A CFD and FEM Approach to a Multicompartmental Poroelastic Model for CSF Production and Circulation with Applicationsin Hydrocephalus Treatment and Cerebral Oedema

This paper was presented at the 4th Micro and Nano Flows Conference (MNF2014), which was held at University College, London, UK. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute, ASME Press, LCN London Centre for Nanotechnology, UCL University College London, UCL Engineering, the International NanoScience Community, www.nanopaprika.eu.This study introduces a Multiple-Network Poroelastic Theory (MPET) model, coupled with finite-volume based Computational fluid dynamics (CFD) for the purpose of studying, in detail, the effects of obstructing Cerebrospinal fluid (CSF) transport within an image-derived cerebral environment. The MPET representation allows the investigation of fluid transport between CSF, brain parenchyma and cerebral blood, in an integral and comprehensive manner. Key novelties of this model are the casting of multidimensional MPET in a Finite Element Method (FEM) framework, the amalgamation of anatomically accurate choroid plexuses with their feeding arteries and a simple relationship relaxing the constraint of a unique permeability for the CSF compartment. This model is used to demonstrate the impact of fourth ventricle outlet obstruction (FVOO). The implications of treating such a clinical condition with the aid of endoscopic third (ETV) and endoscopic fourth (EFV) ventriculostomy are considered. Finally, we outline the impact of the FEM based MPET framework in understanding oedema, and its ongoing evolution

Exploring neurodegenerative disorders using a novel integrated model of cerebral transport: Initial results

The neurovascular unit (NVU) underlines the complex and symbiotic relationship between brain cells and the cerebral vasculature, and dictates the need to consider both neurodegenerative and cerebrovascular diseases under the same mechanistic umbrella. Importantly, unlike peripheral organs, the brain was thought not to contain a dedicated lymphatics system. The glymphatic system concept (a portmanteau of glia and lymphatic) has further emphasized the importance of cerebrospinal fluid transport and emphasized its role as a mechanism for waste removal from the central nervous system. In this work, we outline a novel multiporoelastic solver which is embedded within a high precision, subject specific workflow that allows for the co-existence of a multitude of interconnected compartments with varying properties (multiple-network poroelastic theory, or MPET), that allow for the physiologically accurate representation of perfused brain tissue. This novel numerical template is based on a six-compartment MPET system (6-MPET) and is implemented through an in-house finite element code. The latter utilises the specificity of a high throughput imaging pipeline (which has been extended to incorporate the regional variation of mechanical properties) and blood flow variability model developed as part of the VPH-DARE@IT research platform. To exemplify the capability of this large-scale consolidated pipeline, a cognitively healthy subject is used to acquire novel, biomechanistically inspired biomarkers relating to primary and derivative variables of the 6-MPET system. These biomarkers are shown to capture the sophisticated nature of the NVU and the glymphatic system, paving the way for a potential route in deconvoluting the complexity associated with the likely interdependence of neurodegenerative and cerebrovascular diseases. The present study is the first, to the best of our knowledge, that casts and implements the 6-MPET equations in a 3D anatomically accurate brain geometry

Multicompartmental poroelastic modelling for CSF production and circulation

This paper was presented at the 3rd Micro and Nano Flows Conference (MNF2011), which was held at the Makedonia Palace Hotel, Thessaloniki in Greece. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, Aristotle University of Thessaloniki, University of Thessaly, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute.This study proposes the implementation of a Multiple-Network Poroelastic Theory (MPET) model for the purpose of investigating in detail the transport of water within the cerebral environment. The advantage of using the MPET representation is that it accounts for fluid transport between CSF, brain parenchyma and cerebral blood. They key novelty in the model discussed in the present study is the amalgamation of anatomically accurate Choroid Plexus regions, with their individual feeding arteries. This model is used to demonstrate the impact of aqueductal stenosis and atresia of the Foramina of Luschka and Magendie on the cerebral ventricles. The possible implications of treating such a condition with the aid of endoscopic third ventriculostomy are investigated and discussed.This study is supported by the Research Councils UK cross council initiative led by EPSRC and contributed to by AHRC, ESRC, and MRC

A multiple-network poroelastic model for biological systems and application to subject-specific modelling of cerebral fluid transport

Biological tissue can be viewed as porous, permeable and deformable media infiltrated by fluids, such as blood and interstitial fluid. A finite element model has been developed based on the multiple-network poroelastic theory to investigate transport phenomenon in such biological systems. The governing equations and boundary conditions are adapted for the cerebral environment as an example. The numerical model is verified against analytical solutions of classical consolidation problems and validated using experimental data of infusion tests. It is then applied to three-dimensional subject-specific modelling of brain, including anatomically realistic geometry, personalised permeability map and arterial blood supply to the brain. Numerical results of smoking and non-smoking subjects show hypoperfusion in the brains of smoking subjects, which also demonstrate that the numerical model is capable of capturing spatio-temporal fluid transport in biological systems across different scales

A fully dynamic multi-compartmental poroelastic system: Application to aqueductal stenosis

This study proposes the implementation of a fully dynamic four-network poroelastic model which is underpinned by multiple-network poroelastic theory (MPET), in order to account for the effects of varying stages of aqueductal stenosis and atresia during acute hydrocephalus. The innovation of the fully dynamic MPET implementation is that it avoids the commonplace assumption of quasi-steady behaviour; instead, it incorporates all transient terms in the casting of the equations and in the numerical solution of the resulting discrete system. It was observed that the application of mild stenosis allows for a constant value of amalgamated ventricular displacement in under 2.4 h, whereas the application of a severe stenosis delays this settlement to approximately 10 h. A completely blocked aqueduct does not show a clear sign of reaching a steady ventricular displacement after 24 h. The increasing ventricular pressure (complemented with ventriculomegaly) during severe stenosis is causing the trans-parenchymal tissue region to respond, and this coping mechanism is most attenuated at the regions closest to the skull and the ventricles. After 9 h, the parenchymal tissue shows to be coping well with the additional pressure burden, since both ventriculomegaly and ventricular CSF (cerebrospinal fluid) pressure show small increases between 9 and 24 h. Localised swelling in the periventricular region could also be observed through CSF fluid content, whilst dilation results showed stretch and compression of cortical tissue adjacent to the ventricles and skull

Multiscale Modelling for Cerebrospinal Fluid Dynamics: Multicompartmental Poroelacticity and the Role of AQP4

Cerebrospinal fluid (CSF) is recognized to play an important role in the brain environment and central nerv-ous system (CNS). At the microscopic level, glial cells and water channel proteins (WCPs), also known as aquaporins (AQPs), are believed to be central in regulating CSF. Furthermore, such elements are postulated to associate with numerous cerebral and neurological pathologies. The novelty of the present research is the attempt to investigate such pathophysi-ological phenomena via a multi scale physical model incorporating mechanisms across all scales, including the AQP effects. The proposed physical multiscale model can explore the relationship between CSF and glial cells via the incorporation of AQPs (as microscopic channels) and elaborate on the macroscopic manifestations of this interplay. This study aims to make a tangible contribution to the understanding of cerebral or neurological pathologies via virtual physiological human (VPH) in silico

Subject-specific multi-poroelastic model for exploring the risk factors associated with the early stages of Alzheimer's disease

none14siThere is emerging evidence suggesting that Alzheimer’s disease is a vascular disorder, caused by impaired cerebral perfusion, which may be promoted by cardiovascular risk factors that are strongly influenced by lifestyle. In order to develop an understanding of the exact nature of such a hypothesis, a biomechanical understanding of the influence of lifestyle factors is pursued. An extended poroelastic model of perfused parenchymal tissue coupled with separate workflows concerning subject-specific meshes, permeability tensor maps and cerebral blood flow variability is used. The subject-specific datasets used in the modelling of this paper were collected as part of prospective data collection. Two cases were simulated involving male, non-smokers (control and mild cognitive impairment (MCI) case) during two states of activity (high and low). Results showed a marginally reduced clearance of cerebrospinal fluid (CSF)/interstitial fluid (ISF), elevated parenchymal tissue displacement and CSF/ISF accumulation and drainage in the MCI case. The peak perfusion remained at 8 mm s-1 between the two cases.noneGuo L.; Vardakis J.C.; Lassila T.; Mitolo M.; Ravikumar N.; Chou D.; Lange M.; Sarrami-Foroushani A.; Tully B.J.; Taylor Z.A.; Varma S.; Venneri A.; Frangi A.F.; Ventikos Y.Guo L.; Vardakis J.C.; Lassila T.; Mitolo M.; Ravikumar N.; Chou D.; Lange M.; Sarrami-Foroushani A.; Tully B.J.; Taylor Z.A.; Varma S.; Venneri A.; Frangi A.F.; Ventikos Y

Highly integrated workflows for exploring cardiovascular conditions: Exemplars of precision medicine in Alzheimer's disease and aortic dissection = Processus à haut degré d’intégration pour l’étude de troubles cardiovasculaires : exemples de médecine de précision appliquée à la maladie d’Alzheimer et à la dissection aortique

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. / Pour que la médecine actuelle puisse profiter de la technologie in silico, il est impératif que les flux de recherche biophysique offrent un aperçu précis des traitements spécifiques à une maladie particulière et à un sujet particulier. Les limites de la médecine peuvent être repoussées à l’aide de flux de travail multi-échelles, centrés sur la biophysique, qui tiennent compte des constituants fondamentaux des cellules et des tissus, et de leurs environnements dynamiques. L’utilisation de techniques numériques permettant de capter le large spectre des flux biologiques au sein d’organes et de tissus complexes, déformables et perméables est d’une importance capitale lorsqu’il s’agit d’examiner les conditions essentielles de tout pipeline médical de précision de pointe. Dans ce travail, une analyse succinte de deux pipelines de médecine de précision développés dans le cadre de deux projets VPH (Virtual Physiological Human) est donnée. Le premier flux de travail se concentre sur la trajectoire de la maladie d’Alzheimer et permet de tester de nouvelles hypothèses au moyen d’un modèle poroélastique à plusieurs compartiments qui est intégré à un flux de travail d’imagerie à haut débit et à un modèle de variabilité du débit sanguin spécifique au sujet. Le deuxième flux de travail donne lieu à l’exploration spécifique des dissections aortiques chez le patient par le biais d’un modèle multi-échelle conforme, exploitant l’imagerie, la dynamique des fluides computationnelle (CFD) et les conditions limites dynamiques. Les résultats relatifs au premier flux de travail comprennent certains des principaux extrants du cadre de modélisation multiporoélastique et la représentation des zones de gonflement péri-artériel et de solution de drainage périveineux. Ces dernières zones de solutions ont été analysées statistiquement sur une cohorte de trente-cinq sujets (stratifiés en fonction de l’état pathologique, du sexe et du niveau d’activité). Le deuxième flux de travail a permis de mieux comprendre les cas complexes de dissection aortique à l’aide d’un modèle à parois rigides fondé sur des ensembles de données minimales et cliniquement communes et d’un modèle à parois mobiles reposant sur de riches données

Fluid–structure interaction for highly complex, statistically defined, biological media: Homogenisation and a 3D multi-compartmental poroelastic model for brain biomechanics

Numerous problems of relevance in physiology and biomechanics, have at their core, the presence of a deformable solid matrix which experiences flow-induced strain. Often, this fluid-structure interaction (FSI) is directed the opposite way, i.e. it is solid deformation that creates flow, with the heart being the most prominent example. In many cases, this interaction of fluid and solid is genuinely bidirectional and strongly coupled, with solid deformation inducing flow and fluid pressure deforming the solid. Although an FSI problem, numerous cases in biomechanics are not tractable via the traditional FSI methodologies: in the internal flows that are of interest to use, the number and range of fluid passages is so vast that the direct approach of a deterministically defined boundary between fluid and solid is impossible to apply. In these cases, homogenisation and statistical treatment of the material-fluid system is possibly the only way forward. Such homogenisation, quite common to flow-only systems through porous media considerations, is also possible for FSI systems, where the loading is effectively internal to the material. A prominent technique of this type is that of poroelasticity. In this paper, we discuss a class of poroelastic theory techniques that allow for the co-existence of a multitude of – always statistically treated –channels and passages of widely different properties: termed multiple-network poroelasticity (or multicompartmental poroelasticity). This paradigm is particularly suitable for the study of living tissue, that is invariably permeated – perfused – by fluids, often different in nature and across a wide range of scales. Multicompartmental poroelasticity is capable of accounting for a full bidirectional coupling between the fluids and the solid matrix and allows us to track transport of a multitude of substances together with the deformation of the solid material that this transport gives rise to or is caused by, or both. For the purposes of demonstration, we utilise a complex and physiologically very important system, the human brain (specifically, we target the hippocampus), to exemplify the qualities and efficacy of this methodology during the course of Alzheimer’s Disease. The methodology we present has been implemented through the Finite Element Method, in a general manner, allowing for the co-existence of an arbitrary number of compartments. For the applications used in this paper to exemplify the method, a four-compartment implementation is used. A unified pipeline is used on a cohort of 35 subjects to provide statistically meaningful insight into the underlying mechanisms of the neurovascular unit (NVU) in the hippocampus, and to ascertain whether physical activity would have an influence in both swelling and drainage by taking into account both the scaled strain field and the proportion of perfused blood injected into the brain tissue. A key result garnered from his study is the statistically significant differences in right hemisphere hippocampal NVU swelling between males in the control group and females with mild cognitive impairment during high and low activity states