Chemical and Biomolecular Engineering - Theses
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ItemSupramolecular polymers as building blocks for the formation of particles( 2014)Over the last two decades, there has been a growing interest in the development of supramolecular polymers, linear macromolecules whose monomeric components are held together by non-covalent interactions. Such supramolecular assemblies are commonly found in nature and are crucial for the function of living tissues and cells. The recent development of synthetic supramolecular polymers has shown promise for enhancing the properties of polymeric materials. Indeed, studies have shown that such materials have significant benefits when compared to conventional, covalently bound, polymers. These benefits are due to the ability of supramolecular assemblies to respond to stimulus, and to dynamically rearrange their structure in a manner unachievable using conventional, covalently bound polymers. Resemblances between the dynamics of synthetic supramolecular polymers and naturally occurring supramolecular polymers are suggestive of their potential for biomedical applications. In this trend, the most promising supramolecular polymer, cyclodextrin (CD) based polyrotaxanes (PRXs), is now emerging as a potential tool to synthetically form dynamic interfaces for applications in the biomedical field. The recent popularity of these polymers in this field is not only due to their inherent, non-covalent properties but also to the low cost, high engineerability and low toxicity of the components they are made of. In this work, CD-based PRXs have been used as building blocks to form particles that were designed for developments in drug delivery. Specifically, the properties specific to PRXs have been exploited to design particles with degradation or stimuli-based response. The unique characteristics of PRXs were found to translate into similarly unique characteristics of the assembled particles. Different approaches have been studied and their advantages and limitations are highlighted. Initial investigations were aimed at designing particles fitting the requirements in properties and specific characteristics highlighted by recent in vivo and in vitro studies. In this direction, we demonstrated controlled degradation of self-assembled PRX-based structures through stimuli triggered disassembly. Such control was also shown for PRX particles dynamically formed using a templated approach, for which disassembly through judicious selection of specific building blocks is highlighted. The use of the templated approach was shown to be more straightforward and versatile in its applications, laying out a framework to form and engineer particles using PRXs as a building block. Lastly, by using CD’s molecular mobility in the PRX as an additional handle for tuning; a “one block” polymer, able to reversibly segregate into multi-blocks leading to the formation of nanoparticles, was developed. This approach is particularly interesting as many responsive polymeric materials have their response due to a stretched-to-coiled transition of individual chain while we show here a transition between a mono-block like architecture to a multi-block like architecture. The preliminary results highlight the potential of PRXs as building blocks for applications in drug delivery systems.
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ItemNovel biocompatible and biodegradable poly(ethylene glycol)- based scaffolds for soft tissue engineering( 2013)The development of new three-dimensional (3D) biocompatible constructs with improved properties for tissue regeneration is central to advances in the field of tissue engineering. Materials of natural and synthetic origin have been widely investigated for the production of tissue engineering scaffolds via various fabrication methods. Continuing research aims to fabricate scaffolds that possess the important properties of biodegradability, biocompatibility, mechanical integrity, and minimal immunogenicity. Achieving this objective is generally quite difficult since these properties are often dependant on each other and tailoring one property often compromises the other. In this research, we have employed novel synthetic approaches utilising epoxy/amine and acid chloride/alcohol chemistries to prepare poly(ethylene glycol) (PEG)-based scaffolds that are biocompatible and biodegradable, and possess excellent mechanical integrities, making them suitable for various soft-tissue engineering applications. Initially ultrathin Chitosan-PEG hydrogel films (CPHFs) were prepared using epoxy-amine chemistry via diepoxy functionalised PEG, chitosan amines and the co-cross-linker cystamine. The resultant films were very robust and possessed desirable biocompatible and biodegradable properties while supporting the attachment and proliferation of corneal endothelial cells (CECs). To eliminate the issues associated with the use of naturally sourced polymers, we were able to subsequently develop fully synthetic 50 μm thin PEG hydrogel films (PHFs). Acid chloride/alcohol chemistry, together with a facile fabrication method was utilised to produce the PHFs. PHFs were found to possess excellent tensile properties and promoted the in vitro attachment and proliferation of corneal endothelial cells with natural morphologies. In vitro degradation and cytotoxicity studies demonstrated the biodegradable and non-toxic characteristics. In an in vivo ovine model, the hydrogel films adhered naturally onto the interior corneal surface while displaying neither toxicity nor immunogenicity. The PHFs did not hinder the function of the native corneal endothelium, demonstrating their suitability for implantation. To further exploit acid chloride/alcohol chemistry, 3D porous PEG sponges and scaffolds were produced via novel gas foaming, and salt-templating techniques respectively. The rapid exothermic reaction and the HCl gas production results in the formation of highly porous polyester PEG sponges (PPSs), while a salt template was utilised to control pore sizes to produce the hydrogel scaffolds (SPHs). Both PPSs and SPHs possessed excellent mechanical integrities and demonstrated biodegradability and minimal toxicity in vitro. In vivo studies revealed complete infiltration of PPSs and SPHs with vascular tissue within 8 weeks. The porous scaffolds have minimal immunogenicity, and non-toxicity as demonstrated by an in vivo rat model, and can undergo complete degradation to non-toxic products by 16 weeks. The novel PEG hydrogel films and porous scaffolds demonstrate highly desirable physico-chemical properties with excellent biocompatible responses in vivo. Encompassing all the desirable properties of biocompatibility, biodegradability, mechanical integrity and complete tissue integration in vivo, the fabricated scaffolds are excellent candidates for advanced soft-tissue engineering applications.
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ItemMultifunctional, covalently stabilised capsules from biodegradable materials( 2010)One of the most promising and fast-developing areas of nanotechnology is the design of carrier systems for biomedical applications. These particulate delivery vehicles can be engineered with highly defined properties with a range of sizes, shapes and functionalities. Polymeric nanocapsules assembled using the Layer-by-Layer (LbL) technique are widely regarded as promising candidates for the delivery of biologically relevant agents. By choosing to use naturally occurring polyelectrolyte as LbL materials, such as poly(L-Lysine) (PLL) and poly(L-glutamic acid) (PGA, the resulting capsules can be degraded using enzymes that are present in certain environments within the body. In order to produce covalently stabilised multilayer films, PLL and PGA were modified with alkyne and azide moieties, respectively, enabling the formation of a covalent triazole bond between adjoining layers in the presence of copper during LbL assembly (click chemistry reaction). Stable one-component films and capsules were prepared and characterised. Properties such as enzymatic degradation, tuneable pH-responsive swelling, cytotoxicity, permeability and protein adhesion to the capsule surface were investigated. PLL click films were also equipped with targeting moieties as a proof of concept. The concept of stratified LbL assembly was introduced to tailor the degradation kinetics of the biodegradable hybrid capsules. To investigate drug loading, polymer-drug conjugates of PGA and anticancer drugs (doxorubicin or paclitaxel) were synthesised. The modular LbL assembly approach allowed for loading of these conjugates to multilayer films. A high level of control over drug position and dose was achieved and drugs could subsequently be release by enzymatic degradation. The uptake to colorectal cancer cells and the effect of drug-loaded capsules on cell viability was also investigated. In addition, a drug-resistant cell line was established and the capsular delivery method of anticancer-drugs was found to restore sensitivity of the drug-resistant cell line towards these drugs. In a different approach, PGA was modified with dopamine for continuous assembly of biodegradable capsules with defined properties. Overall, this thesis suggests various promising approaches for the assembly of biodegradable, multifunctional and covalently-stabilised capsules with potential application in targeted drug delivery.