The objective of the work carried out in this thesis was to develop analytical and computational tools to model and investigate musculoskeletal human joints. It was recognised that the FEA was used by many researchers in modelling human musculoskeletal motion, loading and stresses. However the continuum mechanics played only a minor role in determining the articular joint motion, and its value was questionable. This is firstly due to the computational cost and secondly due to its impracticality for this application. On the other hand, there isn’t any suitable software for precise articular joint motion analysis to deal with the local joint stresses or non standard joints. The main requirement in orthopaedics field is to develop a modeller software (and its associated theories) to model anatomic joint as it is, without any simplification with respect to joint surface morphology and material properties of surrounding tissues. So that the proposed modeller can be used for evaluating and diagnosing different joint abnormalities but furthermore form the basis for performing implant insertion and analysis of the artificial joints. The work which is presented in this thesis is a new frame work and has been developed for human anatomic joint analysis which describes the joint in terms of its surface geometry and surrounding musculoskeletal tissues. In achieving such a framework several contributions were made to the 6DOF linear and nonlinear joint modelling, the mathematical definition of joint stiffness, tissue path finding and wrapping and the contact with collision analysis. In 6DOF linear joint modelling, the contribution is the development of joint stiffness and damping matrices. This modelling approach is suitable for the linear range of tissue stiffness and damping properties. This is the first of its kind and it gives a firm analytical basis for investigating joints with surrounding tissue and the cartilage. The 6DOF nonlinear joint modelling is a new scheme which is described for modelling the motion of multi bodies joined by non-linear stiffness and contact elements. The proposed method requires no matrix assembly for the stiffness and damping elements or mass elements. The novelty in the nonlinear modelling, relates to the overall algorithmic approach and handling local non-linearity by procedural means. The mathematical definition of joint stiffness is also a new proposal which is based on the mathematical definition of stiffness between two bodies. Based on the joint stiffness matrix properties, number of joint stiffness invariants was obtained analytically such as the centre of stiffness, the principal translational stiffnesses, and the principal rotational stiffnesses. In corresponding to these principal stiffnesses, their principal axes have been also obtained. Altogether, a joint is assessed by six principal axes and six principal stiffnesses and its centre of stiffness. These formulations are new and show that a joint can be described in terms of inherent stiffness properties. It is expected that these will be better in characterising a joint in comparison to laxity based characterisation. The development of tissue path finding and wrapping algorithms are also introduced as new approaches. The musculoskeletal tissue wrapping involves calculating the shortest distance between two points on a meshed surface. A new heuristic algorithm was proposed. The heuristic is based on minimising the accumulative divergence from the straight line between two points on the surface and the direction of travel on the surface (i.e. bone). In contact and collision based development, the novel algorithm has been proposed that detects possible colliding points on the motion trajectory by redefining the distance as a two dimensional measure along the velocity approach vector and perpendicular to this vector. The perpendicular distance determines if there are potentially colliding points, and the distance along the velocity determines how close they are. The closest pair among the potentially colliding points gives the “time to collision”. The algorithm can eliminate the “fly pass” situation where very close points may not collide because of the direction of their relative velocity. All these developed algorithms and modelling theories, have been encompassed in the developed prototype software in order to simulate the anatomic joint articulations through modelling formulations developed. The software platform provides a capability for analysing joints as 6DOF joints based on anatomic joint surfaces. The software is highly interactive and driven by well structured database, designed to be highly flexible for the future developments. Particularly, two case studies are carried out in this thesis in order to generate results relating to all the proposed elements of the study. The results obtained from the case studies show good agreement with previously published results or model based results obtained from Lifemod software, whenever comparison was possible. In some cases the comparison was not possible because there were no equivalent results; the results were supported by other indicators. The modelling based results were also supported by experiments performed in the Brunel Orthopaedic Research and Learning Centre.

Les dystrpohies musculaires sont des maladies génétiques rares qui se caractérisent par une dégénérescence musculaire progressive. la Dystrophie Musculaire de Duchenne (DMD) qui est la plus sévère d'entre elles est due à des mutations dans le gène de la dystrophine. Les mécanismes cellulaires impliqués dans le processus de dégénérescence des muscles restent peu compris et aucun traitement efficace n'existe à ce jour. Notre équipe a développé un modèle de la DMD chez le nématode C. elegans qui présente une dégénérescence musculaire progressive. Pendant ma thèse, j'ai caractérisé le processus de dégénérescence musculaire chez ce modèle par microscopie électronique. J'ai également contribué à une étude du rôle des mitochondries dans la dégénérescence musculaire dystrophine-dépendante chez le nématode. Par ailleurs, j'ai étudié l'effet de suppresseurs pharmacologique et génétiques de la dégénérescence musculaire dystrophine-dépendante. Enfin, j'ai pu mettre en évidence que la force exercée par le muscle influence le taux de dégénérescence musculaire. L'ensemble des résultats obtenus au cours de ma thèse, suggèrent que la perte de fonctions de la dystrophine affecte chez le nématode l'intégrité du sarcolemme et des structures d'ancrage des sarcomères et déclenche ainsi une cascade d'événements intracellulaires conduisant in fin à la mort de la cellule musculaire. Ainsi mes travaux dethèse mettent en évidence de nouveau mécanismes cellulaires impliqués dans la dégénérescence musculaire et ouvrent de nouvelles perspectives pour le développement de thérapie visant à cibler les défauts primaires ou secondaires induits par la perte de fonction de la dystrophine / Muscle dystrophies are genetic diseases caraterized by progressive muscle degeneration. Duchenne Muscular Dystrophy (DMD) is the most severe and is due to a mutation in the gene coding the dystrophin protein. The cellular mechanisms implicated in the degenerating process arte not understood yet and there is still no efficient treatment to cure the disease. Our group decvelopped a DMD model in C. elegans that presents progressive muscle degeneration. During my PhD thesis, I characterized the process of muscle degeneration in this model by electron microscopy. I also contribued to an investigation of the role of mitochondira in dystophin-dependant muscle degeneration. I also studied the effect of pharmacological and genetic suppressors of muscle degeneration. Finally, I showed that the force developped by the worm to move influences the level of muscle degeneration. Altogether, the results I obtained during my PhD thesis, suggest that the loss of funciotnof the dystrophin protein affects the integrity of the muscle plasma membrane and the sarcomeres anchoring structures triggering a cascade of intracellular events leading to the muscle cell death in C. elegans. Therefore, my results highlight new cellular mechanisms implicated in the phenomenon of muscle degeneration and open new perspectives for the development of therapies targeting primary and secondary defects induced by the dystrophin loss of function.