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Background: Silicon nanopore membrane‐based implantable bioartificial organs are dependent on arteriovenous implantation of a mechanically robust and biocompatible hemofilter. The hemofilter acts as a low‐resistance, high‐flow network, with blood flow physiology similar to arteriovenous shunts commonly created for hemodialysis access. A mock circulatory loop (MCL) that mimics shunt physiology is an essential tool for refinement and durability testing of arteriovenous implantable bioartificial organs and silicon blood‐interfacing membranes. We sought to develop a compact and cost‐effective MCL to replicate flow conditions through an arteriovenous shunt and used data from the MCL and swine to inform a bond graph mathematical model of the physical setup. Methods: Flow physiology through bioartificial organ prototypes was obtained in the MCL and during extracorporeal attachment to swine for biologic comparison. The MCL was tested for stability overtime by measuring pressurewave variability over a 48‐h period. Data obtained in vitro and extracorporeally informed creation of a bond graph model of the MCL. Results: The arteriovenous MCL was a cost‐effective, portable system that reproduced flow rates and pressures consistent with a pulsatile arteriovenous shunt as measured in swine. MCL performance was stable over prolonged use, providing a cost‐effective simulator for enhanced testing of peripherally implanted bioartificial organ prototypes. The corresponding bond graph model recapitulates MCL and animal physiology, offering a tool for further refinement of the MCL system. [ABSTRACT FROM AUTHOR]

Background: Vascular cognitive impairment and dementia results from blood components passing through disrupted blood brain barriers (BBBs). Current treatments can reduce further progress of neuronal damage but do not treat the primary cause. Instead, these treatments typically aim to temporarily disrupt the BBB. Alternatively, this study computationally assessed the feasibility of delivering carbon monoxide (CO) from ultrasound-sensitive microbubbles (MBs) as a strategy to promote BBB repair and integrity. CO can interact with heme-containing compounds within cells and promote cell growth. However, careful dose control is critical for safety and efficacy because CO also binds at high affinity to hemoglobin (Hb). Methods: Ultrasound activation was simulated at the internal carotid artery, and CO released from the resulting MB rupture was tracked along the shortest path to the BBB for several activation times and doses. The CO dose available to brain capillary endothelial cells (BCECs) was predicted by considering hemodynamics, mass transport, and binding kinetics. Results: The half-life of CO binding to Hb indicated that CO is available to interact with BCECs for several cardiac cycles. Further, MB and COHb concentrations would not be near toxic levels and free Hb would be available. The axisymmetric model indicated that biologically-relevant CO concentrations will be available to BCECs, and these levels can be sustained with controlled ultrasound activation. A patient-specific geometry shows that while vessel tortuosity provides a heterogeneous response, a relevant CO concentration could still be achieved. Conclusions: This computational study demonstrates feasibility of the CO / MB strategy, and that controlled delivery is important for viability of this strategy. [ABSTRACT FROM AUTHOR]

As frequency of endovascular treatments for intracranial aneurysms increases, there is a growing need to understand the mechanisms for coil embolization failure. Computational fluid dynamics (CFD) modeling often simplifies modeling the endovascular coils as a homogeneous porous medium (PM), and focuses on the vascular wall endothelium, not considering the biomechanical environment of platelets. These assumptions limit the accuracy of computations for treatment predictions. We present a rigorous analysis using X-ray microtomographic imaging of the coils and a combination of Lagrangian (platelet) and Eulerian (endothelium) metrics. Four patient-specific, anatomically accurate in vitro flow phantoms of aneurysms are treated with the same patient-specific endovascular coils. Synchrotron tomography scans of the coil mass morphology are obtained. Aneurysmal hemodynamics are computationally simulated before and after coiling, using patient-specific velocity/pressure measurements. For each patient, we analyze the trajectories of thousands of platelets during several cardiac cycles, and calculate residence times (RTs) and shear exposure, relevant to thrombus formation. We quantify the inconsistencies of the PM approach, comparing them with coil-resolved (CR) simulations, showing the under- or overestimation of key hemodynamic metrics used to predict treatment outcomes. We fully characterize aneurysmal hemodynamics with converged statistics of platelet RT and shear stress history (SH), to augment the traditional wall shear stress (WSS) on the vascular endothelium. Incorporating microtomographic scans of coil morphology into hemodynamic analysis of coiled intracranial aneurysms, and augmenting traditional analysis with Lagrangian platelet metrics improves CFD predictions, and raises the potential for understanding and clinical translation of computational hemodynamics for intracranial aneurysm treatment outcomes. [ABSTRACT FROM AUTHOR]

As frequency of endovascular treatments for intracranial aneurysms increases, there is a growing need to understand the mechanisms for coil embolization failure. Computational fluid dynamics (CFD) modeling often simplifies modeling the endovascular coils as a homogeneous porous medium (PM), and focuses on the vascular wall endothelium, not considering the biomechanical environment of platelets. These assumptions limit the accuracy of computations for treatment predictions. We present a rigorous analysis using X-ray microtomographic imaging of the coils and a combination of Lagrangian (platelet) and Eulerian (endothelium) metrics. Four patient-specific, anatomically accurate in vitro flow phantoms of aneurysms are treated with the same patient-specific endovascular coils. Synchrotron tomography scans of the coil mass morphology are obtained. Aneurysmal hemodynamics are computationally simulated before and after coiling, using patient-specific velocity/pressure measurements. For each patient, we analyze the trajectories of thousands of platelets during several cardiac cycles, and calculate residence times (RTs) and shear exposure, relevant to thrombus formation. We quantify the inconsistencies of the PM approach, comparing them with coil-resolved (CR) simulations, showing the under- or overestimation of key hemodynamic metrics used to predict treatment outcomes. We fully characterize aneurysmal hemodynamics with converged statistics of platelet RT and shear stress history (SH), to augment the traditional wall shear stress (WSS) on the vascular endothelium. Incorporating microtomographic scans of coil morphology into hemodynamic analysis of coiled intracranial aneurysms, and augmenting traditional analysis with Lagrangian platelet metrics improves CFD predictions, and raises the potential for understanding and clinical translation of computational hemodynamics for intracranial aneurysm treatment outcomes. [ABSTRACT FROM AUTHOR]

Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young's modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm2) and low (510 dyn/cm2) FSS. The PrEC LH cells were ∼140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ∼77% in Young's modulus after exposure to high FSS and a ∼47% increase in Young's modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young's modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young's modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future. [ABSTRACT FROM AUTHOR]

Introduction: Left ventricular assist devices (LVAD) play an increasingly important role for the medical-therapy refractory end-stage heart failure (HF) patient population, in the context of stagnant donor heart availability. Thromboembolic and hemorrhagic complications such as strokes, however, remain high, and in some cases have seen increased incidence. There are a lack of guidelines governing LVAD surgical implantation configurations, which have been shown to have a strong influence on the thrombogenicity of LVAD therapy. Methods: We use a platelet-focused approach to simulate the thrombogenicity of virtual LVAD implantations under a wide range of clinically-relevant parameters. We investigate the hemodynamic microenvironment in the LVAD inflow (left ventricle inflow cannula angulation, inflow cannula insertion depth, left ventricle size) and outflow (outflow graft anastomoses angles, outflow graft diameters and partial intermittent aortic valve opening) regions, analyzing platelet biomechanics. Rigorous statistical methods are used to analyze hundreds of thousands of platelet trajectories to characterize thrombogenic indices such as residence time (RT), shear history (SH) and shear loading (SL) for platelet activation. Results: An unfavorable hemodynamic microenvironment in the left ventricle due to malangulation of the inflow cannula predisposes platelets, to activate and agglomerate before entering the LVAD. Similarly, small left ventricles pose a markedly elevated thrombosis risk, especially in the presence of deep inflow cannula insertion depths. These intraventricular hemodynamics, coupled with non-optimal outflow graft anastomosis angles, represent an additional risk of stroke, via flow-mediated platelet activation. Thrombogenic risk can be mitigated to a significant extent by optimizing surgical configurations and patient management strategies for LVAD speed, conducive to intermittent aortic valve flow. Conclusions: The novel comprehensive simulation approach followed in this study to evaluate thrombogenicity via platelet-based metrics can be implemented in surgical implantation guidelines to reduce the rate of thromboembolic complications, improving long-term outcomes of LVAD therapy. [ABSTRACT FROM AUTHOR]

Background: 2D angiographic parametric imaging (API) quantitatively extracts imaging biomarkers related to contrast flow and is conventionally applied to 2D digitally subtracted angiograms (DSA's). In the interventional suite, API is typically performed using 1–2 projection views and is limited by vessel overlap, foreshortening, and depth‐integration of contrast motion. Purpose: This work explores the use of a pathlength‐correction metric to overcome the limitations of 2D‐API: the primary objective was to study the effect of converting 3D contrast flow to projected contrast flow using a simulated angiographic framework created with computational fluid dynamics (CFD) simulations, thereby removing acquisition variability. Methods: The pathlength‐correction framework was applied to in‐silico angiograms, generating a reference (i.e., ground‐truth) volumetric contrast distribution in four patient‐specific intracranial aneurysm geometries. Biplane projections of contrast flow were created from the reference volumetric contrast distributions, assuming a cone‐beam geometry. A Parker‐weighted reconstruction was performed to obtain a binary representation of the vessel structure in 3D. Standard ray tracing techniques were then used to track the intersection of a ray from the focal spot with each voxel of the reconstructed vessel wall to a pixel in the detector plane. The lengths of each ray through the 3D vessel lumen were then projected along each ray‐path to create a pathlength‐correction map, where the pixel intensity in the detector plane corresponds to the vessel width along each source‐detector ray. By dividing the projection sequences with this correction map, 2D pathlength‐corrected in‐silico angiograms were obtained. We then performed voxel‐wise (3D) API on the ground‐truth contrast distribution and compared it to pixel‐wise (2D) API, both with and without pathlength correction for each biplane view. The percentage difference (PD) between the resultant API biomarkers in each dataset were calculated within the aneurysm region of interest (ROI). Results: Intensity‐based API parameters, such as the area under the curve (AUC) and peak height (PH), exhibited notable changes in magnitude and spatial distribution following pathlength correction: these now accurately represent conservation of mass of injected contrast media within each arterial geometry and accurately reflect regions of stagnation and recirculation in each aneurysm ROI. Improved agreement was observed between these biomarkers in the pathlength‐corrected biplane maps: the maximum PD within the aneurysm ROI is 3.3% with pathlength correction and 47.7% without pathlength correction. As expected, improved agreement with ROI‐averaged ground‐truth 3D counterparts was observed for all aneurysm geometries, particularly large aneurysms: the maximum PD for both AUC and PH was 5.8%. Temporal parameters (mean transit time, MTT, time‐to‐peak, TTP, time‐to‐arrival, TTA) remained unaffected after pathlength correction. Conclusions: This study indicates that the values of intensity‐based API parameters obtained with conventional 2D‐API, without pathlength correction, are highly dependent on the projection orientation, and uncorrected API should be avoided for hemodynamic analysis. The proposed metric can standardize 2D API‐derived biomarkers independent of projection orientation, potentially improving the diagnostic value of all acquired 2D‐DSA's. Integration of a pathlength correction map into the imaging process can allow for improved interpretation of biomarkers in 2D space, which may lead to improved diagnostic accuracy during procedures involving the cerebral vasculature. [ABSTRACT FROM AUTHOR]

Pediatric heart failure is associated with high mortality rates and is a current clinical burden. There is only one FDA approved pediatric VAD, Berlin Heart EXCOR, for treatment. Thrombo-embolic complications are a significant clinical challenge, which can lead to devastating complications such as stroke and impair efficient EXCOR function. Currently, clinicians perform largely qualitative periodic assessment of EXCOR operation by observing the motion of a rapidly moving membrane, which can be prone to human error and can lead to missing out on crucial information.In this study, we design and implement a quantitative early warning system for accurate and quantitative assessment of the EXCOR membrane, named EXCOR Membrane Motion Analyzer (EMMA). Using a combination of image analysis, computer vision and custom designed algorithm, we perform rigorous frame by frame analysis of EXCOR membrane video data. We developed specialized metrics to identify relative smoothness between successive peaks, time between peaks and overall smoothness indicators to quantify and compare between multiple cases.Our results demonstrate that EMMA can successfully identify the motion and wrinkles on each video frame and quantify the smoothness and identify the phases of each cardiac cycle. Moreover, EMMA can obtain the smoothness of each frame and the temporal evolution of membrane smoothness across all image frames for the video sequence.EMMA allows for a fast, accurate, quantitative assessment to be completed and reduces user error. This enables EMMA to be used effectively as an early warning system to rapidly identify device abnormalities. [ABSTRACT FROM AUTHOR]