Development and applications of in-vitro and in-silico models of the cardiovascular system to study the effects of mechanical circulatory support.

Cardiovascular diseases (CVDs) are the leading cause of mortality globally. With ongoing interest in CVDs treatment, preclinical models for drug/therapeutic development that allow for fast iterative research are needed. Owing to the inherent complexity of the cardiovascular system, current in-vitro models of the cardiovascular system fail to replicate many of the physiological aspects of the cardiovascular system. In this dissertation, the main concern is with heart failure (HF). In advanced HF, patients may receive Left Ventricular Assist Devices (LVADs) as a bridge to transplant or destination therapy. However, LVADs have many limitations, including inability to adapt to varying tissue demand conditions, risk of ventricular suction, and diminished arterial pulsatility. To address these issues, this dissertation aims to use and develop computer, cellular, and tissue models of the cardiovascular system. 1) Use an in-silico model of the cardiovascular system to develop a novel control algorithm for LVADs. The control system was rigorously tested and showed adequate perfusion during rest and exercise, protect against ventricular suction under reduced heart preload, and augment arterial pulsatility through pulse modulation without requiring sensor implantation or model-based estimations. 2) While pulsatility augmentation was feasible through the developed control algorithm, the pulse waveform that could normalize the vascular phenotype is unknown. To address this, an endothelial cell-smooth muscle cell microfluidic coculture model was developed to recreate the physiological mechanical stimulants in the vascular wall. The results demonstrated different effects of pulsatile shear stress and stretch on endothelial cells and may indicate that a pulse pressure of at least 30 mmHg is needed to maintain normal endothelial morphology. 3) In order to study the effects of mechanical unloading on the native ventricle, a novel cardiac tissue culture model (CTCM) was developed. CTCM provided physiological electromechanical and humoral stimulation with 25% preload stretch and thyroid and glucocorticoid treatment maintained the cardiac phenotype for 12 days. The device was thoroughly characterized and tested. Results demonstrated improved viability, energy utilization, fibrotic remodeling, and structural integrity compared to available culture systems. The system was also used to reproduce ventricular volume-overload and the results demonstrated hypertrophic and fibrotic remodeling, typical of volume-overload pathology

Estimation and control of the pump pressure rise and flow from intrinsic parameters for a magnetically-levitated axial blood pump

An increase in the number of cardiac patients and a decrease in number of heart donors has triggered the development of artificial heart pump to support the proper functioning of the heart. There is also an increase in demand for smaller sized pumps with long term application. All these factors have stimulated the use of a magnetically-levitated rotary blood pump as Left Ventricular Assistant Devices. The demand of volume and pressure of blood varies from person to person. Moreover, the prevention of cannular ventricle collapse at suction, dependence of pump performance on its inlet, and outlet conditions has necessitated control of the pump. Also, the available invasive pressure and flow transducers limit the use, due to their low reliability, periodic calibration, and assembling problem. In this work, three independent and quantitative non-invasive measurement methods for the estimation of pump parameters from intrinsic parameters were developed, substantiated, and compared. The first method used DC motor current and the motor speed as the inputs to the system. In this method, behavior of brushless DC motor was studied using its working model. Pump speed and bearing current were the inputs for the second estimation technique. In this method, pump performance and impeller behavior were continuously monitored in three axes (X,Y, ). The third method is conceptualized on the output of the Hall Effect sensors, which were used for sensing the position of impeller, and the pump speed. The behavior of the sensor output with the impeller position in four axes (X,Y,Z, ) was developed using a real impeller in model housing. The data were analyzed in Microsoft Excel 2007 and MATLAB using least square estimation techniques and Fourier series expansion. An algorithm for each technique was developed. In addition, the propagation of errors and uncertainties at each step of estimation method were accounted and calculated, with the results for each method compared

Doctor of Philosophy

dissertationHeart disease is the leading cause of death in the United States. Mechanical circulatory support by ventricular assist devices (VADs) is a means by which deteriorating heart function can be supplemented, and is a leading therapy for latestage heart failure patients. The devices are commonly connected to the apex of the left ventricle (LV) to move oxygenated blood to the body via the aorta. Recent developments have made continuous-flow pumps commonplace in the clinical environment when compared to their pulsatile-flow predecessors. Typically, continuous-flow VADs are designed with axial- or centrifugal- (radial) configurations. The pressures and flow rates vary dramatically in the native heart as blood is moved from the LV to the aorta. This dissertation presents pressure-flow characteristics for both axial- and centrifugal-flow VADs within a wide range of pressure differential values under uniform conditions, by means of a novel, open-loop flow system. Current techniques employ a closed-loop system to determine pump performance. A closed-loop system does not allow pressure differentials less than or equal to zero to be achieved. The native heart experiences pressure gradients near zero across the aortic valve during systole, which is essentially where the VAD is placed. Thus, an open-loop flow system with independently adjustable preload and afterload pressures is required to reach physiologically-relevant pressure differential regions that approximate the pressure gradient across the aortic valve during systole. Additional modifications made to the open-loop flow system generate pulsatile flow type conditions, which mimic those of the native LV. With this type of in vitro test system, not only can general hydrodynamic performance and hydraulic efficiency of VADs be measured, but also off-design operational performance under dynamic flow conditions can be characterized. This research explores hydrodynamic performance characteristics of axial- and centrifugal-flow VADs to determine design advantages that each have. Device characteristics include pressure-flow performance curves, pressure sensitivity, pulsatility index, and pulsatility ratio. Performance curves and other relevant attributes are investigated at previously unreported pressure-flow regions. Performance is evaluated theoretically, computationally, and experimentally under both steady-state, continuous-flow and pulsatile-flow circumstances

Review of Zero-D and 1-D Models of Blood Flow in the Cardiovascular System

<p>Abstract</p> <p>Background</p> <p>Zero-dimensional (lumped parameter) and one dimensional models, based on simplified representations of the components of the cardiovascular system, can contribute strongly to our understanding of circulatory physiology. Zero-D models provide a concise way to evaluate the haemodynamic interactions among the cardiovascular organs, whilst one-D (distributed parameter) models add the facility to represent efficiently the effects of pulse wave transmission in the arterial network at greatly reduced computational expense compared to higher dimensional computational fluid dynamics studies. There is extensive literature on both types of models.</p> <p>Method and Results</p> <p>The purpose of this review article is to summarise published 0D and 1D models of the cardiovascular system, to explore their limitations and range of application, and to provide an indication of the physiological phenomena that can be included in these representations. The review on 0D models collects together in one place a description of the range of models that have been used to describe the various characteristics of cardiovascular response, together with the factors that influence it. Such models generally feature the major components of the system, such as the heart, the heart valves and the vasculature. The models are categorised in terms of the features of the system that they are able to represent, their complexity and range of application: representations of effects including pressure-dependent vessel properties, interaction between the heart chambers, neuro-regulation and auto-regulation are explored. The examination on 1D models covers various methods for the assembly, discretisation and solution of the governing equations, in conjunction with a report of the definition and treatment of boundary conditions. Increasingly, 0D and 1D models are used in multi-scale models, in which their primary role is to provide boundary conditions for sophisticate, and often patient-specific, 2D and 3D models, and this application is also addressed. As an example of 0D cardiovascular modelling, a small selection of simple models have been represented in the CellML mark-up language and uploaded to the CellML model repository <url>http://models.cellml.org/</url>. They are freely available to the research and education communities.</p> <p>Conclusion</p> <p>Each published cardiovascular model has merit for particular applications. This review categorises 0D and 1D models, highlights their advantages and disadvantages, and thus provides guidance on the selection of models to assist various cardiovascular modelling studies. It also identifies directions for further development, as well as current challenges in the wider use of these models including service to represent boundary conditions for local 3D models and translation to clinical application.</p

Control of a rotary blood pump

Implantable rotary blood pumps (RBPs) are an emerging technology designed to provide sufferers of heart failure with a viable treatment option which improves their medical prognosis and quality of life. The broad aim of this thesis is to address the need for a pump control strategy, and develop a solution whereby the implant recipient’s physiological requirements are continuously monitored in a non-invasive manner and met with an appropriate response by the RBP. Employing only the non-invasive signal of instantaneous pump impeller speed to assess flow dynamics, five physiologically significant pumping states have been identified in acute ex vivo porcine experiments (N=6). Two broader states, corresponding to normal and ventricular suction conditions, were readily discernable in clinical data from human implant recipients (N=10). Employing a classification and regression tree (CART) model, an automated real-time algorithm was developed to detect pumping states with a high degree of sensitivity and specificity. Both suction and normal states were detected without error in data from the animal experiments, and with a peak sensitivity/specificity, for detecting suction, of 99.11% / 98.76% in the human patient data. Algorithms to non-invasively estimate RBP flow and differential pressure in both steady- and pulsatile-flow environments were developed. Taking the pump feedback signals of speed and power, together with the blood haematocrit (or equivalent viscosity) level, as input parameters, several estimation models were developed via polynomial surface fitting and/or system identification methods, yielding clinically acceptable results (mean flow errors of 3.09% and 5.49%, and mean pressure errors of 1.80% and 6.47%, for the steady- and pulsatile-flow cases, respectively). An RBP control algorithm based on a non-invasive indicator of the implant recipient’s activity level has been proposed and evaluated in a software simulation environment. An Activity Level Index (ALI) forms the basis of an adaptive control module operating within a hierarchical multi-objective framework which imposes several constraints on the pump’s operating region. Three class IV heart failure cases of varying severity were simulated under rest and exercise conditions, and a comparison with other popular RBP control strategies was performed. Simulations of the proposed control algorithm exhibited the effective intervention of each constraint, resulting in an improved flow response and the maintenance of a safe operating condition, compared with other control modes

Contrôle physiologique des assistances ventriculaires

Physiologie cardiaque -- Modèle du système cardiovasculaire hémodynamique -- Modélisation du système cardiovasculaire -- Représentation des ventricules -- Système à six chambres -- Systèmes à huit chambres -- Modélisation du système baroréflexe -- Modélisation du système cardiovasculaire avec régulation carotidienne -- Simulations du systèmes cardiovasculaire avec régulation carotidienne -- Physiologie de l'insuffisance cardiaque -- Effets sur le système cardiovasculaire avec régulation carotidienne -- Simulation de l'insuffisance cardiaque du système avec et sans régulation -- Modèle de l'assistance ventriculaire -- Système cardiovasculaire assisté -- Système cardiovasculaire assisté avec régulation carotidienne -- Variable de contrôle -- Controleur proposé

A RULE-BASED CONTROLLER BASED ON SUCTION DETECTION FOR ROTARY BLOOD PUMPS

A new rule-based control system for rotary ventricular assist devices (rVADs) is proposed. The control system is comprised of two modules: a suction detector and a rule-based controller. The suction detector can classify pump flow patterns, based on a discriminant analysis (DA) model that combines several indices derived from the pump flow signal, to make a decision about the pump status. The indices considered in this approach are frequency, time, and time-frequency-domain indices. These indices are combined in a DA decision system to generate a suction alarm. The suction detector performance was assessed using experimental data and in simulations. Experimental results comprise predictive discriminant analysis (classification accuracy: 100% specificity, 93% sensitivity on training set and 97% specificity, 86% sensitivity on test set) of the detector and descriptive discriminant analysis (explained variance) of the DA model. To perform the simulation studies, the suction detector was coupled to a cardiovascular-pump model that included a suction model. Simulations were carried out to access the detector performance, under different physiological conditions, i.e., by varying preload and the contractility state of the left ventricle. To verify its robustness to noise, simulations were carried out to verify how the accuracy of the detector is affected when increasing levels of noise are added to the pump flow signal.The rule-based controller uses fuzzy logic to combine the discriminant scores from the DA model to automatically adjust the pump speed. The effects on controller performance of symmetric or asymmetric membership output sets and the dimension of the rule base were evaluated in simulations. The same parameter changes, i.e., preload and contractility, were used to assess the control system performance under different physiologic scenarios in simulations. The proposed control system is capable of automatically adjusting pump speed, providing pump flow according to the patient's level of activity, while sustaining adequate perfusion pressures and avoiding suction. In addition, the control system performance was not adversely affected by noise until SNR was less than 20dB, which is a higher noise level than is commonly encountered in flow sensors used clinically for this type of application