3-D computational modelling of the human spine provides a sophisticated and cost-effective medium for bioengineers, researchers, and ergonomics designers in order to study the biomechanical behaviour of the human spine under different loading conditions. Developing a generic parametric computational human spine model to be employed in biomechanical modelling introduces a considerable potential to reduce the complexity of implementing and amending the intricate spinal geometry. The main objective of this research is to develop a 3-D parametric human spine model generation framework based on a command file system, by which the parameters of each vertebra are read from the database system, and then modelled within commercial 3-D CAD software. A novel data acquisition and generation system was developed as a part of the framework for determining the unknown vertebral dimensions, depending on the correlations between the parameters estimated from existing anthropometrical studies in the literature. The data acquisition system embodies a predictive methodology that comprehends the relations between the features of the vertebrae by employing statistical and geometrical techniques. Relations amongst vertebral parameters such as golden ratio were investigated and successfully implemented into the algorithms. The validation of the framework was carried out by comparing the developed 3-D computational human spine models against various real life human spine data, where good agreements were achieved. The constructed versatile framework possesses the capability to be utilised as a basis for quickly and effectively developing biomechanical models of the human spine such as finite element models.

Mathematical modelling is widely used in the field of biomechanics. The traditional approach to investigate spine related injuries is to check the strength of the components of the spine. Spinal stability approach focuses on the force polygons formed by the body weight, muscle forces, ligament forces and external load. This force polygon is expected to stay within the boundaries of the spine to ensure stability. Proving the possibility of one force polygon within the spine boundaries proves the stability of the spine. This study focuses on the full curvature of the spine for spinal stability investigations in a lifting activity. An experiment has been designed to investigate the postural differences in males and females by measuring the full spinal curvature with a skin surface device. Distributed body weight force, with increased detail of muscle and ligament forces acting on the spine have been modelled by writing a code in Visual Basic, while lifting a load from the boot of a car in the sagittal plane. This model is flexible enough to reflect changes in body weight parameter. Results show that there is a difference between male and female postures during the full span of lifting activities. Application of individual muscle forces provides greater control of stability at each vertebral level. By considering the elongation of the ligaments and the force requirements of the muscle groups, it is possible to diagnose soft tissue failure. The differences in posture result in different moment arms for muscles and ligaments causing different loading on the spine. Most critical postures have been identified as the fully flexed postures with external load acting on the spine. Conceptual design ideas have been proposed to assist lifting a load from the boot of a car to eliminate the excessive flexion and loading on the spine.

Au cours de ma thèse, j'ai observé que la microglie est nécessaire à la maturation des circuits hippocampaux par la formation de boutons multi-synaptiques. J'ai également étudié la mécanique d'élimination des synapses, et observé que la microglie n'élimine pas directement les compartiments post-synaptiques. En revanche, elle contacte spécifiquement et rapidement certaines épines, en induisant un étirement de la tête de l'épine. Les petites épines sont préférentiellement contactées, et leur proximité avec les compartiments phagocytiques de la microglie suggère qu'elles pourraient être digérées sans être détachées du dendrite auquel elles appartiennent. Enfin, le système du complément n'est pas requis pour la reconnaissance ni les interactions entre microglie et épines, mais semble nécessaire à leur maturation. / During my thesis, I found that microglia is necessary for the maturation of hippocampalcircuits through the formation of multiple synapse boutons. I investigated how microgliacould mechanistically eliminate synapses, and found that microglia do not eliminate entirepost-synaptic spines but instead make fast and specific contacts that often result in spinehead stretching. Small, immature spines are preferentially targeted by microglia, and theirproximity to phagocytic compartment suggests that microglia could subtly erode themwithout to challenge their attachment to the dendritic shaft. Last, the complement system isnot necessary for recognition and interaction of microglia with spines, however seemsnecessary for proper maturation of post-synaptic spines.

La scoliose infantile est une déformation rachidienne évolutive survenant chez l'enfant de moins de 3 ans. La technique de correction la plus répandue actuellement est celle des « tiges de croissance ». Cependant, la rigidité du matériel provoque la dégénérescence des disques intervertébraux, ce qui di-minue l'efficacité du traitement. Des études récentes ont montré l'effet bénéfique d'implants flexibles sur les disques. Notre équipe a donc développé le concept d'une suspension implantable qui permet de garder la mobilité axiale des segments instrumentés, associé à un nouveau système de fixation rotulée. Cepen-dant, quelle valeur de raideur permet de préserver les disques tout en corrigeant efficacement la sco-liose ? Cette thèse a donc pour objectifs de démontrer l'intérêt d'une suspension pour les disques inter-vertébraux et d'obtenir des informations quantifiables sur la valeur optimale de raideur. Pour cela des prototypes de suspension avec fixation rotulée, implantables chez le mammifère quadrupède et l'Homme, ont été développés afin d'étudier in vivo et in silico plusieurs gammes de flexibilité. Une étude in vivo sur chèvres adultes saines a été menée pour tester ces prototypes pour 2 raideurs différentes. L'état des disques intervertébraux après 6 mois a été évalué par IRM et par coupes histologiques. En parallèle la biomécanique d'un rachis humain sain puis scoliotique, instrumenté avec différents disposi-tifs (tiges classiques, suspensions, avec ou sans rotules), a été étudiée avec un modèle numérique mul-ti-corps rigides, préalablement validé par comparaison avec des données in vitro de la littérature. Les résultats de l'étude in vivo n'ont pas montré de différence significative entre les différentes instrumentations testées. Un temps d'essai plus long semble nécessaire pour voir apparaître la dégéné-rescence discale. Les simulations numériques ont montré une nette amélioration de la mobilité des segments ins-trumentés avec une suspension rotulée. La majorité de la mobilité est cependant assuré par le nouveau système de fixation et non par la présence d'une plus grande souplesse axiale. La suspension permet néanmoins un gain supplémentaire pour certains mouvements du rachis. Aucune différence significative n'a été constatée entre les 2 valeurs de raideurs étudiées. La présence de fixations rotulée diminue par contre fortement la correction obtenue lors des simulations de chirurgie de distraction. La suspension seule présente un intérêt certain lors de la correc-tion en diminuant les efforts transmis au matériel. Les développements futurs s'orienteraient donc vers une suspension combinée à des fixations rotulées présentant également des raideurs en rotation pour conserver correction et mobilité / Infantile scoliosis is a progressive spinal deformity occurring in children under 3 years-old. The most common currently correction technic is the "growing rods" one. However, the implant rigidity causes intervertebral discs degeneration, which decreases the treatment efficiency. Recent studies have shown the benefic effect of flexible implants on discs. Our team has developed the concept of an implantable suspension that keeps the axial mobility of the instrumented segments, associated with a new fastening ball joint system. However, which is the stiffness value that preserves discs while correcting scoliosis? This thesis goal is to demonstrate the effectiveness of a suspension device for preserving inter-vertebral discs health and obtain quantifiable information on the optimum stiffness value. Prototype suspensions with ball joint fastenings, implantable in quadruped mammals and humans, have been de-veloped to study several ranges of stiffness values in vivo and in silico. An in vivo study on healthy adult goats was conducted to test these prototypes for two different stiffness values. The intervertebral discs health after 6 months was evaluated by MRI and histological sections. In parallel the biomechanics of a human spine was studied with a rigid multi-body numerical model previously validated against in vitro literature data. Healthy and scoliosis subjects instrumented with different devices (traditional rods, sus-pensions, with or without the ball) were modeled. The results of the in vivo study showed no significant difference between the several instrumen-tations. A longer test time seems necessary to observe the onset of disc degeneration. Numerical simulations have shown a marked mobility improvement for the segments in the in-strumented area with a suspension device associated with a ball joint system. However, the majority of the mobility is provided by the new fixing system and not by a greater axial flexibility. The suspension still allows additional gain for certain spine movements. No significant differences were found between the two studied stiffness values. The presence of a ball joint fastening decreases strongly the correction obtained during surgery distraction simulations. The suspension has an interest during correction by reducing the forces trans-mitted to the material when used alone. Future developments thus would lead to a suspension device associated with ball joint fasten-ings that also have rotational stiffness to keep both good scoliosis correction and segments mobility

Abstract Modic changes are vertebral bone marrow signal intensity changes adjacent to the endplates of the degenerated intervertebral discs in magnetic resonance imaging (MRI). This study evaluated the prevalence and the determinants of Modic changes and their association with low back pain symptoms in an occupational cohort of middle-aged Finnish men. The prevalence and the natural course of Modic changes were assessed over a 3-year follow-up period among sciatica patients. Finally, in a patient population, the characteristics of bone marrow changes in MRI were compared to the imaging findings in CT. The prevalence of Modic changes was 56% in an occupational cohort of middle-aged males. Besides age, the determinants of Modic changes and disc degeneration were different. Weight-related factors, which add to the load of the lumbar spine, were associated with Modic changes, whereas whole-body vibration was associated with severe disc degeneration. The prevalence of Modic changes among sciatica patients was 65%, type II change being the most frequent. During the 3-year follow-up, 14% of changes converted to another type, while the incidence of new Modic changes was 6%. Among middle-aged working males, Modic changes located at L5–S1 and type I Modic changes were more likely to be associated with pain symptoms than other types of Modic changes or changes located at other lumbar levels. Thirty-eight percent of the endplates with Modic changes had sclerosis in CT. Of specific Modic types, mixed I/II and II/III associated significantly with endplate sclerosis. Endplate sclerosis was not detected in MRI. In conclusion, Modic changes are a common MRI finding both among patients and middle-aged working males. In addition to age, weight-related factors seem to be important in the pathogenesis of Modic changes. Modic changes can convert from one type to another and type II changes may be less stable than previously assumed. A considerable proportion of Modic changes are sclerotic as observed in CT. Modic changes were always found in combination with a degenerative intervertebral disc and thus they are assumed to be a specific phenotype of degenerative disc disease. Finally, Modic changes may be painful – especially when located at L5–S1 and type I changes.

Radiography is a common radiologic investigation despite abundant evidence of its limited diagnostic value. On the other hand, computed tomography (CT) has a high diagnostic value and is widely considered to be among the most important advances in medicine. However, CT exposes patients to a higher radiation dose and it might therefore not be acceptable simply to replace radiography with CT, despite the powerful diagnostic value of this technique. At the expense of reduced CT image quality, which could be adjusted to the diagnostic needs, low-dose CT of abdomen and lumbar spine can be performed at similar dose to radiography. The aim of the current thesis project was to evaluate low-dose CT of the abdomen and lumbar spine and to compare it with radiography. The hypothesis was that CT would give better image quality and diagnostic information compared to radiography at similar dose levels. Firstly, the diagnostic accuracy of low-dose CT of the abdomen was evaluated. Results showed that low-dose CT of abdomen has a high sensitivity and specificity compared to radiography, i.e., it has higher diagnostic accuracy. Similar results were obtained from our systematic review. Secondly, in a phantom study, an ovine phantom was scanned at various CT settings. The image quality was evaluated to obtain a protocol for the optimal settings for low-dose CT of lumbar spine at 1 mSv. This new protocol was then used in a clinical study to assess the image quality of low-dose CT of the lumbar spine and compare it to radiography. Results showed that low-dose CT has significantly better image quality than radiography. Finally, the impact of Iterative reconstruction (IR) on image quality of lumbar spine CT was tested. Iterative reconstruction is a recent CT technique aimed to reduce radiation dose and/or improve image quality. The results showed that the use of medium strength IR levels in the reconstruction of CT image improves image quality compared to filtered back projection. In conclusion, low-dose CT of the abdomen and lumbar spine, at about 1 mSv, has better image quality and gives diagnostic information compared to radiography at similar dose levels and it could therefore replace radiography.

Title: Comparison of the effectiveness of manual therapy and therapy using exercises in muscle postural ligations for painful neck syndromes. Objective: The main aim of this work is to compare commonly used physiotherapeutic techniques, exercise and mobilization, (manipulation) techniques in chronic, painful neck syndromes. Methods: The study involved a total of 30 probands with chronic neck pain, randomly divided into three groups of 10. In the first group the subject was health exercise, in the second group therapy with mobilization (manipulations) techniques and in the third group was a combination of both therapies. Probands were individually treated in five visits, 30 minutes for one visit. The evaluation methods were NRS, NDI and goniometry. The data was evaluated in Microsoft Office Excel. Results: The results showed that after 5 therapies there was a statistically significant reduction in pain on the NRS scale in all three groups. Within the NDI questionnaire there was a very small reduction in the ADL limitation, for all three groups, the changes were statistically significant. There were no changes in goniometry in any of the groups and changes were not statistically significant. Keywords: chronic neck pain, cervical spine, exercise, mobilization, NDI

M.Tech. / Purpose: A study to determine the efficacy of Traumeel® gel using phonophoresis in the treatment of a latent trapezius myofascial trigger point, with regards to pain perception, cervical spine range of motion and pressure pain tolerance.Methods: A single-blinded, controlled study design was utilised. Thirty participants who all presented with a latent trapezius myofascial trigger point were randomly divided into two groups of fifteen. Each individual was subjectively and objectively assessed from baseline values prior to receiving treatment. Group A received ultrasound utilising ultrasound gel over the trapezius myofascial trigger point, as the control group. Group B received phonophoresis with Traumeel® gel over the trapezius myofascial trigger point. All participants received two treatments per week, with a total of seven consultations, over the three week study period. The subjective data was obtained utilising a Numerical Pain Rating Scale (NPRS) whilst a hand held Algometer tested pressure pain tolerance and a Cervical Range of Motion Measuring Instrument (CROM) measured cervical spine range of motion. These were utilised to form the objective data. The Data was analysed using non-parametric tests. The two independent treatment groups were assessed for capability at treatments one, four and seven using the Mann-Whitney U-test (non-parametric version of the independent sample T-test). Changes over the three week period were observed and analyzed using the Repeated Measures test or the Friedman Test (Devey, 2010). Results: In this study ultrasound utilising ultrasound gel had a statistically significant impact on the trapezius myofascial trigger point. Statistical analysis of the Traumeel® gel suggests that there was no statistical significance with regards to any of the treatment parameters or variables measured. Subjectively ultrasound gel proved to be statistically and clinically significant in decreasing the participant’s pain perception. There was no statistical improvement but there was a clinical improvement in the Traumeel® gel group.

M.Ing. (Mechanical Engineering) / A stand-alone anterior lumbar interbody fusion device is used to stabilise the spine and restore the disc space height without any other instrumentation. The stand-alone anterior lumbar interbody device is fixed to the adjacent vertebrae using titanium screws. In this research an experimental and numerical investigation on the structural strength of the SASCATM stand-alone anterior lumbar interbody fusion device are presented. The outcome of the investigation will be used as part of the device validation documentation necessary for market approval. The SASCATM device is manufactured from PEEK (a high strength polymer). Tensile and compressive testing was conducted to determine the appropriate mechanical properties of PEEK. The structural integrity of the SASCA device was evaluated by conducting full scale compression testing on a limited number of different design revisions. Comparisons as regards to their loaddisplacement behaviour were made. All specimens were visually inspected. The Finite Element Analysis (FEA) method was used in the numerical investigation of the SASCATM stand-alone anterior lumbar interbody device. Three studies were conducted. The first study aimed at comparing the full scale experimental compressive testing results with the FEA simulation. Although the desired results weren’t achieved, the model gave a fair representation of the initial region of the experimental setup in the sense that it had a similar slope. It was concluded that the nominal stress (4.1 MPa) fell within the proportional limit (35 MPa) as measured during the materials testing. The second study was aimed at determining the displacement at a worst-case load determined from the literature (2.7 kN). The study showed that the maximum Von Mises stress does not exceed the yield strength of the material. The third and final (parametric) study aimed at geometric optimisation of the cages. The motivation for the changes was based on the literature and customer suggestions for improvement. The geometric optimisation intended to show whether a desired increase in graft hole size would have an effect on the structural integrity of the device. The suggestion to move the screw holes of the threehole version closer to the center of the cage was also assessed. It was shown that enlarging the two graft holes does have an effect on the compressive strength. Higher stresses were presented in all but one case. Combining the holes also had an effect on the compressive strength. Movement of the screw holes more medially did have an impact on the compressive strength of the cages. The effect was significant. The closer the holes were to the center of the cage, the higher the Von Mises stress was. This change should therefore be considered before implementation. The results showed that different shapes and sizes of the graft holes do have an impact on the stress of this particular cage. None of the models exceeded the compressive yield strength of the material. The proposed graft hole opening design changes are therefore not warranted for the current SASCATM stand-alone anterior lumbar interbody device.

Calpains, a highly conserved family of calcium-dependent cysteine proteases, are divided in two groups; classical and non-conventional calpains. Calpain-1 and calpain-2, the classical ones, are ubiquitously expressed and abundant in the CNS. Findings through different experimental approaches, predominantly pharmacological calpain inhibitors, proposed the necessity of the proteases for the modulation of various biological events particularly in the CNS, or a functional link between calpain and neurodegeneration. Significant functions associated with calpain activity are neuronal proliferation/differentiation, signal transduction, apoptosis, and synaptic plasticity; or neuronal death in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and ischemic stroke. However, due to limited insights of the approaches taken, such as non-specificity of the inhibitors, the exact roles of calpains in the CNS and the key mechanisms underlying them remain controversial. Calpain-1/calpain-2 germline knock-out are embryonic lethal at a very early stage hindering the use of these lines as mouse models for CNS studies. Accordingly, this thesis research introduced a unique brain-specific calpain-1/calpain-2 knock-out and explored the role of the proteases in brain development/function and in neuronal death. The first set of analyses examined how the elimination of calpain-1/calpain-2 activities in mouse brain impacts CNS development in general and synaptic plasticity in CA1 neurons of hippocampus. CNS-specific elimination of CAPNS1, the common small subunit, abolished calpain-1/calpain-2 activities in mouse brain. In contrast to Calpain-1/calpain-2 germ line knock-outs, the brain-specific knock-outs are viable and the general development of mouse brain is normal. However, morphology of dendrites in pyramidal neurons of the hippocampal CA1 region showed significantly decreased dendritic branching complexity and spine density. Consistent with dendrite morphological abnormalities, electrophysiological analyses revealed a significant decrease in field excitatory postsynaptic potentials, long term potentiation, and learning and memory in the hippocampal CA1 neurons of the mutants. In the second part of this research we investigated the direct role of the calpains in neuronal death and their potential downstream targets in in vitro models of PD and ischemic stroke. Our findings indicated that ablation of calpains activity improves survival of different types of neurons against mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+), glutamate, and hypoxia. Importantly, we demonstrated an increase in p35-cleavage to p25, a cyclin dependent kinase 5 (Cdk5) activator, and that restoration of p25 significantly suppresses the neuronal survival associated with calpain deficiency. Taken together, this work unequivocally establishes two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.