Caitríona Lally

Elastic behavior of porcine coronary artery tissue under uniaxial and equibiaxial tension.

The aim of this study was to characterize the nonlinear anisotropic elastic behavior of healthy porcine coronary arteries under uniaxial and equibiaxial tension. Porcine coronary tissue was chosen for its availability and similarity to human arterial tissue. A biaxial test device previously used to test human femoral arterial tissue samples (Prendergast, P. J., C. Lally, S. Daly, A. J. Reid, T. C. Lee, D. Quinn, and F. Dolan. ASMEJ. Biomech. Eng., Vol. 125, pp. 692–699, 2003) was further developed to test porcine coronary tissue specimens. The device applies an equal force to the four sides of a square specimen and therefore creates a biaxial stretch that demonstrates the anisotropy of arterial tissue. The nonlinear elastic behavior was marked in both uniaxial and biaxial tests. The tissue demonstrated higher stiffness in the circumferential direction in four out of eight cases subjected to biaxial tension. Even though anisotropy is demonstrated it is proposed that an isotropic hyperelastic model may adequately represent the properties of an artery, provided that an axial stretch is applied to the vessel to simulate the in vivo longitudinal tethering on the vessel. Isotropic hyperelastic models based on the Mooney-Rivlin constitutive equation were derived from the test data by averaging the longitudinal and circumferential equibiaxial data. Three different hyperelastic models were established to represent the test specimens that exhibited a high stiffness, an average stiffness, and a low stiffness response; these three models allow the analyst to account for the variability in the arterial tissue mechanical properties. These models, which take account of the nonlinear elastic behavior of coronary tissue, may be implemented in finite element models and used to carry out preclinical tests of intravascular devices. The errors associated with the hyperelastic models when fitting to both the uniaxial and equibiaxial data for the low stiffness, average stiffness, and high stiffness models were found to be 0.836, 5.206, and 2.980, respectively.

The influence of plaque composition on underlying arterial wall stress during stent expansion: The case for lesion-specific stents

Intracoronary stent implantation is a mechanical procedure, the success of which depends to a large degree on the mechanical properties of each vessel component involved and the pressure applied to the balloon. Little is known about the influence of plaque composition on arterial overstretching and the subsequent injury to the vessel wall following stenting. An idealised finite element model was developed to investigate the influence of both plaque types (hypercellular, hypocellular and calcified) and stent inflation pressures (9, 12 and 15 atm) on vessel and plaque stresses during the implantation of a balloon expandable coronary stent into an idealised stenosed artery. The plaque type was found to have a significant influence on the stresses induced within the artery during stenting. Higher stresses were predicted in the artery wall for cellular plaques, while the stiffer calcified plaque appeared to play a protective role by reducing the levels of stress within the arterial tissue for a given inflation pressure. Higher pressures can be applied to calcified plaques with a lower risk of arterial vascular injury which may reduce the stimulus for in-stent restenosis. Results also suggest that the risk of plaque rupture, and any subsequent thrombosis due to platelet deposition at the fissure, is greater for calcified plaques with low fracture stresses.

Simulation of a balloon expandable stent in a realistic coronary artery; Determination of the optimum modelling strategy

Computational models of stent deployment in arteries have been widely used to shed light on various aspects of stent design and optimisation. In this context, modelling of balloon expandable stents has proved challenging due to the complex mechanics of balloon-stent interaction and the difficulties involved in creating folded balloon geometries. In this study, a method to create a folded balloon model is presented and utilised to numerically model the accurate deployment of a stent in a realistic geometry of an atherosclerotic human coronary artery. Stent deployment is, however, commonly modelled by applying an increasing pressure to the stent, thereby neglecting the balloon. This method is compared to the realistic balloon expansion simulation to fully elucidate the limitations of this procedure. The results illustrate that inclusion of a realistic balloon model is essential for accurate modelling of stent deformation and stent stresses. An alternative balloon simulation procedure is presented however, which overcomes many of the limitations of the applied pressure approach by using elements which restrain the stent as the desired diameter is achieved. This study shows that direct application of pressure to the stent inner surface may be used as an optimal modelling strategy to estimate the stresses in the vessel wall using these restraining elements and hence offer a very efficient alternative approach to numerically modelling stent deployment within complex arterial geometries. The method is limited however, in that it can only predict final stresses in the stented vessel and not those occurring during stent expansion, in which case the balloon expansion model is required.

Determination of the influence of stent strut thickness using the finite element method: implications for vascular injury and in-stent restenosis

Many clinical studies, including the ISAR-STEREO trial, have identified stent strut thickness as an independent predictor of in-stent restenosis where thinner struts result in lower restenosis than thicker struts. The aim of this study was to more conclusively identify the mechanical stimulus for in-stent restenosis using results from such clinical trials as the ISAR-STEREO trial. The mechanical environment in arteries stented with thin and thicker strut stents was investigated using numerical modelling techniques. Finite element models of the stents used in the ISAR-STEREO clinical trial were developed and the stents were deployed in idealised stenosed vessel geometries in order to compare the mechanical environment of the vessel for each stent. The stresses induced within the stented vessels by these stents were compared to determine the level of vascular injury caused to the artery by the stents with different strut thickness. The study found that when both stents were expanded to achieve the same initial maximum stent diameter that the thinner strut stent recoiled to a greater extent resulting in lower luminal gain but also lower stresses in the vessel wall, which is hypothesised to be responsible for the lower restenosis outcome. This study supports the hypothesis that arteries develop restenosis in response to injury, where high vessel stresses are a good measure of that injury. This study points to a critical stress level in arteries, above which an aggressive healing response leads to in-stent restenosis in stented vessels. Stents can be designed to reduce stresses in this range in arteries using preclinical tools such as numerical modelling.

Tensile and compressive properties of fresh human carotid atherosclerotic plaques

Accurate characterisation of the mechanical properties of human atherosclerotic plaque is important for our understanding of the role of vascular mechanics in the development and treatment of atherosclerosis. The majority of previous studies investigating the mechanical properties of human plaque are based on tests of plaque tissue removed following autopsy. This study aims to characterise the mechanical behaviour of fresh human carotid plaques removed during endarterectomy and tested within 2h. A total of 50 radial compressive and 17 circumferential tensile uniaxial tests were performed on samples taken from 14 carotid plaques. The clinical classification of each plaque, as determined by duplex ultrasound is also reported. Plaques were classified as calcified, mixed or echolucent. Experimental data indicated that plaques were highly inhomogeneous; with variations seen in the mechanical properties of plaque obtained from individual donors and between donors. The mean behaviour of samples for each classification indicated that calcified plaques had the stiffest response, while echolucent plaques were the least stiff. Results also indicated that there may be a difference in behaviour of samples taken from different anatomical locations (common, internal and external carotid), however the large variability indicates that more testing is needed to reach significant conclusions. This work represents a step towards a better understanding of the in vivo mechanical behaviour of human atherosclerotic plaque.

Bacterial cellulose as a potential vascular graft: Mechanical characterization and constitutive model development

Bacterial cellulose (BC) is a polysaccharide produced by Acetobacter Xylinum bacteria with interesting properties for arterial grafting and vascular tissue engineering including high-burst pressure, high-water content, high crystallinity, and an ultrafine highly pure fibrous structure similar to that of collagen. Given that compliance mismatch is one of the main factors contributing to the development of intimal hyperplasia in vascular replacement conduits, an in depth investigation of support mechanical properties of BC is required to further supporting its use in cardiovascular-grafting applications. The aim of this study was to mechanically characterize BC and also study its potential to accommodate vascular cells. To achieve these aims, inflation tests and uniaxial tensile tests were carried out on BC samples. In addition, dynamic compliance tests were conducted on BC tubes, and the results were compared to that of arteries, saphenous vein, expanded polytetrafluoroethylene, and Dacron grafts. BC tubes exhibited a compliance response similar to human saphenous vein with a mean compliance value of 4.27 × 10(-2) % per millimeter of mercury over the pressure range of 30-120 mmHg. In addition, bovine smooth muscle cells and endothelial cells were cultured on BC samples, and histology and fluorescent imaging analysis were carried out showing good adherence and biocompatibility. Finally, a method to predict the mechanical behavior of BC grafts in situ was established, whereby a constitutive model for BC was determined and used to model the BC tubes under inflation using finite element analysis.

A multiscale mechanobiological modelling framework using agent-based models and finite element analysis: application to vascular tissue engineering

Computational models of mechanobiological systems have been widely used to provide insight into these systems and also to predict their behaviour. In this context, vascular tissue engineering benefits from further attention given the challenges involved in developing functional low calibre vascular grafts with long-term patency. In this study, a novel multiscale mechanobiological modelling framework is presented, which takes advantage of lattice-free agent-based models coupled with the finite element method to investigate the dynamics of VSMC growth in vascular tissue engineering scaffolds. The results illustrate the ability of the mechanobiological modelling approach to capture complex multiscale mechanobiological phenomena. Specifically, the framework enabled the study of the influence of scaffold compliance and loading regime in regulating the growth of VSMCs in vascular scaffolds and their role in development of intimal hyperplasia (IH). The model demonstrates that low scaffold compliance compared to host arteries leads to increased luminal ingrowth and IH development. In addition, culture of a tissue-engineered blood vessel under a pulsatile luminal pressure reduced luminal ingrowth and enhanced collagen synthesis within the scaffold compared to non-pulsatile culture. The mechanobiological framework presented provides a robust platform for testing hypotheses in vascular tissue engineering and lends itself to use as an optimisation design tool.

Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival

The role of glycogen synthase kinase 3 beta (GSK-3β) in modulating Notch control of vascular smooth muscle cell (vSMC) growth (proliferation and apoptosis) was examined in vitro under varying conditions of cyclic strain and validated in vivo following changes in medial tension and stress. Modulation of GSK-3β in vSMC following ectopic expression of constitutively active GSK-3β, siRNA knockdown and pharmacological inhibition with SB-216763 demonstrated that GSK-3β positively regulates Notch intracellular domain expression, CBF-1/RBP-Jκ transactivation and downstream target gene mRNA levels, while concomitantly promoting vSMC proliferation and inhibiting apoptosis. In contrast, inhibition of GSK-3β attenuated Notch signaling and decreased vSMC proliferation and survival. Exposure of vSMC to cyclic strain environments in vitro using both a Flexercell™ Tension system and a novel Sylgard™ phantom vessel following bare metal stent implantation revealed that cyclic strain inhibits GSK-3β activity independent of p42/p44 MAPK and p38 activation concomitant with reduced Notch signaling and decreased vSMC proliferation and survival. Exposure of vSMC to changes in medial strain microenvironments in vivo following carotid artery ligation revealed that enhanced GSK-3β activity was predominantly localized to medial and neointimal vSMC concomitant with increased Notch signaling, proliferating nuclear antigen and decreased Bax expression, respectively, as vascular remodeling progressed. GSK-3β is an important modulator of Notch signaling leading to altered vSMC cell growth where low strain/tension microenvironments prevail.

An analysis of the strain field in biaxial Flexcell membranes for different waveforms and frequencies

Mechanical stimuli have been shown to affect cell behaviour in terms of proliferation, apoptosis, and protein expression. In terms of cardiovascular diseases, for example, endothelial and smooth muscle cells exposed to an abnormal strain environment have been associated with atherosclerosis and in-stent restenosis. The FX-4000™ system (Flexercell® Tension Plus System, Flexcell Corporation, McKeesport, Pennsylvania, USA) is an in-vitro system that is widely used to strain cells in order to evaluate their response to strain. The precision, accuracy, and repeatability of the strains controlled by the system are therefore crucial to analyse and interpret the results confidently. The aim of this study was to investigate the mechanical behaviour of the FX-4000™ Flexercell® six-well-plate silicon membranes for static and dynamic cyclic strains by measuring the maximum peak strain and analysing the change in the membrane deformation after cyclic strain for 0 h, 24 h, and 48 h at different strain amplitudes and frequencies. The results of the tests conducted demonstrate notable differences between the measured strains of the membranes in comparison with both the inputs and the outputs of the Flexcell® software. The calibration method used by Flexcell® International assumes that the strain values determined for a given vacuum pressure on the silicone membranes are reliable for different waveforms and frequencies. The data reported here clearly indicate that this is not the case. The results indicate that a unique calibration pressure—strain curve must be determined for each test given the viscoelastic nature of the Flexcell system. A new method to calibrate the machine in house was applied using new pressure—strain equations. This new calibration method has been presented and should enable researchers using the Flexcell® machine to set up their cell experiments more accurately.

An anisotropic inelastic constitutive model to describe stress softening and permanent deformation in arterial tissue.

Inelastic phenomena such as softening and unrecoverable inelastic strains induced by loading have been observed experimentally in soft tissues such as arteries. These phenomena need to be accounted for in constitutive models of arterial tissue so that computational models can accurately predict the outcomes of interventional procedures such as balloon angioplasty and stenting that involve non-physiological loading of the tissue. In this study, a novel constitutive model is described that accounts for inelastic effects such as Mullins-type softening and permanent set in a fibre reinforced tissue. The evolution of inelasticity is governed by a set of internal variables. Softening is introduced through a typical continuum damage mechanics approach, while the inelastic residual strains are introduced through an additive split in the stress tensor. Numerical simulations of aorta and carotid arterial tissue subjected to uniaxial testing in the longitudinal, circumferential and axial directions are used to demonstrate the models ability to reproduce the anisotropic inelastic behaviour of the tissue. Material parameters derived from best-fits to experimental data are provided to describe these inelastic effects for both aortic and carotid tissue.