Michalis Xenos

Pulsatile cerebrospinal fluid dynamics in the human brain

Disturbances of the cerebrospinal fluid (CSF) flow in the brain can lead to hydrocephalus, a condition affecting thousands of people annually in the US. Considerable controversy exists about fluid and pressure dynamics, and about how the brain responds to changes in flow patterns and compression in hydrocephalus. This paper presents a new model based on the first principles of fluid mechanics. This model of fluid-structure interactions predicts flows and pressures throughout the brains ventricular pathways consistent with both animal intracranial pressure (ICP) measurements and human CINE phase-contrast magnetic resonance imaging data. The computations provide approximations of the tissue deformations of the brain parenchyma. The model also quantifies the pulsatile CSF motion including flow reversal in the aqueduct as well as the changes in ICPs due to brain tissue compression. It does not require the existence of large transmural pressure differences as the force for ventricular expansion. Finally, the new model gives an explanation of communicating hydrocephalus and the phenomenon of asymmetric hydrocephalus.

Patient-Based Abdominal Aortic Aneurysm Rupture Risk Prediction with Fluid Structure Interaction Modeling

Elective repair of abdominal aortic aneurysm (AAA) is warranted when the risk of rupture exceeds that of surgery, and is mostly based on the AAA size as a crude rupture predictor. A methodology based on biomechanical considerations for a reliable patient-specific prediction of AAA risk of rupture is presented. Fluid–structure interaction (FSI) simulations conducted in models reconstructed from CT scans of patients who had contained ruptured AAA (rAAA) predicted the rupture location based on mapping of the stresses developing within the aneurysmal wall, additionally showing that a smaller rAAA presented a higher rupture risk. By providing refined means to estimate the risk of rupture, the methodology may have a major impact on diagnostics and treatment of AAA patients.

A mathematical model of blood, cerebrospinal fluid and brain dynamics

Using first principles of fluid and solid mechanics a comprehensive model of human intracranial dynamics is proposed. Blood, cerebrospinal fluid (CSF) and brain parenchyma as well as the spinal canal are included. The compartmental model predicts intracranial pressure gradients, blood and CSF flows and displacements in normal and pathological conditions like communicating hydrocephalus. The system of differential equations of first principles conservation balances is discretized and solved numerically. Fluid–solid interactions of the brain parenchyma with cerebral blood and CSF are calculated. The model provides the transitions from normal dynamics to the diseased state during the onset of communicating hydrocephalus. Predicted results were compared with physiological data from Cine phase-contrast magnetic resonance imaging to verify the dynamic model. Bolus injections into the CSF are simulated in the model and found to agree with clinical measurements.

Device Thrombogenicity Emulation: A Novel Method for Optimizing Mechanical Circulatory Support Device Thromboresistance

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation – mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device – ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers – before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device ‘thrombogenic footprint’, indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops – before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology – demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization – indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.

Dynamics of lateral ventricle and cerebrospinal fluid in normal and hydrocephalic brains.

To develop quantitative MRI techniques to measure, model, and visualize cerebrospinal fluid (CSF) hydrodynamics in normal subjects and hydrocephalic patients.

Design Optimization of a Mechanical Heart Valve for Reducing Valve Thrombogenicity—A Case Study with ATS Valve

Patients implanted with mechanical heart valves (MHV) or with ventricular assist devices that use MHV require mandatory lifelong anticoagulation for secondary stroke prevention. We recently developed a novel Device Thrombogenicity Emulator (DTE) methodology that interfaces numerical and experimental approaches to optimize the thrombogenic performance of the device and reduce the bleeding risk associated with anticoagulation therapy. Device Thrombogenicity Emulator uses stress-loading waveforms in pertinent platelet flow trajectories that are extracted from highly resolved numerical simulations and emulates these flow conditions in a programmable hemodynamic shearing device (HSD) by which platelet activity is measured. We have previously compared two MHV, ATS and the St. Jude Medical, and demonstrated that owing to its nonrecessed hinge design, the ATS valve offers improved thrombogenic performance. In this study, we further optimize the ATS valve thrombogenic performance, by modifying various design features of the valve, intended to achieve reduced thrombogenicity: 1) optimizing the leaflet-housing gap clearance; 2) increasing the effective maximum opening angle of the valve; and 3) introducing a streamlined channel between the leaflet stops of the valve that increases the effective flow area. We have demonstrated that the DTE optimization methodology can be used as test bed for developing devices with significantly improved thombogenic performance.

Microcalcifications Increase Coronary Vulnerable Plaque Rupture Potential: A Patient-Based Micro-CT Fluid–Structure Interaction Study

Asymptomatic vulnerable plaques (VP) in coronary arteries accounts for significant level of morbidity. Their main risk is associated with their rupture which may prompt fatal heart attacks and strokes. The role of microcalcifications (micro-Ca), embedded in the VP fibrous cap, in the plaque rupture mechanics has been recently established. However, their diminutive size offers a major challenge for studying the VP rupture biomechanics on a patient specific basis. In this study, a highly detailed model was reconstructed from a post-mortem coronary specimen of a patient with observed VP, using high resolution micro-CT which captured the microcalcifications embedded in the fibrous cap. Fluid–structure interaction (FSI) simulations were conducted in the reconstructed model to examine the combined effects of micro-Ca, flow phase lag and plaque material properties on plaque burden and vulnerability. This dynamic fibrous cap stress mapping elucidates the contribution of micro-Ca and flow phase lag VP vulnerability independently. Micro-Ca embedded in the fibrous cap produced increased stresses predicted by previously published analytical model, and corroborated our previous studies. The ‘micro-CT to FSI’ methodology may offer better diagnostic tools for clinicians, while reducing morbidity and mortality rates for patients with vulnerable plaques and ameliorating the ensuing healthcare costs.

Thromboresistance Comparison of the HeartMate II Ventricular Assist Device With the Device Thrombogenicity Emulation-Optimized HeartAssist 5 VAD

Approximately 7.5 × 106 patients in the US currently suffer from end-stage heart failure. The FDA has recently approved the designations of the Thoratec HeartMate II ventricular assist device (VAD) for both bridge-to-transplant and destination therapy (DT) due to its mechanical durability and improved hemodynamics. However, incidence of pump thrombosis and thromboembolic events remains high, and the life-long complex pharmacological regimens are mandatory in its VAD recipients. We have previously successfully applied our device thrombogenicity emulation (DTE) methodology for optimizing device thromboresistance to the Micromed Debakey VAD, and demonstrated that optimizing device features implicated in exposing blood to elevated shear stresses and exposure times significantly reduces shear-induced platelet activation and significantly improves the device thromboresistance. In the present study, we compared the thrombogenicity of the FDA-approved HeartMate II VAD with the DTE-optimized Debakey VAD (now labeled HeartAssist 5). With quantitative probability density functions of the stress accumulation along large number of platelet trajectories within each device which were extracted from numerical flow simulations in each device, and through measurements of platelet activation rates in recirculation flow loops, we specifically show that: (a) Platelets flowing through the HeartAssist 5 are exposed to significantly lower stress accumulation that lead to platelet activation than the HeartMate II, especially at the impeller-shroud gap regions (b) Thrombus formation patterns observed in the HeartMate II are absent in the HeartAssist 5 (c) Platelet activation rates (PAR) measured in vitro with the VADs mounted in recirculation flow-loops show a 2.5-fold significantly higher PAR value for the HeartMate II. This head to head thrombogenic performance comparative study of the two VADs, one optimized with the DTE methodology and one FDA-approved, demonstrates the efficacy of the DTE methodology for drastically reducing the device thrombogenic potential, validating the need for a robust in silico/in vitro optimization methodology for improving cardiovascular devices thromboresistance.

Cardiovascular disease management: the need for better diagnostics

Current diagnostic testing for cardiovascular pathology usually rests on either physiological or anatomic measurement. Multiple tests must then be combined to arrive at a conclusion regarding treatment of a specific pathology. Much of the diagnostic decisions currently made are based on rough estimates of outcomes, often derived from gross anatomic observations or extrapolation of physical laws. Thus, intervention for carotid and coronary disease is based on estimates of diameter stenosis, despite data to suggest that plaque character and lesion anatomy are important determinants of outcome. Similarly, abdominal aortic aneurysm (AAA) intervention is based on maximal aneurysm diameter without regard for arterial wall composition or individual aneurysm geometry. In other words, our current diagnostic tests do not reflect the sophistication of our current knowledge of vascular disease. Using a multimodal approach, computer modeling has the potential to predict clinical outcomes based on a variety of factors including arterial wall composition, surface anatomy and hemodynamic forces. We term this more sophisticated approach “patient specific diagnostics”, in which the computer models are reconstructed from patient specific clinical visualizing modalities, and material properties are extracted from experimental measurements of specimens and incorporated into the modeling using advanced material models (including nonlinear anisotropic models) and performed as dynamic simulations using the FSI (fluid structure interaction) approach. Such an approach is sorely needed to improve the effectiveness of interventions. This article will review ongoing work in “patient specific diagnostics” in the areas of carotid, coronary and aneurismal disease. We will also suggest how this approach may be applicable to management of aortic dissection. New diagnostic methods should allow better patient selection, targeted intervention and modeling of the results of different therapies.

Systematic design of drug delivery therapies

This paper presents an engineering approach for optimal drug delivery to the human brain. The hierarchical design procedure addresses three major challenges: (i) physiologically consistent geometric models of the brain anatomy, (ii) discovery of unknown transport and metabolic reaction rates of therapeutic drugs by problem inversion, and (iii) a rigorous method for determining optimal parameters for delivering therapeutic agents to desired target anatomy in the brain. The proposed interdisciplinary approach integrates medical imaging and diagnosis with systems biology and engineering optimization in order to better quantify transport and reaction phenomena in the brain in vivo. It will enhance the knowledge gained from clinical data by combining advanced imaging techniques with large scale optimization of distributed systems. The new procedure will allow physicians and scientists to design and optimize invasive drug delivery techniques systematically based on in vivo drug distribution data and rigorous first principles models.