Nonlinear multiscale analysis of coronary atherosclerotic vulnerable plaque artery: fluid-structural modeling with micromechanics.

A unique three-dimensional (3D) computational multiscale modeling approach is proposed to investigate the influence of presence of microcalcification particles on the stress field distribution in the thin cap layer of a coronary atherosclerotic vulnerable plaque system. A nested 3D modeling analysis framework spanning the multiscale nature of a coronary atherosclerotic vulnerable plaque is presented. At the microscale level, a micromechanical modeling approach, which is based on computational finite-element (FE) representative unit cell, is applied to obtain the homogenized nonlinear response of the calcified tissue. This equivalent response effectively allows the integration of extremely small microcalcification inclusions in a global biomechanical FE model. Next, at the macroscale level, a 3D patient-based fluid-structure interaction FE model, reconstructing a refined coronary artery geometry with calcified plaque lesion, is generated to study the mechanical behavior of such multi-component biomechanical system. It is shown that the proposed multiscale modeling approach can generate a higher resolution of stress and strain field distributions within the coronary atherosclerotic vulnerable plaque system and allow the assessment of the local concentration stress around the microcalcifications in plaque cap layers. A comparison of stress field distributions within cap layers with and without inclusion of microcalcifications is also presented.

A predictive multiscale model for simulating flow-induced platelet activation: Correlating in silico results with in vitro results.

Flow-induced platelet activation prompts complex filopodial formation. Continuum methods fail to capture such molecular-scale mechanisms. A multiscale numerical model was developed to simulate this activation process, where a Dissipative Particle Dynamics (DPD) model of viscous blood flow is interfaced with a Coarse Grained Molecular Dynamics (CGMD) platelet model. Embedded in DPD blood flow, the macroscopic dynamic stresses are interactively transferred to the CGMD model, inducing intra-platelet associated events. The platelets activate by a biomechanical transductive linkage chain and dynamically change their shape in response. The models are fully coupled via a hybrid-potential interface and multiple time-stepping (MTS) schemes for handling the disparity between the spatiotemporal scales. Cumulative hemodynamic stresses that may lead to platelet activation are mapped on the surface membrane and simultaneously transmitted to the cytoplasm and cytoskeleton. Upon activation, the flowing platelets lose their quiescent discoid shape and evolve by forming filopodia. The model predictions were validated by a set of in vitro experiments, Platelets were exposed to various combinations of shear stresses and durations in our programmable hemodynamic shearing device (HSD). Their shape change was measured at multiple time points using scanning electron microscopy (SEM). The CGMD model parameters were fine-tuned by interrogating a parameter space established in these experiments. Segmentation of the SEM imaging streams was conducted by a deep machine learning system. This model can be further employed to simulate shear mediated platelet activation thrombosis initiation and to study the effects of modulating platelet properties to enhance their shear resistance via mechanotransduction pathways.

New Insights into Valve Hemodynamics.

Heart valve diseases are common disorders with five million annual diagnoses being made in the United States alone. All heart valve disorders alter cardiac hemodynamic performance; therefore, treatments aim to restore normal flow. This paper reviews the state-of-the-art clinical and engineering advancements in heart valve treatments with a focus on hemodynamics. We review engineering studies and clinical literature on the experience with devices for aortic valve treatment, as well as the latest advancements in mitral valve treatments and the pulmonic and tricuspid valves on the right side of the heart. Upcoming innovations will potentially revolutionize treatment of heart valve disorders. These advancements, and more gradual enhancements in the procedural techniques and imaging modalities, could improve the quality of life of patients suffering from valvular disease who currently cannot be treated.

Improving the Mechanical Rigidity of Hyaluronic Acid by Integration of a Supramolecular Peptide Matrix.

Hyaluronic acid (HA), a major component of the extracellular matrix, is an attractive material for various medical applications. Yet, its low mechanical rigidity and fast in vivo degradation hinder its utilization. Here, we demonstrate the reinforcement of HA by its integration with a low-molecular-weight peptide hydrogelator to produce a composite hydrogel. The formulation of HA with the fluorenylmethoxycarbonyl diphenylalanine (FmocFF) peptide, one of the most studied self-assembling hydrogel-forming building blocks, showing notable mechanical properties, resulted in the formation of stable, homogeneous hydrogels. Electron microscopy analysis demonstrated a uniform distribution of the two matrices in the composite forms. The composite hydrogels showed improved mechanical properties and stability to enzymatic degradation while maintaining their biocompatibility. Moreover, the storage modulus of the FmocFF/HA composite hydrogels reached up to 25 kPa. The composite hydrogels allowed sustained release of curcumin, a hydrophobic polyphenol showing antioxidant, anti-inflammatory, and antitumor activities. Importantly, the rate of curcumin release was modulated as a function of the concentration of the FmocFF peptide within the hydrogel matrix. This work provides a new approach for conferring mechanical rigidity and stability to HA without the need of cross-linking, thus potentially facilitating its utilization in different clinical applications, such as sustained drug release.

Mechanical Compression Effects on the Secretion of vWF and IL-8 by Cultured Human Vein Endothelium.

Short peripheral catheters are ubiquitous in today's healthcare environment enabling effective delivery of fluids and medications directly into a patient's vasculature. However, complications related to their use, such as short peripheral catheter thrombophlebitis (SPCT), affect up to 80% of hospitalized patients. While indwelling within the vein, the catheters exert prolonged constant pressure upon the endothelium which can trigger inflammation processes. We have developed and studied an in-vitro model of cultured endothelial cells subjected to mechanical compression of modular self-designed weights, and explored their inflammatory response by quantification of two key biomarkers- vWF and IL-8. Evaluation was performed by ELISA immunoassay and processing of vWF-labeled immunofluorescence images. We found that application of weights correspond to 272 Pa yielded increased release of vWF and IL-8 up to 150% and 250% respectively, comparing to the exertion of 136 Pa. Analyses of the immunofluorescence images revealed significantly longer and more extracellular vWF-strings as well as higher intensity stained-pixels in cells exposed to elevated pressures. The release of both factors found to be significantly dependent on the extent of the exerted pressure. The research shed a light on the relationship between induced mechanical compression and the pathogenesis of SPCT. Minimizing, let alone eliminating the contact between the catheter and the vein wall will mitigate the pressure acting on the endothelium, thereby reducing the secretion of inflammatory factors and lessen the incidence of SPCT.

Quantitative T2 mapping for detection and quantification of thrombophlebitis in a rabbit model.

Short peripheral catheter thrombophlebitis (SPCT), a sterile inflammation of the vein wall, is the most common complication associated with short peripheral catheters (SPCs) and affects up to 80% of hospitalized patients receiving IV therapy. Extensive research efforts have been devoted for improvement and optimization of the catheter material, but means for examination of any novel design are limited, inaccurate and require costly comprehensive pre-clinical and clinical trials. Therefore, there is a conclusive need for a reliable quantitative method for evaluation of SPCT, in particular for research purposes examining the thrombophlebitis-related symptoms of any novel catheter design. In this study, we developed for the first time a quantitative MRI based tool for evaluation of SPCT. The extent and severity of SPCT caused by two different commercially available SPCs with known predisposition for thrombophlebitis, were studied in a rabbit model. MRI analysis was consistent with the standardized pathology evaluation and showed remarkable difference in the percent of edema between the experimental groups. These differences were in line with previous studies and provide evidence that this type of analysis may be useful for future assessment of SPCT in vivo. As a non-invasive method, it may constitute a cost effective solution for examination of new catheters and other medical devices, thereby reducing the need for animal sacrifice.

Pressure drop and arterial compliance - Two arterial parameters in one measurement.

Coronary artery pressure-drop and distensibility (compliance) are two major, seemingly unrelated, parameters in the cardiovascular clinical setting, which are indicative of coronary arteries patency and atherosclerosis severity. While pressure drop is related to flow, and therefore serves as a functional indicator of a stenosis severity, the arterial distensibility is indicative of the arterial stiffness, and hence the arterial wall composition. In the present study, we hypothesized that local pressure drops are dependent on the arterial distensibility, and hence can provide information on both indices. The clinical significance is that a single measurement of pressure drop could potentially provide both functional and bio-mechanical metrics of lesions, and thus assist in real-time decision making prior to stenting. The goal of the current study was to set the basis for understanding this relationship, and define the accuracy and sensitivity required from the pressure measurement system. The investigation was performed using numerical fluid-structure interaction (FSI) simulations, validated experimentally using our high accuracy differential pressure measurement system. Simplified silicone mock coronary arteries with zero to intermediate size stenoses were used, and various combinations of arterial distensibility, diameter, and flow rate were simulated. Results of hyperemic flow cases were also compared to fractional flow reserve (FFR). The results indicate the potential clinical superiority of a high accuracy pressure drop-based parameter over FFR, by: (i) being more lesion-specific, (ii) the possibility to circumvent the FFR dependency on pharmacologically-induced hyperemia, and, (iii) by providing both functional and biomechanical lesion-specific information.

Ventricular Assist Device Implantation Configurations Impact Overall Mechanical Circulatory Support System Thrombogenic Potential.

Ventricular assist devices (VADs) became in recent years the standard of care therapy for advanced heart failure with hemodynamic compromise. With the steadily growing population of device recipients, various postimplant complications have been reported, mostly associated with the hypershear generated by VADs that enhance their thrombogenicity by activating platelets. Although VAD design optimization can significantly improve its thromboresistance, the implanted VAD need to be evaluated as part of a system. Several clinical studies indicated that variability in implantation configurations may contribute to the overall system thrombogenicity. Numerical simulations were conducted in the HeartAssist 5 (HA5) and HeartMate II (HMII) VADs in the following implantation configurations: 1) inflow cannula angles: 115° and 140° (HA5); 2) three VAD circumferential orientations: 0°, 30°, and 60° (HA5 and HMII); and 3) 60° and 90° outflow graft anastomotic angles with respect to the ascending aorta (HA5). The stress accumulation of the platelets was calculated along flow trajectories and collapsed into a probability density function, representing the "thrombogenic footprint" of each configuration-a proxy to its thrombogenic potential (TP). The 140° HA5 cannula generated lower TP independent of the circumferential orientation of the VAD. Sixty-degree orientation generated the lowest TP for the HA5 versus 0° for the HMII. An anastomotic angle of 60° resulted in lower TP for HA5. These results demonstrate that optimizing the implantation configuration reduces the overall system TP. Thromboresistance can be enhanced by combining VAD design optimization with the surgical implantation configurations for achieving better clinical outcomes of implanted VADs.

The effect of pathologic venous valve on neighboring valves: fluid-structure interactions modeling.

Understanding the hemodynamics surrounding the venous valve environment is of a great importance for prosthetic valves design. The present study aims to evaluate the effect of leaflets' stiffening process on the venous valve hemodynamics, valve's failure on the next proximal valve hemodynamics and valve's failure in a secondary daughter vein on the healthy valve hemodynamics in the main vein when both of these valves are distal to a venous junction. Fully coupled, two-way fluid-structure interaction computational models were developed and employed. The sinus pocket region experiences the lowest fluid shear stress, and the base region of the sinus side of the leaflet experiences the highest tissue stress. The leaflets' stiffening increases the tissue stress the valve is experiencing in a very low fluid shear region. A similar effect occurs with the proximal healthy valve as a consequence of the distal valve's failure and with the mother vein valve as a consequence of daughter vein valve's failure. Understanding the described mechanisms may be helpful for elucidating the venous valve stiffness-function relationship in nature, the reasons for a retrograde development of reflux and the relationship between venous valves located near venous junctions, and for designing better prosthetic valves and for improving their positioning.

Modelling catheter-vein biomechanical interactions during an intravenous procedure.

A reliable intravenous (IV) access into the upper extremity veins requires the insertion of a temporary short peripheral catheter (SPC). This so common procedure is, however, associated with a risk of developing short peripheral catheter thrombophlebitis (SPCT) which causes distress and potentially prolongs patient hospitalization. We have developed and studied a biomechanical SPC-vein computational model during an IV procedure, and explored the biomechanical effects of repeated IV episodes on onset and reoccurrences of SPCT. The model was used to determine the effects of different insertion techniques as well as inter-patient biological variability on the catheter-vein wall contact pressures and wall deformations. We found that the maximal pressure exerted upon the vein wall was inhomogeneously distributed, and that the bending region was exposed to significantly greater pressures and deformations. The maximal exerted contact pressure on the inner vein's wall was 2938 Pa. The maximal extent of the SPC penetration into the vein wall reached 3.6 µm, which corresponds to approximately 100% of the average height of the inner layer, suggesting local squashing of endothelial cells at the contact site. The modelling describes a potential biomechanical damage pathway that can explain the reoccurrence of SPCT.

High accuracy differential pressure measurements using fluid-filled catheters - A feasibility study in compliant tubes.

High accuracy differential pressure measurements are required in various biomedical and medical applications, such as in fluid-dynamic test systems, or in the cath-lab. Differential pressure measurements using fluid-filled catheters are relatively inexpensive, yet may be subjected to common mode pressure errors (CMP), which can significantly reduce the measurement accuracy. Recently, a novel correction method for high accuracy differential pressure measurements was presented, and was shown to effectively remove CMP distortions from measurements acquired in rigid tubes. The purpose of the present study was to test the feasibility of this correction method inside compliant tubes, which effectively simulate arteries. Two tubes with varying compliance were tested under dynamic flow and pressure conditions to cover the physiological range of radial distensibility in coronary arteries. A third, compliant model, with a 70% stenosis severity was additionally tested. Differential pressure measurements were acquired over a 3 cm tube length using a fluid-filled double-lumen catheter, and were corrected using the proposed CMP correction method. Validation of the corrected differential pressure signals was performed by comparison to differential pressure recordings taken via a direct connection to the compliant tubes, and by comparison to predicted differential pressure readings of matching fluid-structure interaction (FSI) computational simulations. The results show excellent agreement between the experimentally acquired and computationally determined differential pressure signals. This validates the application of the CMP correction method in compliant tubes of the physiological range for up to intermediate size stenosis severity of 70%.

Single additive mechanism predicts lateral interactions effects-computational model.

The mechanism underlying the lateral interactions (LI) phenomenon is still an enigma. Over the years, several groups have tried to explain the phenomenon and suggested models to predict its psychophysical results. Most of these models comprise both inhibitory and facilitatory mechanisms for describing the LI phenomenon. Their studies' assumption that a significant inhibition mechanism exists is based on the classical interpretation of the threshold elevation perceived in psychophysical experiments. In this work, we suggest a different interpretation of the threshold elevation obtained experimentally. Our model proposes and demonstrates how a facilitatory additive mechanism can solely predict both the facilitation and "inhibition" aspects of the phenomenon, without the need for an additional inhibitory mechanism, at least for the two flankers' configurations. Though the model is simple it succeeds to predict the LI effect under a large variety of stimuli configurations and parameters. The model is in agreement with both classical and recent psychophysical and neurophysiological results. We suggest that the LI mechanism plays a role in creating an educated guess to form a continuation of gratings and textures based on the surrounding visual stimuli.

Progression of abdominal aortic aneurysm towards rupture: refining clinical risk assessment using a fully coupled fluid-structure interaction method.

Rupture of abdominal aortic aneurysm (AAA) is associated with high mortality rates. Risk of rupture is multi-factorial involving AAA geometric configuration, vessel tortuosity, and the presence of intraluminal pathology. Fluid structure interaction (FSI) simulations were conducted in patient based computed tomography scans reconstructed geometries in order to monitor aneurysmal disease progression from normal aortas to non-ruptured and contained ruptured AAA (rAAA), and the AAA risk of rupture was assessed. Three groups of 8 subjects each were studied: 8 normal and 16 pathological (8 non-ruptured and 8 rAAA). The AAA anatomical structures segmented included the blood lumen, intraluminal thrombus (ILT), vessel wall, and embedded calcifications. The vessel wall was described with anisotropic material model that was matched to experimental measurements of AAA tissue specimens. A statistical model for estimating the local wall strength distribution was employed to generate a map of a rupture potential index (RPI), representing the ratio between the local stress and local strength distribution. The FSI simulations followed a clear trend of increasing wall stresses from normal to pathological cases. The maximal stresses were observed in the areas where the ILT was not present, indicating a potential protective effect of the ILT. Statistically significant differences were observed between the peak systolic stress and the peak stress at the mean arterial pressure between the three groups. For the ruptured aneurysms, where the geometry of intact aneurysm was reconstructed, results of the FSI simulations clearly depicted maximum wall stress at the a priori known location of rupture. The RPI mapping indicated several distinct regions of high RPI coinciding with the actual location of rupture. The FSI methodology demonstrates that the aneurysmal disease can be described by numerical simulations, as indicated by a clear trend of increasing aortic wall stresses in the studied groups, (normal aortas, AAAs and rAAAs). Ultimately, the results demonstrate that FSI wall stress mapping and RPI can be used as a tool for predicting the potential rupture of an AAA by predicting the actual rupture location, complementing current clinical practice by offering a predictive diagnostic tool for deciding whether to intervene surgically or spare the patient from an unnecessary risky operation.

Numerical models of net-structure stents inserted into arteries.

INTRODUCTION: Restenosis is strongly attributed to stresses caused by stent-artery interactions generated in the artery after balloon angioplasty. Numerical methods are often used to examine the stent-artery mechanical interactions. To overcome the extensive computational requirements demanded by these simulations, simplifications are needed. OBJECTIVE: We introduce simplified models to calculate the mechanical interactions between net-structured stents and arteries, and discuss their validity and implications. METHODS: 2D simplified numerical models are suggested, which allow cost effective assessment of arterial stresses and the potential damage factor (DF). In these models, several contact problems were solved for arteries with hyper elastic mechanical properties. Stresses were calculated for a large range of cases and for different numerical model types. The effects of model simplifications, oversizing mismatch and stenosis rate and length and symmetry on the resulting stresses were analyzed. RESULTS & CONCLUSIONS: Results obtained from planar 2D models were found in good agreement with results obtained from complex 3D models for cases with axisymmetric constant or varying stenosis. This high correlation between the results of 3D cases with varying stenosis and the more simple 2D cases can be used as a simplified and convenient tool for calculating the arterial wall stresses in complex cases. Maximal stresses obtained by the 2D model with an asymmetric stenosis are lower than the maximal stresses obtained in the axisymmetric case with the same stenosis percentage. Therefore, axisymmetric models may provide the worst-case estimation values for a stent of interest.

Method for high accuracy differential pressure measurements using fluid-filled catheters.

The advantage of measuring differential pressure using fluid-filled catheters is that the system is relatively inexpensive, but the readings are not accurate and affected by the common mode pressure (CMP) distortion. High accuracy differential pressure measurements are required in various biomedical applications, such as in fluid-dynamic test rigs, or in the cath-lab, from cardiac valves efficacy to functional assessment of arterial stenoses. We have designed and built a unique system in which the pressure difference was measured along the fluid flow inside a rigid circular tube using a fluid-filled double-lumen catheter. The differential pressure measurements were taken across two side-holes near the catheter distal tip, spaced apart by 3 cm. The goal was to overcome the CMP error, which significantly distorted the output differential pressure signal and to formulate a restoration factor. A restoration formula was developed based on simultaneous gauge pressure measurements, and was tested in several different cases. Several representative cases are presented and show that the common mode artifact was reduced by factors of 12-27. The restored pressure gradient signal was validated using direct pressure drop measurements, and showed very good agreement.

Wall shear stress effects on endothelial-endothelial and endothelial-smooth muscle cell interactions in tissue engineered models of the vascular wall.

Vascular functions are affected by wall shear stresses (WSS) applied on the endothelial cells (EC), as well as by the interactions of the EC with the adjacent smooth muscle cells (SMC). The present study was designed to investigate the effects of WSS on the endothelial interactions with its surroundings. For this purpose we developed and constructed two co-culture models of EC and SMC, and compared their response to that of a single monolayer of cultured EC. In one co-culture model the EC were cultured on the SMC, whereas in the other model the EC and SMC were cultured on the opposite sides of a membrane. We studied EC-matrix interactions through focal adhesion kinase morphology, EC-EC interactions through VE-Cadherin expression and morphology, and EC-SMC interactions through the expression of Cx43 and Cx37. In the absence of WSS the SMC presence reduced EC-EC connectivity but produced EC-SMC connections using both connexins. The exposure to WSS produced discontinuity in the EC-EC connections, with a weaker effect in the co-culture models. In the EC monolayer, WSS exposure (12 and 4 dyne/cm(2) for 30 min) increased the EC-EC interaction using both connexins. WSS exposure of 12 dyne/cm(2) did not affect the EC-SMC interactions, whereas WSS of 4 dyne/cm(2) elevated the amount of Cx43 and reduced the amount of Cx37, with a different magnitude between the models. The reduced endothelium connectivity suggests that the presence of SMC reduces the sealing properties of the endothelium, showing a more inflammatory phenotype while the distance between the two cell types reduced their interactions. These results demonstrate that EC-SMC interactions affect EC phenotype and change the EC response to WSS. Furthermore, the interactions formed between the EC and SMC demonstrate that the 1-side model can simulate better the arterioles, while the 2-side model provides better simulation of larger arteries.

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.

Biomechanical factors in coronary vulnerable plaque risk of rupture: intravascular ultrasound-based patient-specific fluid-structure interaction studies.

OBJECTIVES: The aim of this study was to elucidate the mechanisms and underlying biomechanical factors that may play a role in the risk of rupture of vulnerable plaques (VPs) by studying patient-based geometries of coronary arteries reconstructed from intravascular ultrasound (IVUS) imaging utilizing fluid-structure interaction (FSI) numerical simulations. BACKGROUND: According to recent estimates, coronary artery disease is responsible for one in six deaths in the USA, and causes about one million heart attacks each year. Among these, the rupture of coronary VPs followed by luminal blockage is widely recognized as a major cause of sudden heart attacks; most importantly, the patients may appear as asymptomatic under routine screening before the occurrence of the index event. MATERIALS AND METHODS: FSI simulations of patient-based geometries of coronary arteries reconstructed from IVUS imaging were performed to establish the dependence of the risk of rupture of coronary VP on biomechanical factors, such as the fibrous cap thickness, presence of microcalcification in the fibrous cap, arterial anisotropy, and hypertension. RESULTS: Parametric FSI simulations indicated that mechanical stresses (von Mises stresses) increase exponentially with the thinning of the fibrous cap as well as with increasing levels of hypertension. The inclusion of a microcalcification in the fibrous cap considerably increases the risk of rupture of VP , with an ∼two-fold stress increase in the VP stress burden. Furthermore, the stress-driven reorientation and biochemical degradation of the collagen fibers in the vessel wall because of atherosclerosis (studied with an anisotropic fibrous cap 65° fiber reorientation angle) results in a 30% increase in the stress levels as compared with simulations with isotropic material models, clearly indicating that the latter, which are commonly used in such studies, underestimate the risk of rupture of VP. CONCLUSION: The results indicate that IVUS-based patient-specific FSI simulations for mapping the wall stresses, followed by analysis of the biomechanical risk factors, may be used as an additional diagnostic tool for clinicians to estimate the plaque burden and determine the proper treatment and intervention.

The Syncardia(™) total artificial heart: in vivo, in vitro, and computational modeling studies.

The SynCardia(™) total artificial heart (TAH) is the only FDA-approved TAH in the world. The SynCardia(™) TAH is a pneumatically driven, pulsatile system capable of flows of >9L/min. The TAH is indicated for use as a bridge to transplantation (BTT) in patients at imminent risk of death from non-reversible bi-ventricular failure. In the Pivotal US approval trial the TAH achieved a BTT rate of >79%. Recently a multi-center, post-market approval study similarly demonstrated a comparable BTT rate. A major milestone was recently achieved for the TAH, with over 1100 TAHs having been implanted to date, with the bulk of implantation occurring at an ever increasing rate in the past few years. The TAH is most commonly utilized to save the lives of patients dying from end-stage bi-ventricular heart failure associated with ischemic or non-ischemic dilated cardiomyopathy. Beyond progressive chronic heart failure, the TAH has demonstrated great efficacy in supporting patients with acute irreversible heart failure associated with massive acute myocardial infarction. In recent years several diverse clinical scenarios have also proven to be well served by the TAH including severe heart failure associated with advanced congenital heart disease. failed or burned-out transplants, infiltrative and restrictive cardiomyopathies and failed ventricular assist devices. Looking to the future a major unmet need remains in providing total heart support for children and small adults. As such, the present TAH design must be scaled to fit the smaller patient, while providing equivalent, if not superior flow characteristics, shear profiles and overall device thrombogenicity. To aid in the development of a new "pediatric," TAH an engineering methodology known as "Device Thrombogenicity Emulation (DTE)", that we have recently developed and described, is being employed. Recently, to further our engineering understanding of the TAH, as steps towards next generation designs we have: (1) assessed of the degree of platelet reactivity induced by the present clinical 70 cc TAH using a closed loop platelet activity state assay, (2) modeled the motion of the TAH pulsatile mobile diaphragm, and (3) performed fluid-structure interactions and assessment of the flow behavior through inflow and outflow regions of the TAH fitted with modern bi-leaflet heart valves. Developing a range of TAH devices will afford biventricular replacement therapy to a wide range of patients, for both short and long-term therapy.