Design and synthesis of novel hydrogels for biological applications

The aims of this project were:1) the synthesis of a range of new polyether-based vinylic monomers and their incorporation into poly(2-hydroxyethyl methacrylate) (poly(HEMA)) based hydrogel networks, of interest to the contact lens industry.2) the synthesis of a range of alkyltartronic acids, and their derivatives. These molecules may ultimately be used to produce functionalised poly(-hydroxy acids) of potential interest in either drug delivery or surgical suture applications. The novel syntheses of a range of both methoxy poly(ethylene glycol) acrylates (MPEGAs) and poly(ethylene glycol) acrylates (PEGAs) are described. Products were obtained in very good yields. These new polyether-based vinylic monomers were copolymerised with 2-hydroxyethyl methacrylate (HEMA) to produce a range of hydrogels. The equilibrium water contents (EWC) and surface properties of these copolymers containing linear polyethers were examined. It was found that the EWC was enhanced by the presence of the hydrophilic polyether chains.Results suggest that the polyether side chains express themselves at the polymer surface, thus dictating the surface properties of the gels. Consequentially, this leads to an advantageous reduction in the surface adhesion of biological species. A synthesis of a range of alkyltartronic acids is also described. The acids prepared were obtained in very good yields using a novel four-stage synthesis. These acids were modified to give potassium monoethyl alkyltartronates. Although no polyesterification is described in this thesis, these modified alkyltartronic acid derivatives are considered to be potentially excellent starting materials for poly (alkyltartronic acid) synthesis via anhydrocarboxylate or anhydrosulphite cyclic monomers.

Hydrogels containing linear and cyclic polyethers

Hydrogels are a unique class of polymer which swell, but do not dissolve in, water. A range of 2-hydroxyethyl methacrylate based copolymer hydrogels containing both cyclic and linear polyethers have been synthesised and are described in this thesis. Initially, cyclic polyethers were occluded within the polymer matrix and the transport properties investigated. The results indicated that the presence of an ionophore can be used to modulate ion transport and that ion transport is described by a dual-sorption mechanism. However, these studies were limited due to ionophore loss during hydration. Hence, the synthesis of a range of acrylate based crown ether monomers was considered. A pure sample of 4-acryolylaminobenzo-15-crown-5 was obtained and a terpolymer containing this monomer was prepared. Transport studies illustrated that the presence of a `bound' ionophore modulates ion transport in a similar way to the occluded systems. The transport properties of a series of terpolymers containing linear polyethers were then investigated. The results indicated that the dual-sorption mechanism is observed for these systems with group II metal cations while the transport of group I metal cations, with the exception of sodium, is enhanced. Finally, the equilibrium water contents (EWC) surface and mechanical properties of these terpolymers containing linear polyethers were examined. Although subtle variations in EWC are observed as the structure of the polyether side chain varies, generally EWC is enhanced due to the hydrophilicity of the polyether side chain. The macroscopic surface properties were investigated using a sessile drop technique and FTIR spectroscopy. At a molecular level surface properties were probed using an in vitro ocular spoilation model and preliminary cell adhesion studies. The results indicate that the polyethylene oxide side chains are expressed at the polymer surface thus reducing the adhesion of biological species.

Protein deposition at polymer surfaces:the bulk and surface structure-property effects of hydrogels

The primary objective of this research has been to investigate the interfacial phenomenon of protein adsorption in relation to the bulk and surface structure-property effect s of hydrogel polymers. In order to achieve this it was first necessary to characterise the bulk and surface properties of the hydrogels, with regard to the structural chemistry of their component monomers. The bulk properties of the hydrogels were established using equilibrium water content measurements, together with water-binding studies by differential scanning calorimetry (D.S.C.). Hamilton and captive air bubble-contact angle techniques were employed to characterise the hydrogel-water interface and from which by a mathematical derivation, the interfacial free energy (ðsw) and the surface free energy components (ð psv, ðdsv, ðsv) were obtained. From the adsorption studies using the radio labelled iodinated (125I) proteins of human serum albumin (H.S.A.) and human fibrinogen (H.Fb.), it was Found that multi-layered adsorption was occurring and that the rate and type of this adsorption was dependent on the physico-chemical behaviour of the adsorbing protein (and its bulk concentration in solution), together with the surface energetics of the adsorbent polymer. A potential method for the invitro evaluation of a material's 'biocompatibility' was also investigated, based on an empirically observed relationship between the adsorption of albumin and fibrinogen and the 'biocompatibility' of polymeric materials. Furthermore, some consideration was also given to the biocompatibility problem of proteinaceous deposit formation on hydrophilic soft' contact lenses and in addition a number of potential continual wear contact lens formulations now undergoing clinical trials,were characterised by the above techniques.

Polymer-lipid interactions:biomimetic self-assembly behaviour and surface properties of poly(styrene-alt-maleic acid) with diacylphosphatidylcholines

Abstract Various lubricating body fluids at tissue interfaces are composed mainly of combinations of phospholipids and amphipathic apoproteins. The challenge in producing synthetic replacements for them is not replacing the phospholipid, which is readily available in synthetic form, but replacing the apoprotein component, more specifically, its unique biophysical properties rather than its chemistry. The potential of amphiphilic reactive hypercoiling behaviour of poly(styrene-alt-maleic acid) (PSMA) was studied in combination with two diacylphosphatidylcholines (PC) of different chain lengths in aqueous solution. The surface properties of the mixtures were characterized by conventional Langmuir-Wilhelmy balance (surface pressure under compression) and the du Noüy tensiometer (surface tension of the non-compressed mixtures). Surface tension values and 31P NMR demonstrated that self-assembly of polymer-phospholipid mixtures were pH and concentration-dependent. Finally, the particle size and zeta potential measurements of this self-assembly showed that it can form negatively charged nanosized structures that might find use as drug or lipids release systems on interfaces such as the tear film or lung interfacial layers. The structural reorganization was sensitive to the alkyl chain length of the PC.

Dehydration at the lens surface:surface energy and surfactant persistence

Purpose: Most published surface wettability data are based on hydrated materials and are dominated by the air-water interface. Water soluble species with hydrophobic domains (such as surfactants) interact directly with the hydrophobic domains in the lens polymer. Characterisation of relative polar and non-polar fractions of the dehydrated material provides an additional approach to surface analysis. Method: Probe liquids (water and diiodomethane) were used to characterise polar and dispersive components of surface energies of dehydrated lenses using the method of Owens and Wendt. A range of conventional and silicone hydrogel soft lenses was studied. The polar fraction (i.e. polar/total) of surface energy was used as a basis for the study of the structural effects that influence surfactant persistence on the lens surface. Results: When plotted against water content of the hydrated lens, polar fraction of surface energy (PFSE) values of the dehydrated lenses fell into two rectilinear bands. One of these bands covered PFSE values ranging from 0.4 to 0.8 and contained only conventional hydrogels, with two notable additions: the plasma coated silicone hydrogels lotrafilcon A and B. The second band covered PFSE values ranging from 0.04 to 0.28 and contained only silicone hydrogels. Significantly, the silicone hydrogel lenses with lowest PFSE values (p<0.15) are found to be prone to lipid deposition duringwear. Additionally, more hydrophobic surfactants were found to be more persistent on lenses with lower PFSE values. Conclusions: Measurement of polar fraction of surface energy provides an importantmechanistic insight into surface interactions of silicone hydrogels.

Polymer-phospholipid complexes for the solubilisation and delivery of drugs to the eye

Aim: Topical application of ophthalmic drugs is very inefficient; contact lenses used as drug delivery devices could minimize the drug loss and side effects. Styrene-maleic acid copolymers (PSMA) can form polymer-phospholipid complexes with dipalmitoyl phosphatidylcholine (DMPC) in the form of nanometric vesicles, which can easily solubilise hydrophobic drugs. They can be dispersed on very thin contact lens coatings to immobilize the drug on their surface. Methods: Two types of complexes stable at different pH values (5 and 7 respectively) where synthesized and loaded with drugs of different hydrophilicities during their formation process. The drug release was studied in vitro and compared to the free drug. Results: The mean sizes of the complexes obtained by light scattering were 50 nm and 450 nm respectively with low polydispersities. However, they were affected by the drugs load and release. An increase was observed in the duration of the release in the case of hydrophobic drugs, from days to weeks, avoiding initial “burst” and with a lesser amount of total drug released due to the interaction of the drug with the phospholipid core. The size and charge of the different drugs and the complexes nature also affected the release profile. Conclusions: Polymer-phospholipid complexes in the form of nanoparticles can be used to solubilise and release hydrophobic drugs in a controlled way. The drug load and release can be optimised to reach therapeutic values in the eye.

Hypercoiling and hydrophobically associating polymers : interfacial synthesis, surface properties and pharmaceutical applications

The objective of the work described was to identify and synthesize a range of biodegradable hypercoiling or hydrophobically associating polymers to mimic natural apoproteins, such as those found in lung surfactant or plasma apolipoproteins. Stirred interfacial polymerization was used to synthesize potentially biodegradable aromatic polyamides (Mw of 12,000-26,000) based on L-Iysine, L-Iysine ethyl ester, L-ornithine and DL-diaminopropionic acid, by reaction with isophthaloyl chloride. A similar technique was used to synthesize aliphatic polyamides based on L-Iysine ethyl ester and either adipoyl chloride or glutaryl chloride resulting in the synthesis of poly(lysine ethyl ester adipamide) [PLETESA] or poly(lysine ethyl ester glutaramide) (Mw of 126,000 and 26,000, respectively). PLETESA was found to be soluble in both polar and non-polar solvents and the hydrophobic/hydrophilic balance could be modified by partial saponification (66-75%) of the ethyl ester side chains. Surface or interfacial tension/pH profiles were used to assess the conformation of both the poly(isophthalamides) and partially saponified PLETESA in aqueous solution. The results demonstrated that a loss of charge from the polymer was accompanied by an initial fall in surface activity, followed by a rise in activity, and ultimately, by polymer precipitation. These observations were explained by a collapse of the polymer chains into non-surface active intramolecular coils, followed by a transition to an amphipathic conformation, and finally to a collapsed hydrophobe. 2-Dimensional NMR analysis of polymer conformation in polar and non-polar solvents revealed intramolecular associations between the hydrophobic groups within partially saponified PLETESA. Unsaponified PLETESA appeared to form a coiled structure in polar solvents where the ethyl ester side chains were contained within the polymer coil. The implications of the secondary structure of PLETESA and potential biomedical applications are discussed.

Compatibilisation and stabilisation of immiscible polymer blends by reactive processing

The main objectives of this research were to develop optimised chemical compositions and reactive processing conditions for grafting a functional monomer maleic anhydride (MA) in polypropylene (PP), ethylene propylene diene monomer (EPDM) and mixtures of PP-EPDM, and to optimise synthetic routes for production of PP/EPDM copolymers for the purpose of compatibilisation of PP/EPDM blends. The MA-functionalisation was achieved using an internal mixer in the presence of low concentrations (less than 0.01 molar ratio) of a free radical initiator. Various methods were used to purify MA-functionalised PP and the grafting yield was determined using either FTIR or titrametry. The grafting yield of MA alone, which due to its low free-radical reactivity towards polymer macroradicals, was accompanied by severe degradation in the case of PP and crosslinking for EPDM. In the case of MA-functionalised PP/EPDM, both degradation and crosslinking occurred though not to a great extent. The use of tri-functional coagents e.g. trimethylopropane triacrylates (TRIS) with MA, led to high improvement of the grafting yield of MA on the polymers. This is almost certainly due to high free-radical activity of TRIS leading to copolymerisation of MA and TRIS which was followed by grafting of the copolymer onto the polymer backbone. In the case of PP, the use of coagent was also found to reduce the polymer degradation. PP/EPDM copolymers with optimum tensile properties were synthesised using a 'one-step' continues reactive processing procedure. This was achieved firstly by functionalisation of a mixture of PP (higher w/w ratio) and EPDM (low w/w ratio) with MA, in the presence of the coagent TRIS and a small concentration of a free radical initiator. This was then followed by an imidisation reaction with the interlinking agent hexamethylene diamine (HEMDA). Small amount of copolymers, up to 5 phr, which were interlinked with up to 15 phr of HEMDA, were sufficient to compatibilise PP/EPDM75/25 blends resulting in excellent tensile properties compared to binary PP/EPDM 75/25 blend. Improvement in blend's compatibility and phases-stabilisation (observed through tensile and SEM analysis) was shown in all cases with significant interphases adhesion improvement between PP and EPDM, and reduction in domain size across the fractured surface indicating efficient distribution of the compatibiliser.

Novel hydrogel copolymers and semi-interpenetraing polymer networks

Interpenetrating polymer networks (lPN's), have been defined as a combination of two polymers each in network form, at least one of which has been synthesised and / or crosslinked in the presence of the other. A semi-lPN, is formed when only one of the polymers in the system is crosslinked, the other being linear. lPN's have potential advantages over homogeneous materials presently used in biomedical applications, in that their composite nature gives them a useful combination of properties. Such materials have potential uses in the biomedical field, specifically for use in hard tissue replacements, rigid gas permeable contact lenses and dental materials. Work on simply two or three component systems in both low water containing lPN's supplemented by the study of hydrogels (water swollen hydrophilic polymers) can provide information useful in the future development of more complex systems. A range of copolymers have been synthesised using a variety of methacrylates and acrylates. Hydrogels were obtained by the addition of N-vinyl pyrrolidone to these copolymers. A selection of interpenetrants were incorporated into the samples and their effect on the copolymer properties was investigated. By studying glass transition temperatures, mechanical, surface, water binding and oxygen permeability properties samples were assessed for their suitability for use as biomaterials. In addition copolymers containing tris-(trimethylsiloxy)-y-methacryloxypropyl silane, commonly abbreviated to 'TRlS', have been investigated. This material has been shown to enhance oxygen permeability, a desirable property when considering the design of contact lenses. However, 'TRIS' has a low polar component of surface free energy and hence low wettability. Copolymerisation with a range of methacrylates has shown that significant increases in surface wettability can be obtained without a detrimental effect on oxygen permeability. To further enhance to surface wettability 4-methacryloxyethyl trimellitic anhydride was incorporated into a range of promising samples. This study has shown that by careful choice of monomers it is possible to synthesise polymers that possess a range of properties desirable in biomedical applications.

Development of an electrically tuneable Bragg grating filter in polymer optical fibre operating at 1.55 µm

We present a thorough study on the development of a polymer optical fibre-based tuneable filter utilizing an intra-core Bragg grating that is electrically tuneable, operating at 1.55 µm. The Bragg grating is made tuneable using a thin-film resistive heater deposited on the surface of the fibre. The polymer fibre was coated via the photochemical deposition of a Pd/Cu metallic layer with the procedure induced by VUV radiation at room temperature. The resulting device, when wavelength tuned via Joule heating, underwent a wavelength shift of 2 nm for a moderate input power of 160 mW, a wavelength to input power coefficient of -13.4 pm mW-1 and time constant of 1.7 s-1. A basic theoretical study verified that for this fibre type one can treat the device as a one-dimensional system. The model was extended to include the effect of input electrical power changes on the refractive index of the fibre and subsequently to changes in the Bragg wavelength of the grating, showing excellent agreement with the experimental measurements.

Polymer modified cement: hydration microstructure and diffusion properties

Investigations concentrated on the styrene butadiene rubber (SBR) latex and formulations included standard carboxylated and special carboxylated latexes. The aqueous component, containing the stabilisers and antifoaming agent but not the polymer solids, was also used. For comparison, limited investigations were carried out using other polymer types e.g. acrylic, ethylene-vinyl acetate (EVA), and redispersible powders rather than emulsions. The major findings were: 1) All latex systems investigated acted as retarders for cement hydration. The extent of retardation depends on the type of polymer. The mechanism for cement hydration may be changed, and excessive retardation influences properties. 2) Polymer modified cements exhibited either similar or coarser pore structures compared with unmodified cements. Results suggest that polymer mainly exists in a mixture of cement hydrates and polymer phase. Very little evidence was found for the formation of a distinct polymer film phase. 3) During the first few days of curing the polymer solids are removed from the pore solution and concentrations of OH-, Na+ and K+ are reduced. These observations are probably a result of polymer-cement surface interactions since there was no evidence of any chemical reactions or degradation of the polymer. 4) Improved diffusional resistance of modified cements depends on the ability to achieve adequate workability at low w/c ratio, rather than modification of matrix structure.

Influence of pretreatment on corrosion behaviour of duplex zinc/polymer coatings on steel substrates

An investigation has been undertaken to determine the major factors influencing the corrosion resistance of duplex-zinc coatings on steel substrates.Premature failure of these systems has been attributed to the presence of defects such as craters and pinholes in the polymer film and debonding of the polymer film from the zinc substrate.Defects found on commercially produced samples have been carefully characterised using metallographic and scanning electron microscopy techniques. The influence of zinc substrate surface roughness, polymer film thickness and degassing of conversion coatings films on the incidence of defects has been determined.Pretreatments of the chromate, chromate-phosphate, non chromate, and alkali-oxide types were applied and the conversion coatings produced characterised with respect to their nature and composition. The effect of degassing on the properties of the films was also investigated. Electrochemical investigations were carried out to determine the effect of the presence of the eta or zeta phase as the outermost layer of the galvanized coating.Flow characteristics of polyester on zinc electroplated hot-dip continuous and batch galvanized and zinc sprayed samples were investigated using hot-stage microscopy. The effects of different pretreatments and degassing after conversion coating formation on flow characteristics were determined.Duplex coatings were subjected to the acetic acid salt spray test. The effect on adhesion was determined using an indentation debonding test and the results compared with those obtained using cross-cut/peel and pull-off tests. The locus of failure was determined using scanning electron microscopy and X-ray photoelectron spectroscopy techniques.

Properties and performance of polymer modified cements and mortars

Polymer modified cements and mortars have become popular for use as patch repair materials. General evidence suggests that these materials offer considerable improvements compared to traditional mortars although the mechanisms for this are not fully understood. This work elucidates the factors which govern some properties and performance of different polymer systems. In view of the wide range of commercial systems available, investigations concentrated on the use of three of the most commonly available groups of polymers. These were: (1) Styrene Butadiene Rubber (SBR), (2) Acrylics and, (3) Ethylene Vinyl Acetates (EVA). The later two were in the form of both emulsions and redispersible powders. Experiments concentrated on: (1) Rheological behaviour of polymer modified cement pastes; (2) Workability of polymer modified mortars; (3) Influence of curing conditions on the pore size distribution and diffusion of chloride ions; (4) Bond strength of polymer modified cement and mortar patches; and (5) Microscopic examination and semi-quantitative analyses of the bulk and interfacial microstructures. The following main conclusions were reached: (1) The addition of polymer emulsions have a considerable influence on the workability of fresh cement pastes, the extent of this depending on the type of system used. (2) The rheological parameters of fresh polymer modified mortars can be established using a two-point workability test which may be used when comparing the properties of different systems at constant workability. (3) Curing conditions affect the properties of polymer modified systems and a wet/dry curing regime was essential for good adhesion of these materials to mortar substrates. (4) In contrast, the wet/dry curing regime resulted in a curing affected zone at the surface of patch materials. This can result in a much coarser pore structure and enhanced diffusion of e.g. chloride ions. (5) The microstructure of polymer modified systems was very different compared with the unmodified cement/mortar and varied depending on curing conditions.

In situ imaging and height reconstruction of phase separation processes in polymer blends during spin coating

Spin coating polymer blend thin films provides a method to produce multiphase functional layers of high uniformity covering large surface areas. Applications for such layers include photovoltaics and light-emitting diodes where performance relies upon the nanoscale phase separation morphology of the spun film. Furthermore, at micrometer scales, phase separation provides a route to produce self-organized structures for templating applications. Understanding the factors that determine the final phase-separated morphology in these systems is consequently an important goal. However, it has to date proved problematic to fully test theoretical models for phase separation during spin coating, due to the high spin speeds, which has limited the spatial resolution of experimental data obtained during the coating process. Without this fundamental understanding, production of optimized micro- and nanoscale structures is hampered. Here, we have employed synchronized stroboscopic illumination together with the high light gathering sensitivity of an electron-multiplying charge-coupled device camera to optically observe structure evolution in such blends during spin coating. Furthermore the use of monochromatic illumination has allowed interference reconstruction of three-dimensional topographies of the spin-coated film as it dries and phase separates with nanometer precision. We have used this new method to directly observe the phase separation process during spinning for a polymer blend (PS-PI) for the first time, providing new insights into the spin-coating process and opening up a route to understand and control phase separation structures. © 2011 American Chemical Society.

Comparison of hydrophilic and hydrophobic active molecules release from polymer-phospholipid complexes

Hypercoiling polymers can be suited for application to living systems because they are similar in structure to the protein-based lipid assemblies found at fluid interfaces within the body. This leads to a range of exciting possibilities, not only in membrane transport applications but also in biosensors, drug delivery and mechanistic studies of biological membrane function. This study is focused in the study of the stability and suitability of nanostructures made of a hypercoiling polymer for drug delivery applications. The polymer poly (styrene-maleic acid) (PSMA) was combined with the phospholipid dimyristoylphosphatidylcholine (DMPC) to form amphiphilic nanostructures. The stability and suitability of these polymer-phospholipid nanocarriers for hydrophobic and hydrophilic molecules load and release was analyzed by several techniques. It was found that several of the studied molecules had a substantial effect on the surface charge and stability of the nanocarrier. It was also demonstrated that two types of nanocarriers, chemically modified and unmodified, were able to control the release of the molecules, especially in the case of hydrophobic compounds. In addition, as the hydrophobicity increased the release slowed down. These clear nanocarriers have the potential to behave very favorably at interfaces such as the tear lipid film were transparency is a requirement, giving a new way of controlled drug release in the eye.