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Regeneration of large bone defects presents a critical challenge to orthopaedic clinicians as the current treatment strategies are severely limited. Tissue engineering has therefore emerged as a promising alternative to bone grafting techniques. This approach features the delivery of bioactive agents such as stem cells, genes, or proteins using biomaterial delivery systems which together stimulate endogenous repair mechanisms to regenerate the tissue. Because bone is a highly mechanosensitive tissue which responds and adapts dynamically to its mechanical environment, application of mechanical stimuli may enhance endogenous tissue repair. While mechanical loading has been shown to stimulate bone fracture healing, the ability of loading to enhance large bone defect regeneration has not been evaluated. The goal of this thesis was to evaluate the ability of sustained osteogenic growth factor delivery and functional biomechanical loading to stimulate vascularized repair of large bone defects in a rat segmental defect model. First, we evaluated the hypothesis that the relationship between protein dose and regenerative efficacy depends on delivery system. We determined the dose-response relationship between dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) and bone regeneration in a hybrid alginate-based protein delivery system and compared with the current clinically-used collagen sponge. The hybrid delivery system improved bone formation and reduced the effective dose due to its sustained delivery properties in vivo. Next, we tested the hypothesis that transfer of compressive ambulatory loads during segmental defect repair enhances bone formation and subsequent limb regeneration. We found that delayed application of axial loads enhanced bone regeneration by altering bone formation, tissue differentiation and remodeling, and local strain distribution. Finally, we evaluated the hypothesis that in vivo mechanical loading can enhance neovascular growth to influence bone formation. We found that early mechanical loading disrupted neovascular growth, resulting in impaired bone healing, while delayed loading induced vascular remodeling and enhanced bone formation. Together, this thesis presents the effects of dose and delivery system on BMP-mediated bone regeneration and demonstrates for the first time the effects of in vivo mechanical loading on vascularized regeneration of large bone defects.

Thesis--University of Oklahoma. / Includes bibliographical references (leaves 51-55).

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 176-207).

Thesis (M.S.)--University of Michigan, 1995. / Includes bibliographical references.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Oct. 30, 2007). Includes bibliographical references (p. 45-56).

Orientador: Carlos Rossa Júnior / Banca: José Eduardo Cezar Sampaio / Banca: Ana Paula Vieira Colombo / Resumo: O objetivo do presente estudo foi avaliar in vitro o efeito do condicionamento radicular com fator de crescimento de fibroblastos básico (b-FGF) sobre a morfologia e densidade de fibroblastos. Para tal, blocos de dentina com 4 mm2 de área de superfície foram obtidos de raízes de dentes humanos extraídos devido severo envolvimento periodontal, sendo instrumentados manualmente e autoclavados. Noventa amostras foram selecionadas aleatoriamente e distribuídas em 3 grupos segundo o tratamento de superfície prévio ao condicionamento com o b-FGF: sem tratamento - controle; 50 mg/mL de cloridrato de tetraciclina e EDTA a 24%. As 30 amostras de cada um destes 3 grupos foram distribuídas em 3 subgrupos quanto à dose de b-FGF: 0 æg/mL - controle; 50 æg/mL e 125 æg/mL. Após os tratamentos, as amostras foram incubadas a 37º C e 98% de umidade com 2mL de meio Eagle, sendo 1mL com fibroblastos de linhagem contínua (células McCoy) na concentração de 1 x 105 células/mL e 1mL meio sem células, por 24 h. Após as 24 h, as amostras foram submetidas a preparo de rotina para MEV e então, fotomicrografadas nos aumentos de 500X (densidade celular) e 1000X (morfologia celular). Em seguida, as fotomicrografias foram avaliadas por 3 examinadores treinados, calibrados, independentes e cegos, os quais verificaram morfologia e densidade celular segundo os escores propostos por Gamal et al. (1998) e Jenkins et al. (1988), respectivamente. A aplicação da Análise de Regressão pela Técnica da Árvore demonstrou haver diferenças estatisticamente significantes para a densidade celular (p<0,0001) entre os grupos EDTA, tetraciclina e controle, sendo que também houve diferenças entre as doses de 0/50 æg e 125 æg de b-FGF nas amostras condicionadas com EDTA (p<0,0001) e entre as doses de 0 e 50/125 æg de b-FGF nas amostras condicionadas com tetraciclina... (Resumo completo, clicar acesso eletrônico abaixo). / Abstract: The aim of this study was to evaluate in vitro the effect of the root surface conditioning with basic fibroblast growth factor (b-FGF) about morphology and density of fibroblasts. Dentin slices of with 4 mm2 of surface area were obtained from roots of teeth extracted due to severe periodontal involvment. These were scaled and sterilized. Ninety samples were randomly distributed into 3 groups according to treatment before application of b-FGF: non-treated - control; 50mg/mL of tetracycline HCl and EDTA 24%. The thirty samples of each group were distributed into 3 subgroups according to the concentration of b-FGF: 0 æg/mL - control; 50 æg/mL and 125 æg/mL. After treatments, the samples were incubated at 37ºC and 98% humidity with 1mL of Eagle Medium with 1 x 105 cells/mL of fibroblast from continuos lineage (McCoy Cells) plus 1mL this solution without cells during 24 hours. The samples were submitted to routine preparation for SEM and photographed at 500x (density celular) and 1000x (morphology celular). Three independent and blind examiners evaluated the fibroblast's morphology and density, according to Gamam et al. (1998) and Jenkins et al. (1998), respectively. Classification and Regression Trees test results indicated significant differences on the density (p<0,0001) among EDTA, tetracycline and control groups with also differences between concentrations of 0/50æg and 125æg of b-FGF at the samples conditioning with EDTA (p<0,0001) and between concentrations of 0 and 50/125 æg of b-FGF at the samples conditioning with tetracycline(p<0,0001). The results of this test to morphology indicated significant differences between treatment or non-treatment with b-FGF, and that concentration of 125 æg demonstrated to be more favorable than the concentration of 50 æg. In conclusion, the treatment of root surfaces with b-FGF influenced the density... (Complete abstract, click electronic address below). / Mestre

Made available in DSpace on 2014-06-11T19:33:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-02-14Bitstream added on 2014-06-13T21:06:14Z : No. of bitstreams: 1 oliveira_ca_dr_arafo.pdf: 373237 bytes, checksum: 63181781c60cf9cb130f5b53b34e9b3d (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O propósito deste estudo foi avaliar histológica e histometricamente o resultado da utilização das matrizes de colágeno de Pericárdio Bovino (MPB) e Dérmica Acelular (MAD) no tratamento de deiscências ósseas criadas cirurgicamente em cães. Foram criados defeitos periodontais do tipo deiscência óssea na superfície vestibular dos 2os, 3os e 4os pré-molares inferiores de seis cães. Estes dentes foram divididos em 3 grupos: grupo I: MAD; grupo II: controle e grupo III: MPB, ambos com reposição coronária do retalho. Após 70 dias os animais foram sacrificados, os dentes retirados em bloco e processados histologicamente. Realizou-se análise histológica descritiva e histométrica, medindo-se a extensão do tecido epitelial, neoformação óssea e cementária e nível gengival para os grupos I, II e III. Os resultados demonstraram valores estatisticamente iguais para as medianas (em mm) dos valores de epitélio: 1,49, 1,91 e 1,82; cemento: 3,18, 3,09 e 3,31 respectivamente para os grupos I, II e III. Foi encontrada diferença estatisticamente significante em relação à neoformação óssea, com medianas (em mm) de 1,23, 1,82 e 1,62, respectivamente para os grupos I, II e III. Foi observado escasso infiltrado inflamatório. Com isso, pudemos concluir que as matrizes de MPB e MAD são materiais que permitem a reparação dos tecidos periodontais. / The goal of this investigation was to compare, histologically and histometrically, the healing process of dehiscence-type defects treated by acellular dermal matrix (AD) and bovine pericardium matrix (PB). Six mongrel dogs were used. Buccal osseous deiscences were surgically created on mesial roots of the mandibular second, third and fourth premolars. The defects were randomly assigned to one of the treatments: AD, control and PB. After 70 days of healing, the dogs were sacrificed and the blocks were processed. The histometric parameters evaluated included: gingival level, epithelial length, new cementum and new bone. No statistically significant differences were found between PB, AD and control groups for epithelial length and new cementum parameters (p<0,05). Statistically significant differences were found between PB, AD and control groups for new bone (minor for AD). The presence of a slight inflammation was observed. Withim the limits of this study, it can be concluded that PB and AD showed good biocompatibility, but did not bring a complete periodontal tissue regeneration.

Orientador: Cláudia Valéria Seullner Brandão / Banca: Maria Jaqueline Mamprim / Banca: Nilza Maria Freres Mascarenhaz / Resumo: O objetivo deste trabalho foi avaliar a aplicação de membrana biossintética de celulose (MBC) nacional, após a realização de trocleoplastia experimental em cães, com intuito de verificar se o uso desta poderia favorecer a migração de células com potencial condrogênico, assim como ocorre no tecido ósseo. A evolução pós-operatória dos cães foi analisada com especial interesse nos processos de reparação frente ao defeito osteocondral, estabelecendo as vantagens e desvantagens do uso do biomaterial. Foram utilizados 12 cães (Canis familiaris) adultos, sadios e sem alterações no aparelho locomotor. Todos os animais foram submetidos ao procedimento de trocleoplastia bilateral, sendo que a MBC foi aplicada no membro esquerdo. Os animais foram avaliados clínica e radiograficamente aos 15, 30, 60 e 90 dias de pós-operatório. A função locomotora do membro foi avaliada em escores pré-definidos, nos referidos momentos. A avaliação macroscópica da articulação foi realizada, nos momentos pré-estabelecidos, seguida da artrotomia exploratória, bem como da coleta de biópsia para o exame microscópico. Todos os animais apresentaram função normal dos membros nos momentos avaliados. Não houve diferença clínica e radiográfica entre os grupos controle (GC) e tratado (GT). Na avaliação histopatológica, aos 30 dias, notou-se intensa celularidade em ambos os grupos, sendo que no GC esta era constituída por fibroblastos ativos e no GT por condrócitos imaturos, formando um tecido conjuntivo mais organizado. O GC apresentava fibrose e muitos fibroblastos aos 60 dias, enquanto o GT apresentava maior número de condrócitos. Aos 90 dias, constatou-se formação de tecido do tipo fibrocartilaginoso maduro em ambos os grupos. Histomorfometricamente, o GT apresentou melhor resposta ao processo de reparação nos momentos iniciais quanto ao número de células e espessura do tecido...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this study was to evaluate the application of national biosynthetic cellulose membrane after experimental trochleoplasty, to verify if its utilization could support chondrogenic cells migration like occurs in osseous tissue. The advantages and disadvantages of the use of this biomaterial were evaluated through the observation of the reparative process of the osteochondral injury. Twelve adult healthy dogs (Canis familiaris) were used. All dogs were submitted to trochleoplasty in both pelvic limbs and the biosynthetic cellulose membrane was applied in the left limb. Clinical and radiographic evaluation was performed at 15, 30, 60 and 90 postoperatively. The locomotor function of the limb was evaluated in scores on the differents moments. The joint macroscopic evaluation was performed before exploratory arthrotomy and biopsy for microscopic exam. All dogs showed normal function of the limbs in all differents moments. Radiographic results showed no difference in control (CG) and treated groups (TG). Microscopic results showed at 30 days an increase of the celularity in both groups was observed. In the CG it was constituted by active fibroblasts and in TG by immatures condrocytes forming a more organized connective tissue. In the CG a fibrous tissue and many fibroblasts appear at 60 days and in the TG more condrocytes appear. A mature fibrocartilaginous tissue formed in both groups at 90 days. Histomorphometrically, TG presents better response of repair process in the fist moments as the number of cells and the tissue thickness. The biosynthetic cellulose membrane didn't cause deleterious effects showing good adaptation in intrarticular environment...(Complete abstract, access undermentioned eletronic address) / Mestre

Made available in DSpace on 2014-06-11T19:28:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2004-02-09Bitstream added on 2014-06-13T20:36:53Z : No. of bitstreams: 1 silva_vc_me_arafo.pdf: 1730174 bytes, checksum: ce33d44b50196aca4d9f0d95f23a7f81 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Este trabalho teve como objetivo determinar as reações teciduais em lesões de furca Grau II em 2ºs pré-molares de cães após tratamento com matriz mineral óssea bovina e membrana absorvível e movimentação ortodôntica de translação para mesial. Foram criadas lesões de furca Grau II nos 2º pré-molares superiores de 4 cães, totalizando 8 lesões. Após 75 dias, estas foram tratadas pela técnica de Regeneração Tecidual Guiada com membrana absorvível associada ao preenchimento com matriz mineral óssea bovina. Deu-se início ao controle de placa com gel de clorexidina 0,2% 5 vezes por semana até o final do estudo. Após 2 meses do tratamento, os 2ºs pré-molares foram divididos aleatoriamente em dois grupos (teste e controle) e foi instalado aparelho ortodôntico em ambos os lados, sendo os 3ºs pré-molares e caninos superiores usados como ancoragem. No lado teste a movimentação ortodôntica foi realizada durante 3 meses. Os animais foram sacrificados, e os 2ºs pré-molares removidos em bloco e processados para análise histológica. Não houve diferenças estatisticamente significantes entre os grupos em relação a área total de preenchimento ósseo, de biomaterial e extensão linear de regeneração periodontal na superfície radicular. Porém, houve uma tendência do grupo teste apresentar maior quantidade óssea e menor quantidade de biomaterial, além de deslocamento do biomaterial para o lado de pressão na região de furca, no grupo teste. / The aim of this study was to establish the tissue reactions on Degree II furcation lesions in the 2nd premolars of dogs after treatment with bovine osseous mineral source, absorbable membrane and orthodontic movement of translation to mesial and also evaluate the effect of movement on the grafting material used. It was produced Degree II furcation lesions in upper second premolars of 4 dogs, resulting in 8 lesions. After75 days, they were treated by the method of Guided Tissue Regeneration with absorbable membrane associated with bovine osseous mineral source. The plaque control was started with 0,2% chlorhexidine gel, 5 times a week until the end of the study. After 2 months of treatment, the second premolars were randomly divided in two groups (test and control) and it was installed orthodontic appliance in both sides, using the third premolars and upper canine as anchorage. The orthodontic movement was achieved only in the test side, during 3 months. The animals were sacrificed and the second premolars were removed in block and processed for histological analysis. There weren't any differences that were statistically significant among the groups with relation to the total area of osseous filling, biomaterial and linear periodontal regeneration. However, there was a trend of the group to present more osseous amount and less biomaterial amount, besides the dislocation of the biomaterial for the furcation pressure side. The orthodontic movement could be done without intercurrences. Key- words: Periodontics; Guided tissue regeneration; Biocompatible materials; Orthodontic.