Structural parameters defining distribution of collagen fiber directions in human carotid arteries.

Collagen fiber arrangement is decisive for constitutive description of anisotropic mechanical response of arterial wall. In this study, their orientation in human common carotid artery was investigated using polarized light microscopy and an automated algorithm giving more than 4·106 fiber angles per slice. In total 113 slices acquired from 18 arteries taken from 14 cadavers were used for fiber orientation in the circumferential-axial plane. All histograms were approximated with unimodal von Mises distribution to evaluate dominant direction of fibers and their concentration parameter. 10 specimens were analyzed also in circumferential-radial and axial-radial planes (2-4 slices per specimen in each plane); the portion of radially oriented fibers was found insignificant. In the circumferential-axial plane, most specimens showed a pronounced unimodal distribution with angle to circumferential direction µ = 0.7° ± 9.4° and concentration parameter b = 3.4 ± 1.9. Suitability of the unimodal fit was confirmed by high values of coefficient of determination (mean R2 = 0.97, median R2 = 0.99). Differences between media and adventitia layers were not found statistically significant. The results are directly applicable as structural parameters in the GOH constitutive model of arterial wall if the postulated two fiber families are unified into one with circumferential orientation.

In silico hemodynamical simulations show additional benefits of artery wall softening induced by antihypertensive drugs.

BACKGROUND AND OBJECTIVES: Age-related arterial stiffening increases peripheral resistance and decreases arterial distensibility, thus contributing to hypertension, an important risk factor of atherosclerosis. It causes abnormal blood flow, endothelial dysfunction, higher pulse wave velocity, and consequently elevated pressure wave amplitude. METHODS: This paper presents the influence of these changes via multiscale 3D-0D transient computational fluid dynamics simulations of blood flow in five patient-specific geometries of human carotid bifurcation using archetypal flow waveforms for young and old subjects. RESULTS: The proposed model shows a significant decrease in the time-averaged wall shear stress (TAWSS) for the old archetypal flow waveform. This is in good agreement with clinical data on a straight segment of common carotid arteries available for young and old subjects. Moreover, our study showed that the decrease of area-averaged TAWSS related to the old flow waveform is much more pronounced (2.5 ÷ 4.5 times higher) at risk areas (areas showing TAWSS below its threshold value of 0.48 Pa) than in straight segments commonly considered in clinical studies. CONCLUSIONS: Since arterial stiffness can be lowered through long-term usage of any of the five basic groups of antihypertensives, possible benefits of such medical therapy could be not only lowering blood pressure and peripheral resistance but also in increasing the TAWSS and thus attenuating an important mechanism of the atherosclerotic process.

Need for transverse strain data for fitting constitutive models of arterial tissue to uniaxial tests.

The study deals with the process of estimation of material parameters from uniaxial test data of arterial tissue and focuses on the role of transverse strains. Two fitting strategies are analyzed and their impact on the predictive and descriptive capabilities of the resulting model is evaluated. The standard fitting procedure (strategy A) based on longitudinal stress-strain curves is compared with the enhanced approach (strategy B) taking also the transverse strain test data into account. The study is performed on a large set of material data adopted from literature and for a variety of constitutive models developed for fibrous soft tissues. The standard procedure (A) ignoring the transverse strain test data is found rather hazardous, leading often to unrealistic predictions of the model exhibiting auxetic behaviour. In contrast, the alternative fitting method (B) ensures a realistic strain response of the model and is proved to be superior since it does not require any significant demands of computational effort or additional testing. The results presented in this paper show that even the artificial transverse strain data (i.e., not measured during testing but generated ex post based on assumed Poisson's ratio) are much less hazardous than total disregard of the transverse strain response.

Biaxial stretch can overcome discrepancy between global and local orientations of wavy collagen fibres.

Most frequently used structure-based constitutive models of arterial wall apply assumptions on two symmetric helical (and dispersed) fibre families which, however, are not well supported with histological findings where two collagen fibre families are seldom found. Moreover, bimodal distributions of fibre directions may originate also from their waviness combined with ignoring differences between local and global fibre orientations. In contrast, if the model parameters are identified without histological information on collagen fibre directions, the resulting mean angles of both fibre families are close to ±45°, which contradicts nearly all histologic findings. The presented study exploited automated polarized light microscopy for detection of collagen fibre directions in porcine aorta under different biaxial extensions and approximated the resulting histograms with unimodal and bimodal von Mises distributions. Their comparison showed dominantly circumferential orientation of collagen fibres. Their concentration parameter for unimodal distributions increased with circumferential load, no matter if acting uniaxially or equibiaxially. For bimodal distributions, the angle between both dominant fibre directions (chosen as measure of fibre alignment) decreased similarly for both uniaxial and equibiaxial loads. These results indicate the existence of a single family of wavy circumferential collagen fibres in all layers of the aortic wall. Bimodal distributions of fibre directions presented sometimes in literature may come rather from waviness of circumferentially arranged fibres than from two symmetric families of helical fibres. To obtain a final evidence, the fibre orientation should be analysed together with their waviness.

Effect of aortic bifurcation geometry on pressure and peak wall stress in abdominal aorta: Fluid-structure interaction study.

BACKGROUND AND OBJECTIVE: Geometry of aorto-iliac bifurcation may affect pressure and wall stress in aorta and thus potentially serve as a predictor of abdominal aortic aneurysm (AAA), similarly to hypertension. METHODS: Effect of aorto-iliac bifurcation geometry was investigated via parametric analysis based on two-way weakly coupled fluid-structure interaction simulations. The arterial wall was modelled as isotropic hyperelastic monolayer, and non-Newtonian behaviour was introduced for the fluid. Realistic boundary conditions of the pulsatile blood flow were used on the basis of experiments in literature and their time shift was tailored to the pulse wave velocity in the model to obtain physiological wave shapes. Eighteen idealized and one patient-specific geometries of human aortic tree with common iliac and renal arteries were considered with different angles between abdominal aorta (AA) and both iliac arteries and different area ratios (AR) of iliac and aortic luminal cross sections. RESULTS: Peak wall stress (PWS) and systolic blood pressure (SBP) were insensitive to the aorto-iliac angles but sensitive to the AR: when AR decreased by 50%, the PWS and SBP increased by up to 18.4% and 18.8%, respectively. CONCLUSIONS: Lower AR (as a result of the iliac stenosis or aging), rather than the aorto-iliac angles increases the BP in the AA and may be thus a risk factor for the AAA development.

Importance of experimental evaluation of structural parameters for constitutive modelling of aorta.

The study compares stresses and strains in the aortic wall derived using different constitutive models for various stress-strain conditions. Structure-based constitutive models with two fibre families with (GOH) and without (HGO) dispersion of collagen fibres are compared. The constitutive models were fitted to data from equibiaxial tension tests of two separated layers of the porcine aortic wall. The initial fit was evaluated with unrestricted parameters and subsequently, the mean angles of the fibre families and the angular dispersion were fixed to the values obtained from histology. Surprisingly, none of the tested models was capable to provide a good quality fit with histologically obtained structural parameters. Fitting the HGO model to experimental data resulted in two fibre families under angles close to ±45°, while the GOH model resulted in a nearly isotropic fibre distribution. These results indicate that both of these models suffer from the absence of isotropic strain stiffening. After having modified both models with corresponding additional members based on the Yeoh model of matrix, we obtained a perfect fit to the measured data while keeping the structural histology-based parameters. Finally, significant differences in compliance and resulting stresses and strains between different models are shown by means of simulations of uniaxial tension test, equibiaxial tension tests and inflation of the aorta.

Poisson's ratio and compressibility of arterial wall - Improved experimental data reject auxetic behaviour.

Poisson's ratio of fibrous soft tissue is analyzed in this paper on the basis of direct experimental measurements of porcine arterial wall layer under uniaxial tension and immersed in tempered saline bath. The current study follows the previously published testing methodology but with a new totally redesigned testing apparatus allowing more credible and precise evaluation of arterial wall behaviour. The new results confirm most of previous findings focused on positivity/negativity of Poisson's ratio playing a crucial role in (in)validation aspects of some constitutive models widely used in recent computational vascular mechanics. The effect of frozen & thawed conditions is also evaluated in comparison with fresh specimens. The in-plane Poisson's ratio of arterial wall was identified in the range of 0.3-0.4, whereas its out-of-plane component is much higher ranging from 0.5 to 0.7. These results contrast with predictions of some frequently used constitutive models. The volumetric (in)compressibility of arterial specimens is also analyzed, quantified and discussed in the paper, as a key property of soft tissues closely related to the topic of their constitutive modelling.

Impact of physiological loads of arterial wall on nucleus deformation in endothelial cells: A computational study.

INTRODUCTION: Computational modeling can enhance the understanding of cell mechanics. To achieve this, finite element models of endothelial cells were proposed with shapes mimicking their natural state inside the endothelium within the cardiovascular system. Implementing the recently proposed bendo-tensegrity concept, these models consider flexural (buckling) as well as tensional/compressional behavior of microtubules and also incorporate the waviness of intermediate filaments. MATERIALS AND METHODS: Four different models were created (flat and domed hexagons, both regular and elongated in the direction of blood flow) and loaded by biaxial deformation, blood pressure, and shear load from blood flow - natural physiological conditions of the arterial endothelium - aiming to investigate the "in situ" mechanical response of the cell. RESULTS: The impact of individual components of loads on the nucleus deformation (more specifically on the first principal strain) potentially influencing mechanotransduction was investigated and the role of the cytoskeleton and its constituents in the mechanical response of the endothelial cell was assessed. The results show (i) the impact of pulsating blood pressure on cyclic deformations of the nucleus, which increase substantially with decreasing axial pre-stretch of the cell, (ii) the importance of relatively low shear stresses in the cell response and nucleus deformation. CONCLUSION: Not only the pulsatile blood pressure but also the wall shear stress may induce significant deformation of the nucleus and thus trigger remodelation processes in endothelial cells.

Full-Range Optical Imaging of Planar Collagen Fiber Orientation Using Polarized Light Microscopy.

A novel method for semiautomated assessment of directions of collagen fibers in soft tissues using histological image analysis is presented. It is based on multiple rotated images obtained via polarized light microscopy without any additional components, i.e., with just two polarizers being either perpendicular or nonperpendicular (rotated). This arrangement breaks the limitation of 90° periodicity of polarized light intensity and evaluates the in-plane fiber orientation over the whole 180° range accurately and quickly. After having verified the method, we used histological specimens of porcine Achilles tendon and aorta to validate the proposed algorithm and to lower the number of rotated images needed for evaluation. Our algorithm is capable to analyze 5·105 pixels in one micrograph in a few seconds and is thus a powerful and cheap tool promising a broad application in detection of collagen fiber distribution in soft tissues.

Constitutive models and failure properties of fibrous tissues of carotid artery atheroma based on their uniaxial testing.

To obtain an experimental background for the description of mechanical properties of fibrous tissues of carotid atheroma, a cohort of 141 specimens harvested from 44 patients during endarterectomies, were tested. Uniaxial stress-strain curves and ultimate stress and strain at rupture were recorded. With this cohort, the impact of the direction of load, presence of calcifications, specimen location, patient's age and sex were investigated. A significant impact of sex was revealed for the stress-strain curves and ultimate strains. The response was significantly stiffer for females than for males but, in contrast to ultimate strain, the strength was not significantly different. The differences in strength between calcified and non-calcified atheromas have reached statistical significance in the female group. At most of the analysed stress levels, the loading direction was found significant for the male cohort which was also confirmed by large differences in ultimate strains. The representative uniaxial stress-strain curves (given by median values of strains at chosen stress levels) were fitted with an isotropic hyperelastic model for different groups specified by the investigated factors while the observed differences between circumferential and longitudinal direction were captured by an anisotropic hyperelastic model. The obtained results should be valid also for the tissue of the fibrous cap, the rupture of which is to be predicted in clinics using computational modelling because it may induce arterial thrombosis and consequently a brain stroke.

Interpretation of Experimental Data is Substantial for Constitutive Characterization of Arterial Tissue.

The paper aims at evaluation of mechanical tests of soft tissues and creation of their representative stress-strain responses and respective constitutive models. Interpretation of sets of experimental results depends highly on the approach to the data analysis. Their common representation through mean and standard deviation may be misleading and give nonrealistic results. In the paper, raw data of seven studies consisting of 11 experimental data sets (concerning carotid wall and atheroma tissues) are re-analyzed to show the importance of their rigorous analysis. The sets of individual uniaxial stress-stretch curves are evaluated using three different protocols: stress-based, stretch-based, and constant-based, and the population-representative response is created by their mean or median values. Except for nearly linear responses, there are substantial differences between the resulting curves, being mostly the highest for constant-based evaluation. But also the stretch-based evaluation may change the character of the response significantly. Finally, medians of the stress-based responses are recommended as the most rigorous approach for arterial and other soft tissues with significant strain stiffening.

Finite Element Simulations of Mechanical Behaviour of Endothelial Cells.

Biomechanical models based on the finite element method have already shown their potential in the simulation of the mechanical behaviour of cells. For instance, development of atherosclerosis is accelerated by damage of the endothelium, a monolayer of endothelial cells on the inner surface of arteries. Finite element models enable us to investigate mechanical factors not only at the level of the arterial wall but also at the level of individual cells. To achieve this, several finite element models of endothelial cells with different shapes are presented in this paper. Implementing the recently proposed bendotensegrity concept, these models consider the flexural behaviour of microtubules and incorporate also waviness of intermediate filaments. The suspended and adherent cell models are validated by comparison of their simulated force-deformation curves with experiments from the literature. The flat and dome cell models, mimicking natural cell shapes inside the endothelial layer, are then used to simulate their response in compression and shear which represent typical loads in a vascular wall. The models enable us to analyse the role of individual cytoskeletal components in the mechanical responses, as well as to quantify the nucleus deformation which is hypothesized to be the quantity decisive for mechanotransduction.

Failure properties of abdominal aortic aneurysm tissue are orientation dependent.

INTRODUCTION: Biomechanical rupture risk assessment of abdominal aortic aneurysm (AAA) requires information about failure properties of aneurysmal tissue. There are large differences between reported values. Among others, studies vary in using either axially or circumferentially oriented samples. This study investigates the effect of sample orientation on failure properties. METHODS: Aneurysmal tissues from 45 patients (11 females) were harvested during open AAA repair, cut into uniaxial samples (90) and tested mechanically within 3 h. If possible, the samples were cut in both axial (49 samples) and circumferential (41 samples) directions. Wall thickness, First Piola-Kirchhoff strength Pult and ultimate tension Tult were recorded. Influence of sample orientation and other clinical parameters were investigated using non parametric tests. RESULTS: Medians of Pult (values 1100 kPa for circumferential vs. 715 kPa for axial direction, p < 10-4) and Tult (17.4 N/cm in circumferential vs. 11.2 N/cm in axial direction, p < 10-4) were significantly higher in circumferential direction. For paired data, the median of difference was 411 kPa (p < 10-3) in Pult and 7.4 N/cm (p < 10-4) in Tult in favor of circumferential direction. CONCLUSIONS: In this first study of anisotropy in AAA wall failure properties using paired comparisons, the strength in circumferential orientation was found to be higher than in axial orientation.

Consideration of stiffness of wall layers is decisive for patient-specific analysis of carotid artery with atheroma.

The paper deals with the impact of chosen geometric and material factors on maximal stresses in carotid atherosclerotic plaque calculated using patient-specific finite element models. These stresses are believed to be decisive for the plaque vulnerability but all applied models suffer from inaccuracy of input data, especially when obtained in vivo only. One hundred computational models based on ex vivo MRI are used to investigate the impact of wall thickness, MRI slice thickness, lipid core and fibrous tissue stiffness, and media anisotropy on the calculated peak plaque and peak cap stresses. The investigated factors are taken as continuous in the range based on published experimental results, only the impact of anisotropy is evaluated by comparison with a corresponding isotropic model. Design of Experiment concept is applied to assess the statistical significance of these investigated factors representing uncertainties in the input data of the model. The results show that consideration of realistic properties of arterial wall in the model is decisive for the stress evaluation; assignment of properties of fibrous tissue even to media and adventitia layers as done in some studies may induce up to eightfold overestimation of peak stress. The impact of MRI slice thickness may play a key role when local thin fibrous cap is present. Anisotropy of media layer is insignificant, and the stiffness of fibrous tissue and lipid core may become significant in some combinations.

Impact of Decreased Transmural Conduction Velocity on the Function of the Human Left Ventricle: A Simulation Study.

This study investigates the impact of reduced transmural conduction velocity (TCV) on output parameters of the human heart. In a healthy heart, the TCV contributes to synchronization of the onset of contraction in individual layers of the left ventricle (LV). However, it is unclear whether the clinically observed decrease of TCV contributes significantly to a reduction of LV contractility. The applied three-dimensional finite element model of isovolumic contraction of the human LV incorporates transmural gradients in electromechanical delay and myocyte shortening velocity and evaluates the impact of TCV reduction on pressure rise (namely, (dP/dt)max) and on isovolumic contraction duration (IVCD) in a healthy LV. The model outputs are further exploited in the lumped "Windkessel" model of the human cardiovascular system (based on electrohydrodynamic analogy of respective differential equations) to simulate the impact of changes of (dP/dt)max and IVCD on chosen systemic parameters (ejection fraction, LV power, cardiac output, and blood pressure). The simulations have shown that a 50% decrease in TCV prolongs substantially the isovolumic contraction, decelerates slightly the LV pressure rise, increases the LV energy consumption, and reduces the LV power. These negative effects increase progressively with further reduction of TCV. In conclusion, these results suggest that the pumping efficacy of the human LV decreases with lower TCV due to a higher energy consumption and lower LV power. Although the changes induced by the clinically relevant reduction of TCV are not critical for a healthy heart, they may represent an important factor limiting the heart function under disease conditions.

Biomechanical indices are more sensitive than diameter in predicting rupture of asymptomatic abdominal aortic aneurysms.

OBJECTIVE: Several studies of biomechanical rupture risk assessment (BRRA) showed its advantage over the diameter criterion in rupture risk assessment of abdominal aortic aneurysm (AAA). However, BRRA studies have not investigated the predictability of biomechanical risk indices at different time points ahead of rupture, nor have they been performed blinded for biomechanical analysts. The objective of this study was to test the predictability of the BRRA method against diameter-based risk indices in a quasi-prospective patient cohort study. METHODS: In total, 12 women and 31 men with intact AAAs at baseline have been selected retrospectively at two medical centers. Within 56 months, 19 cases ruptured, whereas 24 cases remained intact within 2 to 56 months. This outcome was kept confidential until all biomechanical activities in this study were finished. The biomechanical AAA rupture risk was calculated at baseline using high-fidelity and low-fidelity finite element method models. The capability of biomechanics-based and diameter-based risk indices to predict the known outcomes at 1 month, 3 months, 6 months, 9 months, and 12 months after baseline was validated. Besides common cohort statistics, the area under the curve (AUC) of receiver operating characteristic curves has been used to grade the different rupture risk indices. RESULTS: Up to 9 months ahead of rupture, the receiver operating characteristic analysis of biomechanics-based risk indices showed a higher AUC than diameter-based indices. Six months ahead of rupture, the largest difference was observed with an AUC of 0.878 for the high-fidelity biomechanical risk index, 0.859 for the low-fidelity biomechanical risk index, 0.789 for the diameter, and 0.821 for the sex-adjusted diameter. In predictions beyond 9 months, none of the risk indices proved to be superior. CONCLUSIONS: High-fidelity biomechanical modeling improves the predictability of AAA rupture. Asymptomatic AAA patients with high biomechanical AAA rupture risk indices have an increased risk of rupture. Integrating biomechanics-based diagnostic indices may significantly decrease the false-positive rate in AAA treatment. CLINICAL RELEVANCE: Rupture of abdominal aortic aneurysm (AAA) is the tenth leading cause of death in men older than 60 years; however, the currently used maximal diameter criterion has a high false-positive rate. In this study, we have compared this criterion with biomechanical rupture risk assessment on the unique data set of 43 asymptomatic AAAs, of which 19 ruptured later. Moreover, the AAA outcome was blinded to the operator for the first time. Our data demonstrated that the biomechanical rupture risk assessment is superior to maximal diameter in predicting AAA rupture up to 9 months ahead and significantly decreases the false-positive rate.

Moderate thickness of lipid core in shoulder region of atherosclerotic plaque determines vulnerable plaque A parametric study.

Peak stress in the fibrous cap of atherosclerotic plaque is largely determined by the cap thickness which cannot be accurately estimated in vivo. This parametric study investigates idealized atherosclerotic plaque geometries. Finite element modeling is applied to search for larger morphological features associated with high cap stresses. By varying seven geometrical and two loading parameters, 100 3D model geometries of atherosclerotic plaques in common iliac artery were generated. In each model peak cap stress was calculated, and statistical comparison of the geometries generating the highest and lowest peak cap stresses was performed. The analysis showed that, compared to geometries generating the lowest stresses, those with high peak cap stress had a significantly lower cap thickness, higher stenosis ratio, lower relative lipid core volume, and cap shoulder radius larger than lipid core radius. High cap stress was observed for cap thicknesses up to 0.13 mm. It can be concluded that vulnerable plaques contain thin fibrous cap, large stenosis ratio and only moderate small-radius lipid core which reaches the shoulder region of the fibrous cap.

Compressibility of arterial wall - Direct measurement and predictions of compressible constitutive models.

Volumetric compressibility and Poisson's ratios of fibrous soft tissues are analyzed in this paper on the basis of constitutive models and experimental data. The paper extends the previous work of Skacel and Bursa (J Mech Behav Biomed Mater, 54, pp. 316-327, 2016), dealing with incompressible behaviour of constitutive models, to the area of compressibility. Both recent approaches to structure-based constitutive modelling of anisotropic fibrous biomaterials (based on either generalized structure tensor or angular integration) are analyzed, including their compressibility-related aspects. New experimental data related to compressibility of porcine arterial layer are presented and compared with the theoretical predictions of analyzed constitutive models. The paper points out the drawbacks of recent models with distributed fibres orientation since none of the analyzed constitutive models seems to be capable to predict the experimentally observed Poisson's ratios and volume change satisfactory.

A Finite Element Bendo-Tensegrity Model of Eukaryotic Cell.

Mechanical interaction of cell with extracellular environment affects its function. The mechanisms by which mechanical stimuli are sensed and transduced into biochemical responses are still not well understood. Considering this, two finite element (FE) bendo-tensegrity models of a cell in different states are proposed with the aim to characterize cell deformation under different mechanical loading conditions: a suspended cell model elucidating the global response of cell in tensile test simulation and an adherent cell model explicating its local response in atomic force microscopy (AFM) indentation simulation. The force-elongation curve obtained from tensile test simulation lies within the range of experimentally obtained characteristics of smooth muscle cells (SMCs) and illustrates a nonlinear increase in reaction force with cell stretching. The force-indentation curves obtained from indentation simulations lie within the range of experimentally obtained curves of embryonic stem cells (ESCs) and exhibit the influence of indentation site on the overall reaction force of cell. Simulation results have demonstrated that actin filaments (AFs) and microtubules (MTs) play a crucial role in the cell stiffness during stretching, whereas actin cortex (AC) along with actin bundles (ABs) and MTs are essential for the cell rigidity during indentation. The proposed models quantify the mechanical contribution of individual cytoskeletal components to cell mechanics and the deformation of nucleus under different mechanical loading conditions. These results can aid in better understanding of structure-function relationships in living cells.

Applicability of simplified computational models in prediction of peak wall stress in abdominal aortic aneurysms.

In the paper impact of different material models on the calculated peak wall stress (PWS) and peak wall rupture risk (PWRR) in abdominal aortic aneurysms (AAAs) is assessed. Computational finite element models of 70 patient-specific AAAs were created using two different material models - a realistic one based on mean population results of uniaxial tests of AAA wall considered as reference, and a 100 times stiffer artificial model. The calculated results of PWS and PWRR were tested to evaluate statistical significance of differences caused by the non-realistic material model. It was shown that for majority of AAAs the differences are insignificant but for some 10% of them their relative differences exceed 20% which may lead to incorrect decisions on their surgical treatment. This percentage of failures favours application of realistic material models in clinical practise although they are much more time-consuming.