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Note:

Centric relation, centric occlusion, power eccentric, ccentric occlusion, acquired occlusion, habitual occlusion, maximum intercuspation, rest position, intercuspal position, retruded position; - these are just some of the many terms that have been used in attempting to describe dental occlusion. This multitude of terms, and the many different eanings that have been applied to the same terms, is indicative of the confusion that has existed, and still exists today in our understanding of occlusion.[...]

Advisors/Committee Members: (Supervisor).

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A prospective, randomized, experimental study was performed to assess the treatment of mandibular continuity defects by distraction osteogenesis, using the rabbit model. This method of treatment was compared to a control group, which had treatment by traditional means, using a fixation plate. Eight animals were randomized into one of the two groups.

The treatment methods were assessed by clinical, radiographic, and histologic examinations.

Clinically, the experimental specimens had greater dimensions of bone formation in the defects than their matched controls.

Radiographically, there was a higher percentage of radiopacity in the defects of the experimental group compared to the controls, although not statistically significant.

Histologically, there was a statistically significant higher percentage of bone fill in the defects of the experimental group compared to the controls. Three of the four experimental specimens (75%) developed bony union at the 'docking site'.

A cost-efficient animal model was developed for the study of bifocal distraction in the treatment of mandibular continuity defects. The critical-sized mandibular defect in the rabbit model was found to be a minimum of 4mm.

Advisors/Committee Members: Clokie, Cameron (advisor).

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Calcium phosphate-based materials have become the first choice for surgeons when they look for a synthetic material for the repair and augmentation of bone. Numerous studies and commercial use over the last three decades have made these materials popular options. These materials are not without their negative aspects, and properties such as poor in vivo resorption and low setting pH are well documented. Magnesium phosphates represent a poorly investigated group of materials with chemical structures similar to those of the calcium phosphates.In this thesis we investigate magnesium phosphates for use as inorganic materials for bone repair. We demonstrated that heat-treatment of magnesium phosphate created a cement reactant, which upon mixing with citric acid or sodium phosphate solutions set to form a cement. Investigation into alternate applications for the cement showed the cement could be dip-coated onto titanium rods. The dip coating formulations were also tested for their ability to release bioactive compounds, showing a relationship between initial burst and sustained release with powder-to-liquid ratio. In vitro testing of the cement showed good biocompatibility with osteoblast-like cells, inducing the expression of osteoblast markers. Preliminary in vivo data showed good material resorption and osteoconduction compared to brushite by four weeks time.Our results demonstrate that magnesium phosphate can be used in bone repair applications. Further study and development may lead to them becoming a viable alternative to calcium phosphates.

Les matériaux à base de phosphate de calcium sont devenus le premier choix pour les chirurgiens quand ils choisissent un matériau synthétique pour la réparation et l'augmentation osseuse. De nombreuses études et d'utilisation commerciale au cours des trois dernières décennies ont fait de ces matériaux une option populaire. Ces matériaux ne sont pas sans désavantages, et les propriétés telles que une résorption lente in vivo et une faible mise en pH sont bien documentés. Les phosphates de magnésium représente un groupe de matériaux peu étudié avec des structures chimiques similaires à celles des phosphates de calcium. Dans cette thèse, nous avons examine les phosphates de magnésium pour l'utilisation en taut que matériaux inorganiques pour la réparation osseuse. Nous avons démontré que le traitement thermique du phosphate de magnésium crée un réactif de ciment, qui apres mélange avec de l'acide citrique ou de solutions de phosphate de sodium forment un ciment. Enquête sur les demandes de remplacement pour le ciment ont démontré que le ciment pourrait être enduit (revêti) sur des tiges de titane. Les formulations de revêtement ont également été testés pour leur capacité à libérer des composés bioactifs, démontrant une relation entre l'éclatement initial et à la libération prolongée avec un rapport poudre-liquide. Des essais in vitro ont démontré que ce ciment a une bonne biocompatibilité avec des cellules ostéoblastiques, ce qui induit l'expression des marqueurs ostéoblastiques.…

Advisors/Committee Members: Jake Barralet (Internal/Supervisor).

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Recent research indicated that certain neurons (brain cells) can regulate bone metabolism and that their damage results in weaker bones. But little was known about the potential that increased activity by these neurons might have on bone. A family of drugs frequently used to treat Alzheimer disease, Acetylcholinesterase inhibitors, is known to stimulate a group of neurons that play a major role in maintaining memory. While these drugs have been widely used in the treatment of Alzheimer disease and other forms of dementia since the mid-1990s, their potential effects on bone biology had not been explored. This thesis presents a group of in vivo and clinical studies that were conducted to test the effects of these drugs on bone. We first have determined that the use of centrally acting acetylcholinesterase inhibitors, such as donepezil, is associated with a beneficial effect on bone strength in mice. Donepezil promoted bone mass accrual by altering the activity of the autonomous nervous system two-arms: the cholinergic and the adrenergic systems. We next have illustrated that the use of peripherally acting acetylcholinesterase inhibitors, such as neostigmine, is associated with an increase in bone quantity and quality. Neostigmine positive-effects on bone were not related to the activity of the central nervous system. However, it was induced by a local effect on the immune system, causing an alteration in the serum level of different immunocytokines (such as IL-17 and IL-23) that are known to regulate bone mass.We then have demonstrated through two cohort retrospective studies that the use of acetylcholinesterase inhibitors in clinics might have beneficial effects on bone. We observed that Alzheimer disease patients who were treated with the acetylcholinesterase inhibitors had lower risk of osteoporotic fracture and faster healing, if the fracture occurred, compared to non-users. Taken together, we believe that the results presented in this thesis might be useful for Alzheimer Disease patients who suffer from bone diseases such as osteoporosis.

Des études récentes ont démontré que les neurones peuvent réguler le métabolisme osseux et que leur déséquilibre peut résulter en une faiblesse osseuse. Peu d'information est disponible sur l'activité osseuse lorsque ces neurones sont stimulées. Certains médicaments connue pour contrôler la maladie Alzheimer, les inhibiteurs de l'acétylcholinestérase, stimulent ces neurones et ont un rôle dans le maintien de la mémoire. Ces médicaments ont été largement utilisés dans le traitement de l'Alzheimer et de d'autres types de démence depuis environ l'an 1995. Cependant, leurs effets potentiels sur la biologie de l'os n'ont pas été encore élucidés. Cette thèse comprend des études in vivo ainsi que des études cliniques qui ont permis de tester l'effet de cette classe de médicaments sur le métabolisme osseux. Tout d'abord, nous avons prouvé que l'utilisation centrale des inhibiteurs de l'acétylcholinestérase tel le donépézil est associée à un effet bénéfique sur la force…

Advisors/Committee Members: Faleh Tamimi Marino (Supervisor).

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Breast cancer is a major health problem. Metastatic disease is generally incurable. In the majority of patients, the skeleton bears the major metastatic burden. Bony lesions of metastatic breast cancer are usually osteolytic. Osteolytic metastases are formed by the pathological activation of osteoclasts. Anti-osteoclastic drugs are standard of care for patients suffering from breast cancer metastases. We conducted this project to decipher the signalling mechanisms responsible for osteoclasts activation in response to exposure to mediators released from mammary carcinoma cells. We evaluated the apoptotic profiles of osteoclasts in vitro in the presence of soluble factors derived from mammary carcinoma cells cultures. We observed a significant inhibition of osteoclasts apoptosis secondary to exposure to breast cancer cells-derived factors. This effect was not reversed with bisphosphonates. The pro-apoptotic protein BIM in osteoclasts was a target of modulation by breast cancer cells-derived factors. We proceeded to characterize the osteoclasts intracellular signalling pathways modulated by mammary carcinoma cells-derived factors. We identified phospholipase C γ (PLC γ) and the mammalian target of rapamycin (mTOR) as mechanistic meditors of the anti-apoptotic effect of cancer cells on osteoclasts. We tested the therapeutic benefit of rapamycin administration in a mouse model of experimental bone metastases of mammary carcinoma. In this model, rapamycin therapy inhibited metastasis-associated osteolysis, prolonged animal survival and reversed some tumour-induced immune changes in the host. Taken together, these studies provide new insights into the pathophysiology of breast cancer metastasis to bone, and demonstrate that targeting osteoclast signalling mediators, such as mTOR provides therapeutic benefits in experimental bone metastasis model.

Le cancer du sein est un problème de santé important. La maladie métastatique est généralement incurable. Dans la majorité de patients, le squelette soutient le fardeau métastatique principal. Les lésions osseuses du cancer du sein métastatique sont habituellement ostéolytique. Des métastases ostéolytique sont constituées par l'activation pathologique des osteoclasts. Les drogues anti-osteoclastiques sont mesures de soin essentiales pour des patients souffrant des métastases de cancer du sein. Nous avons conduit ce projet pour déchiffrer les mécanismes de signalisation responsables de l'activation d'osteoclasts en réponse à l'exposition aux médiateurs libérés des cellules mammaires de carcinome. Nous avons évalué les profils apoptotiques des osteoclasts in vitro en présence des facteurs solubles dérivés des cultures mammaires de cellules de carcinome. Nous avons observé une inhibition significative d'apoptosis d'osteoclasts secondaire à l'exposition aux facteurs cellule-dérivés par cancer du sein. Cet effet n'a pas été renversé avec des bisphosphonates. La pro-apoptotic protéine BIM dans les osteoclasts était une cible de la modulation par des facteurs cellule-dérivés par cancer…

Advisors/Committee Members: Svetlana Komarova (Internal/Supervisor).

▼ Miniaturized titanium implants placed in the diaphysis of mouse femurs were used as a model to examine concurrent effects on bone marrow lymphocytes, while attempting to accelerate the osseointegration of titanium implants by applying human recombinant Transforming Growth Factor Beta1 (TGF-beta 1) in carrier medium to the implant site, prior to implant placement. While the response of lymphocytes to titanium implants has been addressed, at present, the response of these cells in vivo to TGF-beta 1 remains unknown. The use of double immunofluorescence to bind molecular markers has allowed the detection of the various phenotypic stages during B cell differentiation, including both precursor B cells and early progenitor cells, as well as CD4-, and CD8- T cells, in femurs receiving 1mug, 10mug, and 100mug TGF-beta 1/100mul carrier medium, and carrier medium alone prior to implant placement. (Abstract shortened by UMI.) Advisors/Committee Members: Rahal, Dwayne (advisor).