Delivering computationally-intensive digital patient applications to the clinic: An exemplar solution to predict femoral bone strength from CT data.

BACKGROUND AND OBJECTIVE: Whilst fragility hip fractures commonly affect elderly people, often causing permanent disability or death, they are rarely addressed in advance through preventive techniques. Quantification of bone strength can help to identify subjects at risk, thus reducing the incidence of fractures in the population. In recent years, researchers have shown that finite element models (FEMs) of the hip joint, derived from computed tomography (CT) images, can predict bone strength more accurately than other techniques currently used in the clinic. The specialised hardware and trained personnel required to perform such analyses, however, limits the widespread adoption of FEMs in clinical contexts. In this manuscript we present CT2S (Computed Tomography To Strength), a system developed in collaboration between The University of Sheffield and Sheffield Teaching Hospitals, designed to streamline access to this complex workflow for clinical end-users. METHODS: The system relies on XNAT and makes use of custom apps based on open source software. Available through a website, it allows doctors in the healthcare environment to benefit from FE based bone strength estimation without being exposed to the technical aspects, which are concealed behind a user-friendly interface. Clinicians request the analysis of CT scans of a patient through the website. Using XNAT functionality, the anonymised images are automatically transferred to the University research facility, where an operator processes them and estimates the bone strength through FEM using a combination of open source and commercial software. Following the analysis, the doctor is provided with the results in a structured report. RESULTS: The platform, currently available for research purposes, has been deployed and fully tested in Sheffield, UK. The entire analysis requires processing times ranging from 3.5 to 8 h, depending on the available computational power. CONCLUSIONS: The short processing time makes the system compatible with current clinical workflows. The use of open source software and the accurate description of the workflow given here facilitates the deployment in other centres.

A particle-based model for endothelial cell migration under flow conditions.

Endothelial cells (ECs) play a major role in the healing process following angioplasty to inhibit excessive neointima. This makes the process of EC healing after injury, in particular EC migration in a stented vessel, important for recovery of normal vessel function. In that context, we present a novel particle-based model of EC migration and validate it against in vitro experimental data. We have developed a particle-based model of EC migration under flow conditions in an in vitro vessel with obstacles. Cell movement in the model is a combination of random walks and directed movement along the local flow velocity vector. For model calibration, a set of experimental data for cell migration in a similarly shaped channel has been used. We have calibrated the model for a baseline case of a channel with no obstacles and then applied it to the case of a channel with ridges on the bottom surface, representative of stent strut geometry. We were able to closely reproduce the cell migration speed and angular distribution of their movement relative to the flow direction reported in vitro. The model also reproduces qualitative aspects of EC migration, such as entrapment of cells downstream from the flow-disturbing ridge. The model has the potential, after more extensive in vitro validation, to study the effect of variation in strut spacing and shape, through modification of the local flow, on EC migration. The results of this study support the hypothesis that EC migration is strongly affected by the direction and magnitude of local wall shear stress.

Location-Specific Comparison Between a 3D In-Stent Restenosis Model and Micro-CT and Histology Data from Porcine In Vivo Experiments.

BACKGROUND: Coronary artery restenosis is an important side effect of percutaneous coronary intervention. Computational models can be used to better understand this process. We report on an approach for validation of an in silico 3D model of in-stent restenosis in porcine coronary arteries and illustrate this approach by comparing the modelling results to in vivo data for 14 and 28 days post-stenting. METHODS: This multiscale model includes single-scale models for stent deployment, blood flow and tissue growth in the stented vessel, including smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. The validation procedure uses data from porcine in vivo experiments, by simulating stent deployment using stent geometry obtained from micro computed tomography (micro-CT) of the stented vessel and directly comparing the simulation results of neointimal growth to histological sections taken at the same locations. RESULTS: Metrics for comparison are per-strut neointimal thickness and per-section neointimal area. The neointimal area predicted by the model demonstrates a good agreement with the detailed experimental data. For 14 days post-stenting the relative neointimal area, averaged over all vessel sections considered, was 20 ± 3% in vivo and 22 ± 4% in silico. For 28 days, the area was 42 ± 3% in vivo and 41 ± 3% in silico. CONCLUSIONS: The approach presented here provides a very detailed, location-specific, validation methodology for in silico restenosis models. The model was able to closely match both histology datasets with a single set of parameters. Good agreement was obtained for both the overall amount of neointima produced and the local distribution. It should be noted that including vessel curvature and ECM production in the model was paramount to obtain a good agreement with the experimental data.

Global sensitivity analysis of a model for venous valve dynamics.

Chronic venous disease is defined as dysfunction of the venous system caused by incompetent venous valves with or without a proximal venous obstruction. Assessing the severity of the disease is challenging, since venous function is determined by various interacting hemodynamic factors. Mathematical models can relate these factors using physical laws and can thereby aid understanding of venous (patho-)physiology. To eventually use a mathematical model to support clinical decision making, first the model sensitivity needs to be determined. Therefore, the aim of this study is to assess the sensitivity of the venous valve model outputs to the relevant input parameters. Using a 1D pulse wave propagation model of the tibial vein including a venous valve, valve dynamics under head up tilt are simulated. A variance-based sensitivity analysis is performed based on generalized polynomial chaos expansion. Taking a global approach, individual parameter importance on the valve dynamics as well as importance of their interactions is determined. For the output related to opening state of the valve, the opening/closing pressure drop (dpvalve,0) is found to be the most important parameter. The venous radius (rvein,0) is related to venous filling volume and is consequently most important for the output describing venous filling time. Finally, it is concluded that improved assessment of rvein,0 and dpvalve,0 is most rewarding when simulating valve dynamics, as this results in the largest reduction in output uncertainty. In practice, this could be achieved using ultrasound imaging of the veins and fluid structure interaction simulations to characterize detailed valve dynamics, respectively.

A 1D pulse wave propagation model of the hemodynamics of calf muscle pump function.

The calf muscle pump is a mechanism which increases venous return and thereby compensates for the fluid shift towards the lower body during standing. During a muscle contraction, the embedded deep veins collapse and venous return increases. In the subsequent relaxation phase, muscle perfusion increases due to increased perfusion pressure, as the proximal venous valves temporarily reduce the distal venous pressure (shielding). The superficial and deep veins are connected via perforators, which contain valves allowing flow in the superficial-to-deep direction. The aim of this study is to investigate and quantify the physiological mechanisms of the calf muscle pump, including the effect of venous valves, hydrostatic pressure, and the superficial venous system. Using a one-dimensional pulse wave propagation model, a muscle contraction is simulated by increasing the extravascular pressure in the deep venous segments. The hemodynamics are studied in three different configurations: a single artery-vein configuration with and without valves and a more detailed configuration including a superficial vein. Proximal venous valves increase effective venous return by 53% by preventing reflux. Furthermore, the proximal valves shielding function increases perfusion following contraction. Finally, the superficial system aids in maintaining the perfusion during the contraction phase and reduces the refilling time by 37%.

Adaptation and development of software simulation methodologies for cardiovascular engineering: present and future challenges from an end-user perspective.

This paper describes the use of diverse software tools in cardiovascular applications. These tools were primarily developed in the field of engineering and the applications presented push the boundaries of the software to address events related to venous and arterial valve closure, exploration of dynamic boundary conditions or the inclusion of multi-scale boundary conditions from protein to organ levels. The future of cardiovascular research and the challenges that modellers and clinicians face from validation to clinical uptake are discussed from an end-user perspective.

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 thermal analogy for modelling drug elution from cardiovascular stents.

Restriction of blood flow by the narrowing or occlusion of arteries is one of the most common presentations of cardiovascular disease. One treatment involves the introduction of a metal scaffold, or stent, designed to prevent recoil and to provide structural stability to the vessel. On the occasions that this treatment is ineffective, failure is usually associated with re-invasion of tissue. This can be prevented by local delivery of drugs which inhibit tissue growth. The drug might be delivered locally in a polymer coating on the stent. This paper develops and explores the use of a thermal analogue of the drug delivery process and the associated three-dimensional convection-diffusion equation to model the spatial and temporal distribution of drug concentration within the vessel wall. This allows the routine use of commercial finite element analysis software to investigate the dynamics of drug distribution, assist in the understanding of the treatment process and develop improved delivery systems. Two applications illustrate how the model might be used to investigate the effects of controllable or measurable parameters on the progression of the process. It is demonstrated that the geometric characteristics of the stent can have significant impact on the homogeneity of the dosing in the vessel wall.

Measurement of the symmetry of in vitro stent expansion: a stereo-photogrammetric approach.

Balloon-expandable stents are used routinely in the treatment of coronary artery disease. Their effectiveness is limited by the occurrence of restenosis. Previous studies have suggested that the level of restenosis may be related to the deployed stent geometry, and in particular to the symmetry of the deployment profile. It is suggested that the symmetry of deployment might be influenced by the folding pattern of the balloon on which the stent is delivered. This paper describes a stereo-photogrammetric system for the three-dimensional reconstruction of stent geometry during expansion, including appropriate specification and calibration procedures. Calibration testing of the system indicated an accuracy of +/-0.05 mm in the reconstruction of the position of a point on the stent surface. Methods for processing the 3D data are described, including a technique for quantitatively differentiating between results from two alternative balloon folding patterns. This study may aid future balloon and stent design with respect to the optimization of stent deployment characteristics.

Fluid-solid interaction: benchmarking of an external coupling of ANSYS with CFX for cardiovascular applications.

Fluid-solid interaction is a primary feature of cardiovascular flows. There is increasing interest in the numerical solution of these systems as the extensive computational resource required for such studies becomes available. One form of coupling is an external weak coupling of separate solid and fluid mechanics codes. Information about the stress tensor and displacement vector at the wetted boundary is passed between the codes, and an iterative scheme is employed to move towards convergence of these parameters at each time step. This approach has the attraction that separate codes with the most extensive functionality for each of the separate phases can be selected, which might be important in the context of the complex rheology and contact mechanics that often feature in cardiovascular systems. Penrose and Staples describe a weak coupling of CFX for computational fluid mechanics to ANSYS for solid mechanics, based on a simple Jacobi iteration scheme. It is important to validate the coupled numerical solutions. An extensive analytical study of flow in elastic-walled tubes was carried out by Womersley in the late 1950s. This paper describes the performance of the coupling software for the straight elastic-walled tube, and compares the results with Womersley's analytical solutions. It also presents preliminary results demonstrating the application of the coupled software in the context of a stented vessel.

Neonatal lungs: maturational changes in lung resistivity spectra.

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Electrical impedance tomographic measurements have been used on 155 normal children over the first three years of life and 25 pre-term infants, to determine the absolute resistivity of lung tissue as a function of frequency. The results show consistent changes with increasing age in both lung tissue resistivity (5.8 ohm m at birth to 20.9 ohm m at 3 years of age) and in the changes of resistivity with frequency (Cole parameter ratio R/S=0.41 at birth and 0.84 at 3 years of age). Comparison with a lung model showed that the measurements are consistent with maturational changes in the number and size of alveoli, the extracapillary blood volume and the size of the extracapillary vessels. However, the results show that the process of maturation is not complete at the age of three years.

Neonatal lungs--can absolute lung resistivity be determined non-invasively?

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Conditions such as pulmonary oedema and emphysema have been shown to change lung resistivity. However, direct access to the lungs to enable resistivity to be measured is very difficult. We have developed a new method of using electrical impedance tomographic (EIT) measurements on a group of 142 normal neonates to determine the absolute resistivity of lung tissue. The methodology involves comparing the measured EIT data with that from a finite difference model of the thorax in which lung tissue resistivity can be changed. A mean value of 5.7 +/- 1.7 omega(m) was found over the frequency range 4 kHz to 813 kHz. This value is lower than that usually given for adult lung tissue but consistent with the literature on the composition of the neonatal lung and with structural modelling.

Development of an ex vivo model to investigate the effects of altered haemodynamics on human bypass grafts.

The insertion of vein grafts into the arterial circulation may contribute to vessel wall thickening and accelerated atherosclerosis, a common feature of late vein graft failure. We aimed to develop a model suitable for investigation of the effects of altered haemodynamics on human saphenous vein following its implantation into the arterial circulation. Segments of human saphenous vein obtained from patients undergoing coronary artery bypass surgery were sutured at each end to PTFE and placed into a flow system. Pressure and flow rates to stimulate the arterial and venous systems were achieved. A theoretical model of the flow chamber was created and computational fluid dynamics software (FLOTRAN, Swanson Analysis Systems) was used to determine the flow profile within the model. In summary, a flow model has been developed to investigate the effect of altered haemodynamics on the molecular and pathological changes that occur in vein grafts incorporated into the arterial circulation.