Development and synthesis of innovative approaches to the surgical assessment of articular cartilage degeneration

This research has established, through ultrasound, near infrared spectroscopy and biomechanics experiments, parameters and parametric relationships that can form the framework for quantifying the integrity of the articular cartilage-on-bone laminate, and objectively distinguish between normal/healthy and abnormal/degenerated joint tissue, with a focus on articular cartilage. This has been achieved by: 1. using traditional experimental methods to produce new parameters for cartilage assessment; 2. using novel methodologies to develop new parameters; and 3. investigating the interrelationships between mechanical, structural and molec- ular properties to identify and select those parameters and methodologies that can be used in a future arthroscopic probe based on points 1 and 2. By combining the molecular, micro- and macro-structural characteristics of the tissue with its mechanical properties, we arrive at a set of critical benchmarking parameters for viable and early-stage non-viable cartilage. The interrelationships between these characteristics, examined using a multivariate analysis based on principal components analysis, multiple linear regression and general linear modeling, could then to deter- mine those parameters and relationships which have the potential to be developed into a future clinical device. Specifically, this research has found that the ultrasound and near infrared techniques can subsume the mechanical parameters and combine to characterise the tissue at the molecular, structural and mechanical levels over the full depth of the cartilage matrix. It is the opinion in this thesis that by enabling the determination of the precise area of in uence of a focal defect or disease in the joint, demarcating the boundaries of articular cartilage with dierent levels of degeneration around a focal defect, better surgical decisions that will advance the processes of joint management and treatment will be achieved. Providing the basis for a surgical tool, this research will contribute to the enhancement and quanti�cation of arthroscopic procedures, extending to post- treatment monitoring and as a research tool, will enable a robust method for evaluating developing (particularly focalised) treatments.

Pro-inflammatory growth factors reduce secondary degeneration after traumatic spinal cord injury

The role of inflammatory response after spinal cord injury remains unclear. This thesis was a step forward in studying how promoting the inflammation, by delivery pro-inflammatory growth factors, affects the outcomes of spinal cord injury. A significant functional improvement was observed after treatment and these results suggest an interesting avenue for future clinical treatments and may provide a platform to improve the efficacy of other treatments.

The mechanics of disc degeneration from an engineering and computational modelling viewpoint

The anatomy and microstructure of the spine and in particular the intervertebral disc are intimately linked to how they operate in vivo and how they distribute loads to the adjacent musculature and bony anatomy. The degeneration of the intervertebral discs may be characterised by a loss of hydration, loss of disc height, a granular texture and the presence of annular lesions. As such, degeneration of the intervertebral discs compromises the mechanical integrity of their components and results in adaption and modification in the mechanical means by which loads are distributed between adjacent spinal motion segments.

Reduction of Secondary Degeneration after Spinal Cord Injury by Acute Delivery of Proinflammatory Growth Factors

INTRODUCTION Inflammation is a protective attempt to facilitate the removal of damaged tissue and to initiate the healing response in other tissues. However, after spinal cord injury (SCI), this response is prolonged leading to secondary degeneration and glial scarring. Here, we investigate the potential of sustained delivery of pro-inflammatory factors vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) to increase early inflammatory events and promote inflammatory resolution. Method Animal ethics approval was obtained from the Queensland University of Technology. Adult Wistar-Kyoto rats (12-16 weeks old) were subjected to laminectomies and T10 hemisections. Animals were then randomised to treatment (implantation of osmotic pump (Alzet) loaded with 5ug VEGF & 5 ug PDGF) or control groups (lesion control or lesion plus pump delivering PBS). Rats were sacrificed at one month and the spinal cords were harvested and examined by immunohistology, using anti-neurofilament-200(NF200) and anti- ionized calcium binding adapter molecule 1 (Iba1). One way ANOVA was used for statistic analysis. Results At 1 month, active pump-treated cords showed a high level of axonal filament throughout the defects as compared to the control groups. The mean lesion size, as measured by NF200, was 0.47mm2 for the lesion control, 0.39mm2 for the vehicle control and 0.078mm2 for the active pump group. Significant differences were detected between the active pump group and the two control groups (AP vs LC p= 0.017 AG vs VC p= 0.004). Iba-1 staining also showed significant differences in the post-injury inflammatory response. Discussion We have shown that axons and activated microglia are co-located in the lesion of the treated cord. We hypothesise the delivery of VEGF/PDGF increases the local vessel permeability to inflammatory cells and activates these along with the resident microglia to threshold population, which ultimately resolved the prolonged inflammation. Here, we have shown that maintaining the inflammatory signals for at least 7 days improved the morphology of the injured cord. Conclusion This study has shown that boosting inflammation, by delivery VEGF/PDGF, in the early phase of SCI helps to reduce secondary degeneration and may promote inflammation resolution. This treatment may provide a platform for other neuro-regenrative therapies.

Choreographing research : supervising the dancing thesis

The dancing doctorate is an interrogative endeavour which can but nurture the art form and forge a beneficial dynamism between those who seek and those who assess the emerging knowledges of dance’. (Vincs, 2009) From 2006-2008 three dance academics from Perth, Brisbane and Melbourne undertook a research project entitled Dancing between Diversity and Consistency: Refining Assessment in Postgraduate Degrees in Dance, funded by the ALTC Priority Projects Program. Although assessment rather than supervision was the primary focus of this research, interviews with 40 examiner/supervisors, 7 research deans and 32 candidates across Australia and across the creative arts, primarily in dance, provide an insight into what might be considered best practice in preparing students for higher research degrees, and the challenges that embodied and experiential knowledges present for supervision. The study also gained the industry perspectives of dance professionals in a series of national forums in 5 cities, based around the value of higher degrees in dance. The qualitative data gathered from these two primary sources was coded and analysed using the NVivo system. Further perspectives were drawn from international consultant and dance researcher Susan Melrose, as well as recent publications in the field. Dance is a young addition to academia and consequently there tends to be a close liaison between the academy and the industry, with a relational fluidity that is both beneficial and problematic. This partially explains why dance research higher degrees are predominantly practice-led (or multi-modal, referring to those theses where practice comprises the substantial examinable component). As a physical, embodied art form, dance engages with the contested territory of legitimising alternative forms of knowledge that do not sit comfortably with accepted norms of research. In supporting research students engaged with dance practice, supervisors traverse the tricky terrain of balancing university academic requirements with studies that are emergent, not only in the practice and attendant theory but in their methodologies and open-ended outcomes; and in an art form in which originality and new knowledge also arises from collaborative creative processes. Formal supervisor accreditation through training is now mandatory in most Australian universities, but it tends to be generic and not address supervisory specificity. This paper offers the kind of alternative proposed by Edwards (2002) that improving postgraduate supervision will be effective if supervisors are empowered to generate their own standards and share best practice; in this case, in ways appropriate to the needs of their discipline and alternative modes of thesis presentation. In order to frame the qualities and processes conducive to this goal, this paper will draw on both the experiences of interviewees and on philosophical premises which underpin the research findings of our study. These include the ongoing challenge of dissolving the binary oppositions of theory and practice, especially in creative arts practice where theory resides in and emerges from the doing as much as in articulating reflection about the doing through what Melrose (2003) terms ‘mixed mode disciplinary practices’. In guiding practitioners through research higher degrees, how do supervisors deal with not only different forms of knowledge but indeed differing modes of knowledge? How can they navigate tensions that occur between the ‘incompatible competencies’ (Candlin, 2000) of the ‘spectating’ academic experts with their ‘irrepressible drive ... to inscribe, interpret, and hence to practise temporal closure’, and practitioner experts who create emergent works of ‘residual unfinishedness’ (Melrose 2006) which are not only embodied but ephemeral, as in the case of live performance?

Dancing doctorates down-under? Defining and assessing ‘doctorateness’ when embodiment enters the thesis

Assessment frames the focus of this paper, which emerges from our collaborative research, Dancing Between Diversity and Consistency: Refining Assessment in Postgraduate Degrees in Dance, funded by the Australian Learning and Teaching Council (ALTC). We examine the attributes of danced ‘doctorateness’, giving special attention to those factors in the Australian environment, which may endow resilience to concepts of excellence, independent thinking and originality when kinaesthetic knowledge becomes pivotal to research. Have the small pool of examiners and relationships between academia and the professional artistic environment shaped these doctorates in a particular way? Can these perspectives illuminate and forge parameters by which to legitimate danced insight? These and related issues are interrogated giving voice to supervisors, research deans, candidates and industry professionals across Australia who participated in this research project.

A news story as big as a doctoral thesis? : deploying journalistic methodology in academic research

The purpose of this paper is to identify and recommend the emergence of an academic research methodology for Journalism the academic discipline, through reviewing various journalistic methods of research – those making up a key element in such methodology. Its focus is on journalistic styles of work employed in academic contexts especially research on mass media issues. It proposes that channelling such activity into disciplined academic forms will enhance both: allowing the former to provide more durable and deeper outcomes, injecting additional energy and intensity of purpose into the latter. It will briefly consider characteristics of research methodologies and methods, generally; characteristics of the Journalism discipline, and its relationship with mass media industries and professions. The model of journalism used here is the Western liberal stream. A proposition is made, that teaching and research in universities focused on professional preparation of journalists, has developed so that it is a mature academic discipline. Its adherents are for the most part academics with background in journalistic practice, and so able to deploy intellectual skills of journalists, while also accredited with Higher Degrees principally in humanities. Research produced in this discipline area stands to show two characteristics: (a) it employs practices used generally in academic research, e.g. qualitative research methods such as ethnographic studies or participant observation, or review of documents including archived media products, and (b) within such contexts it may use more specifically journalistic techniques, e.g. interviewing styles, reflection on practice of journalism, and in creative practice research, journalistic forms of writing – highlighting journalistic / practitioner capabilities of the author. So the Journalism discipline, as a discipline closely allied to a working profession, is described as one where individual professional skills and background preparation for media work will be applicable to academic research. In this connection the core modus operandi will be the directly research-related practices of: insistent establishment of facts, adept crafting of reportage, and economising well with time. Prospective fields for continuing research are described:- work in new media; closer investigation of relations among media producers and audiences; journalism as creative practice, and general publishing by journalists, e.g. writing histories.

Dancing the Thesis : Potentials and Pitfalls in Practice-led Research

Practice-led or multi modal theses (describing examinable outcomes of postgraduate study which comprise the practice of dancing/choreography with an accompanying exegesis) are an emerging strength of dance scholarship; a form of enquiry that has been gaining momentum for over a decade, particularly in Australia and the United Kingdom. It has been strongly argued that, in this form of research, legitimate claims to new knowledge are embodied predominantly within the practice itself (Pakes, 2003) and that these findings are emergent, contingent and often interstitial, contained within both the material form of the practice and in the symbolic languages surrounding the form. In a recent study on ‘dancing’ theses Phillips, Stock, Vincs (2009) found that there was general agreement from academics and artists that ‘there could be more flexibility in matching written language with conceptual thought expressed in practice’. The authors discuss how the seemingly intangible nature of danced / embodied research, reliant on what Melrose (2003) terms ‘performance mastery’ by the ‘expert practitioner’ (2006, Point 4) involving ‘expert’ intuition (2006, Point 5), might be accessed, articulated and validated in terms of alternative ways of knowing through exploring an ongoing dialogue in which the danced practice develops emergent theory. They also propose ways in which the danced thesis can be ‘converted’ into the required ‘durable’ artefact which the ephemerality of live performance denies, drawing on the work of Rye’s ‘multi-view’ digital record (2003) and Stapleton’s ‘multi-voiced audio visual document’(2006, 82). Building on a two-year research project (2007-2008) Dancing Between Diversity and Consistency: Refining Assessment in Postgraduate Degrees in Dance, which examined such issues in relation to assessment in an Australian context, the three researchers have further explored issues around interdisciplinarity, cultural differences and documentation through engaging with the following questions:  How do we represent research in which understandings, meanings and findings are situated within the body of the dancer/choreographer?  Do these need a form of ‘translating’ into textual form in order to be accessed as research?  What kind of language structures can be developed to effect this translation: metaphor, allusion, symbol?  How important is contextualising the creative practice?  How do we incorporate differing cultural inflections and practices into our reading and evaluation?  What kind of layered documentation can assist in producing a ‘durable’ research artefact from a non-reproduce-able live event?

An experimental and finite element investigation of the biomechanics of vertebral compression fractures

Osteoporosis is a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis affects over 200 million people worldwide, with an estimated 1.5 million fractures annually in the United States alone, and with attendant costs exceeding $10 billion dollars per annum. Osteoporosis reduces bone density through a series of structural changes to the honeycomb-like trabecular bone structure (micro-structure). The reduced bone density, coupled with the microstructural changes, results in significant loss of bone strength and increased fracture risk. Vertebral compression fractures are the most common type of osteoporotic fracture and are associated with pain, increased thoracic curvature, reduced mobility, and difficulty with self care. Surgical interventions, such as kyphoplasty or vertebroplasty, are used to treat osteoporotic vertebral fractures by restoring vertebral stability and alleviating pain. These minimally invasive procedures involve injecting bone cement into the fractured vertebrae. The techniques are still relatively new and while initial results are promising, with the procedures relieving pain in 70-95% of cases, medium-term investigations are now indicating an increased risk of adjacent level fracture following the procedure. With the aging population, understanding and treatment of osteoporosis is an increasingly important public health issue in developed Western countries. The aim of this study was to investigate the biomechanics of spinal osteoporosis and osteoporotic vertebral compression fractures by developing multi-scale computational, Finite Element (FE) models of both healthy and osteoporotic vertebral bodies. The multi-scale approach included the overall vertebral body anatomy, as well as a detailed representation of the internal trabecular microstructure. This novel, multi-scale approach overcame limitations of previous investigations by allowing simultaneous investigation of the mechanics of the trabecular micro-structure as well as overall vertebral body mechanics. The models were used to simulate the progression of osteoporosis, the effect of different loading conditions on vertebral strength and stiffness, and the effects of vertebroplasty on vertebral and trabecular mechanics. The model development process began with the development of an individual trabecular strut model using 3D beam elements, which was used as the building block for lattice-type, structural trabecular bone models, which were in turn incorporated into the vertebral body models. At each stage of model development, model predictions were compared to analytical solutions and in-vitro data from existing literature. The incremental process provided confidence in the predictions of each model before incorporation into the overall vertebral body model. The trabecular bone model, vertebral body model and vertebroplasty models were validated against in-vitro data from a series of compression tests performed using human cadaveric vertebral bodies. Firstly, trabecular bone samples were acquired and morphological parameters for each sample were measured using high resolution micro-computed tomography (CT). Apparent mechanical properties for each sample were then determined using uni-axial compression tests. Bone tissue properties were inversely determined using voxel-based FE models based on the micro-CT data. Specimen specific trabecular bone models were developed and the predicted apparent stiffness and strength were compared to the experimentally measured apparent stiffness and strength of the corresponding specimen. Following the trabecular specimen tests, a series of 12 whole cadaveric vertebrae were then divided into treated and non-treated groups and vertebroplasty performed on the specimens of the treated group. The vertebrae in both groups underwent clinical-CT scanning and destructive uniaxial compression testing. Specimen specific FE vertebral body models were developed and the predicted mechanical response compared to the experimentally measured responses. The validation process demonstrated that the multi-scale FE models comprising a lattice network of beam elements were able to accurately capture the failure mechanics of trabecular bone; and a trabecular core represented with beam elements enclosed in a layer of shell elements to represent the cortical shell was able to adequately represent the failure mechanics of intact vertebral bodies with varying degrees of osteoporosis. Following model development and validation, the models were used to investigate the effects of progressive osteoporosis on vertebral body mechanics and trabecular bone mechanics. These simulations showed that overall failure of the osteoporotic vertebral body is initiated by failure of the trabecular core, and the failure mechanism of the trabeculae varies with the progression of osteoporosis; from tissue yield in healthy trabecular bone, to failure due to instability (buckling) in osteoporotic bone with its thinner trabecular struts. The mechanical response of the vertebral body under load is highly dependent on the ability of the endplates to deform to transmit the load to the underlying trabecular bone. The ability of the endplate to evenly transfer the load through the core diminishes with osteoporosis. Investigation into the effect of different loading conditions on the vertebral body found that, because the trabecular bone structural changes which occur in osteoporosis result in a structure that is highly aligned with the loading direction, the vertebral body is consequently less able to withstand non-uniform loading states such as occurs in forward flexion. Changes in vertebral body loading due to disc degeneration were simulated, but proved to have little effect on osteoporotic vertebra mechanics. Conversely, differences in vertebral body loading between simulated invivo (uniform endplate pressure) and in-vitro conditions (where the vertebral endplates are rigidly cemented) had a dramatic effect on the predicted vertebral mechanics. This investigation suggested that in-vitro loading using bone cement potting of both endplates has major limitations in its ability to represent vertebral body mechanics in-vivo. And lastly, FE investigation into the biomechanical effect of vertebroplasty was performed. The results of this investigation demonstrated that the effect of vertebroplasty on overall vertebra mechanics is strongly governed by the cement distribution achieved within the trabecular core. In agreement with a recent study, the models predicted that vertebroplasty cement distributions which do not form one continuous mass which contacts both endplates have little effect on vertebral body stiffness or strength. In summary, this work presents the development of a novel, multi-scale Finite Element model of the osteoporotic vertebral body, which provides a powerful new tool for investigating the mechanics of osteoporotic vertebral compression fractures at the trabecular bone micro-structural level, and at the vertebral body level.

Do research thesis examiners need training? : practitioner stories

We are thesis examiners within the Australian academic system who formed a “community of practice” to try to resolve some of the issues we were facing. Stories of examiners reflecting on and examining their own practice are a notable silence in the higher degree research literature. In this study we have adopted a storytelling inquiry method that involved telling our practitioner stories, firstly to each other and then to a wider audience through this paper. We then identified issues that we believe are relevant to other thesis examiners. We have also found that engaging in a “community of practice” is itself a valuable form of examiner professional development. Key Words: Thesis Examiner Training, Storytelling, and Practitioner Research

Physiological investigation of periosteum structure and its application in periosteum tissue engineering

Although many different materials, techniques and methods, including artificial or engineered bone substitutes, have been used to repair various bone defects, the restoration of critical-sized bone defects caused by trauma, surgery or congenital malformation is still a great challenge to orthopedic surgeons. One important fact that has been neglected in the pursuit of resolutions for large bone defect healing is that most physiological bone defect healing needs the periosteum and stripping off the periosteum may result in non-union or non-healed bone defects. Periosteum plays very important roles not only in bone development but also in bone defect healing. The purpose of this project was to construct a functional periosteum in vitro using a single stem cell source and then test its ability to aid the repair of critical-sized bone defect in animal models. This project was designed with three separate but closely-linked parts which in the end led to four independent papers. The first part of this study investigated the structural and cellular features in periostea from diaphyseal and metaphyseal bone surfaces in rats of different ages or with osteoporosis. Histological and immunohistological methods were used in this part of the study. Results revealed that the structure and cell populations in periosteum are both age-related and site-specific. The diaphyseal periosteum showed age-related degeneration, whereas the metaphyseal periosteum is more destructive in older aged rats. The periosteum from osteoporotic bones differs from normal bones both in terms of structure and cell populations. This is especially evident in the cambial layer of the metaphyseal area. Bone resorption appears to be more active in the periosteum from osteoporotic bones, whereas bone formation activity is comparable between the osteoporotic and normal bone. The dysregulation of bone resorption and formation in the periosteum may also be the effect of the interaction between various neural pathways and the cell populations residing within it. One of the most important aspects in periosteum engineering is how to introduce new blood vessels into the engineered periosteum to help form vascularized bone tissues in bone defect areas. The second part of this study was designed to investigate the possibility of differentiating bone marrow stromal cells (BMSCs) into the endothelial cells and using them to construct vascularized periosteum. The endothelial cell differentiation of BMSCs was induced in pro-angiogenic media under both normoxia and CoCl2 (hypoxia-mimicking agent)-induced hypoxia conditions. The VEGF/PEDF expression pattern, endothelial cell specific marker expression, in vitro and in vivo vascularization ability of BMSCs cultured in different situations were assessed. Results revealed that BMSCs most likely cannot be differentiated into endothelial cells through the application of pro-angiogenic growth factors or by culturing under CoCl2-induced hypoxic conditions. However, they may be involved in angiogenesis as regulators under both normoxia and hypoxia conditions. Two major angiogenesis-related growth factors, VEGF (pro-angiogenic) and PEDF (anti-angiogenic) were found to have altered their expressions in accordance with the extracellular environment. BMSCs treated with the hypoxia-mimicking agent CoCl2 expressed more VEGF and less PEDF and enhanced the vascularization of subcutaneous implants in vivo. Based on the findings of the second part, the CoCl2 pre-treated BMSCs were used to construct periosteum, and the in vivo vascularization and osteogenesis of the constructed periosteum were assessed in the third part of this project. The findings of the third part revealed that BMSCs pre-treated with CoCl2 could enhance both ectopic and orthotopic osteogenesis of BMSCs-derived osteoblasts and vascularization at the early osteogenic stage, and the endothelial cells (HUVECs), which were used as positive control, were only capable of promoting osteogenesis after four-weeks. The subcutaneous area of the mouse is most likely inappropriate for assessing new bone formation on collagen scaffolds. This study demonstrated the potential application of CoCl2 pre-treated BMSCs in the tissue engineering not only for periosteum but also bone or other vascularized tissues. In summary, the structure and cell populations in periosteum are age-related, site-specific and closely linked with bone health status. BMSCs as a stem cell source for periosteum engineering are not endothelial cell progenitors but regulators, and CoCl2-treated BMSCs expressed more VEGF and less PEDF. These CoCl2-treated BMSCs enhanced both vascularization and osteogenesis in constructed periosteum transplanted in vivo.