Introduction: The inflammation plays the essential role in the bone loss in juvenile idiopathic arthritis (JIA). Proinflammatory cytokines and also glucocorticoids (GCs) may activate bone resorption by osteoclasts. Simultaneously, bone formation can be attenuated, especially by inhibitors of proteins, which control the osteoblast differentiation. The aim was to verify the hypothesis that in patients with highly active JIA, reduction of bone formation via Wingless (Wnt) proteins inhibitors - Dickkopf 1 (Dkk-1) and sclerostin could be found. Except the densitometry measurements of bone and lean mass, we assessed markers of disease activity, bone metabolism and remodeling in young adult patients with JIA before and during 2 years of anti TNFα (tumour necrosis factor α) treatment, which decreases disease activity. Results: In patients with JIA before antiTNFα treatment, bone mineral density (BMD, g/cmš) was significantly reduced compared to controls. Values of BMD and body composition in JIA significantly depended on disease duration and GCs treatment. Serum concentration of sclerostin was significantly elevated in JIA compared to values in healthy controls. Values of the other monitored markers did not differ between JIA and controls. In patients with JIA, Dkk-1 correlated positively with C-reactive...

Development and evaluation of new cementless revision acetabular components for total hip arthroplasty / type TC / Objective: The aim of the clinical part of the study was to introduce a new revision oval cup type TC, and evaluate its reliability and utility in revision endoprosthesis. Due to the different structure of the implant, we aimed to objectively demonstrate the remodeling of bone tissue in its vicinity. In the experimental part of the work we verified the hypothesis that the use of locking screws has an effect on the bond strength of the implant with bone tissue, and therefore on the primary stability of the acetabular component. Method: We evaluated 31 patients that underwent revision hip surgery between 2004 and 2008. The mean follow-up was 7.1 years (range 5.3 to 9.3 years, minimum 5 years after surgery). Osteointegration of the implant and remodeling of bone tissue around the implant and its ribs were evaluated by digital radiography and computed tomography, and clinical results according to Harris. The experiment was based on the execution of pull-out tests after the implantation of TC cups in cadaveric bovine pelves. We evaluated the dependence of tensile forces in the axis of the implant on extraction of the metal cup from the bone bed. Four tests were conducted with the cup fixed...

Indiana University-Purdue University Indianapolis (IUPUI) / Bone is a dynamic tissue that is constantly remodeling to repair damage and strengthen regions exposed to loads during everyday activities. However, certain conditions, including long-term unloading of the skeleton, hormonal imbalances, and aging can disrupt the normal bone remodeling cycle and lead to low bone mass and osteoporosis, increasing risk of fracture. While numerous treatments for low bone mass have been devised, dynamic mechanical loading modalities, such as axial loading of long bones and lateral loading of joints, have recently been examined as potential methods of stimulating bone formation. The effectiveness of mechanical loading in strengthening bone is dependent both on the structural and geometric characteristics of the bone and the properties of the applied load. For instance, curvature in the structure of a bone causes bending and increased strain in response to an axial load, which may contribute to increased bone formation. In addition, frequency of the applied load has been determined to impact the degree of new bone formation; however, the mechanism behind this relationship remains unknown. In this thesis, the application of mechanical loading to treat osteoporotic conditions is examined and two questions are addressed: What role does the structural geometry of bone play in the mechanical damping of forces applied during loading? Does mechanical resonance enhance geometric effects, leading to localized areas of elevated bone formation dependent on loading frequency? Curvature in the structure of bone was hypothesized to enhance its damping ability and lead to increased bone formation through bending. In addition, loading at frequencies near the resonant frequencies of bone was predicted to cause increased bone formation, specifically in areas that experienced high principal strains due to localized displacements during resonant vibration. To test the hypothesis, mechanical loading experiments and simulations using finite element (FE) analysis were conducted to characterize the dynamic properties of bone. Results demonstrate that while surrounding joints contribute to the greatest portion of the damping capacity of the lower limb, bone absorbs a significant amount of energy through curvature-driven bending. In addition, results show that enhanced mechanical responses at loading frequencies near the resonant frequencies of bone may lead to increased bone formation in areas that experience the greatest principal strain during vibration. These findings demonstrate the potential therapeutic effects of mechanical loading in preventing costly osteoporotic fractures, and explore characteristics of bone that may lead to optimization of mechanical loading techniques. Further investigation of biomechanical properties of bone may lead to the prescribing of personalized mechanical loading treatments to treat osteoporotic diseases.

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Indiana University-Purdue University Indianapolis (IUPUI) / The first part of the study describes the development of a microCT based engineering model to study orthodontic responses. The second part investigated the relationship between orthodontic stimulus, root resorption and bone modeling. It was hypothesized that stress magnitudes are insufficient to portray the mechanical environment and explain the clinical response; directions also play a role. An idealized tooth model was constructed for finite element analysis. The principal stress magnitudes and directions were calculated in tipping and translation. It was concluded that within the same region of root, PDL and bone, there can be compression in one structure, tension in another. At a given point in a structure, compression and tension can coexist in different directions. Magnitudes of compression or tension are typically different in different directions. Previously published data presenting only stress magnitude plots can be confusing, perhaps impossible to understand and/or correlate with biological responses. To avoid ambiguities, a reference to a principal stress should include its predominant direction. Combined stress magnitude/direction results suggest that the PDL is the initiator of mechanotransduction. The third part of this project tested the role of the P2X7 receptor in the dentoalveolar morphology of C57B/6 mice. P2X7R KO (knockout) mice were compared to C57B/6 WT to identify differences in a maxillary molar and bone. Tooth dimensions were measured and 3D bone morphometry was conducted. No statistically significant differences were found between the two mouse types. P2X7R does not have a major effect on alveolar bone or tooth morphology. The final part examines the role of the P2X7 receptor in a controlled biomechanical model. Orthodontic mechanotransduction was compared in wild-type (WT) and P2X7R knock-out (KO) mice. Using Finite Element Analysis, mouse mechanics were scaled to produce typical human stress levels. Relationships between the biological responses and the calculated stresses were statistically tested and compared. There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in WT and KO. Orthodontic responses are related to the principal stress patterns in the PDL and the P2X7 receptor plays a significant role in their mechanotransduction.

The humerus of a racing horse Thoroughbred is highly susceptible to stress fractures at a characteristic location as a result of cyclic loading. The propensity of a Thoroughbred to exhibit humeral fracture has made equines useful models in the epidemiology of stress fractures. In this study, a racing Thoroughbred humerus was simulated during training using a 3D finite element model in conjunction with a bone remodeling algorithm. Nine muscle forces and two contact forces were applied to the 3-dimensional finite element model, which contains four separate load cases representing fore-stance, mid-stance, aft-stance, and standing. Four different training programs were incorporated into the model, which represent Baseline Layup and Long Layup training programs along with two newly implemented programs for racing, which have an absence of a layup period, last a period of 24 weeks, and a race once every four weeks. Muscle and contact forces were rescaled for all load cases to simulate dirt, turf, and synthetic track surfaces. Bone porosity, damage, and BMU activation frequency were examined at the stress fracture site and compared with a control location called the caudal diaphysis. It was found that race programs exhibited similar remodeling patterns between each other. Damage at the stress fracture site and caudal diaphysis was reduced during all training programs for the turf and synthetic track surfaces with respect to the dirt track surface. Key findings also included changes in bone remodeling at the stress fracture site and caudal diaphysis as a result of turf and synthetic track surfaces. This model can serve as a framework for further studies in human or equine athletes who are susceptible to stress fractures.

Long-duration spaceflight has been shown to have significant, lasting effects on the bone strength of astronauts and to contribute to age-related complications later in life. The microgravity environment of space causes a decrease in daily mechanical loading, which signals a state of disuse to bone cells. This affects the bone remodeling process, which is responsible for maintaining bone mass, causing an increase in damage and a decrease in density. This leads to bone fragility and decreases overall strength, posing a risk for fracture. However, there is little information pertaining to the timeline of bone loss and subsequent fracture risk. This study used finite element analysis to model the human femur, the bone most adversely affected by spaceflight, and to simulate the environments of Earth preflight, a six-month mission on the International Space Station, and one year on Earth postflight. Changes in the properties of cortical and trabecular bone in the femoral neck were measured from the simulations, and used to provide evidence for high fracture risk and to predict when it is most prominent. It was found that a risk for fracture is extremely evident in the femoral neck in both cortical and trabecular bone. Cortical bone in the inferior neck exhibited high magnitudes of damage, while the superior neck suffered the greatest increases in damage that proceeded to increase upon return to Earth. The density of trabecular bone decreased the most significantly and was not fully recovered in the following year. While it is still unclear exactly when these changes cause the greatest risk for fracture, it is possible that they will add to and advance the onset of medical complications such as osteoporosis. Additionally, the results of this study support the claim that the current countermeasure of inflight exercise is insufficient in sustaining bone mass and preserving skeletal health. The effects of long-duration spaceflight on bone health should continue to be investigated especially if future missions are to last as long as one to three years.

Open treatment of condylar head fractures (CHF) is considered controversial. In this retrospective cohort study our primary objective was therefore to assess bone resorption and remodeling as well as patients function after open treatment of CHF in a medium-term follow-up (15.1 ± 2.2 months). We included 18 patients with 25 CHF who underwent open reduction and internal fixation, between 2016 and 2021, in our analysis. The clinical data and cone-beam computed tomography (CBCT) datasets were analyzed. The condylar processes were segmented in the postoperative (T1) and follow-up (T2) CBCT scans. Volumetric and linear bone changes were the primary outcome variables, measured by using a sophisticated 3D-algorithm. The mean condylar head volume decreased non-significantly from 3022.01 ± 825.77 mm3 (T1) to 2878.8 ± 735.60 mm3 (T2; p = 0.52). Morphological alterations indicated remodeling and resorption. The pre-operative maximal interincisal opening (MIO) was 19.75 ± 3.07 mm and significantly improved to 40.47 ± 1.7 mm during follow-up (p = 0.0005). Low rates of postoperative complications were observed. Open reduction of CHF leads to good clinical outcomes and low rates of medium-term complications. This study underlines the feasibility and importance of open treatment of CHF and may help to spread its acceptance as the preferred treatment option.

O objetivo deste estudo foi analisar a modulação da expressão de metaloproteinases da matriz-2 e -9, no tecido ósseo neoformado na interface do implante derivado do polímero da mamona (Ricinus communis) com o canal medular da tíbia de coelhos, por meio de análise histológica por microscopia óptica, tomografia computadorizada e imunoistoquímica. Foram selecionados 44 coelhos machos, Oryctolagus cuniculus, da linhagem Nova Zelândia, albinos, divididos em dois grupos, sendo o Grupo 1, composto por 12 animais controle, cujas fresagens do canal medular foram produzidas bilateralmente nas tíbias e não preenchidas e, o Grupo 2, com 30 animais, cujos canais medulares da tíbia, após fresagem, foram preenchidos bilateralmente com os cilindros derivados da poliuretana da mamona. Os animais do Grupo 1 e Grupo 2 foram divididos aleatoriamente em subgrupos experimentais, conforme as datas de eutanásia pré-determinadas em 90, 120, 150 dias após o ato operatório. Um animal não foi submetido ao procedimento de fresagem, sendo utilizado para controle histológico e outro submeteu-se à eutanásia após o implante do polímero, sendo utilizado para controle de imagem do estudo com tomografia computadorizada. Decorridos os períodos experimentais, os animais foram submetidos à eutanásia, as peças removidas e encaminhadas para o exame tomográfico; posteriormente ao processamento histológico, as lâminas foram analisadas em microscópio óptico. As Metaloproteinases da Matriz (MMPs) são um importante grupo de enzimas proteolíticas zinco-dependentes responsáveis pela degradação de matriz extracelular e membranas basais. As enzimas são secretadas em uma forma latente e se tornam ativadas no ambiente pericelular, sendo relacionadas a processos fisiológicos e patológicos. No presente estudo, foram revisados alguns aspectos importantes das MMPs, discutindo-se o papel dessas enzimas em processos fisiológicos como a neoformação e maturação óssea (MMP-2). Dentre os processos patológicos que envolvem a participação das MMPs, destacam-se a reabsorção óssea e processos inflamatórios (MMP-9). A expressão de metaloproteinase da matriz-2 e -9 nos tecidos foi avaliada por meio de imunoistoquímica. Os dados obtidos foram submetidos à análise estatística por meio do teste ANOVA seguido pelo pós-teste de Tukey (α = 0,05). No grupo experimental, aos 90 dias, a interface com o polímero apresentava uma camada espessa de tecido ósseo neoformado rico em osteócitos, o qual apresentou uma maturação com o passar do tempo, aos 120 e 150 dias pós-implantação. No grupo controle, a superfície interna junto ao canal medular apresentava-se revestida por osteoblastos, seguida de faixa de tecido ósseo, com poucas lacunas preenchidas por osteócitos. O amadurecimento do tecido da superfície interna medular acontece na região interior, sendo o osso alamelar, constituído por fibras colágenas menos amadurecidas que o osso lamelar. As imagens tomográficas demonstraram não haver espaço entre a superfície do material e do osso na interface implante/medula óssea, sendo a densidade dos tecidos nesta interface semelhante à densidade das demais porções da medula óssea. O processo de remodelação óssea observado histologicamente foi acompanhado pela modulação positiva de metaloproteinase da matriz-2 durante todo o período de avaliação com baixa expressão de metaloproteinase da matriz-9. / The aim of this study was to evaluate the modulation of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) expression in newly formed bone tissue at the interface between implant derived from castor oil (Ricinus communis) polymer and the medullary canal of rabbit tibia, by histological examination under optical microscopy, computed tomography (CT) and immunohistochemical analysis. For such purpose, 44 rabbits (Oryctolagus cuniculus, New Zealand, albinus) were selected and assigned to two groups. In Group 1, composed of 12 animals (control), reamings of the medullary canal were produced bilaterally in the tibiae of the rabbits and were not filled. In Group 2, composed of 30 animals, the tibial medullary canals, after reaming, were filled bilaterally with cylinders derived from castor oil polyurethane. The animals of Groups 1 and 2 were randomly divided in experimental subgroups, according to the periods of predetermined euthanasia, which were 90, 120, 150 days postoperatively. One animal was not subjected to the reaming procedure, and served as a histological control; another animal was killed after placement of the polymer implant, and served as a control for CT imaging. Euthanasia was undertaken at the established experimental periods, and the anatomic specimens were removed and subjected to CT analysis. Then, after histological processing, the slides were examined under optical microscopy. MMPs are an important group of zinc-dependent proteolytic enzymes responsible for the degradation of extracellular matrix and basal membranes. The enzymes are synthesized in a latent form and are activated in the pericellular environment, being involved in physiological and pathological processes. In the present study, some important aspects of MMPs were reviewed, and the role of these enzymes in physiological processes, such as new bone formation and bone maturation (MMP-2), was discussed. Among the pathological processes that have the participation of MMPs, the most relevant are bone resorption and inflammatory processes (MMP-9). MMP-2 and MMP-9 expression in the tissues was evaluated by immunohistochemistry. Data were subjected to statistical analysis by ANOVA and Tukey post-test (α = 0.05). In the group experimental, at 90 days, the interface with the polymer presented a thick layer of newly formed bone tissue rich in osteocytes. This tissue exhibited an ongoing maturation at 120 and 150 days post-implantation. In the control group, the internal surface close to the medullary canal was lined by osteoblasts, followed by a bone tissue zone with few lacunae filled with osteocytes. Maturation of the tissue of the medullary internal surface occurred in the inner region, with the bone being alamellar, that is, constituted of collagen fibers less maturated than the lamellar bone. The CT scans showed no space between the material surface and the bone at the implant/bone marrow interface, and the density of the tissues at this interface was similar to the density measured in the other regions of the bone marrow. The bone remodeling process observed histologically was accompanied by positive modulation of MMP-2 during the entire evaluation period and low MMP-9 expression.

Le diagnostic et la prise en charge des infections ostéo-articulaires (IOA) sont souvent complexes occasionnant une perte osseuse irréversible. La variabilité intra et inter-patient en terme de présentation clinique rend impossible le recours à une description systématique ou à une analyse statistique pour le diagnostic et l'étude de cette pathologie. Le développement d'IOA résulte d'interactions complexes entre les mécanismes cellulaires et moléculaires du tissu osseux et les bactéries. L'objectif de cette thèse est de modéliser l'IOA afin de simuler le comportement du système suite à des interactions au niveau cellulaire et moléculaire en utilisant l'approche de modélisation à base d'agents. Nous avons utilisé une méthode basée sur l'analyse bibliographique pour extraire les caractéristiques du modèle et les utiliser pour deux aspects. Le premier consiste en l'élaboration de la structure du modèle en identifiant les agents et les interactions, et le deuxième concerne l'estimation quantitative des différents paramètres du modèle. La réponse du système BJI aux différentes tailles d’inoculum bactérien a été simulée par la variation de différents paramètres. L'évolution des agents simulés a ensuite été analysée en utilisant une modélisant par des systèmes dynamiques non linéaires et une méthodologie "Datadriven", grâce auxquelles nous avons décrit le système d'IOA et identifié des relations plausibles entre les agents. Le modèle a réussi à présenter la dynamique des bactéries, des cellules immunitaires innées et des cellules osseuses au cours de la première étape de l'IOA et pour différentes tailles d'inoculum bactérien. La simulation a mis en évidence les conséquences sur le tissu osseux résultant du processus de remodelage osseux au cours de l'IOA. Ces résultats peuvent être considérés comme une base pour une analyse plus approfondie et pour la proposition de différentes hypothèses et scénarios de simulation qui pourraient être étudiés dans ce laboratoire virtuel. / Bone and joint infections are one of the most challenging bone pathologies that associated with irreversible bone loss and long costly treatment. The high intra and inter patient's variability in terms of clinical presentation makes it impossible to rely on the systematic description or classical statistical analysis for its diagnosis or studying. The development of BJI encompasses a complex interplay between the cellular and molecular mechanisms of the host bone tissue and the infecting bacteria. The objective of this thesis is to provide a novel computational modeling framework that simulates the behavior resulting from the interactions on the cellular and molecular levels to explore the BJI dynamics qualitatively and comprehensively, using an agent-based modeling approach. We relied on a meta-analysis-like method to extract the quantitative and qualitative data from the literature and used it for two aspects. First, elaborating the structure of the model by identifying the agents and the interactions, and second estimating quantitatively the different parameters of the model. The BJI system’s response to different microbial inoculum sizes was simulated with respect to the variation of several critical parameters. The simulation output data was then analyzed using a data-driven methodology and system dynamics approach, through which we summarized the BJI complex system and identified plausible relationships between the agents using differential equations. The BJI model succeeded in imitating the dynamics of bacteria, the innate immune cells, and the bone cells during the first stage of BJI and for different inoculum size in a compatible way. The simulation displayed the damage in bone tissue as a result of the variation in bone remodeling process during BJI. These findings can be considered as a foundation for further analysis and for the proposition of different hypotheses and simulation scenarios that could be investigated through this BJI model as a virtual lab.