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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Investigation into synthetic protease-sensitive hydrogels as siRNA nanoparticle delivery vehicles.

Doubell, Emma 18 February 2019 (has links)
RNA interference (RNAi) is receiving increasing attention as a form of gene regulation able to temporarily silence gene expression through post transcriptional mechanisms. RNAi agents have shown promise in targeting a range of ailments from cancers to myocardial infarction. However, RNAi based therapeutics have not passed the clinical trial stage of development, in part due to lack of optimal delivery mechanisms. One means towards improving delivery is the development of localised and sustained delivery systems for the RNAi molecule. Such approaches are important as it has previously been found that systemic delivery often leads to off target effects and rapid clearance. The aim of this project has been to assess the utility of an enzymatically degradable polyethylene glycol (PEG) hydrogel as a localised delivery vehicle. Enzymatically degradable PEG hydrogels that rely on cellular invasion for their degradation might enable the release of entrapped RNAi agents to surrounding cells as well as transfection of invading cells. The cationic polymer poly(ethyleneimine) (PEI), was used as a tool to investigate the PEG hydrogel as a localised delivery vehicle. Thus, an initial objective of this study was the establishment and characterisation of the PEI/siRNA nanoparticle technology in our group. siRNA was found to be fully complexed at a PEI nitrogen to siRNA phosphate ratios of 5:1 and higher. A 10:1 ratio and higher were able to protect the siRNA from RNases present in serum for 7 days with up to 65% of RNA still intact. A 40:1 ratio was found to be cytotoxic. A 20:1 ratio was found to be the most effective at gene knock down and determined to be optimal. As there is a relatively limited volume available in the PEG hydrogel system used here for loading with PEI/siRNA nanoparticles, a study was conducted to assess the maximum concentration of siRNA at which effective nanoparticles could be formed. Somewhat unexpectedly it was found that at a concentration of 7.5 µM siRNA, nanoparticles showed a significant 40% reduction in transfection efficacy of cells cultured in 2D. This finding for PEI nanoparticles indicating a limitation in the dosage attainable in the PEG hydrogel system. The influence of PEG encapsulation for PEI/siRNA nanoparticles on RNase protection was assessed by exposing hydrogels with entrapped nanoparticles to serum RNases. The PEG hydrogel was found to significantly improve PEI based protection from RNase degradation in the initial 24 hours and this protection persisted for up to 5 days. PEI/siRNA nanoparticles were retained after encapsulation within PEG hydrogels for up to 7 days whilst siRNA alone was entirely released after 24 hours. It is possible that this is a limitation of the system. A 3D invasion assay was developed to more closely mimic the in vivo scenario where cells could invade a PEG hydrogel with entrapped nanoparticles but are not initially exposed to high concentrations of nanoparticles prior to hydrogel polymerisation. The assay involved the formation of dermal equivalents (cells entrapped within contracted collagen) that were encapsulated within a PEG hydrogel. Cells were observed invading the hydrogel within 1 hour of polymerising and continued to do so for up to 7 days. Invading cells were seen to take up the fluorescent siRNA although this uptake was scant and challenging to quantify. When commercial cell death siRNA sequence nanoparticles were encapsulated, a trend towards higher death levels was observed. In conclusion, PEI/siRNA nanoparticles and related RNAi based assays have been formally established in our laboratory and can be used in the future for other applications. A 3D cell invasion assay was developed which more closely mimics the in vivo scenario where hydrogels bearing siRNA are polymerised within tissue. The increased RNase protection though relatively slight is important for the use of hydrogels as localised delivery depots in an in vivo environment. Potential dose limitations of the PEG hydrogel system when using PEI nanoparticles and their apparent very tight encapsulation in the PEG hydrogels suggests the need for modifications of both nanoparticles and hydrogels to optimise efficacy. Future investigations into scaffold based localised siRNA delivery should be facilitated by the methodologies and assays established in this study.

Stimulation of angiogenesis through growth factor delivery from synthetic heparinised hydrogels

Chokoza, Cindy January 2017 (has links)
Objectives: Vascular diseases are one of the leading causes of death. Due to minimal regenerative capability of the heart, alternative therapies have been sought after with engineered biomaterials being extensively investigated in this area. In this study, enzymatically degradable heparinised polyethylene glycol (PEG-Hep) hydrogels were synthesized and characterised for the binding and controlled release of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), as well as their bioactivity and angiogenic potential in vivo. Methodology: VEGF and bFGF were combined into 4% (m/v) PEG-Hep hydrogels. The binding and release rates of VEGF and BFGF were analysed via an immunosorbent assay. Released growth factor bioactivity was measured using an XTT metabolic assay on human saphenous vein endothelial cells and human dermal fibroblasts. Neovascularisation was quantified in a subcutaneous rat angiogenesis model in which hydrogel growth factor combinations were implanted within porous polyurethane discs and analysed after a 4 week period. A novel hybrid hydrogel able to degrade proteolytically and hydrolytically was further developed, characterised and analysed as above. Results: PEG-Hep hydrogels demonstrated substantial growth factor binding ability (500-600 ng) and allowed sustained release (10-20 ng/day) for up to 28 days. Bioactivity of the growth factors was retained throughout the release period. The degradation rate of the hydrogels could be controlled in vivo by varying the ratio of monomers capable of forming either hydrolytically or proteolytically degradable crosslinks. Qualitative and quantitative analysis demonstrated a pronounced and significant angiogenic response in vivo (p<0.05). Conclusion: Heparinised PEG hydrogels show significant promise as controlled release vehicles for growth factors and warrant further examination in a myocardial infarction model.

Polymer glass composites for surgical implants

Knowles, Jonathan Campbell January 1991 (has links)
No description available.

Crystallization and molecular conformation of long chain N alkanes

De Silva, D. S. M. January 2002 (has links)
No description available.

The control of bacterial adhesion to polymeric surfaces

Bridgett, Michael Jonathan January 1993 (has links)
No description available.

Hierarchical Micro- and Nanostructured Superhydrophobic Surfaces to Reduce Fibrous Encapsulation of Pacemaker Leads : Nanotechnology in Practical Applications

Carlsson, Louise January 2008 (has links)
The purpose of this master’s thesis was to, by the use of nanotechnology, improve material properties of the biomedical polymer Optim™, used as the insulation of pacemaker leads. Improved material properties are required to reduce the extent of fibrous encapsulation of the leads. Today, laser ablation is used to be able to remove the pacemaker lead because of the fibrous tissue, which can cause the lead to adhere to vascular structures. Consequently, the laser ablation results in risks of damaging cardiovascular structures. Moreover, improved material properties are needed to reduce the friction at the surface and enhance the wear resistance. Large wearing occurs between the lead and the titanium pacemaker shell as well as lead against lead and the wearing can result in a damaged insulation, which in turn might result in removal of the device. To achieve these improved material properties a hierarchically micro- and nanostructured and superhydrophobic surface was fabricated and to enhance the wear resistance, nanocomposites with 1 wt % and 5 wt % added hydroxyapatite nanoparticles were fabricated. The surface structures were fabricated via hot embossing and plasma treatment and were characterised with atomic force microscopy, environment scanning electron microscopy and with contact angle measurements. To evaluate the biological response to the surfaces, adsorption of radioisotope labelled human serum albumin proteins and adhesion of the human fibroblast cell line MRC-5 were studied. The results show that a superhydrophobic surface, with contact angle as high as 170.0 ± 0.4 °, can be fabricated via hierarchically micro- and nanostructures on an Optim™ surface. The fabricated surface is more protein resistant and cell resistant compared to a smooth surface. The nanocomposites fabricated, especially the one with 5 wt % nanoparticles added, show an enhanced abrasive wear resistance compared to Optim™ without added nanoparticles. In conclusion, a hierarchically micro- and nanostructured superhydrophobic surface of the pacemaker lead seems promising for reducing the extent of fibrous encapsulation and by fabricating a nanocomposite, the abrasive wear damage of the lead insulation can be reduced.

Characterisation and evaluation of hydroxyapatite and bioglass-reinforced polyethylene composities for medical implants

Huang, Jie January 1997 (has links)
No description available.

Denture soft linings : clinical and laboratory studies

Jepson, Nicholas John Arnold January 1991 (has links)
No description available.

Biomolecular approaches to nanophase chemistry

Shenton, Wayne January 1998 (has links)
No description available.

Polymer composites incorporating engineered electrospun fibres : flexible design and novel properties for biomedical applications

Zhang, Xi January 2017 (has links)
Due to their unique structure and flexible choice of materials, electrospun degradable and biocompatible polymer fibres are considered to be extremely suitable for biomedical applications such as tissue engineering and drug delivery, either on their own or integrated within composites. Conventional electrospun fibre composites are typically based on non-woven mats and therefore limited to simple-curved geometries (films, membranes, etc.). For aqueous composites such as hydrogels, the hydrophobicity of the materials sometimes prohibits fibres to be easily integrated or distributed in these composites. In this thesis, a review on the topic is firstly presented in Chapter 2, introducing and discussing engineering of electrospun fibre as well as their biomedical applications. In Chapter 3, electrospun polylactide (PLA) fibres reinforced poly(trimethylene carbonate) (PTMC) composites are prepared. The composites are loaded with both continuous and short PLA fibres, achieving significant mechanical enhancement and offering opportunities to produce composites conveniently using liquid formulations. Chapter 4 presents the development of shape memory polymer composites based on a combination of PLA fibres and a PTMC matrix. By loading different amounts of short fibres with different aspect ratios or by using plasticisers, the shape memory behaviour is modulated; and composites of more complex geometries are produced. In Chapter 5, PTMC-PLA fibre composites are made into drug release system. Dexamethasone-loaded PLA fibres are integrated into a PTMC matrix, showing sustained drug release and stimulating stem cell osteogenic differentiation. This concept gives promise to loading various drugs into photo-crosslinked structures without denaturation. In Chapter 6, electrospun PLA fibres are functionalized by amphiphilic block copolymer polylactide-block-poly[2-(dimethylamino)ethyl methacrylate] (PLA-b-PDMAEMA) for the development of carboxymethylcellulose composites hydrogels. Functionalization of PLA fibres not only allows for easy integration and dispersion into the hydrogel, but also enhances the interfacial bonding between fibre and hydrogel. In the last chapter (Chapter 7), some conclusions are drawn and future works are discussed.

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