The Er:YAG laser and the USPL are the most promising when considering the previous study results and their physical characteristics. This investigation compared the healing of various laser ablation units versus conventional mechanical cutting to explore the future applications for bone surgery and the effects when combined with rhBMP-7. A full-thickness circular defect was created on the parietal bones of mice for all the groups. Hard tissue healing was assessed using a microcomputerized tomography. Wound closure analyses suggested that the femtosecond laser created wounds displayed slightly healing delay in closure over the healing period when compared to mechanical instrumentation. The Er:YAG laser showed a healing rate similar to that of the mechanically ablated groups. In summary, femtosecond and Er:YAG lasers are two modalities suitable for bone ablation comparable to mechanical instrumentation.

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The mechanics applied to healing fractures vary widely. At one extreme rigid internal fixation is advocated, while at the other early mobilisation is recommended using external splints. Kuhn's method of paradigm orientated research was used to define the historical context of current assumptions regarding fracture healing. Conflict between the various schools of thought is the main evidence for failure of these assumptions and the need to evolve a new perspective on fracture healing. A paradigm is presented which proposes healing by external callus as an early stage and 'primary healing' as the later stage as of one continuous but changing process. A fundamental hypothesis was tested: that mechanics is the major control of fracture healing in man. A multicentre study of 102 patients with serious fractures were treated with external skeletal fixation. In 60 patients rigid external fixation was applied. In the remaining 42 the same fixation device was used, but adapted to apply 1 to 2mm of cyclic axial micromovement across the fracture. A piston applied 500 cycles of movement over a 30 minute period each day until this could be achieved by the patient on weight-bearing. Objective assessment required development of new techniques of measuring fracture stiffness and defining the point of healing. This objective measure, and clinically defined healing, were significantly faster in the group treated with micromovement (two-way analysis of variance, p = 0.005 and 0.03, respectively). Repeated injury by plastic deformation is proposed to maintain callus growth in the first phase of healing. Evidence for the required parameters of movement was gathered from the trial of micromovement, from measurements in 4 cases of epiphyseolysis and also 8 patients undergoing arthrodesis. It would appear appropriate to apply cyclic axial displacement of 2mm within the first two weeks from injury and of consistent direction until sufficient bulk of callus is formed. Thereafter axial compaction is appropriate in a second phase where callus matures. The mechanics that govern remodelling were considered to apply to the final phase. Failure of a cell culture model to display obvious results from cyclic loading may indicate that the response to mechanical loading is indirect. Intermediate and mechanically dependent biochemical and bioelectrical factors are discussed.

This thesis describes a study characterising some of the material properties of cancellous bone from patients suffering from either osteoporosis or osteoarthritis whose femoral heads were surgically removed during hip replacement operations. For comparison, a variety of animal bones, having a range of mineral contents, and synthetic hydroxyapatite were also studied. These material properties were studied using the following techniques: thermogravimetric analysis linked to mass spectrometer (TGA-MS), powder x-ray diffraction (PXRD), mercury intrusion porosimeter (MIP) and high-temperature x-ray diffraction (HTXRD). The animal bones used were deer antler, whale periotic fin, whale ear bone, whale tympanic bulla, cod clythrum and porpoise ear. The TGA-MS determined the organic and the mineral proportions in bone and within the mineral the amount of the different types of carbonate was identified and quantified. The PXRD was used to measure the lattice dimensions and the crystallite sizes of human bone in order to find out if these parameters are altered in diseased bone. In synthetic hydroxyaptite (SHA), the PXRD was employed to determine the optimum sintering temperature as well as for monitoring the phase change that occurred when SHA was heated to high temperature. Phase monitoring was further carried in two of the animal species using HTXRD. This was used in preference to post-sinter-quenching of samples in order to obtain true, <i>in-situ</i> measurements of the composition at each temperature.

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Bone cell differentiation and remodelling are controlled by hormones, growth factors and specific transcriptional regulators. This thesis aims to investigate the role of two transcription factors, c-Fos/AP-1 and Msx-1/2 in osteoclast and osteoblast differentiation using in vivo and in vitro approaches. c-Fos has been shown previously to be essential for osteoclast differentiation and is overexpressed in osteoclasts of Paget's disease. To investigate the role of c-Fos in osteoclasts, transgenic mice were generated where c-fos was overexpressed in osteoclasts using the TRAP promoter. Several TRAP-c-fosLTR transgenic founders were generated which developed severe bone remodelling lesions with eventual tumour formation. Histological and in situ expression studies showed abundant osteoclasts within these lesions which expressed c-Fos, in addition to the anti-apoptotic gene Bcl-2. These features are reminiscent of Pagetic osteoclasts and suggest that these mice are useful for studying bone remodelling disorders. The effects of c-Fos on osteoblasts was next investigated in vitro using a well defined inducible expression system. Stable MC3T3-E1 osteoblastic subclones expressing a tetracycline-regulatable c-fos gene demonstrated that exogenous c-Fos appeared to augment the proliferation induced by BMP-2, and inhibited BMP-2-induced alkaline phosphatase activity during differentiation. Moreover, ectopic c-Fos expression in these cells stimulated apoptosis induced by serum withdrawal and Etoposide. This apoptosis was not effectively blocked by the caspase inhibitors Z-VAD-fmk and DEVD-CHO, but was blocked by the cell cycle dependent kinase (CDK) inhibitor, Roscovitine, and ectopic Bcl-2 or p2l^{WAF1,CIP1,SD11} expression. These results may provide a novel link between growth control and apoptosis in osteoblasts, such that under environmental stress, c-Fos may drive cell cycle progression and render the cell susceptible to apoptosis. Finally, the regulation of Msx2 by osteotropic factors using two reporter gene constructs was analysed in osteoblastic cells. PTH showed no regulation of Msx2 expression, however, small increases were observed with BMPs. The expression of Msx1 during bone development was also analysed in tissues from Msx1-lacZ transgenic mice. LacZ expression was detected in mineralising tissues of the foetus and neonate, but no LacZ expression was observed after birth. Taken together, these data further delineate the functional roles of these transcription factors in bone development and bone disease. Importantly, these studies provide a role for c-Fos in osteoblast apoptosis and osteoclast function, and may serve as a model for c-Fos overexpression in Paget's disease.

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