Postnatal vascular growth is a complex process involving multiple cells types whose functionality is orchestrated by a variety of soluble extracellular growth factors, mechanical stimuli, and matrix derived cues. The central goal for this dissertation project was to elucidate the role of osteopontin, a non-collagenous extracellular matrix protein, in postnatal vascular growth. At the onset, we concluded that the current methods for measurement of vascularity in small animal models were lacking. To address this shortcoming, we pursued micro-CT imaging for analysis of three-dimensional blood vessel architecture. We were able to demonstrate that micro-CT imaging provides an objective, quantitative, and three-dimensional methodology for evaluation of vascular networks that has broad applicability to preclinical studies. Next, we sought to apply the developed imaging techniques, along with other complementary methodologies, to explore the role of osteopontin in postnatal vascular growth. Osteopontin was previously known to elicit survival, migration, and other relevant activities in multiple cell types involved in postnatal vascular growth. Therefore, we sought to determine the in vivo significance of osteopontin in this process. To do so, we compared wild type and Osteopontin-/- mice for (1) their ability to form collateral vessels and functionally recover following acute induction of hind limb ischemia and (2) their capacity for neovascularization, mineralization, remodeling, and the restoration of mechanical properties during fracture healing. Data suggested that OPN is a critical regulator of collateral vessel formation and that this effect is driven by its role in mediating monocyte/macrophage migration and functionality. Secondly, we found that the presence of osteopontin was essential for normal early callus formation, neovascularization, late stage callus remodeling, and restoration of biomechanical strength. Abnormal collagen organization was observed within the remodeling fractures of Osteopontin-/- mice, and we hypothesize that a unifying link between the vascular and bone defects may be related to deficient matrix organization and remodeling. In conclusion, the imaging techniques developed in this thesis provide a novel methodology for quantitative analysis of vascular structures in small animal models. Secondly, this project has yielded an improved understanding of the basic pathophysiological mechanisms that control postnatal blood vessel growth and bone fracture healing.

Delayed or impaired bone healing occurs in 5-10% of all fractures, yet cost effective solutions to enhance the healing process are limited. Lithium, a current treatment for bipolar disorder, is not clinically indicated for use in fracture management, but has been reported to positively influence bone biology. The objective of this study was to identify lithium administration parameters that maximize bone healing in a preclinical, rodent femur fracture model. Using a three factor, two level, design of experiments (DOE) approach, bone healing was assessed through mechanical testing and μCT-image analysis. Significant improvements in healing were found at a low dose, later onset, longer duration treatment combination, with onset identified as the most influential parameter. The positive results from this DOE screening focuses the optimization phase towards further investigation of the onset component of treatment, and forms a crucial foundation for future studies evaluating the role of lithium in fracture healing.

Delayed or impaired bone healing occurs in 5-10% of all fractures, yet cost effective solutions to enhance the healing process are limited. Lithium, a current treatment for bipolar disorder, is not clinically indicated for use in fracture management, but has been reported to positively influence bone biology. The objective of this study was to identify lithium administration parameters that maximize bone healing in a preclinical, rodent femur fracture model. Using a three factor, two level, design of experiments (DOE) approach, bone healing was assessed through mechanical testing and μCT-image analysis. Significant improvements in healing were found at a low dose, later onset, longer duration treatment combination, with onset identified as the most influential parameter. The positive results from this DOE screening focuses the optimization phase towards further investigation of the onset component of treatment, and forms a crucial foundation for future studies evaluating the role of lithium in fracture healing.

No description available.

Bone is refractory to most conventional biochemical Procedures. However because it is now possible to cut sections (e. g. lopm) of fresh, undemineralized adult bone, this tissue can be analyzed by suitably modified methods of quantitative cytochemistry. A new substrate for assaying hydroxyacyl dehydrogenase activity demonstrated that bone cells may use fatty acids as a major source of energy: detailed analysis of the activities of key enzymes indicated that the paradox of ‘aerobic glycolysis’ of bone could be explained by fatty acid oxidation satisfying the requirements of the Krebs' cycle and directing the conversion of pyruvate to lactate The influence of glucose 6-phosphate dehydrogenase (G6PD) activity in aerobic glycolysis has been considered. The inverse relationships between this activity and that of Na-K-ATPase led to the development of a new method for the latter, based on a new concept in cytochemistry ('hidden-capture' procedure). A major feature of fracture-healing is increased periosteal G6PD activity. The association with the vitamin K cycle has been investigated by feeding rats with dicoumarol which not only inhibited bone-formation but also G6PD activity. The stimulation of this activity in fracture-healing has been linked with ornithine decarboxylase (ODC) activity, for which a new method has been developed. Rats deficient in pyridoxal phosphate (cofactor for ODC) had decreased G6PD responses and also appeared to become osteoporotic. Studies on osteoporotic fractures in the human showed the presence of relatively large apatite crystals close to the fracture-site, and disorganized glycosaminoglycans (demonstrated by the new method of ‘induced birefringence’).

The management of significant bone defects, delayed and non-union of fractures can be extremely challenging. Development of specific treatment is hindered by an absence of information regarding the molecular events which regulate these processes. In this thesis, a bilateral cancellous bone defect model of the femur and tibia was developed in a rodent and the spatiotemporal profile of TGF-β, BMP 2 and 7, Smads 1, 4 and 5 characterised. Next, the capability of acid solution to augment healing was tested in both a bone defect and in a closed femoral fracture model. Finally, a long term oestrogen deficiency (OVX) rat model of postmenopausal osteoporosis was characterised and the spatiotemporal profiles of IGF-1, IGFR-1, MMP-1, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, BMP-2, BMP-4, BMP-7, TGF-β, Smad4, Smad7, VEGF, Flt-1, Ihh and FGF-2 were compared in femoral osteotomies between OVX and Sham groups. The bilateral cancellous defect model was successfully created with a number of advantages with which to recommend its use in future studies. TGF-β, BMP 2 and 7, Smads 1, 4 and 5 had characteristic spatiotemporal profiles during cancellous bone defect healing suggesting that they have a regulatory role. The results of the acid study were inconclusive and problems with substance delivery and maintenance at the desired site need to be addressed in the future to fully test this hypothesis. No significant differences were detected on histology or three-point mechanical testing between the fracture calluses of acid and control groups. In the final study, OVX rats after six months had significantly increased weight and decreased bone mineral density compared to their sham counterparts. A histological delay in osteotomy healing was observed in the OVX group but no significant differences on tensile testing were seen between OVX and Sham groups up to six weeks. Immunohistochemistry revealed that delayed healing may be due to the down-regulation of IGF-1, BMP-2, 4, and 7 and the up-regulation of MMP-3 in OVX compared to Sham groups. In conclusion, the results of this thesis give some insight into the molecular biology of bone defects and osteoporotic fractures. This information may also be useful in the development of specific treatments aimed at augmenting healing in bone defects and osteoporotic fractures.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

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Métodos: Estratégia de busca: abrangeu CENTRAL, MEDLINE, EMBASE e LILACS. Não houve restrições de idioma ou meios de publicações. A última estratégia de busca foi realizada em julho de 2009. Critério de seleção: foram incluídos ensaios clínicos randomizados e quase-randomizados que avaliaram o tratamento de fratura aguda e pseudartrose do terço médio da clavícula em adultos e adolescentes. Os desfechos primários foram: dor, qualidade de vida/função do ombro e falha do tratamento. Coleta e análise dos dados: dois autores, independentemente, selecionaram os estudos elegíveis, avaliaram a qualidade metodológica e extraíram os dados. Calculou-se o risco relativo com 95% de intervalo de confiança para as variáveis dicotômicas; para variáveis contínuas, a diferença entre as médias foi calculada com 95% de intervalo de confiança. Quando possível, os estudos foram agrupados. Resultados: Intervenções não cirúrgicas: dois estudos compararam imobilização em oito versus tipoia. Ambos possuíam baixo poder estatístico e alto risco de viés. Houve maiores níveis de dor e desconforto durante o tratamento nos pacientes submetidos à imobilização em oito. Um terceiro estudo, com baixo risco de viés, mas baixo poder estatístico, avaliou o ultrassom terapêutico. Não houve diferenças significantes entre o ultrassom de baixa intensidade e placebo nos desfechos avaliados. Intervenções não cirúrgicas versus cirúrgicas: Quatro estudos, dois com moderado e dois com alto risco de viés foram incluídos. Dois estudos compararam fixação com placa versus tipoia, com resultados favoráveis ao tratamento cirúrgico ao avaliar falha do tratamento e qualidade de vida/função do ombro. Outros dois estudos compararam fixação intramedular versus tratamento não cirúrgico; a cirurgia foi superior para os desfechos dor e qualidade de vida/função do ombro. Intervenções cirúrgicas: quatro estudos com baixo poder estatístico, cada qual avaliando diferentes comparações, foram incluídos; três possuíam alto risco de viés. Um estudo comparou placa de compressão de baixo contato com placa de compressão dinâmica em pseudartrose da clavícula; os pacientes tratados com placa de baixo contato apresentaram evolução melhor para: função do ombro, consolidação, retorno ao trabalho e menor incidência de sintomas relacionados ao implante. Outro estudo comparou fixação intramedular com pinos de Knowles versus fixação com placa para o tratamento de fratura aguda e pseudartrose da clavícula; a fixação intramedular acarretou em menor consumo de analgésicos após a cirurgia, menor número de complicações associadas ao implante e menor tempo cirúrgico e de internação. Um terceiro estudo, com baixo risco de viés, concluiu que a técnica de fixação tridimensional com placa ocasionou menor incidência de retardo de consolidação em relação à fixação na face superior das fraturas agudas da clavícula. Um último estudo avaliou a fixação intramedular das fraturas agudas da clavícula comparando redução fechada versus redução aberta. Houve diferenças significativas em favor da redução fechada quando avaliados os desfechos primários. Conclusão: os ensaios clínicos disponíveis na literatura não apresentam qualidade metodológica adequada e/ou poder estatístico apropriado, portanto, não há evidência suficiente para determinar quais os mais apropriados métodos de tratamento para a fratura e pseudartrose do terço médio da clavícula. Há uma tendência de melhores resultados funcionais e radiográficos a favor das intervenções cirúrgicas quando comparadas às intervenções não cirúrgicas. / Objectives: To evaluate the effectiveness of different methods of treatment for acute fracture or non-union of the middle third of the clavicle in adults and adolescents. Methods: Search strategy: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, trial registries and reference lists of articles. No language or publication restrictions were applied. Selection criteria: Randomised and quasi-randomised controlled trials evaluating any intervention for treating fractures or non-union of the middle third of the clavicle were considered. The primary outcomes were pain, treatment failure and health-related quality of life or shoulder function. Data collection and analysis: Two authors independently selected eligible trials and three authors assessed methodological quality and cross-checked data extraction. Results: Conservative interventions: Three trials were included in this comparison. Two trials compared the figure-of-eight bandage with sling in a total of 234 participants. Both trials were underpowered and compromised by poor methodology. One trial found slightly higher pain levels in the bandage group at 15 days, and the other trial reported greater discomfort during bandage wear. There were no significant differences in functional or other outcomes reported for either trial. The third trial, which evaluated therapeutic ultrasound in 120 participants, was also underpowered but had a low risk of bias. The trial found no statistically significant difference between low-intensity pulsed ultrasound and placebo in the time to clinical fracture healing or in any of the other reported outcomes. Surgical versus conservative interventions: Four studies, two with moderate and two with high risk of bias were included. Two compared plate fixation versus sling; plate fixation showed better patient-based upper extremity outcome scores and less treatment failure. Other two trials comparing intramedullary fixation versus conservative interventions presented better upper limb function to the surgery treatment. Surgical interventions: Data from four small trials, each testing a different comparison, were included. Three trials had design features that carry a high risk of bias, limiting the strength of their findings. Low-contact dynamic compression plates appeared to be associated with significantly better upper-limb function throughout the year following surgery, earlier fracture union and return to work, and a reduced incidence of implant-associated symptoms when compared with a standard dynamic compression plate in 36 adults with symptomatic non-union of the middle third of the clavicle. One study (69 participants) compared the Knowles pin versus plate for treating middle third clavicle fractures or non-union. Knowles pins appeared to be associated with lower pain levels and use of post-operative analgesics, reduced incidence of implant-associated symptoms, and shorter operation time and hospital stay. One study (133 participants) found that a three-dimensional technique for fixation with a reconstruction plate was associated with a significantly lower incidence of symptomatic delayed union than a standard superior position surgical approach. One study (201 participants) assessed the intramedullary fixation for treating acute clavicle fractures comparing closed and opened reduction; there were statistical significant differences in favour of closed reduction with percutaneous fixation for the primary outcomes. Conclusion: There is limited evidence, from single trials only, regarding the effectiveness of different methods for treating fracture and non-union of the middle third of the clavicle. Further research is warranted. / TEDE / BV UNIFESP: Teses e dissertações

No description available.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / The Ibandronate sodium is a drug used for clinical treatment of osteoporosis and for anti-catabolic action and cause osteoclast apoptosis, an important cell responsible for bone remodeling, it was hypothesized an effect on fractures in the consolidation phase of callus remodeling.The aim of this study was to evaluate the effect of ibandronate sodium in the fracture of femurs of rats subjected to intramedullary fixation. This study used 48 adult male rats, Wistar, with the average weight of 336.63 g. All animals underwent surgery for intramedullary osteosynthesis of the right femur and subsequently performed a standardized fracture. They were divided into two groups: the ibandronate, which was administered a single dose of 15mg/kg by gavage and the control group was administered a single dose of 1.0 ml of 0.9% saline by gavage also on the same day of the procedure surgery. At 7, 14, 28 and 42 days postoperatively six animals from each group were euthanized and the femurs were subjected to X-ray study to analyze the optical density and area of callus and histological study, using samples stained with picrosirius red and analyzed under polarized light, to quantify the density of collagen type I and type III in the cortical region near the fracture and callus. The radiographs showed that the area of the callus showed no statistically significant differences between groups control and ibandronate, but in the intragroup analysis 28 and 42, the callus was significantly higher on day 7 in both groups. The optical density of intergroup evaluation showed that ibandronate group at day 42, showed a higher density than the control group. In the study of collagen in the callus, the density of type I collagen seen in the ibandronate group was higher than that observed in the control group on days 7 and 14, since the density of type III collagen found in the ibandronate group was lower than in the 7 days Control group. In the study of collagen in the cortex, collagen type I in the ibandronate group was significantly greater on day 7 than the control group and type III collagen in the ibandronate group was lower than the Control group. The results are consistent enough to say that this drug has an effect on bone fracture healing by increasing the density of type I collagen in the early stages of consolidation. / O Ibandronato de sÃdio à um medicamento utilizado para o tratamento clÃnico da osteoporose e por ter aÃÃo anticatabÃlica e causar apoptose no osteoclasto, uma importante cÃlula responsÃvel pela remodelaÃÃo Ãssea, foi hipotetizado um efeito na consolidaÃÃo fraturas na fase de remodelaÃÃo do calo Ãsseo. O objetivo deste estudo foi avaliar o efeito do ibandronato de sÃdio na consolidaÃÃo das fraturas de fÃmures de ratos submetidos à osteossÃntese intramedular. Neste estudo foram utilizados 48 ratos machos, adultos, da linhagem Wistar, com o peso mÃdio de 336,63g. Todos os animais foram submetidos a procedimento cirÃrgico para osteossÃntese intramedular do fÃmur direito e posteriormente realizado uma fratura padronizada. Eles foram divididos em dois grupos: o grupo Ibandronato, em que foi administrada dose Ãnica de 15mg/Kg por gavagem e o grupo controle foi administrado dose Ãnica de 1,0ml de soluÃÃo fisiolÃgica 0,9% tambÃm por gavagem, no mesmo dia do procedimento cirÃrgico. No 7Â, 14Â, 28 e 42 dia de pÃs-operatÃrio seis animais de cada grupo eram eutanasiados e os fÃmures foram submetidos a estudo radiogrÃfico para analisar a densidade Ãptica e Ãrea do calo Ãsseo e estudo histolÃgico, utilizando amostras coradas com picrosirius red e analisadas sob a luz polarizada, para quantificar a densidade de colÃgeno tipo I e tipo III na regiÃo cortical prÃxima a fratura e no calo Ãsseo. A anÃlise das radiografias mostrou que a Ãrea do calo Ãsseo nÃo apresentava diferenÃas estatisticamente significantes entre os grupos Controle e Ibandronato, mas que na anÃlise intragrupo os dias 28 e 42 o calo era significantemente maior que no dia 7, em ambos os grupos. A densidade Ãptica na avaliaÃÃo intergrupos mostrou que o grupo Ibandronato, no 42 dia, apresentava uma maior densidade que o grupo controle. No estudo do colÃgeno no calo Ãsseo, a densidade do colÃgeno tipo I verificada no grupo Ibandronato foi maior que a observada no grupo Controle nos dias 7 e 14, jà a densidade de colÃgeno tipo III verificada no grupo Ibandronato foi menor no dia 7 que no grupo Controle. No estudo do colÃgeno da cortical prÃxima ao foco de fratura, o colÃgeno tipo I no grupo Ibandronato foi significantemente maior no dia 7 que o grupo controle e o colÃgeno tipo III no grupo Ibandronato foi menor que o grupo Controle. Os resultados encontrados sÃo consistentes o suficiente para afirmar que este fÃrmaco exerce efeito na consolidaÃÃo de fraturas Ãsseas aumentando a densidade do colÃgeno tipo I nas fases iniciais da consolidaÃÃo. / O Ibandronato de sÃdio à um medicamento utilizado para o tratamento clÃnico da osteoporose e por ter aÃÃo anticatabÃlica e causar apoptose no osteoclasto, uma importante cÃlula responsÃvel pela remodelaÃÃo Ãssea, foi hipotetizado um efeito na consolidaÃÃo fraturas na fase de remodelaÃÃo do calo Ãsseo. O objetivo deste estudo foi avaliar o efeito do ibandronato de sÃdio na consolidaÃÃo das fraturas de fÃmures de ratos submetidos à osteossÃntese intramedular. Neste estudo foram utilizados 48 ratos machos, adultos, da linhagem Wistar, com o peso mÃdio de 336,63g. Todos os animais foram submetidos a procedimento cirÃrgico para osteossÃntese intramedular do fÃmur direito e posteriormente realizado uma fratura padronizada. Eles foram divididos em dois grupos: o grupo Ibandronato, em que foi administrada dose Ãnica de 15mg/Kg por gavagem e o grupo controle foi administrado dose Ãnica de 1,0ml de soluÃÃo fisiolÃgica 0,9% tambÃm por gavagem, no mesmo dia do procedimento cirÃrgico. No 7Â, 14Â, 28 e 42 dia de pÃs-operatÃrio seis animais de cada grupo eram eutanasiados e os fÃmures foram submetidos a estudo radiogrÃfico para analisar a densidade Ãptica e Ãrea do calo Ãsseo e estudo histolÃgico, utilizando amostras coradas com picrosirius red e analisadas sob a luz polarizada, para quantificar a densidade de colÃgeno tipo I e tipo III na regiÃo cortical prÃxima a fratura e no calo Ãsseo. A anÃlise das radiografias mostrou que a Ãrea do calo Ãsseo nÃo apresentava diferenÃas estatisticamente significantes entre os grupos Controle e Ibandronato, mas que na anÃlise intragrupo os dias 28 e 42 o calo era significantemente maior que no dia 7, em ambos os grupos. A densidade Ãptica na avaliaÃÃo intergrupos mostrou que o grupo Ibandronato, no 42 dia, apresentava uma maior densidade que o grupo controle. No estudo do colÃgeno no calo Ãsseo, a densidade do colÃgeno tipo I verificada no grupo Ibandronato foi maior que a observada no grupo Controle nos dias 7 e 14, jà a densidade de colÃgeno tipo III verificada no grupo Ibandronato foi menor no dia 7 que no grupo Controle. No estudo do colÃgeno da cortical prÃxima ao foco de fratura, o colÃgeno tipo I no grupo Ibandronato foi significantemente maior no dia 7 que o grupo controle e o colÃgeno tipo III no grupo Ibandronato foi menor que o grupo Controle. Os resultados encontrados sÃo consistentes o suficiente para afirmar que este fÃrmaco exerce efeito na consolidaÃÃo de fraturas Ãsseas aumentando a densidade do colÃgeno tipo I nas fases iniciais da consolidaÃÃo. / The Ibandronate sodium is a drug used for clinical treatment of osteoporosis and for anti-catabolic action and cause osteoclast apoptosis, an important cell responsible for bone remodeling, it was hypothesized an effect on fractures in the consolidation phase of callus remodeling.The aim of this study was to evaluate the effect of ibandronate sodium in the fracture of femurs of rats subjected to intramedullary fixation. This study used 48 adult male rats, Wistar, with the average weight of 336.63 g. All animals underwent surgery for intramedullary osteosynthesis of the right femur and subsequently performed a standardized fracture. They were divided into two groups: the ibandronate, which was administered a single dose of 15mg/kg by gavage and the control group was administered a single dose of 1.0 ml of 0.9% saline by gavage also on the same day of the procedure surgery. At 7, 14, 28 and 42 days postoperatively six animals from each group were euthanized and the femurs were subjected to X-ray study to analyze the optical density and area of callus and histological study, using samples stained with picrosirius red and analyzed under polarized light, to quantify the density of collagen type I and type III in the cortical region near the fracture and callus. The radiographs showed that the area of the callus showed no statistically significant differences between groups control and ibandronate, but in the intragroup analysis 28 and 42, the callus was significantly higher on day 7 in both groups. The optical density of intergroup evaluation showed that ibandronate group at day 42, showed a higher density than the control group. In the study of collagen in the callus, the density of type I collagen seen in the ibandronate group was higher than that observed in the control group on days 7 and 14, since the density of type III collagen found in the ibandronate group was lower than in the 7 days Control group. In the study of collagen in the cortex, collagen type I in the ibandronate group was significantly greater on day 7 than the control group and type III collagen in the ibandronate group was lower than the Control group. The results are consistent enough to say that this drug has an effect on bone fracture healing by increasing the density of type I collagen in the early stages of consolidation.