A literatura atual aponta o exercício físico como uma das estratégias nãofarmacológicas mais utilizadas no tratamento e prevenção de condições que acometem o tecido ósseo. Ademais, estudos indicam que a suplementação de creatina pode exercer efeitos positivos sobre o ganho de massa óssea. Sendo assim, o objetivo deste estudo foi investigar os efeitos preventivos do exercício físico associado à suplementação de creatina na perda de massa óssea em ratas ovariectomizadas. Diante disso, sessenta e cinco ratas da linhagem Wistar foram pareadas pelo peso corporal e dividas aleatoriamente em cinco grupos, sendo eles: 1) ratas falso-operadas (SHAM); 2) ratas ovariectomizadas (OVX), sedentárias e suplementadas com placebo (PL); 3) ratas OVX, sedentárias e suplementadas com creatina (CR); 4) ratas OVX, treinadas e suplementadas com placebo (PL+TR) e 5) ratas OVX, treinadas e suplementadas com creatina (CR+TR). Os animais foram submetidos a um protocolo de treinamento físico em declive em esteira rolante e suplementados com creatina diariamente por meio de gavagem esofágica. Foi realizada a avaliação de densitometria óssea para a obtenção dos parâmetros ósseos de conteúdo mineral ósseo (CMO) e densidade mineral óssea (DMO) de corpo total e regional, assim como a composição corporal nos períodos pré e pósintervenção. Além disso, foi removido o fêmur direito para a análise biomecânica. Após a intervenção, o grupo PL+TR apresentou maiores valores de CMO e DMO em comparação ao grupo PL (p=0,004 e p=0,020, respectivamente), ao passo que o grupo CR+TR experimentou maiores incrementos para o CMO e tendência ao aumento da DMO em comparação ao grupo CR (p=0,011 e p=0,064). A análise biomecânica do fêmur demonstrou que ambos os grupos treinados (PL+TR e CR+TR) apresentaram valores de força máxima significantemente maiores em relação aos grupos SHAM (p=0,024 e p=0,020, respectivamente), PL (p<0,001 e p<0,001) e CR (p=0,002 e p=0,002). Com relação à rigidez do fêmur, observou-se que o grupo SHAM não apresentou diferença significante quando comparado à ambos os grupos treinados (p=0,973 vs. PL+TR e p=0,998 vs. CR+TR), entretanto, apresentou diferença significante em relação aos grupos sedentários (p=0,048 vs. PL e p=0,024 vs. CR), ainda para esse parâmetro, o grupo PL apresentou diferença significante em relação ao grupo PL+TR (p=0,009), assim como o grupo CR foi significantemente diferente em relação ao grupo CR+TR (p=0,043). Não houve diferenças significantes entre os grupos PL e CR e entre os grupos PL+TR e CR+TR ao longo do estudo. Dessa forma, concluímos que a suplementação de creatina não apresentou efeitos isolados, nem aditivos, quando combinada ao treinamento físico, porém, o exercício físico promoveu efeitos positivos sobre o tecido ósseo, enfatizando, portanto, o seu papel terapêutico ímpar em atenuar a perda de massa óssea / The current literature indicates exercise training as one of the most used nonpharmacological strategies in the treatment and prevention of conditions that affect the bone tissue. Moreover, studies indicate that creatine supplementation may exert positive effects on bone mass gain. Thus, the aim of this study was to investigate the preventive effects of exercise training associated with creatine supplementation on bone loss in ovariectomized rats. Thus, sixty-five female Wistar rats were matched by body weight and randomly assigned into five experimental groups, as follows: 1) shammed (SHAM); 2) ovariectomized (OVX), sedentary and placebo-supplemented rats (PL); 3) OVX, sedentary and creatine-supplemented rats (CR); 4) OVX, trained and placebo-supplemented rats (PL+TR) and 5) OVX rats, trained and creatinesupplemented rats (CR+TR). The animals were submitted to a downhill running training protocol performed on a treadmill and supplemented with creatine on daily basis via gavage. Bone density were evaluated pre and post-intervention to obtain bone mineral content (BMC) and bone mineral density (BMD) from whole body and regional area, as well as body composition. Right femur was removed to biomechanical assessment. After the intervention, PL+TR group had higher BMC and BMD compared to the PL group (p=0.004 and p=0.020, respectively), while the CR+TR group experienced greater increases in BMC and tended to increase BMD compared to the CR group (p=0.011 and p=0.064, respectively). Biomechanical assessment demonstrated significantly higher femur maximum strength of both trained groups (PL+TR and CR+TR) compared to SHAM group (p=0.024 and p=0.020, respectively), PL group (p<0.001 and p<0.001) and CR group (p=0.002 and p=0.002). With respect to femur stiffness, no significant difference was observed from the SHAM group compared to both trained groups (p=0.973 vs. PL+TR and p=0.998 vs. CR+TR), however, significant difference was observed when compared to sedentary groups (p=0.048 vs. PL and p=0.024 vs. CR), moreover, significant difference was observed when the PL group was compared to PL+TR group (p=0.009), as well as the CR group was significantly different compared to the CR+TR group (p=0.043). There were no significant differences between PL and CR groups and between PL+TR and CR+TR groups along the study. Thus, we conclude that creatine supplementation showed no isolated, nor additive effects when combined with exercise training, however, exercise training promoted positive effects on bone tissue, thus emphasizing its unique therapeutic role in attenuating the loss of bone mass

Sowohl der Diabetes mellitus als auch die Osteoporose sind chronische Erkrankungen, die auf Grund Ihrer Häufigkeit eine sehr hohe soziale und medizinische Bedeutung haben. Eine Bewertung der Beziehung zwischen Osteoporose- und DM-Risiko ergab, dass ein hohes und sehr hohes Risiko für Diabetes mellitus mit einem hohen und sehr hohen Risiko für die Entwicklung von Osteoporose kombiniert ist (Drobot et al., 2010). Bei hoher Hyperglykämie und Insulininsuffizienz verschlechtern sich die Mineralisierungsprozesse des Knochengewebes und die Synthese von Protein und Kollagen, was sich negativ auf die Prozesse der Knochenbildung auswirkt. Trotz der bedeutenden Fortschritte bei der Erforschung der Ätiologie und Pathogenese sind die detaillierte Wirkung des DM auf die Mineralzusammensetzung des Knochengewebes nach wie vor unklar (Hofbauer et al., 2007). Somit war es das Hauptziel der vorliegenden Untersuchungen, die strukturellen Veränderungen und die Veränderungen der Mineralzusammensetzung im Knochengewebe im Zusammenhang mit dem DM am etablierten Streptozotocin-Diabetes-Modell der Ratte zu analysieren.

This diploma thesis deals with stress - strain analysis of jaw with decrease of bone tis-sue. At first was created a model of geometry using graphic program Rhinoceros 4.0 upon acquisition by the 3D scanner. That was converted to the computational system ANSYS Workbench 11 which uses for solving the finite element method (FEM). Solving was executed with homogenous, linear and isotropic material model of bone with different characteristics for compact and cancellous bone. Forces of the three working muscles, which participate on chewing, were given on the basis of the force and moment balance mandible. Solving was executed for 12 variant simulating occlusion in places, where was earlier found teeth.

L’ingénierie tissulaire osseuse a pour objectif de repousser les limitesexistantes de la régénération osseuse. Les stratégies proposées consistent àassocier à une matrice tridimensionnelle (3D) des cellules autologues, capables derégénérer en 3D un tissu fonctionnel. Le but de ce travail a été d’étudier l’importancede la communication cellulaire entre les cellules du compartiment stromal et lescellules endothéliales au sein d’une matrice tridimensionnelle poreuse constituée depolysaccharides naturels biodégradables. Nos résultats montrent que l’architecture etla nature de cette matrice permettent de guider la différenciation ostéoblastique descellules humaines mésenchymateuses issues de la moelle osseuse. L’organisationcellulaire en agrégats observée stimule les interactions cellulaires, et plusparticulièrement la formation de jonctions communicantes de type GAP et l’activitédes Connexines 43. Nous avons en également étudié la fonction des Pannexines 1et 3 dans la culture 3D. En conclusion, l’ensemble de nos travaux démontre que lesinteractions cellule-cellule constituent des événements majeurs dans cesmécanismes de régénération tissulaire. Les données cellulaires et expérimentalestémoignent de l’intérêt d’utiliser la totalité de la suspension de moelle osseuse pourfavoriser à la fois l’ostéoformation et la vascularisation du tissu. / Bone tissue engineering aims to resolve the existing limitations of boneregeneration methods. One of the proposed strategies consists on the association,within a three-dimensional (3D) matrix, with autologous cells able to regenerate afunctional 3D tissue. The purpose of this study was therefore to investigate theimpact of cellular communication, between cells of the stromal compartment andendothelial cells, within the three-dimensional porous matrix made of biodegradablenatural polysaccharides, focusing on bone repair. Our results show that thearchitecture and the nature of the 3D macroporous matrix promotes the guidance ofmesenchymal stems cells, derived from human bone marrow, towards theosteoblastic lineage. Also, that the organization in aggregates, promoted by the 3Dmatrices, stimulated cell communication, evidenced by the formation of GAPjunctions and activity of Connexins 43. We also focused on the function ofPannexines 1 and 3 for the 3D culture in these matrices of polysaccharides. Inconclusion, this work shows that cell-cell interactions play a major role in order toimprove bone tissue regeneration. Also, cellular and experimental data demonstratesthe advantage of using a total fraction of bone marrow cells to promote both boneformation and vascularization.

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Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Autologous bone grafting is commonly used throughout the world. Autograft both fills the void and is bone inductive, housing the particular cells that are needed for bone regeneration. However, a regenerative complement to autograft is of great interest as the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of a limited volume of material. Two such regenerative products that utilise bone morphogenetic protein (BMP)-7 and -2 have been used for more than a decade clinically. Unfortunately, several side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery and use of supra physiological doses of the BMPs due to poor localisation and retention of the growth factor. The purpose of this thesis was to harness the strong inductive capacity of the BMP-2 by optimising the carrier of this bioactive protein, thereby minimising the side effects that are associated with the clinical products and facilitating safe and localised bone regeneration. We focused on an injectable hyaluronan-based carrier developed through polymer chemistry at the University of Uppsala. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident enzymes. Earlier studies have shown improved properties when adding hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that bone formation was enhanced when using nano-sized hydroxyapatite. In Paper II, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. We wished to further develop the carrier system, but were lacking an animal model with relatively high throughput, facilitated access, paired data, and we were also committed to the 3Rs of refinement, reduction, and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper III. In Paper IV, we sought to further optimise the biomaterial properties of the hydrogel through covalent bonding of bisphosphonates to the hyaluronan hydrogel. This resulted in exceptional retention of the growth factor BMP-2. In Paper V, SPECT/PET/µCT was combined as a tri-modal imaging method to allow visualisation of the biomaterial’s in situ action, in terms of drug retention, osteoblast activity and mineralisation. Finally, in Paper VI the correlation between existing in vitro results with in vivo outcomes was observed for an array of biomaterials. The study identified a surprisingly poor correlation between in vitro and in vivo assessment of biomaterials for osteogenesis.