Using dissipative particle dynamics (DPD) combined with coarse grained molecular dynamics (CGMD) approaches, we developed a multiscale deformable platelet model to accurately describe the molecular-scale intra-platelet constituents and biomechanical properties of platelets in blood flow. Our model includes the platelet bilayer membrane, cytoplasm and an elaborate elastic cytoskeleton. Correlating numerical simulations with published in-vitro experiments, we validated the biorheology of the cytoplasm, the elastic response of membrane to external stresses, and the stiffness of the cytoskeleton actin filaments, resulting in an accurate representation of the molecular-level biomechanical microstructures of platelets. This enabled us to study the mechanotransduction process of the hemodynamic stresses acting onto the platelet membrane and transmitted to these intracellular constituents. The platelets constituents continuously deform in response to the flow induced stresses. To the best of our knowledge, this is the first molecular-scale platelet model that can be used to accurately predict platelets activation mechanism leading to thrombus formation in prosthetic cardiovascular devices and in vascular disease processes. This model can be further employed to study the effects of novel therapeutic approaches of modulating platelet properties to enhance their shear resistance via mechanotransduction pathways.

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.

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.

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.

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.

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.

Blood pressure drop and arterial distensibility are important, allegedly independent, parameters that are indicative of the coronary arteries patency and atherosclerosis severity. In the present study we show that these two parameters are dependent, allowing to obtain both parameters from a single measurement, and to do so a high-resolution differential pressure measurement system is required. The objective of the study was to unveil the relationship between local fluid pressure drops and tube distensibility, through various scenarios of stenosis severity, tube diameter, and flow rate (for coronary hemodynamic conditions). The investigation was performed using validated Fluid–Structure Interaction (FSI) analysis on silicone mock arteries with intermediate size stenosis (0–65%). Highly accurate pressure drop measurements (±0.05 mmHg) were performed with our in-house fluid-filled double-lumen catheter measurement. The results indicated that our accurate pressure drop measurement method facilitated the differentiation among several levels of the mock arteries’ stiffness, with distensibilities ranging from 1 to 7%. Local pressure drops were markedly affected by the mock arteries’ stiffness and could be best described using a second-order polynomial function. These changes in pressure drop could be detected even when there was no stenosis present, and FFR values remained insensitive at 1.00. The results indicated the clinical potential of a high accuracy pressure drop-based parameter to be superior to FFR. Such a parameter would provide cardiovascular interventionalists with lesion-specific bio-mechanical and functional data, for improved real-time decision-making in the cath-lab.

- The small intestine (SI) is a mechanically active tube-like organ that actuates peristaltic constriction motion. The motion assists capsule endoscopy products to passively travel along the SI tract. The goal of the present study was to design a mechanical simulator of the small intestine. Having such a simulator would allow effective testing of new capsule endoscopic devices, as well as offline practice with endoscopic and other devices. The simulator, loaded with ex-vivo swine SI, was functionally validated using two ingestible capsule products: PillCam® SB3 and SmartPill® (Given Imaging, Ltd.). Excellent agreement was found in comparison to in-vivo recordings, showing the great potential of the simulator.

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.

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 2938Pa. The maximal extent of the SPC penetration into the vein wall reached 3.6m, 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.

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.

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/cm2 for 30 min) increased the EC-EC interaction using both connexins. WSS exposure of 12 dyne/cm2 did not affect the EC-SMC interactions, whereas WSS of 4 dyne/cm2 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.

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%.

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.

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 >9 L/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.