Finite element and mechanobiological modelling of vascular devices

There are two main surgical treatments for vascular diseases, (i) percutaneous stent deployment and (ii) replacement of an atherosclerotic artery with a vascular graft or tissue engineered blood vessel. The aim of this thesis was to develop computational models that could assist in the design of vascular stents and tissue engineered vascular grafts and scaffolds. In this context, finite element (FE) models of stent expansion in idealised and patient specific models of atherosclerotic arteries were developed. Different modelling strategies were investigated and an optimal modelling approach was identified which minimised computational cost without compromising accuracy. Numerical models of thin and thick strut stents were developed using this modelling approach to replicate the ISAR-STEREO clinical trial and the models identified arterial stresses as a suitable measure of stent induced vascular injury. In terms of evaluating vascular graft performance, mechanical characterisation experiments can be conducted in order to develop constitutive models that can be used in FE models of vascular grafts to predict their mechanical behaviour in-situ. In this context, bacterial cellulose (BC), a novel biomaterial, was mechanically characterised and a constitutive model was developed to describe its mechanical response. In addition, the interaction of smooth muscle cells with BC was studied using cell culture experiments. The constitutive model developed for BC was used as an input for a novel multi-scale mechanobiological modelling framework. The mechanobiological model was developed by coupling an FE model of a vascular scaffold and a lattice free agent based model of cell growth dynamics and remodelling in vascular scaffolds. By comparison with published in-vivo and in-vitro works, the model was found to successfully capture the key characteristics of vascular remodelling. It can therefore be used as a predictive tool for the growth and remodelling of vascular scaffolds and graft

A multiscale mechanobiological model using agent based models; Application to vascular tissue engineering

status: publishe

Mechanical integrity of nano-interconnects; the impact of metallization density

In this study the impacts of two main design parameters, namely the metal and via densities on the mechanical integrity of nano-interconnects were investigated. To this aim, analytical modelling was used in order to derive the effective mechanical properties of nano-interconnect layers which were subsequently used as material properties in a layer-specific finite element model of nano-interconnects exposed to bump level mixed mode loading. The energy release rates for nano-interconnect cracks were used to determine the impact of metal and via density variations on the mechanical integrity of nano-interconnects. Using a parametric study, the key parameters that determine the mechanical integrity of nano-interconnects under chip package interaction (CPI) loads were identified to be the via densities in the intermediate layers with ultra low-k dielectric (ULK) and the via and metal densities of the top stiff group of layers often referred to as the “Z” group. Increasing the effective stiffness of the “Z” group by maximizing its via and metal density mitigated the energy release rate at the ULK pre-cracks in the intermediate via layers by means of elastic stress shielding. In addition, increasing the via density of the via layers integrated with ULK, increases the effective critical fracture energy of the via layer (i.e. the effective via layer adhesion), thereby improving the mechanical integrity. Keywords: Nano-interconnect, Mechanical integrity, Delamination, Chip package interaction (CPI), Metal density, Via densit

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.status: publishe

A multiscale mechanobiological model of in-stent restenosis; deciphering the role of matrix metalloproteinase and extracellular matrix changes

Since their first introduction, stents have revolutionised the treatment of atherosclerosis, however the development of in-stent restenosis still remains the Achilles’ heel of stent deployment procedures. Computational modelling can be used as a means to model the biological response of arteries to different stent designs using mechanobiological models whereby the mechanical environment may be used to dictate the growth and remodelling of vascular cells. Changes occurring within the arterial wall due to stent induced mechanical injury, specifically changes within the extracellular matrix have been postulated to be a major cause of activation of vascular smooth muscle cells and the subsequent development of in-stent restenosis. In this study a mechanistic multiscale mechanobiological model of in-stent restenosis using finite element models and agent based modelling is presented which allows quantitative evaluation of the collagen matrix turnover following stent induced arterial injury and the subsequent development of in-stent restenosis. The model is specifically used to study the influence of stent deployment diameter and stent strut thickness on the level of in-stent restenosis. The model demonstrates that there exists a direct correlation between the stent deployment diameter and the level of in-stent restenosis. In addition, investigating the influence of stent strut thickness using the mechanobiological model reveals that thicker strut stents induce a higher level of in-stent restenosis due to a higher extent of arterial injury. The presented mechanobiological modelling framework provides a robust platform for testing hypotheses on the mechanisms underlying the development of in-stent restenosis and lends itself for use as a tool for optimization of the mechanical parameters involved in stent design.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=gcmb20status: publishe

A method to develop mock arteries suitable for cell seeding and in-vitro cell culture experiments

Sylgard((R)) is a biocompatible elastomer which has been widely used in biomedical applications including in simulations of the mechanical response of soft tissues and mechanotransduction investigations. In this study the effect of fabrication parameters including base to curing agent ratio and curing time on the mechanical response of Sylgard((R)) was investigated and a novel fabrication technique for the production of mock arteries with highly uniform thickness, which is essential for mechanotransduction studies, is described. Finally a method for the surface treatment of Sylgard((R)) using sulphuric acid and fibronectin to enhance smooth muscle cell (SMC) adhesion is proposed and examined in vitro. Sylgard((R)) mock coronary arteries fabricated using the proposed technique exhibited a mechanical response close to arterial tissue with cell adhesion enhanced using the surface treatment techniques described.status: publishe

IMPORTANCE OF LOADING CONDITIONS FOR MECHANOREGULATION IN A BONE DEFECT MODEL

status: accepte

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

status: publishe