With the vast array of genetically altered (knockout) mice becoming available there is a need for quantitative, repeatable, and efficient methodologies to characterize the phenotypic consequences of knocking out specific genes. Since knockout animals often have the ability to compensate for a single missing gene, it is important to examine the structural, material and morphological properties to obtain a thorough understanding of the changes occurring. For this project, femurs of knockout mice were first scanned using microcomputed tomography (micro-CT) to obtain high-resolution images of the trabecular bone in the distal femur, as well as cortical bone in the mid-diaphysis. After scanning, the femurs were tested to destruction in four-point bending at the mid-diaphysis about the medial lateral axis of the femur. These methodologies allowed quantification of (1) morphologic properties such as bone volume fraction, trabecular properties and 2nd moment of the area (2) structural properties such as stiffness, maximum load at failure, and post yield deformation and (3) material properties such as bone mineral density, elastic modulus and yield strength. As part of two independent studies, two different knockout mice, cyclooxygenase-2 (COX-2 -/-) and Apolipoprotein E (APOE -/-), were examined for structure-function relationships using these methodologies. COX-2 knockout mice were found to have decreased mineral content in their femurs, and increased post yield deformation. APOE knockout mice at 10 weeks of age had decreased bone mass and structural properties. However, by 40 weeks of age APOE deficient mice caught up to and exceeded the structural properties and bone mass of their wild type counterparts.

Bone is a composite material consisting of hydroxyapatite crystals deposited in an oriented manner on a collagen backbone. The arrangement of the mineral and organic phases provides bone tissue with the appropriate strength, stiffness, and fracture resistance properties required to protect vital internal organs and maintain the shape of the body. A remarkable feature of bone is the ability to alter its properties and geometry in response to changes in the mechanical environment. However, in cases of metabolic bone diseases or aging, bone can no longer successfully adapt to its environment, increasing its fragility. To elucidate the mechanisms of bone microdamage, this research project developed a specimen-specific approach that integrated 3D imaging, histological damage labeling, image registration, and image-based finite element analysis to correlate microdamage events with microstructural stresses and strains under compressive loading conditions. By applying this novel method to different ages of bovine and human bone, we have shown that the local mechanical environment at microdamage initiation is altered with age. We have also shown that formation of microdamage is time-dependent and may have implications in age-related microdamage progression with cyclic and/or sustained static loading. The work presented in this dissertation is significant because it improved our understanding of trabecular bone microdamage initiation and unlocked exciting future research directions that may contribute to the development of therapies for fragility diseases such as osteoporosis.

Top screw pullout is a significant problem in anterior scoliosis correction, with rates of 5-15% reported in the literature. The Mater Misericordiae Hospital in Brisbane currently has a series of 125 patients with scoliosis treated by thoracoscopic anterior fusion, instrumentation and correction between April 2000 and August 2007. In this series 11 top screws are known to have pulled out (a rate of 8.8%), with six occurring in the first week, and all within 6 weeks, suggesting that the problem is one of excessive static force rather than fatigue. This thesis describes a biomechanical investigation into the mechanics of vertebral body screw pullout in anterior scoliosis surgical constructs. Previous biomechanical studies of vertebral body screws have evaluated their resistance to either straight pullout or cephalo-caudad compression forces, however the aim of this study was to assess screw resistance to more realistic loading conditions, namely pullout of initially angled screws, and pullout where the motion path is an arc rather than a straight axial pullout, as would be expected in a single rod anterior construct. The first series of experiments involved straight and angled pullout tests using synthetic bone. In the angled tests, both locked and free-to-pivot configurations were tested. The second series of experiments tested the effect of cephalo-caudad pre-compression (the actual deformity correction step performed during surgery) on subsequent axial pullout strength. A third series of experiments performed arc pullouts using synthetic bone, and the final series of experiments tested the pullout resistance of a newly proposed screw position configuration against the standard screw positioning using ovine lumbar vertebrae. Synthetic bone testing revealed that for initially angled pullout, resistance is greatest as the screw angle approaches 0 (ie a direct axial pullout). Cephalo-caudad pre-compression reduced subsequent pullout strength for cases where a staple was not used under the screw head, but if a staple was used the pre-compression did not decrease pullout force significantly. Arc pullout resistance was greatest when the screw was angled at 10 cephalad, and the mean pullout strength for the proposed screw configuration using ovine lumbar vertebrae (1864N) was almost double that of the standard screw positioning (993N). The clinical implication of this study is that top screw pullout resistance can be maximised by placing the top screw as close as possible to the top endplate and the bottom screw as close as possible to the bottom endplate, although this will have detrimental effects on the pullout of the second screw should the top screw pull out. Screw angulation is a less important factor but any angulation should be in a cephalad direction and around 10º in magnitude. The experimental results also suggest that the use of a staple may play a role in preventing cephalo-caudad pre-compression forces from reducing screw resistance to subsequent pullout forces.

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Des méthodes micromécaniques spécifiques ont été développées pour la détermination du comportement effectif de matériaux cellulaires dotés d’une architecture discrète à l’échelle microscopique. La méthode d’homogénéisation discrète a été appliquée à des structures tissées monocouches ainsi qu’à l’os trabéculaire. La topologie discrète initiale de ces milieux est remplacée à l’échelle mésoscopique par un milieu effectif anisotrope micropolaire, qui rend compte des effets d’échelles observés. Ces méthodes d’homogénéisation permettent d’accéder à des propriétés classiques et non classiques dont la mesure expérimentale est souvent difficile. Des modèles 3D ont été développé afin de décrire la rupture fragile et ductile de l’os trabéculaire, incorporant des effets de taille des surfaces d’écoulement plastique. Nous avons construit par des analyses éléments finis de la microstructure de l’os trabéculaire un milieu de substitution 3D homogène, orthotrope de type couple de contraintes, sur la base d’une équivalence en énergie. Les tissus osseux ont la capacité d’adapter leur densité locale et leur taille et forme aux stimuli mécaniques. Nous avons développé des modèles de remodelage interne et externe dans le cadre de la thermodynamique des processus irréversibles, aux échelles cellulaire et macroscopique. Finalement, le remodelage interne anisotrope a été couplé à l’endommagement de fatigue, dans le cadre de la théorie continue de l’endommagement / A methodology based on micromechanics has been developed to determine the effective behavior of network materials endowed with a discrete architecture at the microscopic level. It relies on the discrete homogenization method, which has been applied to textile monolayers and trabecular bones. The initially discrete topology of the considered network materials results after homogenization at the mesoscopic level in anisotropic micropolar effective continuum, which proves able to capture the observed internal scale effects. Such micromechanical methods are useful to remedy the difficulty to measure the effective mechanical properties at the intermediate mesoscopic level scale. The bending and torsion responses of vertebral trabecular bone beam specimens are formulated in both static and dynamic situations, based on the Cosserat theory. 3D models have been developed for describing the multiaxial yield and brittle fracture behavior of trabecular bone, including the analysis of size-dependent non-classical plastic yield. We have constructed by FE analyses a homogeneous, orthotropic couple-stress continuum model as a substitute of the 3D periodic heterogeneous cellular solid model of vertebral trabecular bone, based on the equivalent strain energy approach. Bone tissues are able to adapt their local density and load bearing capacities as well as their size and shape to mechanical stimuli. We have developed models for combined internal and external bone remodeling in the framework of the thermodynamics of irreversible processes, at both the cellular and macroscopic levels. We lastly combined anisotropic internal remodeling with fatigue continuum damage

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