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Full Text, Thesis (Masters), Master of Medical Research (MMedRes), School of Pharmacy & Med Sci, Griffith Health, Bisphosphonates are a group of drugs widely used in medical practice to prevent bone destruction, occurring in diseases like osteoporosis and bone cancer. An unfortunate sideeffect of these potent drugs is the subsequent death of areas of bone in the jaw following minor local trauma, commonly occurring during dental treatment. This unique, but welldocumented, adverse effect is termed medication-related osteonecrosis of the jaws (MRONJ). While the precise cause of MRONJ is still unclear, research suggests the inhibition of new blood vessel formation, limiting the capacity for bone healing, may be a significant factor. Unfortunately, treatment options for MRONJ are very limited, and despite successful development of bone mimetic materials, most available materials do not induce sufficient formation of blood vessels. Adequate vascularisation is crucial for timely and adequate transport of nutrients and waste removal, and the provision of progenitor cells for tissue remodeling and repair. This study provides a rationale for a new innovative approach using a human-adipose derived microvessel (HAMV)-osteoblast construct, which will potentially support local bone regeneration and healing. This project takes the important first steps in vitro, investigating the growth, migration, and viability of the HAMV within a 3D hydrogel construct and assessing the influence of HAMV development on osteogenesis, in order to provide the data necessary for subsequent testing in a pre-clinical animal model. In this study, HAMV were seeded into tissue culture plates and cultured over 28 days, to evaluate the proliferation potential of the HAMV in a 3-dimensional (3D) collagen hydrogel construct. Growth, proliferation and morphological changes, including cell death, of HAMV were also visualised and were examined via LIVE/DEAD® assay with the aid of confocal microscopy. The human osteoblast cell line, MG63, was cultured in conditioned media derived from the HAMV cultures to understand the inf

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Medical Science, Griffith Health, Chronically recurrent urinary tract infection (rUTI) caused most frequently by uropathogenic strains of Escherichia coli (UPEC) are common infections and cause considerable healthcare burdens. Repeated reintroduction of bacteria into the bladder, such as from sexual intercourse, increases the risk of recurrence and chronicity. Studies have sought to define the complex host-pathogen interactions that occur during chronic rUTI, however many areas of mouse rUTI modelling remain incompletely defined. Interleukin 17A (IL-17A) has important roles in the control of acute UTI and may have important roles in the control of chronic rUTI. This thesis aimed to develop and characterise a mouse model of UPEC superinfection and use this to investigate the roles of IL-17A in the pathogenesis and control of chronic rUTI. A mouse model of superinfection was characterised in BALB/c mice, a previously considered resistant mouse strain for chronic rUTI, using a 2 x 108 CFU infectious dose of UPEC strains EC958 (a multidrug-resistant cystitis strain) or CFT073 (a urosepsis and pyelonephritis strain) 24 hours apart. EC958 exhibited significantly higher bacteriuria loads than CFT073, significantly higher bacterial burdens in the kidney after 28 days of infection, and a higher incidence of chronicity, defined as 104 CFU/ml urine at all collection timepoints and in the bladder after 28-days of infection. In IL-17A-/- mice, CFT073 exhibited a significantly higher incidence of chronicity, and, similar to EC958, exhibited kidney bacterial loads compared to WT BALB/c mice. CFT073 was able to induce IL-17A production in BALB/c WT mice, and both strains induced IL-17A production at day 10 and day 28 post-superinfection, which correlated with bladder bacterial load at day 28 post-superinfection. Plasma collected at 24h after superinfection with EC958 was used in a multiplex assay to reveal interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) as predictors of chronic bacteriuria and

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Dentistry&Oral Hlth, Griffith Health, Successful osseous healing is achieved by highly organised and controlled biological processes. Inflammation is an initial and integral part of these biological processes, influencing the fate of overall healing outcomes. Indeed, it has been well established that the skeletal and immune systems closely interact and influence each other in order to regulate bone homeostasis, both in healthy and diseased conditions. Compromised wound healing is one of the major clinical complications of diabetes, often leading to high morbidity and mortality. Pathophysiological changes, such as chronic hyperglycaemia and a resultant pro-inflammatory microenvironment, are considered to be the main aetiological factors in diabetes, contributing to a compromised immune system and poor wound healing potential. Macrophages play a pivotal role in both the initiation and resolution of inflammation by expressing an array of functional phenotypes (e.g. M1 and M2) in response to diverse local microenvironmental chemical cues. A timely transition of inflammatory status from ‘proinflammatory (M1)’ to ‘anti-inflammatory/pro-healing (M2)’, is believed to be a crucial biological step in order to achieve successful wound healing, and there is increasing evidence supporting the notion that macrophages are responsible for this ‘switch’ of microenvironment. This important cellular phenomenon of M1 and M2 phenotypic transition is disrupted in diabetes due to various systemic and local factors, however the underlying cellular mechanisms are yet to be fully elucidated. Recently, numerous in vitro and in vivo studies have investigated the influence of different biomaterial surface characteristics on the resultant immune responses, demonstrating that the expression of macrophage phenotypes can be modulated by surface topography, chemistry and hydrophilicity, thus resulting in enhanced osseous healing. However, there is insufficient evidence in the current literature to support whether such biomaterial enhanc