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Modification of Anti-Bacterial Activity and Bone Cell Proliferation by Surface Engineering of Ga- or Mn-Doped Ceria-Coated Biomedical Titanium Alloy(2022) Khosravanihaghighi, AydaThesisThe two leading causes of failure of orthopaedic implants are aseptic loosening and periprosthetic joint infection. Since the numbers of primary and revision joint replacement surgeries are increasing, strategies to mitigate these failure modes have become increasingly important. However, most recent work has focused on the design of coatings to prevent infection or to enhance bone mineralisation. However, long-term success of the implants is contingent on addressing both of these issues. Consequently, the present work focussed on multifunctional orthopaedic coatings that inhibit microbial cells while still promoting osseointegration. Nanoceria has considerable potential to be used in biomedical applications owing to its unique bio-responsive redox switching and its capacity to be doped with different therapeutic ions of varying functionalities. Therefore, the effect of different cations incorporated in ceria on cellular behaviour in vitro as well as the anti-bacterial performance were investigated. The two main foci were: (1) characterisation of the bioceramic materials and (2) biological response to undoped and doped ceria ceramics in vitro using bacteria colonies forming unit (CFU) and cytotoxicity Ceria (CeO2) thin films (~820 nm thickness) doped with 0-9 mol% Ga or Mn were fabricated by spin coating on 3D-printed Ti6Al4V followed by heat treatment at 650°C for 2 h, and these were characterised by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM) (microstructure), 3D laser scanning confocal microscopy (topography), glancing angle X-ray diffraction (GAXRD) (structure and mineralogy), and X-ray photoelectron spectroscopy (XPS) (surface chemistry). In vitro testing was conducted, including inhibition of bacterial growth, simulated body fluid (SBF) testing, and cell attachment and proliferation studies. The data are interpreted in terms of the following: (1) The roles of the sol-gel precursor viscosity, which affected pore filling and surface coverage, (2) Lattice contraction, which contradicted the XPS data, (3) Intervalence charge transfer, which increased the Ce3+ concentration but was a minor effect, (4) Substitutional solid solubility, which is consistent with Hume-Rothery’s rules and the GAXRD data, (5) Redox charge compensation, where the defect equilibria highlight the key role of this mechanism, which decreased the Ce3+ concentration and provided the majority effect, (6) Electronegativity, which plays a small, if any, role in affecting the ion valences but is important in initiating intervalence charge transfer, (7) Multivalence charge transfer, which combined the electron exchanges between film matrix, dopants, and Ti substrate. The most significant outcome was that the bioactivity of ceria derives directly from the Ce3+ concentration, which itself results from solid solubility (substitutional and interstitial) and charge compensation and redox. This challenges the common assumption of the dominance of oxygen vacancies in the performance of ceria. The antibacterial activity was dependent on the type, amount, and valence of the dopant, where opposite trends were observed for gram-positive S. aureus and gram-negative E. coli bacteria. All of the doped samples resulted in enhanced cell proliferation, although this was greatest at the lowest dopant concentration. Surface hydroxyapatite formation on the samples was achieved by soaking in SBF at 2 weeks and 1 month.
(2022) Kokkinos, JohnThesisLess than 10% of patients with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years. One of the characteristic features that drive the aggressive nature of PDAC is its multicellular, heterogeneous, and fibrotic microenvironment. We previously identified a cytoskeletal protein, βIII-tubulin, as a novel therapeutic target in PDAC. However, the PDAC cell survival mechanisms controlled by βIII-tubulin were previously unknown. We also identified a major gap in the ability of human PDAC preclinical models to accurately mimic the 3D multicellular architecture and stroma of the disease. Thus, the aims of this work were (1) to evaluate the pro-survival role of βIII-tubulin in PDAC; (2) to establish a new patient derived tumour explant model that maintains all features of the PDAC microenvironment; and (3) to use the tumour explant model to test the clinical potential of silencing βIII-tubulin expression as well as two stromal targets that had been previously explored by our lab: solute carrier 7A11 (SLC7A11) and heat shock protein 47 (HSP47) Here, we identified that silencing βIII-tubulin in pancreatic cancer cells activated extrinsic apoptosis and increased their sensitivity to extrinsic apoptosis inducers including tumour necrosis factor-α (TNFα), Fas-ligand (FasL), and TNF-related apoptosis inducing factor (TRAIL). We next established the patient derived PDAC tumour explant model. We cultured whole-tissue tumour explants from PDAC patients for 12 days and demonstrated that explants maintained their 3D multicellular architecture, proliferative state, and collagen fibrosis. We also demonstrated the ability to deliver chemotherapeutics and siRNA-nanoparticles to the tumour explants. Finally, we tested the utility of this model to investigate the clinical potential of silencing three different therapeutic targets. We showed that therapeutic silencing of βIII-tubulin combined with TRAIL increased extrinsic apoptosis, decreased cell proliferation, and decreased tumour cell number. Inhibition of the stromal target SLC7A11 reduced tumour cell number and inhibited activity of stromal cancer-associated fibroblasts. Silencing of another target, HSP47, also led to a reduction in tumour cells and decreased cell proliferation. Overall, this work has discovered a previously unexplored role of βIII-tubulin as a brake on extrinsic cell death and has developed a new human PDAC preclinical model with utility in the drug development and precision medicine pipeline.
(2022) Gunasekera, SanjivThesisThe arteriovenous fistula (AVF) is a vasculature created for end-stage renal disease patients who undergo haemodialysis. This vasculature is often affected by stenosis in the juxta-anastomotic (JXA) region and the presence of disturbed haemodynamics within the vessel is known to initiate such diseased conditions. A novel treatment involving the implantation of a flexible stent in the JXA region has shown potential for retaining healthy AVFs. Only a limited number of experimental studies have been conducted to understand the disturbed flow conditions, while the impact of stent implantation on the haemodynamics within the AVF is yet to be explored. The study was initiated by developing a benchtop patient-specific AVF model to conduct a Tomographic Particle Image Velocimetry (Tomo-PIV) measurement. The subsequent temporally resolved volumetric velocity field was phase-averaged to quantify fluctuations occurring over the inlet pulsatile conditions. It was noted that high turbulent kinetic energy (TKE) was generated at the JXA region. To study the effects of the stent implantation, Large Eddy Simulations (LES) comparing the AVF geometry with and without the presence of the stent implantation were conducted. The trajectory of the flow in the stented case was funnelled within the stent encapsulated region which in turn, contained the disturbed flow within the stent lumen while mitigating the generation of turbulence. Consequently, the distribution of adverse wall shear stress (WSS) in the stented region was much lower compared to that of the `stent-absent' case. Simulations were also conducted on the diseased patient AVF, before the stent implantation, to make an overall assessment of the effect of treatment. Larger and persistent regions of high TKE were noted in the vessel downstream of the stenosis despite the lower velocity of flow in the diseased model. In summary, the stent implantation in the patient AVF showed the ability to funnel flow disturbances away from the vessel wall, thereby leading to lower adverse WSS distributions. The presence of the stent also mitigated turbulence generation. These findings provide valuable insight into the favourable haemodynamic effects of this novel endovascular procedure, thus, substantiating this treatment strategy to treat vascular disease in AVFs.
(2022) Overton, KristenThesisAddressing antimicrobial resistance (AMR) as a purely medical problem fails to recognise the sociological factors that drive the misuse of antimicrobials. Antimicrobial use is shaped by the local social, cultural, political and economic context. There is now widespread recognition that addressing AMR requires an understanding of the social factors that underpin our use and prescription of antimicrobials. Sociological and anthropological explorations of the global antimicrobial crisis have thus far disproportionately focused on economically wealthier nations. This is despite the recognition of economically poorer nations as sites of considerable, escalating, and often unregulated, antimicrobial use. This thesis examines the social dynamics of antimicrobial use in the Indian context through ethnographic observations and 100 qualitative interviews with doctors, community health practitioners, pharmacists, pharmacy employees and community members in Hyderabad, India. Using a constructivist grounded theory approach to data collection and analysis, the focus is on gaining an understanding of how enduring and emerging inequalities, infective risk and uncertainty, labour risks and precarious work, improvisation and self-medication, and informal and formal pharmaceutical economies shape antimicrobial use in India. Using a critical sociological lens, I explore: the dynamics of biopolitics and risk; the pharmaceuticalisation of everyday life and the vested interests therein; the economies of healthcare and antimicrobial use, including commodification and privatisation; and the vulnerability and structural violence associated with the use of antimicrobials. Knowledge of the social dynamics driving antimicrobial use can then in the future be used to inform policies and programs aimed at optimising antimicrobial use in India, appropriately tailoring them to context, rather than continuing with pan-national approaches that do little to accommodate considerations of the Global South.
(2022) O'Hagan, EdelThesisLow back pain is common and burdensome. The economic burden of low back pain in Australia includes total costs that exceed A$8 billion per year, costs which are projected to increase by 60% over the next 10 years. Less is known about the personal burden of low back pain. The first-line treatment consistently recommended for people with low back pain is patient education and advice. Regardless of the duration of low back pain, clinicians should provide advice to remain active, education on the benign nature of low back pain, and reassurance about the absence of a serious medical condition. Little guidance is available on how best this can be achieved. New treatments are urgently required to stem the rising costs of low back pain. Two proposed strategies are repurposing medicines, such as sleep medicines and media campaigns to target unhelp behaviours and beliefs. The overarching aim of this thesis was to investigate the personal burden of low back pain, evaluate attitudes toward education and advice for low back pain and explore contemporary options for managing low back pain. The methods used included qualitative content analysis, an observational study, development and evaluation of a new measurement tool, a systematic review and a randomised controlled trial. People with and without low back pain, online and in-person were recruited to participate across the five studies. The findings from each study are presented in individual chapters. The evidence in this thesis provides a scientific basis for understanding the personal burden of low back pain. The results describe how evaluating attitude toward education and advice could enable clinicians to tailor the patient education and advice they provide. Specific messages of reassurance rather than information about staying active should be prioritised. The Attitude toward Education and advice for Low back pain Questionnaire (AxEL-Q) is a valid and reliable tool to provide clinicians with an insight into attitudes toward education and advice at the outset of a clinical encounter. Sleep medicines should be further investigated before being endorsed to reduce pain intensity in people with acute low back pain. Social media and digital health interventions such as conversational agents provide options for supplementing low back pain management in the future.