Glaucoma is a common cause of blindness worldwide, yet the etiology of the disease is unclear. A leading hypothesis is that elevated intraocular pressure (IOP) affects the biomechanical environment within the tissues of the optic nerve head (ONH), and that the altered biomechanical environment contributes to optic nerve damage and consequent loss of vision. The biomechanical environment of the ONH is strongly dependent on the biomechanical properties of sclera, particularly scleral stiffness. However there is significant variability in reported stiffness data for human sclera. Therefore, our research goal was to measure the stiffness of human sclera and incorporate this information into finite element models of the human eye to characterize and quantify the biomechanical environment within and around the optic nerve head region at different IOP levels. Human sclera adjacent to the optic nerve head showed highly nonlinear, nearly isotropic and heterogeneous stiffness which was found to be substantially lower than that previously assumed, particularly at lower levels of IOP. The products c*c1 and c*c2, measures of stiffness in the latitudinal and longitudinal directions from the Fung constitutive model, were 2.9 ± 2.0 MPa and 2.8 ± 1.9 MPa, respectively, and were not significantly different (two-sided t-test; p = 0.795). Scleral stiffness was not statistically different between left and right eyes of an individual (p = 0.952) and amongst the quadrants of an eye (p = 0.412 and p = 0.456 in latitudinal and longitudinal directions, respectively). Three stress-strain relationships consistent with the 5th, 50th and 95th percentiles of the measured scleral stiffness distribution were selected as representatives of compliant, median and stiff scleral properties and were implemented in a generic finite element model of the eye using a hyperelastic five-parameter Mooney-Rivlin material model. Models were solved for IOPs of 15, 25 and 50 mmHg. The magnitudes of strains at the optic nerve head region were substantial at even the lowest applied IOP (15 mmHg) and increased at elevated IOPs (e.g. the third principal strain in the compliant model reached as much as 5.25% in the lamina cribrosa at 15mmHg and 8.84% in the lamina cribrosa at 50 mmHg). Scleras that are “weak”, but still within the physiologic range, are predicted to lead to appreciably increased optic nerve head strains and could represent a risk factor for glaucomatous optic neuropathy. As IOP increased from 15 to 50 mmHg, principal strains in the model with a compliant sclera increased at a lower rate than in the model with a stiff sclera. We quantified the biomechanical environment within and around the optic nerve head region using a range of experimentally measured mechanical properties of sclera and at different IOPs. We showed that IOP-related strains within optic nerve head tissues can reach potentially biologically significant levels (capable of inducing a range of effects in glial cells) even at average levels of IOP and for typical human scleral biomechanical properties.

Introduction: Studies show that Total Knee Arthroplasty (TKA) is successful for the majority of patients however some continue to experience some functional limitations and anecdotal evidence indicates that stiffness is a common complaint. Some studies have suggested an association between stiffness and functional limitations however there has been no previous work which has attempted to objectively quantify knee joint stiffness following TKA. The purpose of this study was to pilot and evaluate a method for the quantitative evaluation in joint stiffness in replaced knees, OA knees and healthy controls and to explore whether there is an association between stiffness and functional limitations post-TKA surgery. Methods: The first part of the study created a biomechanical model of knee stiffness and built a system from which stiffness could be calculated. A torque transducer was used to measure the resistance as the knee was flexed and extended passively and an electrogoniometer concurrently measured the angular displacement. Stiffness was calculated from the slope of the line relating the passive resistive torque and displacement. The torque and joint angle at which stiffness was seen to increase greatly was also noted. The system was bench tested and found to be reliable and valid. Further tests on 6 volunteers found stiffness calculations to have acceptable intra-day reliability. The second part was conducted on three groups: those with end-stage knee OA (n = 8); those who were 1 year post-TKA (n = 15) and age matched healthy controls (n = 12). Knee range of motion was recorded and participants then completed the WOMAC, the SF-12 and a Visual Analogue Score for stiffness as well as indicating words to describe their stiffness. Four performance based tests – the Timed Up and Go (TUG), the stair ascent/descent, the 13m walk and a quadriceps strength test were also undertaken. Finally, passive stiffness at the affected knee was measured. Results: 100% of OA, 80% of TKA and 58% of controls reported some stiffness at the knee. The OA group reported significantly higher stiffness than the OA or TKA groups. There was no difference in self-reported stiffness between the TKA and control groups. Of the total number of words used to describe stiffness, 52% related to difficulty with movement, 35% were pain related and 13% related to sensations. No significantly differences were found between groups in the objective stiffness measures. Significant differences were found however in threshold flexion stiffness angles between groups. When this angle was normalised, differences between groups were not significant. No significant differences were found between groups in the threshold stiffness torque. Greater self-reported stiffness was found to be associated with worse self-reported function. A higher flexion stiffness threshold angle was associated with slower timed tests of function but also with better quadriceps muscle strength. Conclusions: The results support anecdotal reports that perceived stiffness is a common complaint following TKA but there was no evidence to show that patients with TKA have greater stiffness than a control group. There was however evidence to show that patients’ were unable to distinguish between sensations of stiffness and other factors such as pain. Self-perceived increased stiffness was associated with worse functional performance. Greater stiffness however was not necessarily negative. Stiffness increases earlier in flexion range were associated with better functional performance. These results suggest that an ideal threshold range for stiffness may exist; above which negative perceptions of the knee result in worse function but below which, knee laxity and instability may also result in worse function.

Hip fracture has been identified as a major worldwide health problem among the elderly population. A fast, accurate and effective evaluation of hip fracture risk is essential for accurate health care planning and selecting a proper treatment. Therefore, the high applicability and the universal availability are required for assessing a technique. The objective of this study was to develop a two-dimensional subject-specific beam model, which is easy to be adopted into a clinical environment to assess hip fracture risk. First, the equivalence between CTXA (computed tomography X-ray absorptiometry) and QCT (quantitative computed tomography) derived femur cross-section stiffness was studied. Then, the CTXA-based femur cross-section stiffness was used in the beam model to calculate the hip fracture risk index (FRI) during sideways fall and single-leg stance loading configuration. Finally, the test of discrimination between PPI (proton-pump inhibitor) users and non-PPI users based on cross-sectional stiffness, BMD (bone mineral density) and FRI was conducted to demonstrate if PPI use is associated with the presence of osteoporosis or accelerated BMD loss. Strong correlation is found between CTXA and QCT derived femur cross-section stiffness, which indicates that QCT can be replaced by CTXA in assessing femur bone quality. Therefore, DXA can be a replacement of QCT to calculate femur cross-sectional properties due to the equivalence between CTXA and DXA derived mechanical properties. It is also demonstrated that the cross-sectional stiffness, BMD, and FRI cannot discriminate the PPI users from non-PPI users, which means that there is no difference between PPI users and non-PPI users in cross-sectional stiffness, BMD, and FRI. This may suggested that PPI use is not associated with the presence of osteoporosis or accelerated BMD loss. The proposed beam model can be easily adopted into clinic to predict hip fracture risk, and this beam model derived FRI can be used in some clinical verification. Yet its accuracy of discriminate fracture will be investigated in a future study. / May 2017

Turbulence is a major factor limiting the achievement of better tokamak performance as it enhances the transport of particles, momentum and heat which hinders the foremost objective of tokamaks. Hence, understanding and possibly being able to control turbulence in tokamaks is of paramount importance, not to mention our intellectual curiosity of it. We take the first step by making measurements of turbulence using the 2D ($8$ radial $imes$ $4$ poloidal channels) beam emission spectroscopy (BES) system on the Mega Amp Spherical Tokamak (MAST). Measured raw data are statistically processed, generating spatio-temporal correlation functions to obtain the physical characteristics of the turbulence such as spatial and temporal correlation lengths as well as its motion. The reliability of statistical techniques employed in this work is examined by generating and utilizing synthetic 2D BES data. The apparent poloidal velocity of fluctuating density patterns is estimated using the cross-correlation time delay method. The experimental results indicate that the poloidal motion of fluctuating density patterns in the lab frame arises because the patterns are advected by the strong toroidal plasma flows while the patterns are aligned with the background magnetic fields which are not parallel to the flows. Furthermore, various time scales associated with the turbulence are calculated using statistically estimated spatial correlation lengths and correlation times of turbulence. We find that turbulence correlation time, the drift time associated with ion temperature or density gradients, the ion streaming time along the magnetic field line and the magnetic drift time are comparable and possibly scale together suggesting that the turbulence, determined by the local equilibrium, is critically balanced. Finally, we argue that we have produced a critical manifold in the experimentally obtained local equilibrium parameter space separating dominant turbulent transport from a non-turbulent or weakly turbulent state. It shows that the inverse ion-temperature-gradient scale length is correlated inversely with $q/arepsilon$ (safety factor/inverse aspect ratio) and positively with the plasma rotational shear. Practically, this means that we can attain the stiffer ion-temperature-gradient, thus hotter plasma core, without increasing the rotational shear.

A madeira tem aplicações já difundidas em diversos setores, no entanto, muitas vezes é utilizada sem o conhecimento de suas propriedades. A caracterização de espécies de madeira consiste em determinar suas propriedades físicas, de resistência e rigidez através de ensaios normalizados. O inconveniente de grande parte desses ensaios é a utilização de equipamentos de alto custo e grande porte, disponíveis apenas em centros de pesquisa. Porém, o ensaio de densidade aparente é de fácil determinação por utilizar equipamentos simples na sua execução. Sendo assim, neste trabalho são determinadas as correlações entre a densidade aparente e as propriedades físicas, de resistência e de rigidez da madeira, de quarenta espécies nativas brasileiras, do grupo dicotiledôneas. Através de análise estatística, foram obtidas expressões matemáticas que permitem estimar, a partir da densidade aparente, grande parte das propriedades de resistência e rigidez da madeira. Tais expressões são apresentadas como proposta para a utilização na caracterização de espécies menos conhecidas, o que viabiliza o adequado emprego de espécies nativas nas mais variadas aplicações para as quais a madeira é indicada. Apresentam-se também aferições das expressões propostas pela norma brasileira NBR 7190, que permitem a caracterização simplificada das resistências da madeira de espécies usuais a partir dos ensaios de resistência à compressão paralela às fibras. / Wood has diffused applications in several sections, however, a lot of times it is used without the knowledge of its properties. The characterization of wood species consists of determining its physical, strength and stiffness properties, through normalized tests. The inconvenience of many of those tests is the use of equipments of high cost and great load, available just in research centers. Even so, the test of specific gravity is of easy determination for using simple equipments in its execution. Being like this, in this study the correlations between the specific gravity, physical and mechanical properties of wood from forty brazilian native species of hardwoods are determined. The mathematical expressions obtained through this study, permit estimate most wood properties of strength and stiffness, based on their specific gravity. Such expressions are proposed as means of characterizing less-known species, what makes possible the appropriate employment of native species in most varied applications for which wood is the indicated material. Furthermore, it is presented the calibration of the expressions proposed by the brazilian code NBR 7190, being these a simplified method of characterizing mechanical properties of common species of wood by means of tests of strength in compression parallel to the grain.

A norma brasileira para o projeto de estruturas de madeira foi alterada, recentemente, abandonando o método determinista das Tensões Admissíveis e adotando o método probabilista dos Estados Limites. Seguindo tendência mundial, a atual norma brasileira, estabelece um teor de umidade de referência de 12%, no qual devem ser reportados os resultados dos ensaios. Dificilmente se conseguirá condicionar, a madeira para o ensaio, com um teor de umidade de exatamente 12%, portanto, será necessário corrigir os resultados do ensaio para este teor de umidade. A atual norma brasileira propõe expressões, para fazer esta correção nas propriedades de resistência e de rigidez da madeira, baseando-se em poucos resultados de ensaios. O objetivo deste trabalho é aferir as expressões propostas pela norma brasileira, sugerindo as alterações necessárias. Uma proposta para a correção da densidade aparente, não prevista na norma brasileira, também será estudada. Para garantir uma base experimental adequada, estuda-se a influência do teor de umidade sobre as propriedades de resistência à compressão paralela às fibras, tração paralela às fibras, cisalhamento paralelo às fibras (no plano radial-longitudinal), bem como sobre o módulo de elasticidade longitudinal e a densidade aparente, em sete diferentes espécies de madeira, correspondentes às sete classes de resistência adotadas pela atual norma brasileira. Conclui-se o trabalho apresentando uma proposta para correção das propriedades de resistência e rigidez ao teor de umidade de 12%. Apresenta-se também uma proposta para a correção da densidade aparente. / The Brazilian Code, NBR 7190/97 - Design of timber structures, was revisited, recently, abandoning the Allowable Stress Method and adopting the States Limits Design Method. Following world tendency, the current Brazilian Code, establishes a reference moisture content of 12%, in which the test\'s results should be registered. It is not possible to keep the specimen, for testing, with exactly 12% moisture content, therefore, it will be necessary to correct the results for this moisture content level. The current Brazilian Code proposes expressions, to do this correction in the strength and stiffness properties of wood, based on few test\'s results. The objective of this work is to judge the expressions proposed by the Brazilian Code, proposing the necessary alterations. A proposal for the correction of the specific gravity, not presented in the Brazilian Code, it will also be studied. To this purpose, the influence of moisture content on the strength in compression and tension parallel to grain, shear parallel to grain (in the radial-longitudinal plane), as well as on the stiffness (modulus of elasticity) and specific gravity, in seven different wood species, corresponding to the seven Brazilian Code strength classes were studied. The conclusions presents a proposal for correction of the strength, stiffness properties and specific gravity, to the 12% moisture content level.

O uso de resíduos de construção e demolição (RCD) vem ganhando espaço crescente em aplicações na engenharia. Este material adquiriu maior importância a partir da década de 70, com seu emprego ampliado como material granular em concretos de cimento para obras civis e no setor de infraestrutura, principalmente como camadas de pavimentos. O presente trabalho tem por objetivo compreender o comportamento físico e mecânico do agregado reciclado de resíduos de construção e demolição com adição de aglomerantes, a cal hidratada e cimento Portland. Foram construídos três trechos experimentais de uma via urbana com uso de RCD misto na sub-base dos pavimentos: (i) um sem aglomerantes adicionais, (ii) um com adição em usina de 3% de cal hidratada, e (iii) um com adição em usina de 3% de cimento Portland. Todas as amostras coletadas em usina foram caracterizadas em laboratório e foram analisados os comportamentos mecânicos das três diferentes misturas por meio de ensaios de (i) resistência à compressão simples aos 7 dias de cura para os materiais com aglomerantes, (ii) ensaios de módulo de resiliência a 7, 28 e 60 dias de cura para todas as misturas, e (iii) ensaios de deformação permanente com diferentes tensões. Analisando os resultados das misturas a 60 dias de cura, a mistura em RCD apresentou com o menor ganho em módulo de resiliência, enquanto que a mistura de RCD com 3% cimento, apresentou os maiores módulos, e a mistura RCD com adição em 3% de cal obteve um valor pouco abaixo daquele com cimento. Quanto ao comportamento à deformação permanente, verificou-se que a baixos níveis de tensão, todas as misturas apresentaram baixas deformações e comportamento similar. Em maiores níveis de diferença de tensões principais, as misturas estabilizadas apresentaram comportamento estável e as misturas em RCD obtiveram deformação permanente mais significativa. Com o monitoramento deflectométrico foi possível realizar retroanálise, e estimar os módulos de resiliência in situ, cujos valores foram similares aos encontrados em laboratório. Passados quase dois anos, o comportamento funcional e estrutural dos trechos experimentais é satisfatório. / The use of construction and demolition waste (CDW) has been increasing in engineering applications the use of CDW has become more important since the 70s as granular material in cement concrete applications in civil engineering and transportation infrastructure, mainly as pavement layers. This study aims to understand the physical and mechanical behavior of recycled aggregate from construction and demolition waste with the addition of hydraulic binders, as hydrated lime and Portland cement. Three experimental urban pavement sections were constructed using CDW as subbase material: (i) the first one using CDW, (ii) the second one using CDW with 3% of hydrated lime (mixed in the plant), and (iii) the third one employing CDW with 3% of cement (also mixed in the plant). All samples collected in the plant were characterized in laboratory. The mechanical behavior of these materials and mixtures were analyzed through the following tests: (i) compressive strength after 7 days of curing for materials with hydraulic binders, (ii) resilient moduli after 7, 28, and 60 days of curing for all mixes, and (iii) permanent deformation. By analyzing the responses of the mixture after 60 days of curing, the CDW mixture presented, as a crushed stone, the smallest gain on resilient modulus, whereas mixture with 3% cement with CDW had the highest modulus. The mixture with 3 % hydrated lime with CDW showed resilient modulus smaller than the mixture with cement. The permanent deformations at low stress levels were low and similar for the three tested materials. On the other hand, at higher stress level, the stabilized mixtures exhibited stable behavior, and the mixture with CDW shows a significant permanent deformation. The backcalculation based on the measurement of field deflections showed values of resilient moduli in situ similar to the laboratory results. After almost two years, the performance of the experimental sections is considered satisfactory.

The goal of this thesis was to investigate the interplay between sodium, glycosaminoglycans, vascular stiffness, and hypertension. In contrast to the traditional view of salt-dependent hypertension, recent studies have found that sodium accumulation can occur without commensurate fluid retention. Researchers hypothesise that this sodium is stored non-osmotically via association with negatively charged glycosaminoglycans (GAGs) in the extracellular matrix. The interaction of sodium and GAGs, the influence of sodium on GAG production, and the ability of GAGs to affect vascular stiffness are of key interest. This thesis first investigates the link between hypertension, vascular stiffness, and GAGs in ex vivo human aortae. Aortae from hypertensive donors were found to be stiffer than normotensive controls even after controlling for both pressure and age, a novel finding in humans. In these aortae, hypertension was associated with GAG remodelling, but not with changes in total GAG content. Next, an interventional rat study is presented to examine the effects of dietary salt on vascular stiffness and GAGs, and to distinguish between salt-dependent and blood pressure-dependent effects. In vivo vascular stiffness was found to be salt-dependent but pressure-independent, with ex vivo stiffness unaffected by salt. Ex vivo stiffness was also independent of aortic GAG content, similar to the human aortae described previously. GAG content in the skin was both salt-dependent and pressure-dependent. Finally, this thesis closes with an interventional study in humans. This study was designed to examine the effects of diuretic-induced salt loss on sodium storage, GAGs, and haemodynamics. An eight-day diuretic course corresponded to a ~10% reduction in skin sodium content, without associated water loss or cardiovascular changes. GAG mRNA expression was decreased in the skin, suggesting reduced GAG content. Pilot work from this study supports the use of 23Na MRI as a non-invasive measurement of skin sodium, but only for pre- vs post-treatment comparisons rather than absolute quantification. In conclusion, this thesis demonstrates that both salt and blood pressure influence GAG accumulation and distribution, but that GAGs do not directly affect vascular stiffness. However, GAGs do play a direct role in osmotically inactive sodium storage, which may modulate development of hypertension.

Aortic stiffness underlies systolic hypertension, promotes heart failure and is associated with increased cardiovascular morbidity and mortality. It is regarded as a primary driver of left ventricular hypertrophy and aortic aneurysms and is linked to the pathogenesis of cognitive impairment, stroke and renal failure. Like most cardiovascular traits, aortic stiffness is a complex trait and is moderately heritable, yet the precise molecular mechanisms that underpin the stiffening process remain poorly defined. This study aimed to employ multiple approaches to further identify the genetic basis of aortic stiffness in a large repository of human donor aortas that had undergone ex vivo pulse wave velocity (PWV) phenotyping. The first part of this work sought to investigate the molecular basis of Loeys-Dietz type 4 syndrome in a pedigree with multiple cases of aortic aneurysms and dissections. A missense variant p.(Arg320Cys) was identified in a highly evolutionary conserved region of TGFB2. There was striking upregulation of TGFB1, TGFB2 and pSMAD2/3 on imunocytochemical straining and western blotting of the aortic tissue from the index case confirming the functional importance of the variant. This case highlighted the striking paradox of predicted loss-of-function mutations in TGFB2 causing enhanced TGFβ signalling in this emerging familial aortopathy and underscored the significance of TGFβ signalling in aortic extracellular matrix biology. The second part of this work attempted to characterise the biological basis for the susceptibility locus identified in the most recent genome wide analysis of carotid-femoral PWV. While the locus lies within the 14q32.2 gene desert, it contains regulatory elements, with the transcriptional regulator B-cell CLL/lymphoma 11B (BCL11B) and non-coding RNA DB129663 representing potential targets for these enhancers. The association of five lead SNPs from the genome-wide association studies (GWAS) meta-analysis was examined for ex vivo aortic stiffness and BCL11B and DB129663 aortic mRNA expression. Three of the five SNPs associated significantly with PWV and showed allele-specific differences in BCL11B mRNA. The risk alleles associated with lower BCL11B suggesting a protective role for BCL11B. Despite the strong association, BCL11B protein was not detected in the human aorta; however, qPCR for CD markers showed that BCL11B transcript correlated strongly with markers for activated lymphocytes. In contrast, DB129663 transcripts were detected in 55% of the samples, and of the five SNPs only one showed allele-specific differences in aortic DB129663 transcripts. No significant differences were observed in PWV between samples expressing or lack- ing DB129663, and therefore the implication of this lncRNA in aortic stiffness remains elusive. The BCL11B transcript detected in the human aorta may reflect lymphocyte infiltration, suggesting that immune mechanisms contribute to the observed association with PWV. For the final part of this work genetic associations with aortic stiffness were explored in a candidate gene-based study utilising tagging SNPs to effectively capture the genetic information from linkage disequilibrium blocks. Association analyses were performed in young, healthy ENIGMA study par- ticipants selected for high and low PWV values then validated in the remaining ENIGMA cohorts. The association of four lead SNPs was then examined for ex vivo aortic stiffness in human donor aortas. The tissue expression of these SNPs and their encoded proteins was also explored. Neither the aggrecan nor the fibulin-1 SNPs showed significant associations with ex vivo PWV in the donor aortas. The exonic aggrecan tagSNP rs2882676 displayed differential transcript abundance between homozygous allele carriers but this did not translate at the protein level. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan, reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

"During heart valve remodeling, and in many disease states, valvular interstitial cells (VICs) shift to an activated myofibroblast phenotype which is characterized by enhanced synthetic and contractile activity. Pronounced alpha smooth muscle actin (alpha-SMA)-containing stress fibers, the hallmark of activated myofibroblasts, are also observed when VICs are placed under tension due to altered mechanical loading in vivo or during in vitro culture on stiff substrates or under high mechanical loads and in the presence of transforming growth factor-beta 1 (TGF-beta 1). The work presented herein describes three distinct model systems for application of controlled mechanical environment to VICs cultured in vitro. The first system uses polyacrylamide (PA) gels of defined stiffness to evaluate the response of VICs over a large range of stiffness levels and TGF-beta 1 concentration. The second system controls the boundary stiffness of cell-populated gels using springs of defined stiffness. The third system cyclically stretches soft or stiff two-dimensional (2D) gels while cells are cultured on the gel surface as it is deformed. Through the use of these model systems, we have found that the level of 2D stiffness required to maintain the quiescent VIC phenotype is potentially too low for a material to both act as matrix to support cell growth in the non-activated state and also to withstand the mechanical loading that occurs during the cardiac cycle. Further, we found that increasing the boundary stiffness on a three-dimensional (3D) cell populated collagen gel resulted in increased cellular contractile forces, alpha-SMA expression, and collagen gel (material)stiffness. Finally, VIC morphology is significantly altered in response to stiffness and stretch. On soft 2D substrates, VICs cultured statically exhibit a small rounded morphology, significantly smaller than on stiff substrates. Following equibiaxial cyclic stretch, VICs spread to the extent of cells cultured on stiff substrates, but did not reorient in response to uniaxial stretch to the extent of cells stretched on stiff substrates. These studies provide critical information for characterizing how VICs respond to mechanical stimuli. Characterization of these responses is important for the development of tissue engineered heart valves and contributes to the understanding of the role of mechanical cues on valve pathology and disease onset and progression. While this work is focused on valvular interstitial cells, the culture conditions and methods for applying mechanical stimulation could be applied to numerous other adherent cell types providing information on the response to mechanical stimuli relevant for optimizing cell culture, engineered tissues or fundamental research of disease states."