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

Nouvelle Théorie Hémodynamique Flux et Rythme Concept et applications précliniques en utilisant des nouveaux dispositifs d'assistance circulatoire Directeur

Le coeur et les vaisseaux sanguins sont directement issus de l'endothélium et dépendent de sa fonction. Le coeur ne représente pas la seule force motrice de notre système circulatoire, la plupart des stratégies thérapeutiques actuelles des maladies cardiovasculaires sont encore focalisées sur le coeur, négligeant l'ensemble du système circulatoire et le système endothélial. Par exemple, le développement de Dispositifs d'Assistance Cardiaque (DAC) est influencé par le coeur, conçu pour suivre,obéir et doit être synchronisé avec un organe malade.De nombreux signaux de nature différente sont capables d activer les cellules endothéliales : les forces de cisaillement créées par le flux sanguin parallèle à la surface de la paroi des vaisseaux, mais également les forces perpendiculaires provoquées par l étirement de la paroi artérielle par les variations de la pression et la qualité cyclique de ces forces. L activation de cellules endothéliales est due à la pulsatilité du flux mais aussi à l action de substances vasoactives et des médiateurs de l inflammation.Dans notre travail de thèse, nous proposons une nouvelle approche thérapeutique,basée sur une révision fondamentale de l'ensemble du système circulatoire: exposer les défauts de la gestion courante des maladies cardiovasculaires (MCV). Notre nouveau concept se concentre sur la dynamique des flux sanguins pour stimuler,restaurer et maintenir la fonction endothéliale, et compris le coeur lui-même. Nous avons développé et évalué une nouvelle génération de DAC pulsatiles, testée in vitro et in vivo.Pendant le déroulement de cette thèse nous avons effectué les études suivantes:1. Etude d un prototype de cathéter pulsatile. Il est testé de manière isolée dans un modèle expérimental d ischémie aiguë du myocarde et dans un modèle d hypertension pulmonaire aiguë.2. Etude d un prototype de tube pulsatile à double lumière. Il est testé in-vitro dans un circuit de circulation extracorporelle, et in vivo comme assistance ventriculaire gauche.73. Etude d un prototype de combinaison pulsatile. Il est testé sur un modèle animal présentant une défaillance aiguë du ventricule droit. Des prototypes de masques et de pantalons pulsatiles sont en développement.En conclusion, notre approche est basée sur l activation de la fonction endothéliale plutôt qu en une assistance cardiaque directe. Ce concept permet une meilleure gestion thérapeutique des maladies circulatoires et cardio-pulmonaires.The Heart is still considered as the main organ to be dealt with, in case ofcardiovascular disease. Nevertheless, the heart is not the only driving force in ourcirculatory system. In fact, the heart and blood vessels are the direct issues of theendothelium and depend on its function. Moreover, almost all current therapeuticstrategies are still focusing on the heart and neglecting the entire circulatoryendothelialsystem. For example, development of cardiac assist devices (CAD) is stillrestrained by the heart, designed to follow, obey and must be synchronized with adiseased organ.Many "signals" of different nature are capable of activating endothelial cells: the shearforces created by the blood flow parallel to the surface of the vessel wall, but alsoforces caused by stretching perpendicular to the artery wall by the cyclic pressuregradient and the quality of these forces. The activation of endothelial cells is due tothat pressurized flow dynamic forces, but also to the action of vasoactive substancesand inflammatory mediators.In this thesis we are proposing a new therapeutic approach, based on a fundamentalrevision of the entire systems: exposing those defects of current management ofcardiovascular diseases (CVD). A concept that focuses on flow dynamics to stimulate,restore and maintain endothelial function including the heart itself. This includespreliminary results of new generations of pulsatile CAD that promote endothelial shearstress (ESS) enhancement. Devices prototypes were tested.During this thesis, pulsatile devices prototypes were tested in vivo, in vitro as well aswith pre-clinical volunteers as follow:1. A pulsatile catheter prototype was tested in 2 pediatric animal models (piglets) of:acute myocardial ischemia; and acute pulmonary arterial hypertension.2. A pulstile tube prototype was tested in vitro (mock circuit) and in vivo (piglets) as aleft ventricular assist device (ongoing).3. Pulsatile suit prototypes were tested: in vivo (piglets) for acute right ventricularfailure treatment. Prototypes of pulsatile mask and trousers are currently in plannedfor pre-clinical studies.9Conclusion, Think endothelial instead of cardiac is our policy for better management ofCVD.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Rotary pump speed modulation to produce pulsatile flow and ventricular volume unloading.

Background: Continuous-flow (CF) left ventricular assist devices (LVADs) have gained widespread clinical acceptance as a treatment option for advanced heart failure (HF); however, they have also been associated with an increased risk of adverse events, including gastrointestinal bleeding, aortic insufficiency, and hemorrhagic stroke. It has been hypothesized that the increase in adverse event incidence may be due in part to diminished vascular pulsatility and high shear stress when CF-LVADs are operated at fixed speeds. Previous studies have shown that pump speed modulation generates greater levels of pulsatility in rotary pumps than when operated at fixed speeds. The objective of this study was to characterize the hemodynamic and pump performance of LVADs operated with a low-frequency asynchronous pump speed modulation algorithm in a chronic healthy bovine model with partial VAD support. Materials and Methods: Clinical-grade LVAD with aortic (HeartWare HVAD, n=3) or transaortic (proprietary VADx, n=4) outflow were implanted into chronic (30-day) healthy male Jersey calves (60-110 kg). An asynchronous pump speed modulation algorithm (frequency = 20 bpm, amplitude = 2500-4000 RPM for HVAD or 11000-19000 RPM for VADx) was implemented by controlling pump current. Hemodynamic measurements (pressures, flows) were recorded throughout the study duration (30s epochs collected hourly at 400Hz), echocardiographic data was recorded during the implant, weekly, and at terminal, and blood laboratory measurements were regularly collected throughout the study. All data were analyzed to characterize aortic pulsatility, LV unloading, blood damage, and device power usage. Statistical analysis was performed to determine significance between fixed and pump speed modulation operating conditions. Results and Discussion: Two HVAD and four VADx animals achieved the 30-day study endpoint. Due to surgical complications, one animal died intraoperatively. Both HVAD devices maintained asynchronous modulation for the full study duration with mean high and low speeds of 4000 RPM and 2500 RPM, respectively. Two of the four VADx devices maintained asynchronous modulation at average high and low speeds of 17238 RPM and 11333 RPM over the 30-day study; however, the other two VADx devices operated at fixed pump speed for 1 and 2 days, respectively, due to unforeseen controller malfunctions, which were corrected to restore asynchronous modulation. Near-physiologic aortic pulse pressure for HVAD (45±4 mmHg) and VADx (46±9 mmHg) was demonstrated. HVAD and VADx with asynchronous modulation reduced stroke volume by 27% and 23%, respectively. HVAD (n=2) and VADx (n=3) maintained plasma free hemoglobin (pfHb) less than 40 mg/dL for the entire study duration while one VADx had pfHb \u3e 40 mg/dL for a period of 3 days, which resolved. Asynchronous modulation increased power consumption with HVAD (25%) and VADx (6%) compared to fixed speed operation. Conclusion: This study demonstrated asynchronous modulation of HVAD and VADx maintained near-physiologic pulsatility and LV unloading at the expense of minimal hemolysis and increased power consumption in the partial VAD support model. Future studies in clinically-relevant heart failure models warrant further investigation

From Benchtop to Beside: Patient-specific Outcomes Explained by Invitro Experiment

Study: Recent analyses show that females have higher early postoperative (PO) mortality and right ventricular failure (RVF) than males after left ventricular assist device (LVAD) implantation; and that this association is partially mediated by smaller LV size in females. Benchtop experiments allow us to investigate patient-specific (PS) characteristics in a reproducible way given the fact that the PS anatomy and physiology is mimicked accurately. With multiple heart models of varying LV size, we can directly study the individual effects of titrating the LVAD speed and the resulting bi-ventricular volumes, shedding light on the interplay between LV and RV as well as resulting inter-ventricular septum (IVS) positions, which may cause the different outcomes pertaining to sex. Methods: In vitro, we studied the impact of the heart size to IVS position using two smaller and two larger sized PS silicone heart phantoms derived from clinical CT images (Fig. 1A). With ultrasound crystals that were integrated on a placeholder inflow cannula, the IVS position was measured during LV and RV volume changes (dV) mimicking varying ventricular loading states (Fig. 1B). Figure 1 A Two small (blue) and two large PS heart phantoms (orange) on B benchtop. C Median septum curvature results. LVEDD/LVV/RVV: LV enddiastolic diameter/LV and RV volume. Results: Going from small to large dV, at zero curvature, the septum starts to shift towards the left; for smaller hearts at dV = -40 mL and for larger hearts at dV = -50 mL (Fig. 1C). This result indicates that smaller hearts are more prone to an IVS shift to the left than larger hearts. We conclude that smaller LV size may therefore mediate increased early PO LVAD mortality and RVF observed in females compared to males. Novel 3D silicone printing technology enables us to study accurate, PS heart models across a heterogeneous patient population. PS relationships can be studied simultaneously to clinical assessments and support the decision-making prior to LVAD implantation

RPM and flow modulation for a continuous flow left ventricular assist device to increase vascular pulsatility : a computer simulation, mock circulation, and in-vivo animal study.

Purpose: Continuous flow (CF) left ventricular assist devices (LVAD) support diminishes vascular pressure pulsatility. Despite its recent clinical success and reliability, CF LVAD support has been associated with adverse events including gastrointestinal bleeding, aortic valve insufficiency, and hemorrhagic strokes. To overcome these limitations, we have developed flow/RPM modulation algorithms to provide vascular pulsatility using a CF LVAD. Methods: The effects of timing and synchronizing the CF LVAD flow/RPM modulation to the native ventricle, modulation amplitude, and modulation widths were studied on the native ventricle and vasculature using computer simulation, mock loop, and animal model studies. A total of over 100 combinations of flow modulation algorithms to modulate CF LVAD flow/RPM were tested for partial and full LVAD support modes. Results: Modulation of CF LVAD flow/RPM resulted in an increased arterial pressure pulsatility of up to 50 mmHg during asynchronous modulation and 20 mmHg during synchronous modulation. Synchronous CF LVAD RPM modulation allowed for a range of reduced left ventricular external work (LVEW) as compared to un-modulated CF LVAD support conditions. Full support co-pulsation (high RPM during systole, low RPM during diastole) created greater pulse pressures as compared to counter pulsation (high RPM during diastole, low RPM during systole). However, all full support modulation timings yielded higher pulse pressure than normal full support CF LVAD flow at low ventricular contractilities. Importantly, reduction in LVEW and increase in pulsatility may be adjusted to user-defined values while maintaining the same average CF LVAD flow rate. Conclusions: These LVAD flow/RPM modulations may reduce the incidence of adverse events associated with the CF LVAD therapy by increasing vascular pulsatility and reducing vascular impedance. Further, these methods of CF LVAD flow/RPM modulation may enable tailored unloading of the native ventricle to provide rest and rehabilitation (maximal unloading to rest followed by gradual reloading to wean), which may promote sustainable myocardial recovery

Shear-promoted drug encapsulation into red blood cells: a CFD model and μ-PIV analysis

The present work focuses on the main parameters that influence shear-promoted encapsulation of drugs into erythrocytes. A CFD model was built to investigate the fluid dynamics of a suspension of particles flowing in a commercial micro channel. Micro Particle Image Velocimetry (μ-PIV) allowed to take into account for the real properties of the red blood cell (RBC), thus having a deeper understanding of the process. Coupling these results with an analytical diffusion model, suitable working conditions were defined for different values of haematocrit

Real-Time Magnetic Resonance Imaging

Real‐time magnetic resonance imaging (RT‐MRI) allows for imaging dynamic processes as they occur, without relying on any repetition or synchronization. This is made possible by modern MRI technology such as fast‐switching gradients and parallel imaging. It is compatible with many (but not all) MRI sequences, including spoiled gradient echo, balanced steady‐state free precession, and single‐shot rapid acquisition with relaxation enhancement. RT‐MRI has earned an important role in both diagnostic imaging and image guidance of invasive procedures. Its unique diagnostic value is prominent in areas of the body that undergo substantial and often irregular motion, such as the heart, gastrointestinal system, upper airway vocal tract, and joints. Its value in interventional procedure guidance is prominent for procedures that require multiple forms of soft‐tissue contrast, as well as flow information. In this review, we discuss the history of RT‐MRI, fundamental tradeoffs, enabling technology, established applications, and current trends