A reabsorção óssea alveolar associada as perdas dentais constitui uma condição inerente ao processo de cicatrização fisiológico natural. Técnicas como a instalação de implantes imediatos e técnicas de preservação alveolar têm sido sugeridas com o objetivo de limitar as alterações adversas sofridas pelo processo alveolar. Contudo, frequentemente as perdas dentárias estão associadas a infecções crônicas que tradicionalmente contraindicariam os procedimentos de enxerto ou implantes imediatos, a menos que meticulosos debridamento e irrigação alveolar associados a adequado protocolo antibiótico pré e pós-operatório sejam empregados. Alternativas precisam ser testadas para a substituição do uso indiscriminado de antibioticoterapia sistêmica. O objetivo do presente estudo foi avaliar o efeito da TFDa na descontaminação de alvéolos infectados previamente a instalação de implantes imediatos e na cicatrização de alvéolos pós-extração associados ou não ao uso de enxertos xenógeno através de análises microtomográficas e histomorfométricas. Para tanto, foram selecionados 8 cães, os quais foram submetidos a uma fase de indução de doença periodontal por ligadura, seguida por um período de estabelecimento da doença. Após a exodontia dos prémolares bilaterais, aleatoriamente os alvéolos de um lado da mandíbula foram descontaminados por debridamento mecânico associado a irrigação com solução salina (grupo controle) e do outro lado por debridamento mecânico e irrigação com solução salina associados a terapia fotodinâmica antimicrobiana (grupo teste), e subsequentemente submetidos a instalação de implantes imediatos, dando origem aos grupos GT-I (Grupo Teste - Implante) e GC-I (Grupo Controle - Implante). Os demais alvéolos, foram utilizados para o estudo da dinâmica de cicatrização alveolar. Os sítios foram aleatoriamente alocados em: GT-C (Grupo teste - Coágulo), GT-BO (Grupo Teste - Bio-Oss®), GT-BOC (Grupo Teste - Bio-Oss® Collagen), GC-C (Grupo Controle - Coágulo), GC-BO (Grupo Controle - Bio-Oss®) e GC-BOC (Grupo Controle - Bio-Oss® Collagen). Após 12 semanas, os cães foram sacrificados e as amostras processadas para as análises de microtomografia computadorizada, histologia e histomorfometria. Na avaliação da cicatrização dos alvéolos pós-extração, embora os alvéolos descontaminados com TFDa (GT-C, GT-BO, GT-BOC) tenham apresentado melhores resultados numéricos, em relação a altura da crista óssea vestibular (ACOV) e a dimensão buco-lingual (DBL), não foram evidenciadas diferenças relevantes na análise histomorfométrica. Apenas a ACOV, mensurada na avaliação microtomográfica bidimensional, demonstrou-se significativamente inferior nos alvéolos do grupo teste que não receberam material de enxerto (GT-C) quando comparados aos respectivos alvéolos do grupo controle (GC-C). Na avaliação dos implantes imediatos, a análise histomorfométrica dos parâmetros: reabsorção da crista óssea vestibular (RCOV) e contato osso implante (BIC) demonstrou resultados significantemente superiores no GT-I em relação ao GC-I, e do parâmetro densidade óssea (DO) demonstrou apenas resultado numericamente superior no GT-I em relação ao GC-I. Todas as análises microtomográficas bidimensionais (RCOV) e tridimensionais (volume ósseo BV, porcentagem óssea BV/TV, densidade de superfície óssea BS/TV, espessura trabecular Tb.TH, número de trabéculas Tb.N e separação trabecular Tb.SP) demonstraram resultados significantemente melhores nos implantes do grupo teste (GT-I) em relação aos implantes do grupo controle (GC-I). A TFDa demonstrou potencial como agente de descontaminação de alvéolos pósextração periodontalmente infectados, previamente a instalação de implantes imediatos e na cicatrização de alvéolos pós-extração associados ou não a materiais de enxerto xenógenos, sem o uso de antibioticoterapia sistêmica associada. / Alveolar bone resorption following tooth loss is an inherent condition of the natural healing process. Therefore, several techniques, such as immediate implants placement and post extraction socket preservation, have been suggested in order to limit the adverse changes suffered by the alveolar process. However, extraction sockets commonly results from the removal of teeth affected by chronic infection, which conventionally contraindicates immediate bone graft and implant placement unless meticulous wound debridement and alveolar irrigation associated to a suitable pre- and post-operatory antibiotic protocol are employed. Alternatives ought to be tested in order to substitute the indiscriminate use of systemic antibiotic therapy. The aim of the present study was to evaluate the effect of the antimicrobial photodynamic therapy (aPDT) in the decontamination of infected post extraction sockets, previously to immediate implant placement and in the healing of post extraction sockets associated or not to xenografts. In the first phase, periodontitis was induced with ligatures in the mandibular premolars of eight beagle dogs. After 2 months, in the second phase of the study the dogs had their mandibular bicuspids bilaterally extracted, and randomly one hemi-mandible was decontaminated by mechanic debridement associated to saline solution irrigation (Control Group - CG), and the other hemi-mandible was decontaminated with mechanic debridement and saline solution irrigation associated to antimicrobial photodynamic therapy (Test Group - TG). Thereafter, 3 immediate implants in each side of the mandible were placed and the following groups were devised: TG-I (Test Group - Implant) and CG-I (Control Group - Implant). The remaining sockets were used for the study of the healing dynamic. The sockets were randomly assigned to the following groups: Test Group - Blood clot (TG-BC), Test Group Bio- Oss® (TG-BO), TG - BOC (Test Group Bio-Oss® Collagen), Control Group - Blood Clot (CG-BC), Control Group - Bio-Oss® (CG-BO) and Control Group - Bio-Oss® Collagen (CG-BOC). After 12 weeks, the dogs were sacrificed and the specimens were processed for microtomographic, histological and histomorphometric analysis. When the post extraction healing process was evaluated, the aPDT decontaminated sockets (TG-BC, TG-BO and TG-BOC) presented better numerical results in comparison to both buccal bone crest height (BCL) and in the bucco-lingual dimension (BLD). However, there were no statistically differences among the groups for these parameters in the histomorphometric analysis. Only the BCL measured in the two-dimensional microtomographic analysis showed statistic better results in the TG-BC when compared to the CG-BC. In the evaluation of the immediate implant placement the histomorphometric analysis presented statistically better results for the TG-I in the bone-implant contact (BIC), as well as in the vertical buccal bone loss (VBBL). The bone density (BD) was numerically better in the TG-I than in the CG-I. Both two-dimensional (VBBL) and three-dimensional (bone volume BV, percentage of the total bone volume - BV/TV, bone surface density - BS/TV, trabecular thickness Tb.Th, trabecular separation Tb.Sp and trabecular number TB.N) microtomographic analysis showed statistically better results in the TG-I. The aPDT showed potential in the decontamination of infected post extraction sockets previously to immediate implant placement and in the healing of post extraction sockets associated or not to xenogeneic grafts, without the use of systemic antibiotics.

Introdução: O diabetes mellitus (DM) é uma doença crônica caracterizada pela hiperglicemia associada a diversas alterações sistêmicas e uma das suas complicações é o processo de reparo ósseo comprometido. Entretanto, ainda não há estudos utilizando análises celulares e biomoleculares que avaliem o processo de reparo ósseo desta desordem metabólica quando associada à expansão rápida da maxila (ERM). Objetivo: O objetivo deste estudo foi avaliar a remodelação óssea e sinalização osteogênica durante a aplicação de mecânica ortodôntica para ERM em ratos diabéticos tipo1- induzidos. Material e Métodos: Cento e cinquenta ratos Wistar, machos, foram divididos aleatoriamente em seis grupos de estudo. Grupos: controle (C, n=30), veículo (V, n=15), diabetes mellitus tipo 1 induzido com estreptozotocina (D, n=30), controle submetido à ERM (Cd, n=30), veículo submetido à ERM (Vd, n=15) e diabetes mellitus tipo 1 induzido com estreptozotocina submetido à ERM (Dd, n=30). Os animais foram eutanasiados aos 3, 7 e 10 dias após ERM . Análises histológicas, mudanças no padrão de expressão gênica e proteica de osteoprotegerina, (OPG), RANK, RANKL, osteonectina (ONC), osteocalcina (OCC), sialoproteína óssea (BSP), osteopontina (OPN) e proteína morfogenética óssea 2 (BMP2), assim como as mudanças no peso corporal, na ingestão de água na glicemia foram avaliadas. A análise da expressão gênica e proteica foram realizadas por qRT-PCR e Western Blotting, respectivamente. Os dados foram submetidos ao teste estatístico ANOVA de duas vias e pós-teste de Tukey (α= 0,05). Resultados: Histologicamente no grupo Dd foi notado maior reabsorção óssea, com diversas áreas em degradação com ausência de osteoblastos, intensa atividade de reabsorção óssea solapante, presença de osteoclastos, células inflamatórias associada ao comprometimento da formação óssea quando comparado aos grupos D e Cd. Estes resultados foram confirmados também nos achados moleculares, uma vez que algumas sinalização gênicas e proteicas relacionadas a osteogênese foram reduzidas, ao passo que a sinalização osteoclastogênica foi estimulada, principalmente no período inicial de reparo ósseo. No grupo D, o processo de formação ósseo estava atrasado comparado ao grupo C, devido a alteração da expressão dos genes e proteínas que regulam o catabolismo e anabolismo ósseo, haja vista que havia maior presença de tecido ósseo imaturo e maior quantidade de áreas de remodelação ativa até o período mais tardio de estudo. No grupo Cd foi observado remodelação óssea, caracterizada por um tecido desorganizado na região da sutura palatina mediana, com intensas áreas inflamatórias, hemorrágicas e reabsortivas comparado ao grupo C. Contudo, até o período de 10 dias pós abertura da sutura, não foi possível observar o completo preenchimento do gap sutural por tecido ósseo. Estes resultados histológicos foram observados na sinalização de genes e proteínas no grupo Cd, uma vez que estes biomarcadores de formação e reabsorção óssea estavam alterados quando comparados aos grupos C e Dd. Conclusões: O DM alterou a sinalização para o metabolismo ósseo e atrasou o processo de reparo após ERM. Estes resultados reforçam a necessidade de avaliar o status do metabolismo ósseo dos pacientes durante tratamento ortopédico e/ ou ortodôntico, visto que a aplicação destas forças na presença do DM podem promover efeitos indesejáveis. / Background: Diabetes mellitus (DM) is a disease associated with several disorders of health in humans and one of the most important is the jeopardizing of bone formation. However, to the best of our knowledge there is no information about the influence of diabetes on orthodontic and orthopedic treatment at cellular and molecular levels. Objective: The aim of this study was to evaluate bone remodeling process in palatal suture during orthopedic mecanotherapy in rats with type 1-induced diabetes mellitus. Material and Methods: One hundred and fifty Wistar male rats were randomly assigned to six groups. Groups: control (C, n=30), vehicle (B, n=15), type 1-induced diabetes mellitus using streptozotocin (D, n=30), control with RME (C+RME, n=30), vehicle with RME (C+RME, n=15) and type 1-induced diabetes mellitus using streptozotocin with RME (D+RME, n=30). The animals were euthanized at 3, 7 and 10 days after RME. Histologic evaluations, changes in genes and proteins expression of osteoprotegerin (OPG), RANK, RANKL, osteonectin (ONC), osteocalcin (OCC), bone sialoprotein (BSP), osteopontin (OPN) and bone morphognetic protein 2 (BMP2) were evaluated along with the changes in body weight, water intake and glycemic profile. Real-Time RT-PCR and Western Blotting were used to evaluate gene and the protein expression. Data were submitted to statistical analysis using two-way ANOVA followed by Tukey test ( α= 0,05). Results: On group D+RME it was observed an increased bone resorption, serveral undermining and tissue degradation areas. On the suture gap there were mainly inflammatory and osteoclasts cells associated with compromised bone formation compared to groups D and Cd. These results were observed also in molecular levels, since there were a reduced osteogenesis and an upregulation of osteoclastogenesis, mainly in early period of healing. On group D, bone formation was compromised compared to group C, due to changes on genes and proteins expression which regulates bone metabolism, considering that there was more immature bone and incresead active remodeling areas until late periods. On group Cd it was observed bone remodeling, characterized by desorganized tissue on the gap of midpalatal suture, with intense inflammatory hemorhagic and resorptive areas compared to group C. However until 10 days after RME, on group D the gap was not completely filled with bone tissue. These results were observed on the signaling of molecular biomarkers on group Cd, since they were changed compared to groups C and Dd. Conclusions: DM modify the signaling for bone metabolism and compromise bone repair after RME. During orthopedic and orthodontic treatment is necessary to evaluate metabolism status of subjects, since the application of these forces have been shown to promote undesirable effects mostly when associated with DM.

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional structural spine deformity with lateral curve and vertebral rotation occurring predominantly in adolescent girls during the peri-pubertal period. The prevalence of AIS is nearly 4% in Hong Kong and 2-3% worldwide. AIS without treatment or with improper treatment may deteriorate progressively and lead to significant cosmetic problems and functional disabilities. In severe cases, increased mortality rate can result from the associated early onset of cardiopulmonary failure. Up to now, the treatment of the AIS is basically passive through bracing and corrective spinal surgery. The current protocol of treatment is not totally satisfactory since the curve may continue to progress with brace treatment and corrective surgery is associated with major surgery and permanent fusion of parts of the spine. This is due to the fact that one is still uncertain about the etiology of AIS and therefore cannot directly treat the AIS. Among the different proposed etiology of AIS, the role of abnormal skeletal growth and development during peri-pubertal period has been one of the main focuses in addition to genetic predisposition in the development of AIS. / It has been well established that girls with idiopathic scoliosis have a tendency to be taller and more slender than their peers. Recently, it has been shown that the trabecular bone mineral density at the spine, hip, and peripheral bones of AIS girls was lower than their healthy peers. Studies from our center have also demonstrated growth discrepancy between anterior and posterior vertebral column using magnetic resonance imaging (MRI) technique. The vertebral bodies were shown to be slender in AIS patients than that in normal controls. The observation pointed to a disproportionate growth of the anterior and posterior spinal column resulting from imbalance in endochondral and membranous ossification. The present study hypothesizes that the abnormality of skeletal growth could be a systemic problem affected by both endochondral ossification and membranous ossification. The degree of abnormal growth could vary with different curve severities. The concurrent finding of abnormal skeletal growth and osteopenia could be related to certain underlying abnormal genetic factors affecting the etiopathogenesis of AIS. The hypothesis leads to the following objectives: (1) To study the anthropometric measurements and the related changes in AIS girls with different curve severity; (2) To document the presence of abnormal systemic growth through endochondral ossification; (3) To document the presence of abnormal membranous ossification through studies of the morphology and bone mineral density of the midshaft of the appendicular skeleton and the skull; (4) To study the association of occurrence of AIS and its related phenotypes with the genes associated with growth and osteopenia. (Abstract shortened by UMI.) / by Yeung Hiu-Yan. / "January 2006." / Adviser: Jack C. Y. Cheng. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6301. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 206-227). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Introdução: A sobrevida dos pacientes com lúpus eritematoso sistêmico juvenil (LESJ) tem melhorado progressivamente nas últimas décadas. Sendo assim, novos aspectos devem ser considerados no acompanhamento destes pacientes, tais como comprometimento da massa óssea e doenças periodontais. Objetivos: 1- Avaliar parâmetros do metabolismo ósseo e saúde oral em pacientes com LESJ comparando com grupo controle saudável; 2 - Avaliar possíveis associações entre parâmetros do remodelamento ósseo e densidade mineral óssea com alterações orais, assim como com: dados demográficos, manifestações clínicas, índices de atividade e dano cumulativo da doença, terapias utilizadas e qualidade de vida relacionada à saúde em pacientes com diagnóstico de LESJ. Métodos: Foram avaliadas 24 adolescentes púberes do sexo feminino com diagnóstico de LESJ e 29 adolescentes púberes saudáveis do sexo feminino quanto aos dados demográficos, antropométricos, clínicos e hábitos de vida.. Nos pacientes também foram determinados os índices de atividade da doença, de dano cumulativo e de qualidade de vida e a terapêutica utilizada. A avaliação do metabolismo ósseo incluiu a medida dos níveis de osteoprotegerina sérica (OPG), soluble receptor activator of nuclear factor kappa B ligand (sRANKL), propeptídeo N-terminal do prócolágeno tipo I (P1NP), telopeptídeo carboxiterminal do colágeno tipo I (CTX), 25-hidroxivitamina D, paratormônio (PTH) e densidade mineral óssea (DMO). Pacientes e controles foram submetidas à avaliação clínica oral, incluindo características clínicas, avaliação dentária e periodontal. Resultados: Pacientes com LESJ apresentaram Z-Score da coluna lombar (p < 0,001), fêmur total (p=0,027), colo do fêmur (p=0,015) e corpo total (p < 0,001) significantemente menores quando comparados aos controles saudáveis. Apresentaram também níveis significantemente mais baixos de P1NP (p=0,007), CTX (p < 0,001) e de PTH (p=0,009) quando comparados ao grupo controle. Foi encontrada correlação negativa estatisticamente significante entre dose cumulativa de glicocorticoides (GC) e o Z-Score do colo do fêmur (r= -0,491 p=0,024). Pacientes com Z-Score <= -2 no fêmur total tinham idade ao diagnóstico significantemente maior quando comparados àquelas com Z-Score > -2 [14,5 anos vs 11 anos (p=0,038)]. A mediana do número de dentes cariados, perdidos e obturados (CPO-D) foi significativamente maior em pacientes com LESJ (p=0,010) comparados aos controles e maiores doses cumulativas de GC estiveram correlacionadas com maiores índices de CPO-D (r= +0,435 p=0,048). Conclusão: Pacientes com LESJ tem redução da massa mineral óssea e do remodelamento ósseo quando comparados a controles saudáveis. Maiores doses cumulativas de GC foram correlacionadas a maior número de CPO-D e a baixa densidade mineral óssea. A DMO do fêmur total é menor em pacientes com idade maior ao diagnóstico, sugerindo que o processo inflamatório e o uso de GC durante as fases de maior formação óssea acarretam maior impacto na massa óssea. Não foi encontrada associação entre densidade ou parâmetros de metabolismo ósseo e alterações orais / Introduction: The survival of Juvenile systemic lupus erythematosus (JSLE) patients has improved progressively. Thus, new aspects must be considered in the monitoring of these patients, such as impairment of bone mass and periodontal disease. Objective: 1- To assess bone mineral density, bone turnover parameters and oral health in patients with JSLE; 2- To evaluate possible associations between parameters of bone remodeling and bone mineral density with oral amendments, as well as demographic data, clinical manifestations, activity rates and cumulative damage, therapy and quality of life related to health in patients with JSLE. Methods: Twenty-four female adolescent JSLE patients were studied and compared to 29 female adolescent healthy controls regarding demographic, anthropometric and clinical data, and habits of life. In patients also were determined indices of quality of life, activity and cumulative damage of disease and therapy used. Evaluation parameters of bone metabolism included serum levels of osteoprotegerin (OPG), soluble receptor activator of nuclear factor KB ligand (sRANKL), propeptídeo N-terminal of type I collagen (P1NP), telopeptide of type I collagen (CTX), 25 hydroxyvitamin D, parathyroid hormone (PTH) and bone mineral density (BMD). Orofacial evaluation included clinical features, dental and periodontal assessment in patients and health controls. Results: Patients with JSLE presented lower Z-score in lumbar spine (p < 0.001), total femur (p=0.027), femoral neck (p=0.015) and total body (p < 0.001) when compared to healthy controls. They also presented lower levels of P1NP (p=0.007), CTX (p < 0.001), and PTH (p=0.009) when compared to the later group. It was found a negative correlation between the cumulative dose of glucocorticoids (GC) and the femoral neck Z-score (r= -0,491 p=0.024). Patients with Z- score <= -2 in total femur had significantly higher age at diagnosis compared to those with Z- score > -2 [14,5 years vs 11 years (p= 0,038)]. Median of decayed, missing and filled teeth (DMFT) was significantly greater in JSLE patients (p=0.010) than controls. Higher cumulative doses of GC were correlated with higher indices of DMFT (r= +0.435 p=0.048). Conclusion: JSLE patients have decreased bone mineral density and bone turnover when compared to healthy controls. Furthermore, they have a larger number of DMFT. Cumulative doses of GC were correlated to the number of DMFT and low BMD. Total femur BMD was lower in patients that were older at diagnosis, suggesting that the inflammatory process and the use of GC during the greatest bone formation period constitute the major impact factors on bone mass. No association was found between BMD, bone metabolism and oral abnormalities

Foi analisada a parte trabecular do colo do fêmur de 13 pacientes do sexo feminino, com idade acima dos 60 anos, com o método da histomorfometria óssea. Sete destas pacientes tiveram fratura do colo do fêmur. Todas foram submetidas a artroplastia do quadril. O exame de densitometria óssea não mostrou diferença significativa. Na espessura média das trabéculas não houve diferença significativa, porém o número de trabéculas foi menor e a separação entre elas foi maior no grupo com fraturas. / A histomorphometry evaluation of the trabecular part of the femoral neck was performed in 13 women over 60 years old submitted to hip arthroplasty. Seven of these patients had a femoral neck fracture. The bone mineral density showed no difference between both groups. The average thickness did not have significant between both groups, but the trabecular separation was higher and the number of trabecular bone was lower in the fracture group.

Le système ostéo-articulaire a un rôle de soutien essentiel pour l’ensemble du corps humain. Il supporte les forces de gravité et les efforts produits par les activités quotidiennes. Ainsi l’os optimise et adapte sa masse et sa géométrie à travers le processus de remodelage osseux. Cette régulation spatio-temporelle peut subir des déséquilibres métaboliques comme l’ostéoporose qui conduisent à la survenue de fracture de l’extrémité supérieure du fémur lors d’une chute latérale ou de traumatismes divers. En effet l’ostéoporose se traduit par une diminution au niveau de la densité osseuse et des détériorations au niveau de la microarchitecture du tissu osseux augmentant ainsi le risque de fractures.Dans le cadre de cette thèse une modélisation mécanique du comportement de l’os ainsi qu’une modélisation biologique des activités cellulaires ont été proposées dans un premier temps. Dans un second temps, la pharmacocinétique de quatre médicaments a été modélisé soient l’Alendronate, le Denosumab,le Romosozumab et l’Odanacatib. Finalement, le couplage de ces modèles a permis d’avoir un modèle mécano-biologique couplé aux effets des médicaments contre l’ostéoporose qui permet de prédire l’évolution de la densité minérale osseuse et celle de l’endommagement par fatigue permettant ainsi d’analyser l’évolution de la qualité osseuse. Ce modèle a été implémenté au code de calcul par éléments finis ABAQUS/standard à travers sa routine utilisateur UMAT. Le modèle a été appliqué pour simuler différents scénarii de remodelage sur des fémurs humains (2D et 3D). Différents facteurs ont été analysés tels que l’amplitude des activités physiques, les doses de médicaments injectées, la durée des traitements, etc. les résultats obtenus sont cohérents (qualitativement) avec les études cliniques existantes. En conclusion, le modèle mécano-biologique couplé aux effets des médicaments proposés contribue à l’analyse fine du comportement de l’os et l’application des algorithmes a permis d’effectuer des essais virtuels permettant d’analyser les effets combinés de nombreux facteurs pluridisciplinaires caractérisant la qualité osseuse. / The osteo-articular system plays the role of crucial support for the whole human body. It supports the gravity forces as well as the efforts generated by daily activities. Thus the bone optimizes and adapts its mass and its geometry through the process of bone remodeling. This spatio temporal regulation can undergo metabolic imbalances such as osteoporosis which lead to the occurrence of the upper end of the femur fracture during a fall side or various traumas. In fact, osteoporosis is reflected into a decrease in bone density and level of damage at the level of the microarchitecture of bone tissue increasing therefore the risk of fractures. In the framework of this thesis, a mechanical modelling of the behaviour of the os as well as a biological modelling of cellular activities were firstly proposed. Secondly, the pharmacokinetics of four drugs were modeled which are Alendronate, Denosumab, the Romosozumaband the Odanacatib. Finally, the coupling of these models allowed us to have a mechanic-biological model coupled with the effects of drugs against osteoporosis that can predict the evolution of bone mineral density and of damage by fatigue allowing to analyze the evolution of the bone quality. This model has been implemented by finite elements ABAQUS/standard through its user routine UMAT.The model has been applied to simulate different scenarios of remodeling on human femurs (2D and3D). Different factors were analysed such as the range of physical activities, the doses of injected drugs,the duration of treatment, etc. Obtained results are consistent (qualitatively) with existing clinical studies.As a conclusion, the mechanic-biological model coupled with the effects of the proposed drugs contributes to the fine analysis of the bone behaviour and the application of algorithms allowed to conduct virtual tests in order to analyze the combined effects of many multidisciplinary factors characterizing the bone quality.

Alors que les phases de résorption et de couplage du cycle de remodelage de l’os sont de plus en plus connues et ont permis le développement d’agents thérapeutiques, la phase d’activation reste peu étudiée. L’objectif global de ce travail est d’analyser les évènements cellulaires mis en jeu au cours de la phase d’activation du remodelage de l’os. Les objectifs spécifiques ont été 1- de caractériser le trafic cellulaire dans le périoste au cours de la phase d’activation du remodelage et 2- d’étudier le rôle d’une enzyme, la nicotinamide phosphorybosyl transférase (Nampt) dans ces évènements. Dans notre premier travail, nous montrons dans un modèle de remodelage synchronisé de l’os alvéolaire, une expression précoce de ICAM-1 par les vaisseaux qui serait impliquée dans la diapédèse observée de monocyte-macrophages CD68+. Ces cellules migreraient à travers le compartiment non ostéogénique puis ostéogénique, guidées par des cellules de type fibroblastes puis des OB exprimant VCAM-1. Le nombre des cellules RANKL+ dans le compartiment ostéogénique augmente graduellement lors de la phase d’activation. En parallèle, l’expression de la sémaphorine 3a, qui inhibe l’ostéoclastogénèse, diminue chez les OB et les ostéocytes superficiels. Dans notre second travail, nous trouvons que l’expression basale de la Nampt est accrue dans les cellules de la couche ostéogénique au cours de la phase d’activation du remodelage. Inhiber son activité via le FK866 permet de diminuer l’ostéoclastogenèse indiquant que la Nampt serait impliquée dans le recrutement et l’activité des OC. En culture primaire d’ostéoblastes murins, nous montrons que son expression augmente au cours de la différentiation et qu’elle régule l’expression de marqueurs tardifs de différentiation. L’ensemble de ces données montre une série d’évènements coordonnés qui servent au recrutement des précurseurs ostéoclastiques et à leur migration vers la surface osseuse à résorber. La Nampt semble jouer un rôle dans l’acquisition des ostéoblastes d’un phénotype favorable à ces évènements. / Resorption and inversion phases of bone remodeling are well understood, which have permitted the development of therapeutic agents. At the opposite, activation phase remains poorly characterized. This work aims to analyze cellular events involved in the activation phase of bone remodeling. Specific goals were: 1- To characterize cellular traffic in the periosteum during the activation phase of bone remodeling. 2- To study the role of NicotinAMide Phosphorybosyl Transférase (NAMPT) enzyme during activation. In the first study, we show an early expression of ICAM-1 by vessels in a synchronized alveolar-bone-remodeling model. The ICAM-1 expression may be involved in the observed diapedesis of monocytes – macrophages CD68+. These cells migrate through non osteogenic and osteogenic layers, steered by fibroblast-like cells and then by VCAM+ osteoblasts (OB). The number of RANKL+ cells in osteogenic layer gradually increases during the activation phase. Simultaneously, the expression of semaphorine 3a inhibiting osteoclastogenesis, decreases in osteoblasts and superficial osteocytes. In the second study, we show that basal expression of NAMPT increases in osteogenic-layer cells during the activation phase of bone remodeling. Inhibiting its activity with FK866 enhables to decrease osteoclastogenesis, suggesting an involvement of NAMPT in osteoclast recruitment and activity. In primary culture of murine OB, we show that NAMPT expression increases during differentiation. It also regulates OB late-differentiation markers expression. All these data show a series of coordinated events which serve in osteoclasts precursors’ recruitment and migration towards bone surface. NAMPT seems to contribute to acquiring an OB phenotype more favorable to OC recruitment.

[Truncated abstract] Bone remodeling is an important process to maintain mechanical integrity. It is accomplished by two important steps, bone resorption followed by new bone formation. Osteoclasts and osteoblasts are the principal cells in bone resorption and bone formation, respectively. A multitude of local and systemic factors regulates this process by controlling the cellular activities in bone remodeling compartments (BRC). An imbalance of osteoblastic bone formation and osteoclastic bone destruction will result in the development of skeletal diseases. Recent studies suggested that angiogenesis is closely associated with bone remodeling. The vasculature in bone is important for skeletal development, growth and repair. During endochondral ossification, cartilage is invaded by blood vessels which bring in osteoblast and osteoclast precursor cells, nutrients, growth factors and differentiation factors. During fracture repair, it has been demonstrated that mature osteoclasts produce heparanase which can degrade heparin sulfate proteoglycans, a major component in extracellular matrix (ECM). The process leads to the release of heparin-binding growth factors including vascular endothelial growth factor (VEGF), a potent angiogenic factor which contributes largely to local angiogenesis. In recent studies, endothelial cells have been found to produce bone morphogenetic protein (BMP)-2 and BMP-4 when they are subjected to mechanical stimuli, or a hypoxia environment. Conversely, inhibition of angiogenesis has been shown to prevent fracture healing. In a distraction osteogenesis model, either inhibition of angiogenesis or disruption of the mechanical environment prevents normal osteogenesis and results in fibrous nonunion. .... A total of 42 mice from F1 and F2 generations were genotyped as transgene positive. Preliminary analysis using radiography did not reveal any difference between the gross structures of transgenic and wild type mice. Interestingly, the preliminary histology revealed a decrease in trabecular bone and an increase of lipid space in metaphysis of transgenic mice overexpressing EGFL6. However, further studies will need to be carried out to investigate the role of EGFL6 in angiogenesis and adipogenesis using a transgenic mice model. This will be a prime focus of future work. Collectively, the results presented in this thesis have identified EGFL6, a member of the EGF-like family, as a potential angiogenic factor which may play an important role in bone remodeling. EGFL6 has been found to be expressed highly in calvarial osteoblasts and upregulated during primary murine osteoblast differentiation. EGFL6 has been 8 characterized to be a secreted homomeric complex. More importantly, EGFL6 has been shown to induce angiogenic activity in endothelial cell migration, tube formation and in vivo chick embryo chorioallantoic membrane assay. Furthermore, conditioned medium containing the EGFL6 recombinant protein was shown to induce phosphorylation of ERK in endothelial cells. Inhibition of ERK impaired EGFL6-induced ERK activation and endothelial cell migration. Taken together these studies raise the possibility that EGFL6 has a potential role in angiogenesis, and mediates a paracrine mechanism of cross-talk between vascular endothelial cells and osteoblasts during osteogenesis. An understanding of this process offers the potential to facilitate the development of therapeutic treatments for bone disease.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O propósito deste estudo foi analisar o comportamento do osso alveolar na remodelação óssea sob carga fisiológica e ortopédica após a disjunção rápida da sutura palatina mediana durante 14 dias, com e sem aplicação de laser de baixa potência e comparar imagens obtidas por técnica radiográfica convencional com microtomografias computadorizadas. O aparelho de laser utilizado foi de diodo de arsenieto de gálio-alumínio (AlGaAs) (830&#61544;m; 100mW, onda contínua, 126J/cm2, 29 segundos) aplicado à sutura palatina mediana de ratos Wistar, machos, de 6 semanas de vida. Foram utilizados 65 ratos divididos em um grupo controle (GC) contendo 5 ratos e dois experimentais I e II (GE I e GE II), com 30 ratos cada, ambos GE submetidos à disjunção imediata, sendo que o GE II foi irradiado imediatamente após a disjunção. Os GE I e II foram subdivididos em períodos de disjunção imediata, 6, 24, 48 horas, 7 e 14 dias. Dois amostras de cada período dos GC e GE foram radiografadas (convencional) e processadas para captura de imagens em scanner micro-CT (Scanco Medical, Zurik, Suíça), com 24KV de energia e 3,8&#956;m de resolução espacial e o restante foram processadas para serem analisadas histologicamente coradas com hematoxilina e eosina e tricrômico de Masson. Os resultados foram avaliados histológica e radiograficamente. O trabeculado ósseo recém-formado a partir dos bordos ósseos da sutura foi observado nos períodos de 2, 7 e 14 dias do GE II, 7 e 14 dias do GE I. O presente experimento demonstrou que a atividade osteoblástica aumenta a atividade da osteosíntese de modo mais expressivo após aplicação do laser de baixa potência, porem é necessários mais estudos em biologia molecular para desvendar os seus efeitos ao nível celular. As microtomografias computadorizadas mostraram maior riqueza de detalhes para analisar o rompimento da sutura palatina mediana e seu reparo com o depósito de tecido ósseo do que as radiografias convencionais. / The purpose of this study was to evaluate the behavior of the alveolar bone on bone remodeling under physiological load and on after rapid midpalatal suture expansion during a 14-day period, with and without low-level laser irradiation and to compare images obtained by conventional radiographic technique with microtomografias computed. The laser device was a gallium-aluminum-arsenide (GaAlAs) diode laser (830 &#61544;m; 100 mW, continuous wave, 126 J/cm2, 29 seconds) applied to the midpalatal suture of 6-week-old male Wistar rats. Sixty-five rats were assigned in a control group (CG) containing 5 rats and two experimental I and II (EG I and EG II), with 30 rats each, both EG submitted to expansion immediately, while the EG II was irradiated pos expansion immediately. The EG I and II were divided into periods of immediate midpalatal suture expansion, 6 hours, 1, 2, 7 and 14 days). . Two samples of each period of CG and EG were radiographed (conventional) and processed to capture images in micro-CT scanner (Scancem Medical, Zurik, Switzerland) with 24kV of energy and 3.8 mm in spatial resolution and the rest were processed for are analyzed histologically stained with hematoxylin and eosin and Masson's trichrome.The results were evaluated histologically and radiographically. Bone trabeculae recently formed from the bone borders of the suture were observed in the periods of 2, 7 and 14 days of EG II, and 7 and 14 days of EG I. The present experiment demonstrated that the osteoblastic activity increases the osteosynthesis activity in a more manner after low-level laser irradiation. However, more studies in the field of molecular biology are necessary to determine its effects at cellular level. The computed microtomographs provided a more detailed analysis of midpalatal suture opening and its repair by bone tissue deposition than conventional radiographs.

Made available in DSpace on 2014-06-11T19:31:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-03-14Bitstream added on 2014-06-13T19:20:07Z : No. of bitstreams: 1 kayatt_fe_dr_araca.pdf: 743751 bytes, checksum: a6f9587cf07b5001b3dd1c88f814cb3e (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Sin Implantes / A estabilidade primária na instalação de implantes dentários é uma das determinantes principais no processo de osseointegração. Algumas situações clínicas impossibilitam o travamento adequado do implante. A diástase provocada por sobrefresagem ou implantações pós-exodônticas indicam o uso de materiais para ocupar este espaço. O objetivo deste estudo foi analisar o uso de copolímero a base de ácido poliláctico na estabilidade primária de implantes osseointegráveis, realizando uma avaliação microscópica através de fluorocromos. Para isso, foram utilizados 14 cilindros de Ti cp GII instalados na tíbia de ratos, divididos em: Grupo Implante Travado (GIT) e Grupo Implante e Biomaterial (GIB), nos períodos de 7, 15 e 21 dias. Resultado: Os implantes suportaram 3N.cm de torque reverso e não foram encontradas diferenças estatisticamente significantes, nos períodos finais, entre as médias das áreas ao redor do implante. O copolímero de PLA/PGA proporcionou o posicionamento dos implantes e não obstou a deposição óssea. / The primary stability in the installation of dental implants is one of the main prerequisite in the osseointegration process. Some clinical situations disable the adequate stability of the implantation. A gap occurred between the bone and the implant provoked by overdrilling or tooth extractions sockets implantations indicates the use of biomaterials to occupy this space. The aim of this study was to analyze the use of PLA/PGA copolymer in the primary stability of osseointegrated implants, through removal torque test and a microscopic evaluation with fluorescent bone markers. For this, 14 cylinders of Ti cp GII had been installed in the tibia of rats, divided in: Group Implant with Stability (GIT) and Group Implant and Biomaterial (GIB), in the periods of 7, 15 and 21 days. Result: The implantations had supported 3N.cm of removal torque and had not been found differences statistically significant, in the final periods, between the averages of the areas of the periphery of the implants. The PLA/PGA copolymer kept the implants position and did not hinder the bone deposition.