Highly integrated workflows for exploring cardiovascular conditions: Exemplars of precision medicine in Alzheimer's disease and aortic dissection.

For precision medicine to be implemented through the lens of in silico technology, it is imperative that biophysical research workflows offer insight into treatments that are specific to a particular illness and to a particular subject. The boundaries of precision medicine can be extended using multiscale, biophysics-centred workflows that consider the fundamental underpinnings of the constituents of cells and tissues and their dynamic environments. Utilising numerical techniques that can capture the broad spectrum of biological flows within complex, deformable and permeable organs and tissues is of paramount importance when considering the core prerequisites of any state-of-the-art precision medicine pipeline. In this work, a succinct breakdown of two precision medicine pipelines developed within two Virtual Physiological Human (VPH) projects are given. The first workflow is targeted on the trajectory of Alzheimer's Disease, and caters for novel hypothesis testing through a multicompartmental poroelastic model which is integrated with a high throughput imaging workflow and subject-specific blood flow variability model. The second workflow gives rise to the patient specific exploration of Aortic Dissections via a multi-scale and compliant model, harnessing imaging, computational fluid-dynamics (CFD) and dynamic boundary conditions. Results relating to the first workflow include some core outputs of the multiporoelastic modelling framework, and the representation of peri-arterial swelling and peri-venous drainage solution fields. The latter solution fields were statistically analysed for a cohort of thirty-five subjects (stratified with respect to disease status, gender and activity level). The second workflow allowed for a better understanding of complex aortic dissection cases utilising both a rigid-wall model informed by minimal and clinically common datasets as well as a moving-wall model informed by rich datasets.

A Virtual Comparison of the eCLIPs Device and Conventional Flow-Diverters as Treatment for Cerebral Bifurcation Aneurysms.

PURPOSE: Effective, consistent, and complication-free treatment of cerebral bifurcation aneurysms remains elusive despite a pressing need, with the majority of lesions presenting in such locations. Current treatment options focus either on aneurysm coil retention, supported by a stent-like device positioned in the parent vessel lumen, or intrasaccular devices that disrupt flow within the aneurysm dome. A third alternative, i.e., the use of conventional (intraluminal) flow-diverters to treat such bifurcation aneurysms raises the problem that at least one daughter vessel needs to be jailed in such a deployment. The eCLIPs is a stent-like device that offers the possibility of flow-diversion at the aneurysm neck, without the drawbacks of daughter vessel occlusion or those of intrasaccular deployment. METHODS: In this study the eCLIPs device was virtually deployed in five cerebral bifurcation aneurysms and compared with a conventional tubular flow-diverter device. Computational fluid dynamics (CFD) simulations of the aneurysm haemodynamic environment pre- and post-implantation were conducted, and focussed on metrics associated with successful aneurysm occlusion. Absolute and relative reductions in aneurysm inflow rate (Q) and time-averaged wall shear stress (TAWSS) were recorded. RESULTS: The eCLIPs device was found to perform in a similar qualitative fashion to tubular flow-diverters, with overall reduction of metrics being somewhat more modest however, when compared to such devices. Aneurysm inflow reduction and TAWSS reduction were typically 10-20% lower for the eCLIPs, when compared to a generic flow diverter (FDBRAIDED) similar to devices currently in clinical use. The eCLIPs was less effective at diffusing inflow jets and at reducing the overall velocity of the flow, when compared to these devices. This result is likely due to the larger device pore size in the eCLIPs. Notably, it was found that the eCLIPs provided approximately equal resistance to flow entering and exiting the aneurysm, which was not true for the FDBRAIDED device, where high-speed concentrations of outflow were seen at the aneurysm neck along with local TAWSS elevation. The clinical implications of such behaviour are not examined in detail here but could be significant. CONCLUSIONS: Our findings indicate that the eCLIPs device acts as a flow-diverter for bifurcation aneurysms, with somewhat diminished occlusion properties comparing to tubular flow diverters but without the jailing and diminished flow evident in a daughter vessel associated with use of conventional devices.

Porcine In Vivo Validation of a Virtual Contrast Model: The Influence of Contrast Agent Properties and Vessel Flow Rates.

BACKGROUND AND PURPOSE: Accurately and efficiently modeling the transport of angiographic contrast currently offers the best method of verifying computational fluid dynamics simulations and, with it, progress toward the lofty goal of prediction of aneurysm treatment outcome a priori. This study specifically examines the influence of estimated flow rate and contrast properties on such in silico predictions of aneurysm contrast residence and decay. MATERIALS AND METHODS: Four experimental sidewall aneurysms were created in swine, with aneurysm contrast flow patterns and decay rates observed under angiography. A simplified computational fluid dynamics model of the experimental aneurysm was constructed from 3D angiography and contrast residence predicted a priori. The relative influence of a number of estimated model parameters (contrast viscosity, contrast density, and blood flow rate) on contrast residence was then investigated with further simulations. RESULTS: Contrast infiltration and washout pattern were accurately predicted by the a priori computational fluid dynamics model; however, the contrast decay rate was underestimated by ∼25%. This error was attributed to the estimated parent vessel flow rate alone, and the effects of contrast viscosity and density on the decay rate were found to be inconsequential. A linear correlation between the parent vessel flow rate and the corresponding contrast decay rate was observed. CONCLUSIONS: In experimental sidewall aneurysms, contrast fluid properties (viscosity and density) were shown to have a negligible effect on variation in the modeled contrast decay rate. A strong linear correlation was observed between parent vessel flow rate and contrast decay over a physiologically reasonable range of flow rates.

Computational modelling of clot development in patient-specific cerebral aneurysm cases.

UNLABELLED: ESSENTIALS: Clotting in cerebral aneurysms is a process that can either stabilize the aneurysm or lead to rupture. A patient-specific computational model capable of predicting cerebral aneurysm thrombosis is presented. The different clotting outcomes highlight the importance of personalization of treatment. Once validated, the model can be used to tailor treatment and to clarify clotting processes in aneurysms. BACKGROUND: In cerebral aneurysms, clotting can either stabilize the aneurysm sac via aneurysm occlusion, or it can have a detrimental effect by giving rise to embolic occlusion. OBJECTIVE: The work presented in this study details the development of an in silico model that combines all the salient, clinically relevant features of cerebral aneurysm clotting. A comprehensive computational model of clotting that accounts for biochemical complexity coupled with three-dimensional hemodynamics in image-derived patient aneurysms and in the presence of virtually implanted interventional devices is presented. METHODS: The model is developed and presented in two stages. First, a two-dimensional computational model of clotting is presented for an idealized geometry. This enables verification of the methods with existing, physiological data before the pathological state is considered. This model is used to compare the results predicted by two different underlying biochemical cascades. The two-dimensional model is then extended to image-derived, three-dimensional aneurysmal topologies by incorporating level set methods, demonstrating the potential use of this model. RESULTS AND CONCLUSION: As a proof of concept, comparisons are then made between treated and untreated aneurysms. The prediction of different clotting outcomes for different patients demonstrates that with further development, refinement and validation, this methodology could be used for patient-specific interventional planning.

Towards Predicting Patient-Specific Flow-Diverter Treatment Outcomes for Bifurcation Aneurysms: From Implantation Rehearsal to Virtual Angiograms.

Despite accounting for the majority of all cerebral aneurysm cases, bifurcation aneurysms present many challenges to standard endovascular treatment techniques. This study examines the treatment of bifurcation aneurysms endovascularly with flow-diverting stents and presents an integrative computational modeling suite allowing for rehearsing all aspects of the treatment. Six bifurcation aneurysms are virtually treated with 70% porosity flow-diverters. Substantial reduction (>50%) in aneurysm inflow due to device deployment is predicted in addition to reductions in peak and average aneurysm wall shear stress to values considered physiologically normal. The subsequent impact of flow-diverter deployment on daughter vessels that are jailed by the device is investigated further, with a number of simulations conducted with increased outlet pressure conditions at jailed vessels. Increased outlet pressures at jailed daughter vessels are found to have little effect on device-induced aneurysm inflow reduction, but large variation (13-86%) is seen in the resulting reduction in daughter vessel flow rate. Finally, we propose a potentially powerful approach for validation of such models, by introducing an angiographic contrast model, with contrast transport modeled both before and after virtual treatment. Virtual angiograms and contrast residence curves are created, which offer unique clinical relevance and the potential for future in vivo verification of simulated results.

Comparison and calibration of a real-time virtual stenting algorithm using Finite Element Analysis and Genetic Algorithms.

In this paper, we perform a comparative analysis between two computational methods for virtual stent deployment: a novel fast virtual stenting method, which is based on a spring-mass model, is compared with detailed finite element analysis in a sequence of in silico experiments. Given the results of the initial comparison, we present a way to optimise the fast method by calibrating a set of parameters with the help of a genetic algorithm, which utilises the outcomes of the finite element analysis as a learning reference. As a result of the calibration phase, we were able to substantially reduce the force measure discrepancy between the two methods and validate the fast stenting method by assessing the differences in the final device configurations.

Personalizing flow-diverter intervention for cerebral aneurysms: from computational hemodynamics to biochemical modeling.

This paper presents the computational modeling of a variety of flow-diverting stents, deployed in a number of patient-specific aneurysm geometries. We consider virtual device deployment and hemodynamics as well as thrombus formation, with the scope to assess pre-operatively the efficacy of specific devices in treating particular aneurysms. An algorithm based on a linear and torsional spring analogy is developed for the fast virtual deployment of stents and similar minimally invasive devices in patient-specific vessel geometries. The virtual deployment algorithm is used to accurately deploy a total of four stent designs in three aneurysm geometries. A variety of different flow-diverting stent designs, representing the commercially available and the entirely novel, are presented, varying in both mesh design and porosity. Transient computational hemodynamics simulations are performed on multiple patient-specific geometries to predict the reduction in aneurysm inflow after the deployment of each device. Further, a thrombosis initiation and growth model is implemented, coupled with the hemodynamic computations. Hemodynamic simulations show large variations in flow reduction between devices and across different aneurysm geometries. The industry standard of flow-diverters with 70% porosity, assumed to offer the best compromise in flexibility and flow reduction, is challenged in at least one aneurysm geometry.

See-saw rocking: an in vitro model for mechanotransduction research.

In vitro mechanotransduction studies, uncovering the basic science of the response of cells to mechanical forces, are essential for progress in tissue engineering and its clinical application. Many varying investigations have described a multitude of cell responses; however, as the precise nature and magnitude of the stresses applied are infrequently reported and rarely validated, the experiments are often not comparable, limiting research progress. This paper provides physical and biological validation of a widely available fluid stimulation device, a see-saw rocker, as an in vitro model for cyclic fluid shear stress mechanotransduction. This allows linkage between precisely characterized stimuli and cell monolayer response in a convenient six-well plate format. Models of one well were discretized and analysed extensively using computational fluid dynamics to generate convergent, stable and consistent predictions of the cyclic fluid velocity vectors at a rocking frequency of 0.5 Hz, accounting for the free surface. Validation was provided by comparison with flow velocities measured experimentally using particle image velocimetry. Qualitative flow behaviour was matched and quantitative analysis showed agreement at representative locations and time points. Maximum shear stress of 0.22 Pa was estimated near the well edge, and time-average shear stress ranged between 0.029 and 0.068 Pa. Human tenocytes stimulated using the system showed significant increases in collagen and GAG secretion at 2 and 7 day time points. This in vitro model for mechanotransduction provides a versatile, flexible and inexpensive method for the fluid shear stress impact on biological cells to be studied.

Modelling the influence of endothelial heterogeneity on the progression of arterial disease: application to abdominal aortic aneurysm evolution.

We sophisticate a fluid-solid growth computational framework for modelling aneurysm evolution. A realistic structural model of the arterial wall is integrated into a patient-specific geometry of the vasculature. This enables physiologically representative distributions of haemodynamic stimuli, obtained from a rigid-wall computational fluid dynamics analysis, to be linked to growth and remodelling algorithms. Additionally, a quasistatic structural analysis quantifies the cyclic deformation of the arterial wall so that collagen growth and remodelling can be explicitly linked to the cyclic deformation of vascular cells. To simulate aneurysm evolution, degradation of elastin is driven by reductions in wall shear stress (WSS) below homeostatic thresholds. Given that the endothelium exhibits spatial and temporal heterogeneity, we propose a novel approach to define the homeostatic WSS thresholds: We allow them to be spatially and temporally heterogeneous. We illustrate the application of this novel fluid-solid growth framework to model abdominal aortic aneurysm (AAA) evolution and to examine how the influence of the definition of the WSS homeostatic threshold influences AAA progression. We conclude that improved understanding and modelling of the endothelial heterogeneity is important for modelling aneurysm evolution and, more generally, other vascular diseases where haemodynamic stimuli play an important role.

Multi-scale interaction of particulate flow and the artery wall.

We discuss, from the perspective of basic science, the physical and biological processes which underlie atherosclerotic (plaque) initiation at the vascular endothelium, identifying the widely separated spatial and temporal scales which participate. We draw on current, related models of vessel wall evolution, paying particular attention to the role of particulate flow (blood is not a continuum fluid), and proceed to propose, then validate all the key components in a multiply-coupled, multi-scale modeling strategy (in qualitative terms only, note). Eventually, this strategy should lead to a quantitative, patient-specific understanding of the coupling between particulate flow and the endothelial state.

Modelling evolution and the evolving mechanical environment of saccular cerebral aneurysms.

A fluid-solid-growth (FSG) model of saccular cerebral aneurysm evolution is developed. It utilises a realistic two-layered structural model of the internal carotid artery and explicitly accounts for the degradation of the elastinous constituents and growth and remodelling (G&R) of the collagen fabric. Aneurysm inception is prescribed: a localised degradation of elastin results in a perturbation in the arterial geometry; the collagen fabric adapts, and the artery achieves a new homeostatic configuration. The perturbation to the geometry creates an altered haemodynamic environment. Subsequent degradation of elastin is explicitly linked to low wall shear stress (WSS) in a confined region of the arterial domain. A sidewall saccular aneurysm develops, the collagen fabric adapts and the aneurysm stabilises in size. A quasi-static analysis is performed to determine the geometry at diastolic pressure. This enables the cyclic stretching of the tissue to be quantified, and we propose a novel index to quantify the degree of biaxial stretching of the tissue. Whilst growth is linked to low WSS from a steady (systolic) flow analysis, a pulsatile flow analysis is performed to compare steady and pulsatile flow parameters during evolution. This model illustrates the evolving mechanical environment for an idealised saccular cerebral aneurysm developing on a cylindrical parent artery and provides the guidance to more sophisticated FSG models of aneurysm evolution which link G&R to the local mechanical stimuli of vascular cells.

Rest versus exercise hemodynamics for middle cerebral artery aneurysms: a computational study.

BACKGROUND AND PURPOSE: Exercise is an accepted method of improving cardiovascular health; however, the impact of increases in blood flow and heart rate on a cerebral aneurysms is unknown. This study was performed to simulate the changes in hemodynamic conditions within an intracranial aneurysm when a patient exercises. MATERIALS AND METHODS: Rotational 3D digital subtraction angiograms were used to reconstruct patient-specific geometries of 3 aneurysms located at the bifurcation of the middle cerebral artery. CFD was used to solve for transient flow fields during simulated rest and exercise conditions. Inlet conditions were set by using published transcranial Doppler sonography data for the middle cerebral artery. Velocity fields were analyzed and postprocessed to provide physiologically relevant metrics. RESULTS: Overall flow patterns were not significantly altered during exercise. Across subjects, during the exercise simulation, time-averaged WSS increased by a mean of 20% (range, 4%-34%), the RRT of a particle in the near-wall flow decreased by a mean of 28% (range, 13%-40%), and time-averaged pressure on the aneurysm wall did not change significantly. In 2 of the aneurysms, there was a 3-fold order-of-magnitude spatial difference in RRT between the aneurysm and surrounding vasculature. CONCLUSIONS: WSS did not increase significantly during simulated moderate aerobic exercise. While the reduction in RRT during exercise was small in comparison with spatial differences, there may be potential benefits associated with decreased RRT (ie, improved replenishment of nutrients to cells within the aneurysmal tissue).

Computational modelling for cerebral aneurysms: risk evaluation and interventional planning.

Advanced computational techniques offer a new array of capabilities in the healthcare provision for cerebral aneurysms. In this paper information is provided on specific simulation methodologies that address some of the unanswered questions about intracranial aneurysm and their treatment. These include the evaluation of rupture risk, the thrombogenic characteristics of specific lesions and the efficacy assessment of particular interventional techniques and devices (e.g. endovascular coil embolisation and flow diversion using stents). The issues connected with ease-of-use and interactivity of computed simulations is discussed, and it is concluded, that the potential of these techniques to optimise planning of complex and multifaceted interventions is very significant, in spite of the fact that most of the methodologies described are still being developed and perfected.

Modelling the interaction of haemodynamics and the artery wall: current status and future prospects.

Clinical research has historically focused on the two main strategies of in vivo and in vitro experimentation. The concept of applying scientific theory to direct clinical applications is relatively recent. In this paper we focus on the interaction of wall shear stress with the endothelium and discuss how 'state of the art' computer modelling techniques can provide valuable data to aid understanding. Such data may be used to inform experiment and further, may help identify the key features of this complex system. Current emphasis is on coupling haemodynamics with models of biological phenomena to test hypotheses or predict the likely outcome of a disease or an intervention. New technologies to enable the integration of models of different types, levels of complexity and scales, are being developed. As will be discussed, the ultimate goal is the translation of this technology to the clinical arena.

On the influence of variation in haemodynamic conditions on the generation and growth of cerebral aneurysms and atherogenesis: a computational model.

A risk-factor criterion, based on near-wall haemodynamic conditions, for the assessment of vascular pathology risk is developed and tested. This criterion has its foundation on experimentally observed vascular wall responses to oscillatory and swirling wall shear stress patterns and is applied to the results of computational simulations. We test this model on two anatomically accurate vascular segments, where pathologies are either commonplace or have already been developed, i.e. a healthy carotid bifurcation and a cerebral fusiform aneurysm. In the case of the former, the risk-assessment criterion predicts the emergence of atherosclerosis of the same locations that the disease is usually encountered. In the case of the latter, the risk factor shows increased probability for the appearance of secondary, "baby", aneurysms at certain locations.

Haemodynamics and wall remodelling of a growing cerebral aneurysm: a computational model.

We have developed a computational simulation model for investigating an often postulated hypothesis connected with aneurysm growth. This hypothesis involves a combination of two parallel and interconnected mechanisms: according to the first mechanism, an endothelium-originating and wall shear stress-driven apoptotic behavior of smooth muscle cells, leading to loss of vascular tone is believed to be important to the aneurysm behavior. Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. The second mechanism is connected to the arterial wall remodeling. Remodeling of the arterial wall under constant tension is a biomechanical process of rupture, degradation and reconstruction of the medial elastin and collagen fibers. In order to investigate these two mechanisms within a computationally tractable framework, we devise mechanical analogues that involve three-dimensional haemodynamics, yielding estimates of the wall shear stress and pressure fields and a quasi-steady approach for the apoptosis and remodeling of the wall. These analogues are guided by experimental information for the connection of stimuli to responses at a cellular level, properly averaged over volumes or surfaces. The model predicts aneurysm growth and can attribute specific roles to the two mechanisms involved: the smooth muscle cell-related loss of tone is important to the initiation of aneurysm growth, but cannot account alone for the formation of fully grown sacks; the fiber-related remodeling is pivotal for the latter.

Oscillatory behavior of nanodroplets.

Molecular dynamics (MD) simulations were performed in order to investigate the phenomenon of free oscillations of nanodroplets and the extent to which the continuum theory for such oscillations holds at nanoscales. The effect of temperature on these oscillations is also studied. The surface tension, a key property for the phenomenon of interest, was evaluated and compared with the experimental values of argon, showing that with an appropriate choice of the cutoff distance in the MD simulations, it is possible to predict the surface tension with good approximation. Nanoscale capillary waves on the free surface of the droplet were observed and compared to continuum theoretical predictions of the same. The nanodroplet interface thickness calculated based on continuum theory for these waves agreed well with the molecular dynamics calculation of the interface thickness. The frequencies of the oscillation of the droplet were calculated for all the studied temperatures and compared with the classical continuum theory. Although the simulated system cannot be considered strictly as a continuum, a good overall agreement was found.