktion reagiert. Diese Kontraktion des Gels konnte ausgenutzt werden, um die chemische Energie eines pH-Reaktionssystems in eine mechanische Kraftwirkung umzuwandeln. / In this thesis nonlinear reaction-transport-systems are presented, which have the ability to form chemical waves and propagating fronts in two-dimensional media. The theoretical basis for an understanding of these kinds of patterns is the theory of excitability in reaction-diffusion-systems. This work is made up of two main sections: One part comprises the investigation of spiral waves in the Belousov-Zhabotinsky reaction (BZ reaction). The other section describes the interaction between polymer networks and nonlinear chemical reactions. Effects of changing excitability in the reaction medium on spiral waves are explained theoretically. In the present thesis for the first time a method was establised, which allows to deliberately control the excitability of the BZ reaction. Another part of the thesis describes nonlinear pH systems in hydrogels. In these autocatalytic reactions a periodic change of the pH can be observed. The pH systems have been coupled to hydrogels. These polymers are hydrophilic and are able to change their volume in aqueous solution. All of the investigated systems generate propagating acidity fronts after locally acidifying the gel with a small amount sulfuric acid. By polymerizing acrylamide together with sodium methacrylate a gel (loaded with a pH oscillator) was produced, that showed a contraction in volume after starting the reaction with a small amount of acid. This contraction was used to convert the chemical energy of a pH reaction system into a mechanical force effect: A small weight fixed to a strip of gel was lifted a few millimeters after starting the reaction inside the gel with acid.

This thesis describes the impact of contact lens-related microbial keratitis in terms of incidence and severity. Disease outcome is defined by visual outcome, costs to the healthcare system, costs to the individual and duration of disease. A successful 12-month surveillance study was conducted of the populations of Australia and New Zealand to detect all cases of contact lens-related microbial keratitis. A random telephone survey of 32,000 households in Australia and 7,500 in New Zealand accurately determined the level of use of various contact lenses in the community. The impact of new contact lens types: silicone hydrogels and daily disposables were investigated. Increased risk persisted in overnight wear with silicone hydrogel materials. Microbial keratitis associated with silicone hydrogel materials had slightly shorter disease duration however other factors had a stronger influence on severity. Rigid gas permeable and frequent replacement soft lenses when used for daily wear constitute the lowest risk. Cost analysis was developed in a hospital case series of microbial keratitis. This analysis was applied in the surveillance study including cases managed in the private health care sector. Disease duration and associated costs are novel indices of severity for contact lens-related disease. The most dramatic effects on disease severity were seen with the type of organism involved. Keratitis attributed to environmental organisms (Gram-negative bacteria, Acanthamoeba, fungi and Nocardia species) were 10x more likely to cause loss of visual acuity, had longer duration of symptoms and incurred higher costs. Importantly, delays in receiving treatment increased disease duration and associated costs. Greater awareness of the need for specialist healthcare is indicated amongst health care providers and contact lens wearers. The hypothesis that overnight wear in silicone hydrogel lenses would not increase the risk of infection has been disproven. This information is of value to practitioners who are responsible for informing contact lens wearers about the risk of contact lens-related infections and should be weighed against the benefits of continuous wear. The identification of factors which contribute to the outcomes of disease will be used in education campaigns amongst health care providers and contact lens wearers to minimise the impact of disease.

Nous avons étudié la dynamique de fracture d'hydrogels thermoréversibles de biopolymères : les gels de gélatine. Nous avons montré, par des expériences de fracture en mode 1, quasi-stationnaire et dans un régime subsonique, que, contrairement à la fracture des gels chimiques et des élastomères, la propagation de la fracture dans les gels de gélatine n'implique pas la scission des chaînes : elles sont extraites entièrement à travers le réseau en tête de fracture, la dissipation provenant simplement de leurs frottements dans le solvant. Nous avons pu produire un modèle simple de type <> qui permet de rendre compte des ordres de grandeur mesurés ainsi que de prédire des lois d'échelle vérifiées expérimentalement.<br /><br />En parallèle, nous avons étudié le faciès des surfaces créées par la propagation de la fracture. Nous avons montré qu'il n'existe pas de lois d'échelle comme celles observées dans d'autres matériaux ductiles ou fragiles mais que la micro-rugosité présente une hauteur RMS croissante avec la vitesse de fracture, observation jamais rapportée auparavant. Nous avons mis en évidence une vitesse critique en-dessous de laquelle des défauts macroscopiques apparaissent, défauts précédemment observés par Gent et al. dans les élastomères et décrit exhaustivement par Sekimoto et al. dans les gels de polyacrylamide. Nous avons pu expliquer la hauteur caractéristique de ces défauts en prenant en compte que ces matériaux très déformables présentent le phénomène d'émoussage de la fracture (<>). Nous observons par ailleurs que ces défauts et la micro-rugosité présentent une anisotropie selon un angle <> indépendant de la vitesse de fracture et des caractéristiques du gel de gélatine.

Le comportement d'hydrogels polyélectrolytiques gonflés de solutions de polymère linéaires soumis à une contrainte mécanique (cisaillement, compression) est étudié avec des outils rhéo-optiques afin d'obtenir une meilleure compréhension du comportement de gel et d'ouvrir la voie vers des applications dans des formulations cosmétiques. L'étude en cisaillement a été effectuée avec des particules de gel isolées suspendues dans une matrice d'huile silicone. Différents régimes ont été identifiés: a faible contrainte, la particule se déforme, mais moins qu'une goutte de son solvant. Au-delà d'un premier seuil de contrainte, nous observons le relargage de bouts de solvant dans la direction de l'écoulement. Ces bouts restent attachés à la particule. Le solvant est libéré et dispersé dans la matrice au-delà d'une deuxième contrainte seuil. Relargage et éjection ont également été observés dans la direction de la vorticité. Des volumes importants de solvant peuvent être libérés. Les effets de la taille de la particule, du degré de gonflement, de la concentration de la solution de polymère et de la tension interfaciale ont été étudiés. L'étude en compression a été réalisée avec des disques de gels gonflés à l'équilibre d'eau ou d'une solution de polymère et entourés d'air. Le gel se déforme et relargue partiellement son solvant dès qu'il est soumis à une contrainte. L'analyse thermodynamique d'un tel système prédit que ce relargage est plus important pour des gels chargés que pour des gels neutres.

Type 1 diabetes affects one in every 400-600 children and adolescents in the US. Standard therapy with exogenous insulin is burdensome, associated with a significant risk of dangerous hypoglycemia, and only partially efficacious in preventing the long term complications of diabetes. Pancreatic islet transplantation has emerged as a promising therapy for type 1 diabetes. However, this cell-based therapy is significantly limited by inadequate islet supply (more than one donor pancreas is needed per recipient), instant blood-mediated inflammatory reaction, and loss of islet viability/function during isolation and following implantation. In particular, inadequate revascularization of transplanted islets results in reduced islet viability, function, and engraftment. Delivery of pro-vascularization factors has been shown to improve vascularization and islet function, but these strategies are hindered by insufficient and/or complex release pharmacokinetics and inadequate delivery matrices as well as technical and safety considerations. We hypothesized that controlled presentation of angiogenic cues within a bioartificial matrix could enhance the vascularization, viability, and function of transplanted islets. The primary objective of this dissertation was to enhance allogenic islet engraftment, survival and function by utilizing synthetic hydrogels as engineered delivery matrices. Polyethylene glycol (PEG)-maleimide hydrogels presenting cell adhesive motifs and vascular endothelial growth factor (VEGF) were designed to support islet activities and promote vascularization in vivo. We analyzed the material properties and cyto-compatibility of these engineered materials, islet engraftment in a transplantation model, and glycemic control in diabetic subjects. The rationale for this project is to establish novel biomaterial strategies for islet delivery that support islet viability and function via the induction of local vascularization.

This master thesis aimed to create and characterize multilayer coatings upon mesoporous silica particles (MSP). The properties of the coating aimed for, was to have a triggerable controlled release, where a targeted enzyme within the intestine, alpha-amylase, is supposed to degrade the coating. The coating was created from a bilayer consisting of DOTAP and DOPC in a 1:3 molar ratio, which serves as a protective coating. The second layer interacting with the surroundings consisted of a starch component, amylopectin, which is degraded by alpha-amylase. The study of the coating was performed with ellipsometry, where the adsorption of the different layers of the coating on a planar silica surface and the enzyme-triggered degradation was recorded. The adsorbed amount of DOTAP/DOPC was 4,22 ± 0,11 mg/m2 and amylopectin 1,82 ± 0,94. The effects of different pH where performed, simulating the coated particle going through the gastro-intestinal system. Two enzymes alpha-amylase and phospholipase A2 (PLA2) where used for degradation of the coating. The knowledge from ellipsometry was applied to coating mesoporous silica particles and it was confirmed that the two layers had formed with zeta- potential measurement.

This thesis develops a novel photopatterning strategy for biomimetic scaffolds that enables spatial and biochemical control of engineered cellular architectures, such as the microvasculature. Intricate tools that allow for the three dimensional (3D) manipulation of biomaterial microenvironments will be critical for organizing cellular behavior, directing tissue formation, and ultimately, developing functional therapeutics to treat patients with critical organ failure. Poly(ethylene glycol) (PEG) based hydrogels, which without modification naturally resist protein adsorption and cellular adhesion, were utilized in combination with a two-photon laser patterning approach to covalently immobilize specific biomolecules in custom-designed, three-dimensional (3D) micropatterns. This technique, known as two-photon laser scanning lithography (TP-LSL), was shown in this thesis to possess the capability to micropattern multiple different biomolecules at modular concentrations into a single hydrogel microenvironment over a broad range of size scales with high 3D resolution. 3D cellular adhesion and migration were then explored in detail using time-lapse confocal microscopy to follow cells as they migrated along micropatterned tracks of various 3D size and composition. Further, in a valuable modification of TP-LSL, images from the endogenous microenvironment were converted into instructions to precisely direct the laser patterning of biomolecules within PEG-based hydrogels. 3D images of endogenous microvasculature from various tissues were directly converted into 3D biomolecule patterns within the hydrogel scaffold with precise pattern fidelity. While tissue engineers have previously demonstrated the formation of vessels through the encapsulation of endothelial cells and pericyte precursor cells within PEG-based hydrogels, the vessel structure had been random, uncoordinated, and therefore, ultimately non-functional. This thesis has utilized image guided TP-LSL to pattern biomolecules into a 3D structure that directs the organization of vessels to mimic that of the endogenous tissue vasculature. TP-LSL now stands as a valuable tool to control the microstructure of engineered cellular architectures, thereby providing a critical step in the development of cellularized scaffolds into functional tissues. Ultimately, this thesis develops new technologies that advance the field of regenerative medicine towards the goal of engineering viable organs to therapeutically treat the 18 patients who die every day waiting on the organ transplant list.

This dissertation describes a structural investigation of hyaluronan (HA) with neutron scattering techniques. HA is a natural biopolymer and one of the major components of the extracellular matrix, synovial fluid, and vitreous humor.  It is used in several biomedical applications like tissue engineering, drug delivery, and treatment of osteoarthritis. Although HA is extensively studied, very little is known about its three-dimensional conformation and how it interacts with ions and other molecules. The study aims to understand the bulk structure of a cross-linked HA hydrogel, as well as the conformational arrangement of HA at solid-liquid interfaces. In addition, the structural changes of HA are investigated by simulation of physiological environments, such as changes in ions, interactions with nanoparticles, and proteins etc. Small-angle neutron scattering and neutron reflectivity are the two main techniques applied to investigate the nanostructure of hyaluronan in its original, hydrated state. The present study on hydrogels shows that they possess inhomogeneous structures best described with two correlation lengths, one of the order of a few nanometers and the other in the order of few hundred nanometers. These gels are made up of dense polymer-rich clusters linked to each other. The polymer concentration and mixing governs the connectivity between these clusters, which in turn determines the viscoelastic properties of the gels. Surface-tethered HA at a solid-liquid interface is best described with a smooth varying density profile. The shape of this profile depends on the immobilization chemistry, the deposition protocol, and the ionic interactions. HA could be suitably modified to enhance adherence to metal surfaces, as well as incorporation of proteins like growth factors with tunable release properties. This could be exploited for surface coating of implants with bioactive molecules. The knowledge gained from this work would significantly help to develop future biomaterials and surface coatings of implants and biomedical devices.

Hydrogels are polymeric materials that have three-dimensional polymeric networks, which are able to absorb and retain a large amount of water within their structures without being dissolved. Among the synthetic hydrogel, poly(2-hydroxylethyl methacrylate) (poly(HEMA)) has been of great interest because of its excellent biocompatibility with the three-dimensional networks. Therefore, poly(HEMA) hydrogels have been widely used in many areas, especially in biomedical and pharmaceutical areas, for such applications as packing materials in chromatography, sorbents in controlled release and drug delivery, implanting materials in tissue engineering. However, the applications of poly(HEMA) are still limited because of its weak mechanical strength and network properties. Therefore, in recent decades, the challenge of how to modify and control the polymer properties and how to build highly porous structures in it has received considerable attention because these modifications could significantly improve the performance of poly(HEMA) hydrogels for more favorable applications. Although HEMA and its polymers have been studied for more than 40 years, few reports about the preparation of micro-/nano-porous poly(HEMA) hydrogel particles and the requirements of their applications have risen. Furthermore, how to control the porous structures and the properties of HEMA copolymers have not been well understood. Accordingly, the objectives of this research were to investigate the synthesis of the porous copolymeric particles of HEMA with various comonomers (MMA, St and NVP), to characterize the porous structures and particle morphology, to simulate the synthesis process and porous characteristics, to explore the effects of the polymer compositions and the porous structures on the swelling properties, and to apply the resultant polymeric particles in the controlled release of the hydrophilic model drug. In the present studies, HEMA was copolymerized with three different comonomers, methyl methacrylate (MMA), styrene (St) and N-vinyl-2-pyrrolidone (NVP), respectively, to prepare highly porous particles crosslinked using ethylene glycol dimethacrylate (EGDMA) in the presence of 1-octanol used as a porogen by means of suspension copolymerization in an aqueous phase initiated by 2,2-azobisisobutyronitrile (AIBN). Nano-pores were observed in the present studies. The pore size and the swelling properties of these particles can be successfully controlled by changing comonomers or adjusting the crosslinker and porogen concentration. The results indicate that lower crosslinker or porogen concentration favors generating smaller pores, whereas a higher concentration of a hydrophilic comonomer, higher crosslinker concentration and higher porogen volume ratio promote the generation of larger pores. In addition, the effects of the porous structures and the network properties on the swelling properties were explored. The swelling capacity of the porous particles is reduced with an increase in the EGDMA molar concentration. However, higher porosity in the particles and higher amount of hydrophilic comonomer result in a higher swelling capacity of the particles. The gel formation and the porous characteristics of HEMA/comonomer/EGDMA systems were simulated using the mathematical models combining the reaction kinetics and the thermodynamics. It was found that the model over-predicted the experimental results of the porosity because the pores and the networks are shrunk or collapsed during the porogen removal. Therefore, the model predicts the maximum porosity that the polymeric particles can reach. If the hydrophobic contents are higher, the model gives better prediction of the porosity. It is concluded that the microporous structures of HEMA related hydrogels could be controlled by a properly designed process based on the knowledge gained via this research. The output of this research helps with a better understanding for industrial production of micro-porous hydrogels and their applications.

The mature central nervous system has a very limited capacity for self-renewal and repair following injury. Neural stem cells (NSCs), however, provide a promising new therapeutic option and can be readily expanded in vitro . Towards the development of an effective therapy, greater understanding and control is needed over the mechanisms regulating the differentiation of these cells into function-restoring neurons. In vivo, the neural stem cell niche plays a critical role in directing stem cell self-renewal and differentiation. By understanding and harnessing the power of this niche, a tissue engineered system with encapsulated neural stem cells could be designed to encourage neuronal differentiation and ultimately regeneration of damaged neural tissue. Poly(ethylene glycol)-based hydrogels were used here as a platform for isolating and investigating the response of neural stem cells to various matrix, soluble, and cellular components of the niche. When covalently modified with a cyclic RGD peptide, the synthetic scaffold was demonstrated to support attachment and proliferation of a human NSC line under conditions permissive to cell growth. Under differentiating conditions, the scaffold maintained appropriate lineage potential of the cells by permitting the development of both neuronal and glial populations. Expansion and differentiation of NSCs was also observed in a more biomimetic, three dimensional environment following encapsulation within a degradable hydrogel material. To simulate the soluble signals in the niche, fibroblast growth factor and nerve growth factor were tethered to the hydrogel and shown to direct NSC proliferation and neuronal differentiation respectively. Finally, as an example of the cell-cell interactions in the niche, the pro-angiogenic capacity of encapsulated neural stem cells was evaluated both in vitro and in vivo. Ideally, the optimal scaffold design will be applied to guide NSCs in a therapeutic application. Toward this goal, a novel method was developed for encapsulation of the cells within injectable hydrogel microspheres. This technique was optimized for high cell viability and microsphere yield and was demonstrated with successful microencapsulation and delivery of neural stem cells in rodent model of ischemic stroke.