A computational model for collagen fibre remodelling in the arterial wall

As the interaction between tissue adaptation and the mechanical condition within tissues is complex, mathematical models are desired to study this interrelation. In this study, a mathematical model is presented to investigate the interplay between collagen architecture and mechanical loading conditions in the arterial wall. It is assumed that the collagen fibres align along preferred directions, situated in between the principal stretch directions. The predicted fibre directions represent symmetrically arranged helices and agree qualitatively with morphometric data from literature. At the luminal side of the arterial wall, the fibres are oriented more circumferentially than at the outer side. The discrete transition of the fibre orientation at the media-adventitia interface can be explained by accounting for the different reference configurations of both layers. The predicted pressure-radius relations resemble experimentally measured sigma-shaped curves. As there is a strong coupling between the collagen architecture and the mechanical loading condition within the tissue, we expect that the presented model for collagen remodelling is useful to gain further insight into the processes involved in vascular adaptation, such as growth and smooth muscle tone adaptation.     

A theoretical model for fibroblast-controlled growth of saccular cerebral aneurysms

A new theoretical model for the growth of saccular cerebral aneurysms is proposed by extending the recent constitutive framework of Kroon and Holzapfel [2007a. A model for saccular cerebral aneurysm growth by collagen fibre remodelling. J. Theor. Biol. 247, 775-787]. The continuous turnover of collagen is taken to be the driving mechanism in aneurysmal growth. The collagen production rate depends on the magnitude of the cyclic deformation of fibroblasts, caused by the pulsating blood pressure during the cardiac cycle. The volume density of fibroblasts in the aneurysmal tissue is taken to be constant throughout the growth process. The growth model is assessed by considering the inflation of an axisymmetric membranous piece of aneurysmal tissue, with material characteristics representative of a cerebral aneurysm. The diastolic and systolic states of the aneurysm are computed, together with its load-free state. It turns out that the value of collagen pre-stretch, that determines growth speed and stability of the aneurysm, is of pivotal importance. The model is able to predict aneurysms with typical berry-like shapes observed clinically, and the predicted wall stresses correlate well with the experimentally obtained ultimate stresses of this type of tissue. The model predicts that aneurysms should fail when reaching a size of about 1.2-3.6 mm, which is smaller than what has been clinically observed. With some refinements, the model may, however, be used to predict future growth of diagnosed aneurysms.     

Inflation of an artery leading to aneurysm formation and rupture

Formation and rupture of aneurysms due to the inflation of an artery with collagen fibers distributed in two preferred directions, subjected to internal pressure and axial stretch are examined within the framework of nonlinear elasticity. A two layer tube model with a fiber-reinforced composite based incompressible anisotropic hyperelastic constitutive material is employed to model the stress-strain behavior of the artery wall with distributed collagen fibers. The artery wall takes up a uniform inflation deformation, and there are no aneurysms in the artery under the normal condition. But an aneurysm may be formed in arteries when the stiffness of the fibers is decreased to a certain value or the direction of the fibers is changed to a certain degree towards the circumferential direction. The aneurysm may expand to much large extent and become complex in shape. One portion of the aneurysm becomes highly distended as a bubble while the rest remains lightly inflated. The rupture of the aneurysm is discussed along with the distribution of stresses. Critical pressures and the rupture pressures are given for different collagen fiber orientations or stiffness. Furthermore, the stability of the solutions is discussed to explain the formation of aneurysm.     

A new constitutive model for multi-layered collagenous tissues

Collagenous tissues such as the aneurysmal wall or the aorta are multi-layered structures with the mean fibre alignments distinguishing one layer from another. A constitutive representation of the multiple collagen layers is not yet developed, and hence the aim of the present study. The proposed model is based on the constitutive theory of finite elasticity and is characterized by an anisotropic strain-energy function which takes the material structure into account. The passive tissue behaviour is modelled and the related mechanical response is assumed to be dominated by elastin and collagen. While elastin is modelled by the neo-Hookean material the constitutive response of collagen is assumed to be transversely isotropic for each individual layer and based on an exponential function. The proposed constitutive function is polyconvex which ensures material stability. The model has five independent material parameters, each of which has a clear physical interpretation: the initial stiffnesses of the collagen fabric in the two principal directions, the shear modulus pertaining to the non-collagenous matrix material, a parameter describing the level of nonlinearity of the collagen fabric, and the angle between the principal directions of the collagen fabric and the reference coordinate system. An extension-inflation test of the adventitia of a human femoral artery is simulated by means of the finite element method and an error function is minimized by adjusting the material parameters yielding a good agreement between the model and the experimental data.     

Dynamic effects on the formation and rupture of aneurysms

Dynamic analysis of an axially stretched arterial wall with collagen fibers distributed in two preferred directions under a suddenly applied constant internal pressure along with the possibility of the formation and rupture of aneurysm are examined within the framework of nonlinear dynamics. A two layer tube model with the fiber-reinforced composite-based incompressible anisotropic hyper-elastic material is employed to model the mechanical behavior of the arterial wall. The maximum amplitudes and the phase diagrams are given by numerical computation of the differential relation. It is shown that the arterial wall undergoes nonlinear periodic oscillation and no aneurysms are formed under the normal condition. However, an aneurysm may be formed under such abnormal conditions as the stiffness of the fibers is deduced or the direction of the fibers is oriented towards the axial direction. Furthermore, the possibility for the rupture of aneurysm is discussed with the distribution of stresses.     

Growth and morphogenesis in Streptomyces

In this report we propose a model of apical growth for streptomycetes. The apical tip is considered as a multilayered wall that expands by an inside-to-outside mechanism of growth. It is also assumed that each layer is made up of peptidoglycan blocks, each of them being the result of the biosynthetic activity of a wall-synthesizing unit or membrane-associated growth zone. According to our model, apical growth occurs as follows: as a consequence of the hydrostatic pressure and the cleavage of some bonds, the layers are pushed and forced to slide (one with respect to the other), migrating from the center of the tip (at the inside of the wall) towards a peripheral location (at the outside of the wall). The model also incorporates a mechanism by which apical growth can be regulated and coordinated with the replication of the chromosome.     

Modelling evolution and the evolving mechanical environment of saccular cerebral aneurysms

A fluid–solid-growth (FSG) model of saccular cerebral aneurysm evolution is developed. It utilises a realistic two-layered structural model of the internal carotid artery and explicitly accounts for the degradation of the elastinous constituents and growth and remodelling (G&R) of the collagen fabric. Aneurysm inception is prescribed: a localised degradation of elastin results in a perturbation in the arterial geometry; the collagen fabric adapts, and the artery achieves a new homeostatic configuration. The perturbation to the geometry creates an altered haemodynamic environment. Subsequent degradation of elastin is explicitly linked to low wall shear stress (WSS) in a confined region of the arterial domain. A sidewall saccular aneurysm develops, the collagen fabric adapts and the aneurysm stabilises in size. A quasi-static analysis is performed to determine the geometry at diastolic pressure. This enables the cyclic stretching of the tissue to be quantified, and we propose a novel index to quantify the degree of biaxial stretching of the tissue. Whilst growth is linked to low WSS from a steady (systolic) flow analysis, a pulsatile flow analysis is performed to compare steady and pulsatile flow parameters during evolution. This model illustrates the evolving mechanical environment for an idealised saccular cerebral aneurysm developing on a cylindrical parent artery and provides the guidance to more sophisticated FSG models of aneurysm evolution which link G&R to the local mechanical stimuli of vascular cells.     

Tensional stress generation in gelatinous fibres: a review and possible mechanism based on cell-wall structure and composition

Gelatinous fibres are specialized fibres, distinguished by the presence of an inner, gelatinous cell-wall layer. In recent years, they have attracted increasing interest since their walls have a desirable chemical composition (low lignin, low pentosan, and high cellulose contents) for applications such as saccharification and biofuel production, and they have interesting mechanical properties, being capable of generating high tensional stress. However, the unique character of gelatinous layer has not yet been widely recognized. The first part of this review presents a model of gelatinous-fibre organization and stresses the unique character of the gelatinous layer as a separate type of cell-wall layer, different from either primary or secondary wall layers. The second part discusses major current models of tensional stress generation by these fibres and presents a novel unifying model based on recent advances in knowledge of gelatinous wall structure. Understanding this mechanism could potentially lead to novel biomimetic developments in material sciences.     

Intrasac pressure changes and vascular remodeling after endovascular repair of abdominal aortic aneurysms: review and biomechanical model simulation

In this paper, we review existing clinical research data on post-endovascular repair (EVAR) intrasac pressure and relation with abdominal aortic aneurysm (AAA) size changes. Based on the review, we hypothesize that intrasac pressure has a significant impact on post-EVAR AAA size changes, and post-EVAR remodeling depends also on how the pressure has changed over a period of time. The previously developed model of an AAA based on a constrained mixture approach is extended to include vascular adaptation after EVAR using an idealized geometry. Computational simulation shows that the same mechanism of collagen stress-mediated remodeling in AAA expansion induces the aneurysm wall to shrink in a reduced sac-pressure after post-EVAR. Computational simulation suggests that the intrasac pressure of 60 mm?Hg is a critical value. At this value, the AAA remains stable, while values above cause the AAA to expand and values below cause the AAA to shrink. There are, however, variations between individuals due to different cellular sensitivities in stress-mediated adaptation. Computer simulation also indicates that an initial decrease in intrasac pressure helps the AAA shrink even if the pressure increases after some time. The presented study suggests that biomechanics has a major effect on initial adaptation after EVAR and also illustrates the utility of a computational model of vascular growth and remodeling in predicting diameter changes during the progression and after the treatment of AAAs.     

Haemodynamics and wall remodelling of a growing cerebral aneurysm: a computational model

We have developed a computational simulation model for investigating an often postulated hypothesis connected with aneurysm growth. This hypothesis involves a combination of two parallel and interconnected mechanisms: according to the first mechanism, an endothelium-originating and wall shear stress-driven apoptotic behavior of smooth muscle cells, leading to loss of vascular tone is believed to be important to the aneurysm behavior. Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. The second mechanism is connected to the arterial wall remodeling. Remodeling of the arterial wall under constant tension is a biomechanical process of rupture, degradation and reconstruction of the medial elastin and collagen fibers. In order to investigate these two mechanisms within a computationally tractable framework, we devise mechanical analogues that involve three-dimensional haemodynamics, yielding estimates of the wall shear stress and pressure fields and a quasi-steady approach for the apoptosis and remodeling of the wall. These analogues are guided by experimental information for the connection of stimuli to responses at a cellular level, properly averaged over volumes or surfaces. The model predicts aneurysm growth and can attribute specific roles to the two mechanisms involved: the smooth muscle cell-related loss of tone is important to the initiation of aneurysm growth, but cannot account alone for the formation of fully grown sacks; the fiber-related remodeling is pivotal for the latter.     

Fluid-structure interaction effects on sac-blood pressure and wall stress in a stented aneurysm

An aneurysm is a local artery ballooning greater than 50% of its nominal diameter with a risk of sudden rupture. Minimally invasive repair can be achieved by inserting surgically a stent-graft, called an endovascular graft (EVG), which is either straight tubular curved tubular or bifurcating. However post-procedural complications may arise because of elevated stagnant blood pressure in the cavity, i.e., the sac formed by the EVG and the weakened aneurysm wall In order to investigate the underlying mechanisms leading to elevated sac-pressures and hence to potentially dangerous wall stress levels and aneurysm rupture, a transient 3-D stented abdominal aortic aneurysm model and a coupled fluid-structure interaction solver were employed. Simulation results indicate that, even without the presence of endoleaks (blood flowing into the cavity), elevated sac pressure can occur due to complex fluid-structure interactions between the luminal blood flow, EVG wall, intra-sac stagnant blood, including an intra-luminal thrombus, and the aneurysm wall. Nevertheless, the impact of sac-blood volume changes due to leakage on the sac pressure and aneurysm wall stress was analyzed as well. While blood flow conditions, EVG and aneurysm geometries as well as wall mechanical properties play important roles in both sac pressure and wall stress generation, it is always the maximum wall stress that is one of the most critical parameters in aneurysm rupture prediction. All simulation results are in agreement with experimental data and clinical observations.     

Computational study of growth and remodelling in the aortic arch

Opening angles (OAs) are associated with growth and remodelling in arteries. One curiosity has been the relatively large OAs found in the aortic arch of some animals. Here, we use computational models to explore the reasons behind this phenomenon. The artery is assumed to contain a smooth muscle/collagen phase and an elastin phase. In the models, growth and remodelling of smooth muscle/collagen depends on wall stress and fluid shear stress. Remodelling of elastin, which normally turns over very slowly, is neglected. The results indicate that OAs generally increase with longitudinal curvature (torus model), earlier elastin production during development, and decreased wall stiffness. Correlating these results with available experimental data suggests that all of these effects may contribute to the large OAs in the aortic arch. The models also suggest that the slow turnover rate of elastin limits longitudinal growth. These results should promote increased understanding of the causes of residual stress in arteries.     

Turbidimetric and morphological studies of type I collagen fibre self assembly in vitro and the influence of fibronectin

Collagen undergoes several stages of self assembly including turbidimetric lag, growth and plateau steps. The later stages of type I collagen self assembly were studied by turbidity—time measurements, low angle laser light scattering and by determination of the birefringence retardation of collagen fibres formed in vitro. These studies were conducted in the presence and absence of fibronectin to evaluate the effect of fibronectin on the kinetics and extent of type I collagen fibrillogenesis. The results of these studies indicate that the collagen fibres observed at the end of the lag phase appear to be identical to fibres seen in the growth phase of turbidity—time curves based on fibre diameter and birefringence retardation measurements. Birefringence retardation measurements suggest that the diffracting unit may be the collagen fibril and that the volume fraction of fibrils in fibres is about 0.95 using a model developed for a series of parallel ellipsoids. Morphological observations suggest that the distribution of fibre diameters formed in vitro during the growth phase is narrow and appears to be independent of time with only the mass of collagen in fibres increasing during the growth phase. During the growth phase, layers of parallel fibres are formed with alternating layers appearing almost orthogonal. In the presence of fibronectin the mechanism of fibre formation appeared unchanged. It was concluded that fibronectin appeared to modify the kinetics of self assembly by preventing collisions between collagen molecules.     

A mathematical model for the growth of the abdominal aortic aneurysm

We present the first mathematical model to account for the evolution of the abdominal aortic aneurysm. The artery is modelled as a two-layered, cylindrical membrane using nonlinear elasticity and a physiologically realistic constitutive model. It is subject to a constant systolic pressure and a physiological axial prestretch. The development of the aneurysm is assumed to be a consequence of the remodelling of its material constituents. Microstructural recruitment and fibre density variables for the collagen are introduced into the strain energy density functions. This enables the remodelling of collagen to be addressed as the aneurysm enlarges. An axisymmetric aneurysm, with axisymmetric degradation of elastin and linear differential equations for the remodelling of the fibre variables, is simulated numerically. Using physiologically determined parameters to model the abdominal aorta and realistic remodelling rates for its constituents, the predicted dilations of the aneurysm are consistent with those observed in vivo. An asymmetric aneurysm with spinal contact is also modelled, and the stress distributions are consistent with previous studies.     

A Geometro-mechanical model for pulsatile morphogenesis

A model is proposed which imitates the morphogenesis of several species of the lower invertebrate animals, the hydroid polyps and permits the derivation of the geometry (surface curvature) of each developmental stage from that of the preceding stage. The model is based upon two experimentally verified assumptions. First, neighbouring cells are assumed to compress each other laterally in a regular and species-specific pulsatile manner. It is this pressure, and/or an active cell reaction to it, which changes the curvature of a cell layer. Secondly, cell layers are assumed to have quasi-elastic properties tending to smooth out their curvature. With our model, the different pulsatile patterns of cell-cell pressure are reproduced and the elasticity parameters are modulated. As a result, within a large zone of parameter values (a so-called "morphogenetic zone", MZ) realistic shapes of the rudiments are reproduced. The main principles of the model can also be used for interpreting the morphogenesis of other groups of animals. A suggested model emphasizes the self-organizing properties of a "stressed geometry" of embryonic rudiments.     

Remodelling of continuously distributed collagen fibres in soft connective tissues

Extracellular matrix remodelling plays an essential role in tissue engineering of load-bearing structures. The goal of this study is to model changes in collagen fibre content and orientation in soft connective tissues due to mechanical stimuli. A theory is presented describing the mechanical condition within the tissue and accounting for the effects of collagen fibre alignment and changes in fibre content. A fibre orientation tensor is defined to represent the continuous distribution of collagen fibre directions. A constitutive model is introduced to relate the fibre configuration to the macroscopic stress within the material. The constitutive model is extended with a structural parameter, the fibre volume fraction, to account for the amount of fibres present within the material. It is hypothesised that collagen fibre reorientation is induced by macroscopic deformations and the amount of collagen fibres is assumed to increase with the mean fibre stretch. The capabilities of the model are demonstrated by considering remodelling within a biaxially stretched cube. The model is then applied to analyse remodelling within a closed stented aortic heart valve. The computed preferred fibre orientation runs from commissure to commissure and resembles the fibre directions in the native aortic valve.     

A structural constitutive model considering angular dispersion and waviness of collagen fibres of rabbit facial veins

Background  

Structural constitutive models of vascular wall integrate information on composition and structural arrangements of tissue. In blood vessels, collagen fibres are arranged in coiled and wavy bundles and the individual collagen fibres have a deviation from their mean orientation. A complete structural constitutive model for vascular wall should incorporate both waviness and orientational distribution of fibres. We have previously developed a model, for passive properties of vascular wall, which considers the waviness of collagen fibres. However, to our knowledge there is no structural model of vascular wall which integrates both these features.     

A goal function approach to remodeling of arteries uncovers mechanisms for growth instability

A novel, goal function-based formulation for the growth dynamics of arteries is introduced and used for investigating the development of growth instability in blood vessels. Such instabilities would lead to abnormal growth of the vessel, reminiscent of an aneurysm. The blood vessel is modeled as a thin-walled cylindrical tube, and the constituents that form the vessel wall are assumed to deform together as a constrained mixture. The growth dynamics of the composite material of the vessel wall are described by an evolution equation, where the effective area of each constituent changes in the direction of steepest descent of a goal function. This goal function is formulated in such way that the constituents grow toward a target potential energy and a target composition. The convergence of the simulated response of the evolution equation toward a target homeostatic state is investigated for a range of isotropic and orthotropic material models. These simulations suggest that elastin-deficient vessels are more prone to growth instability. Increased stiffness of the vessel wall, on the other hand, gives a more stable growth process. Another important finding is that an increased rate of degradation of materials impairs growth stability.     

A constrained mixture model for developing mouse aorta

Mechanical stresses influence the structure and function of adult and developing blood vessels. When these stresses are perturbed, the vessel wall remodels to return the stresses to homeostatic levels. Constrained mixture models have been used to predict remodeling of adult vessels in response to step changes in blood pressure, axial length and blood flow, but have not yet been applied to developing vessels. Models of developing blood vessels are complicated by continuous and simultaneous changes in the mechanical forces. Understanding developmental growth and remodeling is important for treating human diseases and designing tissue-engineered blood vessels. This study presents a constrained mixture model for postnatal development of mouse aorta with multiple step increases in pressure, length and flow. The baseline model assumes that smooth muscle cells (SMCs) in the vessel wall immediately constrict or dilate the inner radius after a perturbation to maintain the shear stress and then remodel the wall thickness to maintain the circumferential stress. The elastin, collagen and SMCs have homeostatic stretch ratios and passive material constants that do not change with developmental age. The baseline model does not predict previously published experimental data. To approximate the experimental data, it must be assumed that the SMCs dilate a constant amount, regardless of the step change in mechanical forces. It must also be assumed that the homeostatic stretch ratios and passive material constants change with age. With these alterations, the model approximates experimental data on the mechanical properties and dimensions of aorta from 3- to 30-day-old mice.     

Blood flow dynamics in saccular aneurysm models of the basilar artery

Blood flow dynamics under physiologically realistic pulsatile conditions plays an important role in the growth, rupture, and surgical treatment of intracranial aneurysms. The temporal and spatial variations of wall pressure and wall shear stress in the aneurysm are hypothesized to be correlated with its continuous expansion and eventual rupture. In addition, the assessment of the velocity field in the aneurysm dome and neck is important for the correct placement of endovascular coils. This paper describes the flow dynamics in two representative models of a terminal aneurysm of the basilar artery under Newtonian and non-Newtonian fluid assumptions, and compares their hemodynamics with that of a healthy basilar artery. Virtual aneurysm models are investigated numerically, with geometric features defined by beta = 0 deg and beta = 23.2 deg, where beta is the tilt angle of the aneurysm dome with respect to the basilar artery. The intra-aneurysmal pulsatile flow shows complex ring vortex structures for beta = 0 deg and single recirculation regions for beta = 23.2 deg during both systole and diastole. The pressure and shear stress on the aneurysm wall exhibit large temporal and spatial variations for both models. When compared to a non-Newtonian fluid, the symmetric aneurysm model (beta = 0 deg) exhibits a more unstable Newtonian flow dynamics, although with a lower peak wall shear stress than the asymmetric model (beta = 23.2 deg). The non-Newtonian fluid assumption yields more stable flows than a Newtonian fluid, for the same inlet flow rate. Both fluid modeling assumptions, however, lead to asymmetric oscillatory flows inside the aneurysm dome.