D. R. Hose

The application of multiscale modelling to the process of development and prevention of stenosis in a stented coronary artery

The inherent complexity of biomedical systems is well recognized; they are multiscale, multiscience systems, bridging a wide range of temporal and spatial scales. While the importance of multiscale modelling in this context is increasingly recognized, there is little underpinning literature on the methodology and generic description of the process. The COAST (complex autonoma simulation technique) project aims to address this by developing a multiscale, multiscience framework, coined complex autonoma (CxA), based on a hierarchical aggregation of coupled cellular automata (CA) and agent-based models (ABMs). The key tenet of COAST is that a multiscale system can be decomposed into N single-scale CA or ABMs that mutually interact across the scales. Decomposition is facilitated by building a scale separation map on which each single-scale system is represented according to its spatial and temporal characteristics. Processes having well-separated scales are thus easily identified as the components of the multiscale model. This paper focuses on methodology, introduces the concept of the CxA and demonstrates its use in the generation of a multiscale model of the physical and biological processes implicated in a challenging and clinically relevant problem, namely coronary artery in-stent restenosis.

Multi-scale simulations of the dynamics of in-stent restenosis: impact of stent deployment and design

Neointimal hyperplasia, a process of smooth muscle cell re-growth, is the result of a natural wound healing response of the injured artery after stent deployment. Excessive neointimal hyperplasia following coronary artery stenting results in in-stent restenosis (ISR). Regardless of recent developments in the field of coronary stent design, ISR remains a significant complication of this interventional therapy. The influence of stent design parameters such as strut thickness, shape and the depth of strut deployment within the vessel wall on the severity of restenosis has already been highlighted but the detail of this influence is unclear. These factors impact on local haemodynamics and vessel structure and affect the rate of neointima formation. This paper presents the first results of a multi-scale model of ISR. The development of the simulated restenosis as a function of stent deployment depth is compared with an in vivo porcine dataset. Moreover, the influence of strut size and shape is investigated, and the effect of a drug released at the site of injury, by means of a drug-eluting stent, is also examined. A strong correlation between strut thickness and the rate of smooth muscle cell proliferation has been observed. Simulation results also suggest that the growth of the restenotic lesion is strongly dependent on the stent strut cross-sectional profile.

A Computational study of the passive mechanisms of eye restraint during head impact trauma

A finite element model of the eye and the orbit was used to examine the hypothesis that the orbital fat provides an important mechanism of eye stability during head trauma. The model includes the globe, the orbital fat, the extra-ocular muscles, and the optic nerve. MRI images of an adult human orbit were used to generate an idealized geometry of the orbital space. The globe was approximated as a sphere 12 mm in radius. The optic nerve and the sclera were represented as thin shells, whereas the vitreous and the orbital fat were represented as nearly incompressible solids of low stiffness. The orbital bone was modelled as a rigid shell. Frontal head impact resulting from a fall onto a hard floor was simulated by prescribing to the orbital bone a triangular acceleration pulse of 200 g (1962 m/s2) peak for a duration of 4.5 ms. The results show that the fat provides the crucial passive mechanism of eye restraint. The mechanism is a consequence of the fact that the fat is incompressible and that its motion is restricted by the rigidity of the orbital walls. Thus, the acceleration loads of short duration cannot generate significant distortion of the fat. In contrast, the passive muscles provide little support to the globe. When the connection between the orbital fat and the eye is absent the eye is held mainly by the optic nerve. We discuss the possible role that this loss of contact may have in some cases of the evulsion of the eye and the optic nerve.

Quality Metrics for High Order Meshes: Analysis of the Mechanical Simulation of the Heart Beat

The quality of a computational mesh is an important characteristic for stable and accurate simulations. Quality depends on the regularity of the initial mesh, and in mechanical simulations it evolves in time, with deformations causing changes in volume and distortion of mesh elements. Mesh quality metrics are therefore relevant for both mesh personalization and the monitoring of the simulation process. This work evaluates the significance, in meshes with high order interpolation, of four quality metrics described in the literature, applying them to analyse the stability of the simulation of the heart beat. It also investigates how image registration and mesh warping parameters affect the quality and stability of meshes. Jacobian-based metrics outperformed or matched the results of coarse geometrical metrics of aspect ratio or orthogonality, although they are more expensive computationally. The stability of simulations of a complete heart cycle was best predicted with a specificity of 61%, sensitivity of 85%, and only nominal differences were found changing the intra-element and per-element combination of quality values. A compromise between fitting accuracy and mesh stability and quality was found. Generic geometrical quality metrics have a limited success predicting stability, and an analysis of the simulation problem may be required for an optimal definition of quality.

Influence of intermittent compression cuff design on calf deformation: computational results

The intermittent compression of the calf with an external pressure cuff for the prevention of deep vein thrombosis (DVT) is a well established treatment for surgical patients. The exact mechanisms by which DVT is prevented are poorly understood. This study presents a finite element model of calf cross section, based on MR images of calf geometry, to examine the variation in calf deformation during compression with four different cuff types. Cuff pressure distribution is modelled using interface pressures obtained in a volunteer study. The model has been validated against gross calf deformation obtained from MR images of the compressed calf. This validation has illustrated the importance of out-of-plane boundary conditions, material properties and the variation in cuff loading in the axial direction. In the future this model may have merit in determining optimum pressure loading regimes for intermittent pneumatic compression (IPC) cuff design.

A Validated Model of Calf Compression and Deep Vessel Collapse During External Cuff Inflation

This paper presents a validated model of calf compression with an external pressure cuff as used for deep vein thrombosis. Magnetic resonance (MR) images of calf geometry were used to generate subject-specific finite-element (FE) models of the calf cross section. Ultrasound images of deep vessel collapse obtained through a water-filled cuff were used to validate model behavior. Calf/cuff pressure interface measurements were applied to the FE model and the resulting tissue deformation was compared with MR image in normal volunteers (three females, four males, age range 20-55) using two distinct cuffs. MR observations and the model results showed good qualitative agreement. A similar reduction in cross-sectional area of the posterior tibial veins was obtained under both symmetric compression (89%) and asymmetric compression (81%), but greater compression of the anterior tibial veins was achieved with symmetric compression. The need to account for the effective compressibility of the calf tissue suggests that external measurements of the calf tissue deformation will not accurately predict deep vessel collapse. These results have implications for the modification of venous haemodynamics by such systems and could help to improve cuff design.

A lattice Boltzmann framework for simulation of thrombogenesis

A lattice Boltzmann framework has been developed which models thrombus formation following physical damage to platelets and activation of the coagulation cascade via one or more of the strands of Virchows triad. The model includes concurrent simulation of flow, activation of blood and modification of the geometry following clot deposition. An extended local clotting rule has been developed which considers the vicinity of the growing clot and local flow factors such as shear stress. This paper will focus on the implementation of these local rules, as an extension to the standard flow solver, for modelling the activation and clotting processes.

The role of venous valves in pressure shielding

BackgroundIt is widely accepted that venous valves play an important role in reducing the pressure applied to the veins under dynamic load conditions, such as the act of standing up. This understanding is, however, qualitative and not quantitative. The purpose of this paper is to quantify the pressure shielding effect and its variation with a number of system parameters.MethodsA one-dimensional mathematical model of a collapsible tube, with the facility to introduce valves at any position, was used. The model has been exercised to compute transient pressure and flow distributions along the vein under the action of an imposed gravity field (standing up).ResultsA quantitative evaluation of the effect of a valve, or valves, on the shielding of the vein from peak transient pressure effects was undertaken. The model used reported that a valve decreased the dynamic pressures applied to a vein when gravity is applied by a considerable amount.ConclusionThe model has the potential to increase understanding of dynamic physical effects in venous physiology, and ultimately might be used as part of an interventional planning tool.

From histology and imaging data to models for in-stent restenosis.

The implantation of stents has been used to treat coronary artery stenosis for several decades. Although stenting is successful in restoring the vessel lumen and is a minimally invasive approach, the long-term outcomes are often compromised by in-stent restenosis (ISR). Animal models have provided insights into the pathophysiology of ISR and are widely used to evaluate candidate drug inhibitors of ISR. Such biological models allow the response of the vessel to stent implantation to be studied without the variation of lesion characteristics encountered in patient studies. This paper describes the development of complementary in silico models employed to improve the understanding of the biological response to stenting using a porcine model of restenosis. This includes experimental quantification using microCT imaging and histology and the use of this data to establish numerical models of restenosis. Comparison of in silico results with histology is used to examine the relationship between spatial localization of fluid and solid mechanics stimuli immediately post-stenting. Multi-scale simulation methods are employed to study the evolution of neointimal growth over time and the variation in the extent of neointimal hyperplasia within the stented region. Interpretation of model results through direct comparison with the biological response contributes to more detailed understanding of the pathophysiology of ISR, and suggests the focus for follow-up studies. In conclusion we outline the challenges which remain to both complete our understanding of the mechanisms responsible for restenosis and translate these models to applications in stent design and treatment planning at both population-based and patient-specific levels.

Digital human modelling: a global vision and a european perspective

The Physiome is an umbrella term that refers to human modelling with mathematics and computational methods, accommodating cross-disciplinary science (chemistry, biology, physics) and a breadth of dimensional and temporal scale (sub-cellular to organs, sub-microsecond to tens-of-years). The Virtual Physiological Human is a European initiative that is intended to provide a unifying architecture for the integration and cooperation of multi-scale physiome models, thereby creating a predictive platform for the description of human beings in silico. Unlike the Genome, the challenge of the Physiome may be almost unbounded, as the desire for increased detail imposes a continuing pressure for ever-finer data granularity, and the necessary Information Technology (IT) infrastructure spawns innovations that surpass conventional solutions. It is foreseen that maturing physiome activities will increasingly influence medicine, biomedical research and commercial developments, and the central role of IT highlights the need for a specific and robust IT infrastructure. The European Commission has experience of supporting challenging technical endeavours through its Framework Programmes of research, and in the forthcoming 7th Framework Programme, it will invite researchers from within and outside Europe to unite in seeking solutions to key issues of the Physiome. The Virtual Physiological Human (VPH) investment programme will establish the necessary infrastructure and address the grand technical challenges identified by experts. This paper examines the background to the strategy and the ways in which the programmes structure has been determined.