This thesis describes the development of artificial disc technology for the replacement of intervertebral discs in the human lumbar spine. The clinical problem is back pain. There may be a relationship between certain forms of back pain and disc degeneration. The mechanical properties of human intervertebral discs are examined in detail. The genetic basis of disc degeneration is presented. The hypothesis is that such degeneration leads to a loss of normal stiffness in the segments affected leading to abnormal mechanical behaviour which in turn leads to pain. The evidence for this is presented. The development of surgical solutions to relieve back pain, from fusion through first generation mechanical artificial discs to elastomeric designs, is traced. The author‘s personal contributions to this area of knowledge are set out. The appreciation of the requirement for a restoration of physiological stiffness is argued throughout, showing where fusion and first generation discs have not met the clinical aim of pain relief, because they have not restored physiological stiffness. The path to an elastomeric, viscoelastic, polyhydrocarbon, rubber solution in the form of the “Freedom“ disc has filled 17 years of the author‘s academic pursuits. It will be shown that this technology may represent a possible solution to the clinical problem. Failure is part of all new advancement and this too is presented, to show how that has influenced thinking, producing original ideas to overcome these failures. Providing lessons are learned from these failures then our patients in the future will benefit.

Cross frames and diaphragms are essential to the stability of straight steel girder bridge systems as they help to resist lateral torsional buckling during construction and horizontal loading conditions. In skewed bridge systems, cross frames are often oriented parallel to the supports and hence, at an angle to the girder. To facilitate construction fit-up, plates, bent to match the skew angle, form the cross frame to stiffener connection. While the bent plate connection is a simple solution, it could introduce undesirable flexibility into the system, potentially compromising the effective brace stiffness. A proposed detail utilizing half pipe stiffeners may provide enhanced structural performance, while possibly reducing overall fabrication costs. Field and laboratory tests to determine the stiffness of both connection types are presented in the thesis. / text

<p>The trabecular meshwork (TM) is comparable to a bioactive filter that plays a major role in regulating outflow of aqueous humor of the eye and setting intraocular pressure (IOP). TM dysfunction may lead to ocular hypertension which is the major risk factor in glaucoma. Although the outflow properties of the TM have been assessed over the last sixty years, very little work has been done assessing its mechanical properties. Therefore, the major goals of these studies were two-fold: (1) to determine the relationship between mechanical properties of TM, specifically the bulk Young's modulus, and outflow function in normal and glaucomatous eyes, and (2) to establish a method and possible animal model for future testing of this relationship.</p><p>Outflow function was assessed by constant pressure perfusion in enucleated eyes at four pressure levels (10, 20, 30, and 40 mmHg) to determine outflow facilities and variability in outflow resistance with pressure elevation. A micro-strain analyzer (MSA) was used to determine the circumferential bulk Young's modulus of the TM post-perfusion. Based on their relative ease of availability, pigs and rats were explored as possible animal models. Due to the small size of rat eyes, atomic force microscopy (AFM) was used to assess the Young's modulus of TM rather than with a MSA.</p><p>We found that there was a relationship with better outflow function and a stiffer TM in normal eyes. Additionally, glaucomatous TM was found to be much softer and more variable than normal TM. Unfortunately, porcine TM did not serve as a good model for the bulk Young's modulus of human TM, presumably due to anatomical difference in its outflow pathway. Lastly, we were able to establish a new method for measuring the Young's modulus of rat TM for future work to determine potential mechanism for evaluating stiffness changes that may be associated with glaucoma.</p> / Dissertation

Understanding cardiac pumping function is crucial to guiding diagnosis, predicting outcomes of interventions, and designing medical devices that interact with the cardiovascular system.  Computer simulations of hemodynamics can show how the complex cardiovascular system is influenced by changes in single or multiple parameters and can be used to test clinical hypotheses. In addition, methods for the quantification of important markers such as elevated arterial stiffness would help reduce the morbidity and mortality related to cardiovascular disease. The general aim of this thesis work was to improve understanding of cardiovascular physiology and develop new methods for assisting clinicians during diagnosis and follow-up of treatment in cardiovascular disease. Both computer simulations and medical imaging were used to reach this goal. In the first study, a cardiac model based on piston-like motions of the atrioventricular plane was developed. In the second study, the presence of the anatomical basis needed to generate hydraulic forces during diastole was assessed in heathy volunteers. In the third study, a previously validated lumped-parameter model was used to quantify the contribution of arterial and cardiac changes to blood pressure during aging. In the fourth study, in-house software that measures arterial stiffness by ultrasound shear wave elastography (SWE) was developed and validated against mechanical testing. The studies showed that longitudinal movements of the atrioventricular plane can well explain cardiac pumping and that the macroscopic geometry of the heart enables the generation of hydraulic forces that aid ventricular filling. Additionally, simulations showed that structural changes in both the heart and the arterial system contribute to the progression of blood pressure with age. Finally, the SWE technique was validated to accurately measure stiffness in arterial phantoms. / <p>QC 20161115</p>

Carbon fiber (CF) 8-harness satin weave, T650/Neximid system of [(+45/-45)/(0/90)]2S and [(0/90)]4S layup was manufactured using resin transfer molding (RTM). The material was cut into 3-point bending specimens and treated for 24 hours in a burn oven at T=(320,350,375,400,450 &amp; 500)°C. The material was tested according to ASTM E1640-13 using dynamic mechanical thermal analysis (DMTA). Un-treated material showed Tg levels of 384°C and 392°C for the respective layups. It was found that pre-Tg treatment between 320-375°C affected this material parameter up to similar levels as previous studies of post Tg exposure for 2h to ~420°C [4]. Subjecting the material for post-Tg exposure at 400°C showed a rapid change up to ~480°C for [(0/90)]4S laminate. Indications that this resin system could reach levels above 500°C was found for [(+45/-45)/(0/90)]2S layup. However, one of these specimens were unfit for testing. DMTA tested material for 400°C showed indications of degradation, found by a broadening of the tan delta peak. This can be put in relation to epoxy where a similar behavior appear after 24h exposure at 150°C. Furthermore, it was showed that poor quality laminate, elevated mass loss at this temperature. When the material was subjected to as high temperatures as 450°C only remaining fibers were found. At 500°C these were almost fully oxidized. 400°C data was predicted by the use of activation energy along with TG extrapolation. It was possible to show that ~1/8 out of this 8-layered structure, (½ of each surface layer), was degraded after 400°C exposure for 24h, resulting in diffusion limited oxidation (DLO). Last but not least, DLO assumptions was used to predict the storage modulus change for thermo-oxidative degradation of 400°C samples with Classic Laminate Theory (CLT). A ~4% stiffness decrease was predicted by this method. The drop is regarded as a loss in tensile stiffness of the outer damaged layer. This was compared by 3-point bending DMTA data showing a ~7% decrease. This model could thus be regarded as a contributing factor for the stiffness decrease of this complex degradation process. / Kolfiber, 8-harness satin väv, T650/NEXIMID system med [(+45/-45)/(0/90)]2S och [(0/90)]4S orientering, tillverkades via RTM. Från materialet tillverkades 3-punkts böjprover. Dessa behandlades i 24 timmar vid T=(320, 350, 375, 400, 450 &amp; 500)°C, i en brännugn. Materialet testades i enighet med ASTM E1640-13 via DMTA. Obehandlat material visade Tg nivåer av 384°C och 392°C för de respektive uppläggningarna. Pre-Tg exponering, vid 320-375°C, påverkade Tg upp till liknande nivåer som tidigare studier, (post-Tg 2h), ~420°C [4]. När materialet utsätts för post Tg exponering under 24 timmar vid 400°C kunde man se en snabb förändring av Tg, upp till ~480°C för [(0/90)]4S laminatet. Från [(+45/-45)/(0/90)]2S laminatet kunde man dessutom se indikationer på att nivån kunde nå över 500°C. Däremot var en av dessa prov inte kvalificerad för test efter behandlingen. DMTA testat material för 400°C visade indikationer av nedbrytning, via en breddning av piken för tan-delta kurvan. Det var dessutom möjligt att se att laminat av sämre kvalitet påverkade viktminskningen signifikant högre vid denna exponering. När material utsattes för så höga temperaturer som 450°C var endas fiber kvar efter test, vilket vid 500°C nästan var fullt nedbrutna. 400°C data förutspåddes via extrapolering av TG och Arrhenius beräkning. Beräkningen ledde till en övre gräns för nedbrytningen. Vidare var det möjligt att visa att ~1/8 av dessa 8-lager bröts ner efter 24 timmars exponering vid 400°C. Nedbrytningen motsvarar ½ av vartdera ytlager via diffusions begränsad oxidation (DLO). Sist men inte minst, kunskapen om DLO användes för att förutspå styvhetsförändringen vid termo-oxiderande nedbrytning med hjälp av klassisk laminat teori (CLT). DLO antogs resultera i en volymfraktionsförändring i det yttersta lagret. Detta implementerades i CLT där man kunde beräkna en ~4% styvhetsminskning via denna modell där det yttre skadade lagret har en reducerad dragstyvhet. Från testade böjprover i DMTA kunde man se en verklig ~7% styvhetsminskning för samma exponeringsvillkor. Modellen kan därmed ses som en bidragande del av denna komplexa nedbrytningsprocess.

Characterization of the effect of physical properties on the performance such as stiffness and drainage of unbound granular materials is necessary in order to incorporate them in pavement design. The stiffness, deformation and permeability behaviour of unbound granular materials are the essential design inputs for Mechanistic-Empirical Pavement Design Guide as well as empirical design methods. The performance based specifications are aimed to design, and construct a durable and cost effective material throughout the design life of a pavement. However, the specification varies among jurisdiction depending on the historical or current practice, locally available materials, landform, climate and drainage. A literature review on the current unbound granular materials virgin and recycled concrete aggregate base construction specification has been carried out in this study. Resilient modulus, permanent deformation and permeability tests have been carried out on seven gradations of materials from locally available sources. Resilient modulus stiffness of unbound granular material at two different conditioning stress level have been compared in the study. The long term deformation behaviour has also been characterized from results of the permanent deformation test using shakedown approach, dissipated energy approach and a simplified approach. The results show improvement in resilient modulus and permanent deformation for the proposed specification compared to the currently used materials as a results of reduced fines content, increased crush count and inclusion of larger maximum aggregate size into the gradation. A significant effect of particle packing on permeability of granular materials have also been found, in addition to the effect of fines. / October 2016

Background: In patients with diabetes, high blood pressure is an established risk factor for cardiovascular disease. The aim of this thesis was to explore the associations between blood pressure levels measured with different techniques and during different circumstances, and the degree of cardiovascular organ damage and subsequent prognosis in patients with diabetes. Methods: We analysed baseline data from patients with type 2 diabetes who participated in the observational cohort study CARDIPP (Cardiovascular Risk factors in Patients with Diabetes – a Prospective study in Primary care), and longitudinal data from patients registered in the Swedish national quality registry RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive care Admissions). Patients in CARDIPP underwent nurse-recorded, 24-hour ambulatory and non-invasive central blood pressure measurements. Patients in RIKS-HIA had their systolic blood pressure measured upon hospitalisation for acute chest pain. Results: In CARDIPP, nearly one in three patients with office normotension (&lt;130/80 mmHg) were hypertensive during the night (≥120/70 mmHg). This phenomenon, masked nocturnal hypertension, was significantly associated with increased arterial stiffness and increased central blood pressure. Furthermore, nearly one in five CARDIPP patients with office normotension had high central pulse pressure (≥50 mmHg), and there was a significant association between high central pulse pressure and increased carotid intima-media thickness and increased arterial stiffness. Among CARDIPP patients who used at least one antihypertensive drug, those who used beta blockers had significantly higher central pulse pressure than those who used other antihypertensive drugs, but there were no significant between-group differences concerning office or ambulatory pulse pressures. In CARDIPP patients with or without antihypertensive treatment, ambulatory systolic blood pressure levels were significantly associated with left ventricular mass, independently of central systolic blood pressure levels. When RIKS-HIA patients, admitted to hospital for chest pain, were stratified in quartiles according to admission systolic blood pressure levels, the risk for all-cause one-year mortality was significantly lower in patients with admission systolic blood pressure in the highest quartile (≥163 mmHg) than in patients with admission systolic blood pressure in the reference quartile (128-144 mmHg). This finding remained unaltered when the analysis was restricted to include only patients with previously known diabetes. Conclusions: In patients with type 2 diabetes, ambulatory or central blood pressure measurements identified patients with residual risk factors despite excellent office blood pressure control or despite ongoing antihypertensive treatment. Ambulatory systolic blood pressure predicted left ventricular mass independently of central systolic blood pressure. In patients with previously known diabetes who were hospitalised for acute chest pain, there was an inverse relationship between systolic blood pressure measured at admission and the risk for one-year all-cause mortality.

Computational joint models provide insight into the biomechanical function of human joints. Through both deformable and rigid body modeling, the structure-function relationship governing joint behavior is better understood, and subsequently, knowledge regarding normal, diseased, and/or injured function is garnered. Given the utility of these computational models, it is imperative to supply them with appropriate inputs such that model function is representative of true joint function. In these models, Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scans and literature inform the bony anatomy and mechanical properties of muscle and ligamentous tissues, respectively. In the case of the latter, literature reports a wide range of values or average values with large standard deviations due to the inability to measure the mechanical properties of soft tissues in vivo. This makes it difficult to determine which values within the published literature to assign to computational models, especially patient-specific models. Therefore, while the use of published literature serves as a reasonable first approach to set up a computational model, a means of improving the supplied input data was sought. This work details the application of artificial neural networks (ANNs), specifically feedforward and radial basis function networks, to the optimization of ligament stiffnesses for the improved performance of pre- and post-operative, patient-specific foot/ankle computational models. ANNs are mathematical models that utilize learning rules to determine relationships between known sets of inputs and outputs. Using knowledge gained from these training data, the ANN may then predict outputs for similar, never‑before-seen inputs. Here, an optimal network of each ANN type was found, per mean square error and correlation data, and then both networks were used to predict optimal ligament stiffnesses corresponding to a single patient’s radiographic measurements. Both sets of predictions were ultimately supplied to the patient-specific computational models, and the resulting kinematics illustrated an improvement over the existing models that utilized literature-assigned stiffnesses. This research demonstrated that neural networks are a viable means to hone in on ligament stiffnesses for the overall objective of improving the predictive ability of a patient-specific computational model.

Le terme invadosome regroupe à la fois les podosomes, dans les cellules normales, et les invadopodes, dans les cellules transformées par l’oncogène Src et les cellules cancéreuses. Ces structures sont capables d’interagir avec et de dégrader la matrice extracellulaire (MEC). Ils sont aussi considérés comme des méchanosenseurs car ils sont capables de sentir la rigidité et la nature de la MEC. Mon travail de thèse s’est focalisé sur l’impact du microenvironnement matriciel sur la formation et l’activité des invadosomes. Au cours d’une première étude, nous avons démontré que les cellules endothéliales microvasculaires forment de façon constitutive des podosomes. L’utilisation de matrices de rigidités contrôlées, a permis la mise en évidence d’une corrélation entre l’augmentation de la rigidité augmentait et le nombre de cellules formant des podosomes ainsi que la taille de ces structures. En plus de la rigidité, d’autres propriétés de la MEC, telles que sa composition moléculaire et son organisation pourraient influencer la formation des invadosomes. Dans une seconde et troisième étude, nous avons pu montrer que seul le collagène fibrillaire de type I était capable d’induire la formation de microdomaines d’actine linéaires qui présentent comme les invadosomes, la capacité de dégrader la MEC. Au vu de leur morphologie originale, nous avons nommés ces structures des invadosomes linéaires (LIs). De façon intéressante, nous avons pu établir que la formation et l’activité de dégradation des LIs étaient indépendantes des intégrines β1 et β3. Au contraire, nous avons démontré que les récepteurs à domaine discoïdine (DDRs) contrôlent la formation et l’activité des LIs. De plus, les voies de signalisation classiques associées aux invadosomes classiques ne sont pas impliquées dans la formation des LIs. Une analyse par spectrométrie de masse des interactants de DDR1 dans un contexte collagène de type I fibrilllaire a permis de mettre en évidence des régulateurs clés et de révéler une voie de signalisation potentiellement impliquée dans la formation des LIs.Ainsi, ce travail de thèse a permis d’identifier la rigidité de la matrice comme un inducteur majeur des podosomes mais aussi la capacité intrinsèque des cellules microvasculaires à former ces structures. De plus, nous avons identifié un nouveau type d’invadosome, les LIs, qui sont associés à un nouveau type de récepteur concernant les invadosomes, les DDRs. / Invadosome is a global term including podosome, found in normal cells, and invadopodia observed in Src-transformed and cancer cells. These structures are specialized cell-matrix contacts able to interact with and degrade the extracellular matrix (ECM). They are considered as mechanosensors as they are able to sense the strength, the nature of the extracellular matrix. My PhD work essentially focuses on the understanding of how matrix microenvironment impacts on invadosome formation and activity. In a first study, we demonstrated that microvascular cell types constitutively form podosomes. Thus, using matrices of controlled rigidity, we found that an increase of stiffness was associated with an enhancement in the number of cells forming podosomes and podosome size. In addition to the matrix rigidity, other microenvironment properties, such as the molecular composition and the organization of the matrix are expected to influence the formation of invadosome.In a second and a third part of this wok, we show that fibrillar type I collagen induce the formation of linear actin microdomains which exhibit invadosome characteristics. In view of their original architecture, we named these new structures, linear invadosomes (LIs).Interestingly, we show that the formation and degradation activity of LIs are independent of β1 and β3-integrins but required discoidin domain receptors (DDRs). Moreover, all the signalling pathways known to induce classical invadosome are not required for the LIs induction. A mass spectrometry analysis of DDR1 partners emphasized key regulators and these results highlight a new potential signalling pathway involved in LIs formation. This work allowed us identifying matrix stiffness as a major inducer of podosomes but also the intrinsic capacity of microvascular cells to form these structures. Moreover, we identify a new type of invadosome, the Linear Invadosome associated with DDRs receptors.

An instrument is being developed at the Department of Biomedical Engineering; Research and Development (MT-FoU), at the University Hospital of Umeå with the aim to detect prostate cancer ex vivo. Using a combination of tactile resonance technology and Raman spectroscopy the instrument is intended to be used in the operating room during radical prostatectomy to identify positive surgical margins. The hypothesis was that the length of the piezoelectric element used in the tactile resonance sensor affects the sensor's sensitivity and reproducibility when measuring the stiffness of soft tissue, and that there might be an optimal impression depth to measure at. The specific aim of this study was to evaluate two piezoelectric elements, of different lengths, by the sensitivity and reproducibility of the measurements they performed. Measurements were performed on five silicone samples of different stiffness, during a 2 mm impression. The standard deviation of the stiffness parameters, the R2 of the linear regression used to determine the stiffness parameter, and the depth at the which the most linear relationship between impression force and frequency shift was found were studied using linear mixed-effects models to identify any significant differences between the elements. The long element had a significantly higher R2 of 0.98 compared to 0.93 for the short element, and a higher measurement depth of 0.47 mm compared to 0.37 mm for the short element. No difference between the elements were found on accuracy as measured by standard deviation of the stiffness parameter. It was concluded that this was not enough to claim that one element was better than the other. / Ett instrument utvecklas på avdelningen för Medicinsk teknik, forskning och utveckling, vid Norrlands universitetssjukhus med målet att detektera prostatacancer ex vivo. Instrumentet kombinerar taktil resonansteknologi med Ramanspektroskopi och är tänkt att användas i operationssalen under radikal prostatektomi för att identifiera positiv kirurgisk marginal. Hypotesen var att längden av det piezoleketriska element som används i den taktila resonanssensorn påverkar sensorns känslighet och reproducerbarhet vid mätning av styvhet av mjukvävnad, och att det kan finnas ett optimalt intryckningsdjup att mäta på. Målet med denna studie var att utvärdera två piezoelektriska element, av olika längd, utifrån känsligheten och reproducerbarheten av mätningarna de utförde. Mätningarna gjordes på fem silikonsprover av olika styvhet, under 2 mm intryckning. Standardavvikelsen av styvhetsparametern, R2 av den linjära regression som användes för att bestämma styvhetsparametern, samt det intryckningsdjup på vilket det mest linjära förhållandet mellan intryckningskraft och frekvensskift hittades, studerade med så kallade linear mixed-effects modeller för att identifiera signifikanta skillnader mellan elementen. Det långa elementet hade ett signifikant högre R2 på 0.98 jämfört med det korta elementets 0.93, och ett högre mätdjup på 0.47 mm jämfört med det korta elementets 0.37 mm. Ingen skillnad mellan elementens standardavvikelser av styvhetsparametern hittades. Slutsatsen drogs att resultatet inte var nog för att påstå att det ena elementet är bättre än det andra.