Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a chronic necrosis of the jawbone that occurs in ≈1-5% of patients receiving bisphosphonate medication for conditions such as osteoporosis and certain cancers. Although the pathogenesis of BRONJ is still uncertain, several recent theories have emerged; these include vascular disruption of the jaw tissue; inappropriate osteoclast activation; and direct cytotoxicity of jaw epithelium. However, despite bisphosphonates having well-documented stimulatory effects on immune cells, and BRONJ being associated with oral microbial infections, an immune-mediated pathology for BRONJ has largely been ignored. Bisphosphonates activate human γδ T cells, specifically those that use T cell receptor (TCR) γ-chain variable-region-9, and TCR δ-chain variable-region-2 (Vγ9Vδ2 T cells). These unconventional T cells typically account for ≈ 1-5% of circulating lymphocytes, make protective responses to microbial challenge, and are promising candidates for cancer immunotherapy. In the context of BRONJ, we have hypothesised that bisphosphonate-mediated activation of jaw-associated Vγ9Vδ2 T cells, in the presence of oral microbiota, may drive the disruption of bone turnover that is central to the disease process. On initiation of these studies, it quickly became apparent that traditional characterisation of Vγ9Vδ2 T cells using CD27/CD45RA was demonstrably sub-optimal, while phenotypic analysis of 63 healthy volunteers revealed an unexpected and surprising degree of Vγ9Vδ2 T cell heterogeneity; both of which are likely to confuse assessment of disease scenarios. Thus, this thesis describes the novel phenotypic and functional characterisation of Vγ9Vδ2 T cells using alternative surface markers and methods of analysis. This reveals that different sets of individuals have different Vγ9Vδ2 T cell “profiles” that predict very different functional capabilities and responses to immunotherapeutic interventions. Using this improved definition of Vγ9Vδ2 T cells, this thesis then describes preliminary investigations of Vγ9Vδ2 T cell development in the human neonatal thymus, and assesses the involvement of Vγ9Vδ22 T cells in a small cohort of eight BRONJ patients.

Advances in the field of medicine have extended the average human life expectancy worldwide. As a result an increasing number of people will suffer from problems associated with their mineralized tissues and will require orthopedic and dental implants to restore their quality of life. Ideally, implants should have mechanical and structural properties compatible with the original mineralized tissue, and should also promote faster and stronger implant fixation. An improved understanding of the properties of mineralized tissues can help with the improvements of implants. This thesis focuses on improving the understanding of two aspects related to mineralized tissues and implant systems: the mechanical properties of peri-implant bone, and the mechanical, composition and structural properties of dentin and jawbone. Studies have shown that local delivery of alendronate, an anti-osteoporosis drug, enhances new bone formation; however, the effects of the drug on the elastic modulus of new formed bone are unknown. In this study, nanoindentation was used to evaluate and compare the elastic modulus of peri-implant bone with and without the presence of alendronate. To better understand the properties of dentin and jawbone, nanoindentation and qualitative backscattered electron imaging were used to measure their elastic modulus, mineral content and volume fraction, and regression analyses were used to establish correlation between the properties. In this thesis, mineralized tissue samples were collected from an animal study. To study the effects of alendronate on the elastic modulus of peri-implant bone, porous tantalum implants with three different coating treatments were used: non-coated (Ta), calcium phosphate coated (Ta-CaP), alendronate-immobilized-calcium-phosphate coated (Ta-CaP-ALN). The calcium phosphate coatings, with or without alendronate, increased the elastic modulus of peri-implant Ingrown Bone by approximately 22% (3GPa). The addition of alendronate did not significantly increase the elastic modulus of peri-implant. For the study of dentin and jawbone, regression analyses showed that the elastic modulus of dentin is strongly dependent on the porosity and to a lesser extent on the calcium content. The elastic modulus of jawbone and dentin were compared and the elasticmodulus of jawbone was generally higher than that of dentin while the mineral content was lower.

Advances in the field of medicine have extended the average human life expectancy worldwide. As a result an increasing number of people will suffer from problems associated with their mineralized tissues and will require orthopedic and dental implants to restore their quality of life. Ideally, implants should have mechanical and structural properties compatible with the original mineralized tissue, and should also promote faster and stronger implant fixation. An improved understanding of the properties of mineralized tissues can help with the improvements of implants. This thesis focuses on improving the understanding of two aspects related to mineralized tissues and implant systems: the mechanical properties of peri-implant bone, and the mechanical, composition and structural properties of dentin and jawbone. Studies have shown that local delivery of alendronate, an anti-osteoporosis drug, enhances new bone formation; however, the effects of the drug on the elastic modulus of new formed bone are unknown. In this study, nanoindentation was used to evaluate and compare the elastic modulus of peri-implant bone with and without the presence of alendronate. To better understand the properties of dentin and jawbone, nanoindentation and qualitative backscattered electron imaging were used to measure their elastic modulus, mineral content and volume fraction, and regression analyses were used to establish correlation between the properties. In this thesis, mineralized tissue samples were collected from an animal study. To study the effects of alendronate on the elastic modulus of peri-implant bone, porous tantalum implants with three different coating treatments were used: non-coated (Ta), calcium phosphate coated (Ta-CaP), alendronate-immobilized-calcium-phosphate coated (Ta-CaP-ALN). The calcium phosphate coatings, with or without alendronate, increased the elastic modulus of peri-implant Ingrown Bone by approximately 22% (3GPa). The addition of alendronate did not significantly increase the elastic modulus of peri-implant. For the study of dentin and jawbone, regression analyses showed that the elastic modulus of dentin is strongly dependent on the porosity and to a lesser extent on the calcium content. The elastic modulus of jawbone and dentin were compared and the elasticmodulus of jawbone was generally higher than that of dentin while the mineral content was lower.

Advances in the field of medicine have extended the average human life expectancy worldwide. As a result an increasing number of people will suffer from problems associated with their mineralized tissues and will require orthopedic and dental implants to restore their quality of life. Ideally, implants should have mechanical and structural properties compatible with the original mineralized tissue, and should also promote faster and stronger implant fixation. An improved understanding of the properties of mineralized tissues can help with the improvements of implants. This thesis focuses on improving the understanding of two aspects related to mineralized tissues and implant systems: the mechanical properties of peri-implant bone, and the mechanical, composition and structural properties of dentin and jawbone. Studies have shown that local delivery of alendronate, an anti-osteoporosis drug, enhances new bone formation; however, the effects of the drug on the elastic modulus of new formed bone are unknown. In this study, nanoindentation was used to evaluate and compare the elastic modulus of peri-implant bone with and without the presence of alendronate. To better understand the properties of dentin and jawbone, nanoindentation and qualitative backscattered electron imaging were used to measure their elastic modulus, mineral content and volume fraction, and regression analyses were used to establish correlation between the properties. In this thesis, mineralized tissue samples were collected from an animal study. To study the effects of alendronate on the elastic modulus of peri-implant bone, porous tantalum implants with three different coating treatments were used: non-coated (Ta), calcium phosphate coated (Ta-CaP), alendronate-immobilized-calcium-phosphate coated (Ta-CaP-ALN). The calcium phosphate coatings, with or without alendronate, increased the elastic modulus of peri-implant Ingrown Bone by approximately 22% (3GPa). The addition of alendronate did not significantly increase the elastic modulus of peri-implant. For the study of dentin and jawbone, regression analyses showed that the elastic modulus of dentin is strongly dependent on the porosity and to a lesser extent on the calcium content. The elastic modulus of jawbone and dentin were compared and the elasticmodulus of jawbone was generally higher than that of dentin while the mineral content was lower. / Applied Science, Faculty of / Materials Engineering, Department of / Graduate

Osseointegration is defined as the direct physical and practical relation between the living tissue and implant surface. Although, success rate of dental implants is high, implant failure occurs. Overloading implants from occlusal forces are known as one of the main reasons. In order to have successful implant, a dynamic balance must be provided between mechanical and biological elements (Isidor, Flemming 1996). Şimşek et al. reported bone quality, oral sanitation, host medical condition and biomechanical parameters as the main reasons for implants failure. Also, implant fixture micromotion and inappropriate stress in the bone implant interface is known as the potential reasons for early bone loss and implant failure (Şimşek, Barış 2006). Even so, implant position in jawbone, bone density; biomaterial properties of implant surface, treatment technique, loading history and patient clinical status are the influential factors in implant success (Brunski, J.B. 1999). Although there are many studies on stress distribution of implants in bone-implant interface, majority are limited to current implants in the market. However, current designs have been developed by marketing purposes rather than scientific considerations. Therefore, there is need to introduce and analyse new designs in order to optimize implant structure. Recent investigations have shown reliability of FEA method in simulating human jawbone situation. This research aims to develop a new dental implant with better life expectancies and introduce an optimized implant based on FEA stress analyses and experimental tests. Therefore, based on literature recommendations a series of new design factors are defined and analysed. In this study, a primary design is created in AutoCAD and yields to 3 different implants developed in SolidWorks. Branemark MK IV was selected as the bench model to play role of control group. Then, CT-scan images of human jawbone are imported to MIMICS to create a host bone model. Implant and jawbone models are assembled in 3-Matic and exported to Abaqus for final analyses. A series of loadings are defined to examine implant performance in different conditions. Branemark and C-3 implants are manufactured from Titanium for experimental analyses. Mechanical tests on sawbone foam blocks and cadavers are targeted to portray realistic performance. This research demonstrates C-3 model as the optimized dental implant, which presents a new design profile and better performance in low bone densities. The FEA and experimental results validate the benefit of the new design compare to the conventional ones. Furthermore, results can provide a basis for future designers to develop further optimizations.

No description available.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.