The Computational Fluid Dynamics Rupture Challenge 2013--Phase II: Variability of Hemodynamic Simulations in Two Intracranial Aneurysms.

With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent "outliers" (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.

Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge.

Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

Magnetic retrieval of prosthetic heart valves for redo-TAVI.

Bioprosthetic aortic heart valves are known to degenerate within 7-15 years of implantation. Currently, the options for treating a failing valve are (a) redo surgical aortic valve replacement or, increasingly, (b) valve-in-valve transcatheter aortic valve implantation (ViV-TAVI). The ViV-TAVI procedure is referred to as redo-TAVI when the failing valve is a TAVI device. Repeated procedures, such as two or three valve-in-valves, significantly reduce the effective valve flow area, putting a limit on recurrent treatments. With increasing life expectancy and the use of TAVI in younger, lower-risk patients, the demand for multiple replacement procedures will inevitably increase. Against this background, we describe a novel valve system named exchangeable-TAVI (e-TAVI) in which an electromagnetic catheter is used to remove and retrieve a failed exchangeable valve, followed by the immediate deployment of a new valve. The e-TAVI system comprises (i) an exchangeable valve, (ii) a permanent holding member that anchors the exchangeable valve and (iii) a dedicated catheter with electromagnets for removal of the exchangeable valve. Simulations have been performed to determine the forces, frame design and electromagnetic parameters required to crimp and retrieve a 26 mm diameter valve. An optimum configuration was found to comprise a 12 cell self-expanding frame with circular ferromagnetic regions of 1 mm radius and 0.5 mm thickness, along with eight electromagnets of 1 mm radius and 2 mm thickness. A force of 2.87 N and a current of 2.52 A per electromagnet were required to partially crimp the frame to an envelope radius of 11 mm. While this amount of force allowed the frame to be crimped solely through magnetic attraction, re-sheathing of the frame was not possible due to the weaker shear holding force of the magnets. Also, the current was close to the fusing current of the copper wire needed to fit sufficient windings into the available volume. These issues led to the conclusion that, in addition to the magnetic coupling, a mechanical mating between the removal catheter and the exchangeable valve is needed. This would decrease both the force that the electromagnets had to exert during crimping and the current required to generate this force.

Exploring a parallel rheological framework to capture the mechanical behaviour of a thin-strut polymeric bioresorbable coronary scaffold.

Computational modelling of bioresorbable scaffolds (BRS) has employed several different material property models, ranging from those based on simple elasto-plastic theory through to anisotropic parallel network models that capture the viscoelastic-plastic behaviour observed in poly-l-lactic acid (PLLA). The increased complexity of higher fidelity material models, particularly in terms of calibration to in-vitro data, can limit their use. Consequently, their suitability for predicting the mechanical response of next-generation BRS is not well understood. Therefore, we have used the Bergstrom-Boyce (BB) parallel network material model, implemented in Abaqus/Explicit (Dassault Systemes), to investigate the mechanical response of a scaffold based upon the ArterioSorbTM BRS (Arterius Ltd, Leeds, UK). In-silico crimping, balloon expansion and radial crushing were simulated and validated against an analogous in-vitro test. Calibration of the model to uniaxial tensile test data was considered given the model's strain rate dependency and the inability to maintain the natural time period of the simulation when using the explicit solution method in finite element analysis. The isotropic limitations of this model were also explored. The model was also compared to an elasto-plastic model developed by the authors in previous work. Relative to bench-top measurements, prediction of the final diameter and radial strength of the scaffold by the BB model was found to be significantly more accurate than other models, within 2% of the in-vitro result. Additionally, the effect of the crimping strategy and an elevated ambient temperature upon the in-silico prediction of the post-crimping scaffold diameter were investigated. A multi-step crimping process with holding to facilitate stress relaxation and the lower stresses induced by the increased temperature were found to improve the accuracy of the predicted post-crimping scaffold diameter.

Investigating the Equivalent Plastic Strain in a Variable Ring Length and Strut Width Thin-Strut Bioresorbable Scaffold.

PURPOSE: The ArterioSorb[Formula: see text] bioresorbable scaffold (BRS) developed by Arterius Ltd is about to enter first in man clinical trials. Previous generations of BRS have been vulnerable to brittle fracture, when expanded via balloon inflation in-vivo, which can be extremely detrimental to patient outcome. Therefore, this study explores the effect of variable ring length and strut width (as facilitated by the ArterioSorb[Formula: see text] design) on fracture resistance via analysis of the distribution of equivalent plastic strain in the scaffold struts post expansion. Scaffold performance is also assessed with respect to side branch access, radial strength, final deployed diameter and percentage recoil. METHODS: Finite element analysis was conducted of the crimping, expansion and radial crushing of five scaffold designs comprising different variations in ring length and strut width. The Abaqus/Explicit (DS SIMULIA) solution method was used for all simulations. Direct comparison between in-silico predictions and in-vitro measurements of the performance of the open cell variant of the ArterioSorb[Formula: see text] were made. Paths across the width of the crown apex and around the scaffold rings were defined along which the plastic strain distribution was analysed. RESULTS: The in-silico results demonstrated good predictions of final shape for the baseline scaffold design. Percentage recoil and radial strength were predicted to be, respectively, 2.8 and 1.7 times higher than the experimentally measured values, predominantly due to the limitations of the anisotropic elasto-plastic material property model used for the scaffold. Average maximum values of equivalent plastic strain were up to 2.4 times higher in the wide strut designs relative to the narrow strut scaffolds. As well as the concomitant risk of strut fracture, the wide strut designs also exhibited twisting and splaying behaviour at the crowns located on the scaffold end rings. Not only are these phenomena detrimental to the radial strength and risk of strut fracture but they also increase the likelihood of damage to the vessel wall. However, the baseline scaffold design was observed to tolerate significant over expansion without inducing excessive plastic strains, a result which is particularly encouraging, due to post-dilatation being commonplace in clinical practice. CONCLUSION: Therefore, the narrow strut designs investigated herein, are likely to offer optimal performance and potentially better patient outcomes. Further work should address the material modelling of next generation polymeric BRS to more accurately capture their mechanical behaviour. Observation of the in-vitro testing indicates that the ArterioSorb[Formula: see text] BRS can tolerate greater levels of over expansion than anticipated.

Do capsular pressure and implant motion interact to cause high pressure in the periprosthetic bone in total hip replacement?

When there is a debonding at the bone-implant interface, the difference in stiffness between the implant and the bone can result in micromotion, allowing existing gaps to open further or new gaps to be created during physiological loading. It has been suggested that periprosthetic fluid flow and high pressure may play an important role in osteolysis development in the proximity of these gaps. To explain this phenomenon, the concepts of "effective joint space" and "pumping stem" have been cited in many studies. However, there is no clear understanding of the factors causing, or contributing to, these mechanisms. It is likely that capsular pressure, gap dimensions, and micromotion of the gap during cyclic loading of an implant can play a defining role in inducing periprosthetic flow. In order to obtain a better understanding of the main influences on periprosthetic flows and the development of osteolysis, steady state and transient 2D computational fluid dynamic simulations were performed for the joint capsule of the lateral side of a stem-femur system, and a gap in communication with the capsule and the surrounding bone. It was shown that high capsular pressure may be the main driving force for high fluid pressure and flow in the bone surrounding the gap, while micromotion of only very long and narrow gaps can cause significant pressure and flow in the bone. At low capsular pressure, micromotion induced large flows in the gap region; however, the flow in the bone tissue was almost unaffected. The results also revealed the existence of high velocity spikes in the bone region at the bottom of the gap. These velocity spikes can exert excessive fluid shear stress on the bone cells and disturb the local biological balance of the surrounding interstitial fluid which can result in osteolysis development. High capsular pressure was observed to be the main cause of these velocity spikes whereas, at low capsular pressure, gap micromotion of only very long and narrow gaps generated significant velocity spikes in the bone at the bottom of the gaps.

Investigating the material modelling of a polymeric bioresorbable scaffold via in-silico and in-vitro testing.

The accurate material modelling of poly-l-lactic acid (PLLA) is vital in conducting finite element analysis of polymeric bioresorbable scaffolds (BRS) to investigate their mechanical performance and seek improved scaffold designs. To date, a large variety of material models have been utilised, ranging from simple elasto-plastic models to high fidelity parallel network models. However, no clear consensus has been reached on the appropriateness of these different models and whether simple, less computationally expensive models can serve as acceptable approximations. Therefore, we present a study which explored the use of different isotropic and anisotropic elasto-plastic models in simulating the balloon expansion and radial crushing of the thin-strut (sub-100 µm) ArterioSorbTM BRS using the Abaqus/Explicit (DS SIMULIA) solution method. Stress-strain data was obtained via tensile tests at two different displacement rates. The use of isotropic and transversely isotropic elastic theories was explored, as well as the implementation of stress relaxation in the plastic regime of the material. The scaffold performance was quantified via its post-expansion diameter, percentage recoil and radial strength. The in-silico results were validated via comparison with in-vitro data of an analogous bench test. Accurately predicting both the post-expansion scaffold shape and radial strength was found to be challenging using the in-built Abaqus models. Therefore, a novel user-defined material model was developed via the VUMAT subroutine which improved functionality by facilitating a variable yield ratio, dependent upon the plastic strain as well as stress relaxation in overly strained elements. This achieved prediction of the radial strength within 1.1% of the in-vitro results and the scaffold's post-expansion diameter within 6.7%. A realistic multi-balloon simulation strategy was also used which confirmed that a mechanism exists in the PLLA which facilitates the extremely low percentage recoil behaviour observed in the ArterioSorbTM BRS. This could not be captured by the aforementioned material property models.

Predictive haemodynamics in a one-dimensional human carotid artery bifurcation. Part II: Application to graft design.

A Bayesian surrogate modeling technique is proposed that may be able to predict an optimal bypass graft configuration for patients suffering with stenosis in the internal carotid artery (ICA). At the outset, this statistical technique is considered as a means for identifying key geometric parameters influencing haemodynamics in the human carotid bifurcation. This methodology uses a design of experiments (DoE) technique to generate candidate geometries for flow analysis. A pulsatile one dimensional Navier-Stokes solver incorporating fluid-wall interactions for a Newtonian fluid which predicts pressure and flow in the carotid bifurcation (comprising a stenosed segment in the internal carotid artery) is used for the numerical simulations. Two metrics, pressure variation factor (PVF) and maximum pressure (p(*)(m)) are employed to directly compare the global and local effects, respectively, of variations in the geometry. The values of PVF and p(*)(m) are then used to construct two Bayesian surrogate models. These models are statistically analyzed to visualize how each geometric parameter influences PVF and p(*)(m). Percentage of stenosis is found to influence these pressure based metrics more than any other geometric parameter. Later, we identify bypass grafts with optimal geometric and material properties which have low values of PVF on five test cases with 70%, 75%, 80%, 85%, and 90% stenosis in the ICA, respectively.5%, 80%, 85%, and 90% stenosis in the ICA, respectively.

A control mechanism for intra-mural peri-arterial drainage via astrocytes: How neuronal activity could improve waste clearance from the brain.

The mechanisms behind the clearance of soluble waste from deep within the parenchyma of the brain remain unclear. Experimental evidence reveals that one pathway for clearance of waste, termed intra-mural peri-arterial drainage (IPAD), is the rapid drainage of interstitial fluid along basement membranes (BM) of the smooth muscle cells of cerebral arteries; failure of IPAD is closely associated with the pathology of Alzheimer's disease (AD), but its driving mechanism remains unclear. We have previously shown that arterial pulsations generated by the heart beat are not strong enough to drive IPAD. Here we present computational evidence for a mechanism for clearance of waste from the brain that is driven by functional hyperaemia, that is, the dilatation of cerebral arterioles as a consequence of increased nutrient demand from neurons. This mechanism is based on our model for the flow of fluid through the vascular BM. It accounts for clearance rates observed in mouse experiments, and aligns with pathological observations and recommendations to lower the individual risk of AD, such as mental and physical activity. Thus, our neurovascular hypothesis should act as the new working hypothesis for the driving force behind IPAD.

Parametric geometry exploration of the human carotid artery bifurcation.

A parametric computational model of the human carotid artery bifurcation is employed to demonstrate that it is only necessary to simulate approximately one-half of a single heart pulse when performing a global exploration of the relationships between shear stress and changes in geometry. Using design of experiments and surface fitting techniques, a landscape is generated that graphically depicts these multi-dimensional relationships. Consequently, whilst finely resolved, grid and pulse independent results are traditionally demanded by the computational fluid dynamics (CFD) community, this strategy demonstrates that it is possible to efficiently detect the relative impact of different geometry parameters, and to identify good and bad regions of the landscape by only simulating a fraction of a single pulse. Also, whereas in the past comparisons have been made between the distributions of appropriate shear stress metrics, such as average wall shear stress and oscillatory shear index, this strategy requires a figure of merit to compare different geometries. Here, an area-weighted integral of negative time-averaged shear stress, tau , is used as the principal objective function, although the discussion reveals that the extent as well as the intensity of reverse flow may be important. Five geometry parameters are considered: the sinus bulb width, the angles and the outflow diameters of the internal carotid artery (ICA) and external carotid artery (ECA). A survey of the landscape confirms that bulb shape has the dominant effect on tau with maximum tau occurring for large bulb widths. Also, it is shown that different sets of geometric parameters can produce low values of tau by either relatively small intense areas, or by larger areas of less intense reverse flow.

Mining data from hemodynamic simulations via Bayesian emulation.

BACKGROUND: Arterial geometry variability is inevitable both within and across individuals. To ensure realistic prediction of cardiovascular flows, there is a need for efficient numerical methods that can systematically account for geometric uncertainty. METHODS AND RESULTS: A statistical framework based on Bayesian Gaussian process modeling was proposed for mining data generated from computer simulations. The proposed approach was applied to analyze the influence of geometric parameters on hemodynamics in the human carotid artery bifurcation. A parametric model in conjunction with a design of computer experiments strategy was used for generating a set of observational data that contains the maximum wall shear stress values for a range of probable arterial geometries. The dataset was mined via a Bayesian Gaussian process emulator to estimate: (a) the influence of key parameters on the output via sensitivity analysis, (b) uncertainty in output as a function of uncertainty in input, and (c) which settings of the input parameters result in maximum and minimum values of the output. Finally, potential diagnostic indicators were proposed that can be used to aid the assessment of stroke risk for a given patient's geometry.

Predictive haemodynamics in a one-dimensional human carotid artery bifurcation. Part I: Application to stent design.

A diagnostic technique is proposed to identify patients with carotid stenosis who could most benefit from angioplasty followed by stent implantation. This methodology involves performing a parametric study to investigate the haemodynamic behavior due to alterations in the stenosis shapes in the internal carotid artery (ICA). A pulsatile 1-D Navier-Stokes solver incorporating fluid-wall interactions for a Newtonian fluid which predicts pressure and flow in the human carotid artery bifurcation is used for the numerical simulations. In order to assess the performance of each individual geometry, we introduce pressure variation factor as a metric to directly compare the global effect of variations in the geometry. It is shown that the probability of an overall catastrophic effect is higher when the stenosis is present in the upstream segment of the ICA. Furthermore, maximum pressure is used to quantify the local effects of geometry changes. The location of the peak and extent of stenosis are found not to influence maximum pressure. We also show how these metrics respond after stent deployment into the stenosed part of the ICA. In particular, it is found that localized pressure peaks do not depend on the length of a stent. Finally, we demonstrate how these metrics may be applied to cost-effectively predict the benefit of stenting.

The implication of the osteolysis threshold and interfacial gaps on periprosthetic osteolysis in cementless total hip replacement.

Osteolysis around joint replacements may develop due to migration of wear particles from the joint space into gaps between the interface bone and the implant where they can accumulate in high concentrations to cause tissue damage. Osteolysis may appear in various postoperative times and morphological shapes which can be generalized into linear and focal. However, there are no clear explanations on the causes of such variations. Patients' degree of sensitivity to polyethylene particles (osteolysis thresholds), the local particle concentration and the access route provided by the interface gaps have been described as determining factors. To study their effects, a 2D computational fluid dynamics model of the hip joint capsule in communication with an interfacial gap and the surrounding bone was employed. Particles were presented using a discrete phase model (DPM). High capsular fluid pressure was considered as the driving force for particle migration. Simulations were run for different osteolysis thresholds ranging from 5×108 to 1×1012 particle number per gram of tissue and fibrous tissue generation in osteolytic lesion due to particles was simulated for the equivalent of ten postoperative years. In patients less sensitive to polyethylene particles (higher threshold), osteolysis may be linear and occur along an interfacial gap in less than 5% of the interfacial tissue. Focal osteolysis is more likely to develop in patients with higher sensitivity to polyethylene particles at distal regions to an interfacial gaps where up to 80% of the interfacial tissue may be replaced by fibrous tissue. In these patients, signs of osteolysis may also develop earlier (third postoperative year) than those with less sensitivity who may show very minor signs even after ten years. This study shows the importance of patient sensitivity to wear particles, the role of interfacial gaps in relation to morphology and the onset of osteolysis. Consequently, it may explain the clinically observed variation in osteolysis development.

The impact of imperfect frame deployment and rotational orientation on stress within the prosthetic leaflets during transcatheter aortic valve implantation.

TAVI devices are manufactured with cylindrical frames. However, the frames are rarely cylindrical post-deployment since deformation due to localised under expansion can be induced by calcified material on the native valve leaflets exerting irregular forces upon the frame. Consequently, the leaflets within a deformed TAVI device may undergo elevated stress during operation, which may lead to premature device failure. Using computational analysis a complete TAVI device model was simulated undergoing deployment into an aortic root model derived from CT data for a patient with severe calcific aortic stenosis, followed by a pressure simulated cardiac cycle. The complete analysis was performed eight times, each with the device at a different rotational orientation relative to the native valve, with an increment spacing of 15°. The TAVI device frames consistently featured significant distortions associated with bulky calcified material at the base of the non-coronary sinus. It was found that the average von Mises stress in the prosthetic valves was only increased in one of the cases relative to an idealised device. However, the maximum von Mises stress in the prosthetic valves was elevated in the majority of the cases. Furthermore, it was found that there were preferable orientations to deploy the prosthetic device, in this case, when the prosthetic leaflets were aligned with the native leaflets. As device orientation deviated from this orientation, the stresses in the valve increased because the distance between the prosthetic commissures decreased. This potentially could represent a sufficient increase in stress to induce variation in device lifespan.

Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aß Drainage.

Alzheimer's Disease (AD) is the most common form of dementia and to date there is no cure or efficient prophylaxis. The cognitive decline correlates with the accumulation of amyloid-ß (Aß) in the walls of capillaries and arteries. Our group has demonstrated that interstitial fluid and Aß are eliminated from the brain along the basement membranes of capillaries and arteries, the intramural periarterial drainage (IPAD) pathway. With advancing age and arteriosclerosis, the stiffness of arterial walls, this pathway fails in its function and Aß accumulates in the walls of arteries. In this study we tested the hypothesis that arterial pulsations drive IPAD and that a valve mechanism ensures the net drainage in a direction opposite to that of the blood flow. This hypothesis was tested using a mathematical model of the drainage mechanism. We demonstrate firstly that arterial pulsations are not strong enough to produce drainage velocities comparable to experimental observations. Secondly, we demonstrate that a valve mechanism such as directional permeability of the IPAD pathway is necessary to achieve a net reverse flow. The mathematical simulation results are confirmed by assessing the pattern of IPAD in mice using pulse modulators, showing no significant alteration of IPAD. Our results indicate that forces other than the cardiac pulsations are responsible for efficient IPAD.

Skin Microstructure is a Key Contributor to Its Friction Behaviour.

Due to its multifactorial nature, skin friction remains a multiphysics and multiscale phenomenon poorly understood despite its relevance for many biomedical and engineering applications (from superficial pressure ulcers, through shaving and cosmetics, to automotive safety and sports equipment). For example, it is unclear whether, and in which measure, the skin microscopic surface topography, internal microstructure and associated nonlinear mechanics can condition and modulate skin friction. This study addressed this question through the development of a parametric finite element contact homogenisation procedure which was used to study and quantify the effect of the skin microstructure on the macroscopic skin frictional response. An anatomically realistic two-dimensional image-based multilayer finite element model of human skin was used to simulate the sliding of rigid indenters of various sizes over the skin surface. A corresponding structurally idealised multilayer skin model was also built for comparison purposes. Microscopic friction specified at skin asperity or microrelief level was an input to the finite element computations. From the contact reaction force measured at the sliding indenter, a homogenised (or apparent) macroscopic friction was calculated. Results demonstrated that the naturally complex geometry of the skin microstructure and surface topography alone can play as significant role in modulating the deformation component of macroscopic friction and can significantly increase it. This effect is further amplified as the ground-state Young's modulus of the stratum corneum is increased (for example, as a result of a dryer environment). In these conditions, the skin microstructure is a dominant factor in the deformation component of macroscopic friction, regardless of indenter size or specified local friction properties. When the skin is assumed to be an assembly of nominally flat layers, the resulting global coefficient of friction is reduced with respect to the local one. This seemingly counter-intuitive effect had already been demonstrated in a recent computational study found in the literature. Results also suggest that care should be taken when assigning a coefficient of friction in computer simulations, as it might not reflect the conditions of microscopic and macroscopic friction one intends to represent. The modelling methodology and simulation tools developed in this study go beyond what current analytical models of skin friction can offer: the ability to accommodate arbitrary kinematics (i.e. finite deformations), nonlinear constitutive properties and the complex geometry of the skin microstructural constituents. It was demonstrated how this approach offered a new level of mechanistic insight into plausible friction mechanisms associated with purely structural effects operating at the microscopic scale; the methodology should be viewed as complementary to physical experimental protocols characterising skin friction as it may facilitate the interpretation of observations and measurements and/or could also assist in the design of new experimental quantitative assays.

Assessing the impact of including leaflets in the simulation of TAVI deployment into a patient-specific aortic root.

Computational simulation of transcatheter aortic valve implantation (TAVI) device deployment presents a significant challenge over and above similar simulations for percutaneous coronary intervention due to the presence of prosthetic leaflets. In light of the complexity of these leaflets, simulations have been performed to assess the effect of including the leaflets in a complete model of a balloon-expandable TAVI device when deployed in a patient-specific aortic root. Using an average model discrepancy metric, the average frame positions (with and without the leaflets) are shown to vary by 0.236% of the expanded frame diameter (26 mm). This relatively small discrepancy leads to the conclusion that for a broad range of replacement valve studies, including new frame configurations and designs, patient-specific assessment of apposition, paravalvular leakage and tissue stress, modelling of the prosthetic leaflets is likely to have a marginal effect on the results

Multi-objective optimisation of stent dilation strategy in a patient-specific coronary artery via computational and surrogate modelling.

Although contemporary stents have been shown to improve short and long term clinical outcomes, the optimum dilation protocol is still uncertain in challenging cases characterised by long, highly calcified and tortuous anatomy. Recent clinical studies have revealed that in these cases, sub-optimal delivery can result in stent thrombosis (ST) and/or neointimal thickening as a result of stent malapposition (SM) and/or severe vessel trauma. One of the major contributors to vessel trauma is the damage caused by balloon dilation during stent deployment. In the present work, a Kriging based response surface modelling approach has been implemented to search for optimum stent deployment strategies in a clinically challenging, patient specific diseased coronary artery. In particular, the aims of this study were: (i) to understand the impact of the balloon pressure and unpressurised diameter on stent malapposition, drug distribution and wall stresses via computer simulations and (ii) obtain potentially optimal dilation protocols to simultaneously minimise stent malapposition and tissue wall stresses and maximise drug diffusion in the tissue. The results indicate that SM is inversely proportional to tissue stresses and drug deliverability. After analytical multi-objective optimisation, a set of "non-dominated" dilation scenarios was proposed as a post-optimisation methodology for protocol selection. Using this method, it has been shown that, for a given patient specific model, optimal stent expansion can be predicted. Such a framework could potentially be used by interventional cardiologists to minimise stent malapposition and tissue stresses whilst maximising drug deliverability in any patient-specific case.

Design Optimisation of Coronary Artery Stent Systems.

In recent years, advances in computing power and computational methods have made it possible to perform detailed simulations of the coronary artery stenting procedure and of related virtual tests of performance (including fatigue resistance, corrosion and haemodynamic disturbance). Simultaneously, there has been a growth in systematic computational optimisation studies, largely exploiting the suitability of surrogate modelling methods to time-consuming simulations. To date, systematic optimisation has focussed on stent shape optimisation and has re-affirmed the complexity of the multi-disciplinary, multi-objective problem at hand. Also, surrogate modelling has predominantly involved the method of Kriging. Interestingly, though, optimisation tools, particularly those associated with Kriging, haven't been used as efficiently as they could have been. This has especially been the case with the way that Kriging predictor functions have been updated during the search for optimal designs. Nonetheless, the potential for future, carefully posed, optimisation strategies has been suitably demonstrated, as described in this review.

A Simulation Model of Periarterial Clearance of Amyloid-ß from the Brain.

The accumulation of soluble and insoluble amyloid-ß (Aß) in the brain indicates failure of elimination of Aß from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aß from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aß into the blood and periarterial lymphatic drainage of Aß. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aß, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aß in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aß diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aß occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.