Cilia and Nodal Flow in Asymmetry: An Engineering Perspective.

Over the past several years, cilia in the primitive node have become recognized more and more for their contribution to development, and more specifically, for their role in axis determination. Although many of the mechanisms behind their influence remain undocumented, it is known that their presence and motion in the primitive node of developing embryos is the determinant of the left-right axis. Studies on cilial mechanics and nodal fluid dynamics have provided clues as to how this asymmetry mechanism works, and more importantly, have shown that direct manipulation of the flow field in the node can directly influence physiology. Although relatively uncommon, cilial disorders have been shown to have a variety of impacts on individuals from chronic respiratory infections to infertility, as well as situs inversus which is linked to congenital heart disease. After first providing background information pertinent to understanding nodal flow and information on why this discussion is important, this paper aims to give a review of the history of nodal cilia investigations, an overview of cilia mechanics and nodal flow dynamics, as well as a review of research studies current and past that sought to understand the mechanisms behind nodal cilia's involvement in symmetry-breaking pathways through a biomedical engineering perspective. This discussion has the additional intention to compile interdisciplinary knowledge on asymmetry and development such that it may encourage more collaborative efforts between the sciences on this topic, as well as provide insight on potential paths forward in the field.

Tailoring left ventricular assist device cannula implantation using coupled multi-scale multi-objective optimization.

BACKGROUND: The frequent occurrence of thromboembolic cerebral events continues to limit the widespread implementation of Ventricular Assist Devices (VAD) despite continued advancements in VAD design and anti-coagulation treatments. Recent studies point to the optimal positioning of the outflow graft (OG) as a potential mitigator of post implantation thromboembolism. OBJECTIVE: This study aims to examine the tailoring of the OG implantation orientation with the goal of minimizing the number of thrombi reaching the cerebral vessels by means of a formal shape optimization scheme incorporated into a multi-scale hemodynamics analysis. METHODS: A 3-D patient-specific computational fluid dynamics model is loosely coupled in a two-way manner to a 0-D lumped parameter model of the peripheral circulation. A Lagrangian particle-tracking scheme models and tracks thrombi as non-interacting solid spheres. The loose coupling between CFD and LPM is integrated into a geometric shape optimization scheme which aims to optimize an objective function that targets a drop in cerebral embolization, and an overall reduction in particle residence times. RESULTS: The results elucidate the importance of OG anastomosis orientation and placement particularly in the case that studied particle release from the OG, as a fivefold decrease in cerebral embolization was observed between the optimal and non-optimal implantations. Another case considered particle release from the ventricle and aortic root walls, in which optimal implantation was achieved with a shallow insertion angle. Particle release from all three origins was investigated in the third case, demonstrating that the optimal configurations were generally characterized by VAD flow directed along the central lumen of the aortic arch. Because optimal configurations depended on the anatomic origin of the thrombus, it is important to determine, in clinical studies, the most likely sites of thrombus formation in VAD patients.

Preliminary in-silico analysis of vascular graft implantation configuration and surface modification.

Vascular grafts are used to reconstruct congenital cardiac anomalies, redirect flow, and offer vascular access. Donor tissue, synthetic, or more recently tissue-engineered vascular grafts each carry limitations spanning compatibility, availability, durability and cost. Synthetic and tissue-engineered grafts offer the advantage of design optimization using in-silico or in-vitro modeling techniques. We focus on an in-silico parametric study to evaluate implantation configuration alternatives and surface finishing impact of a novel silicon-lined vascular graft. The model consists of a synthetic 3D-generic model of a graft connecting the internal carotid artery to the jugular vein. The flow is assumed unsteady, incompressible, and blood is modeled as a non-Newtonian fluid. A comparison of detached eddy turbulence and laminar modeling to determine the required accuracy needed found mild differences mainly dictated by the roughness level. The conduit walls are modeled as non-compliant and fixed. The shunt configurations considered, are straight and curved with varied surface roughness. Following a grid convergence study, two shunt configurations are analyzed to better understand flow distribution, peak shear locations, stagnation regions and eddy formation. The curved shunt was found to have lower peak and mean wall-shear stress, while resulting in lower flow power system and decreased power loss across the graft. The curved smooth surface shunt shows lower peak and mean wall-shear stress and lower power loss when compared to the straight shunt.

Cognitive Skills and DNA Methylation Are Correlating in Healthy and Novice College Students Practicing Preksha Dhyana Meditation.

The impact of different meditation protocols on human health is explored at the cognitive and cellular levels. Preksha Dhyana meditation has been observed to seemingly affect the cognitive performance, transcriptome, and methylome of healthy and novice participant practitioners. In this study, we performed correlation analyses to investigate the presence of any relationships in the changes in cognitive performance and DNA methylation in a group of college students practicing Preksha Dhyana (N = 34). Nine factors of cognitive performance were assessed at baseline and 8 weeks postintervention timepoints in the participants. Statistically significant improvements were observed in six of the nine assessments, which were predominantly relating to memory and affect. Using Illumina 850 K microarray technology, 470 differentially methylated sites (DMS) were identified between the two timepoints (baseline and 8 weeks), using a threshold of p-value < 0.05 and methylation levels beyond -3% to 3% at every site. Correlation analysis between the changes in performance on each of the nine assessments and every DMS unveiled statistically significant positive and negative relationships at several of these sites. The identified DMS were in proximity of essential genes involved in signaling and other important metabolic processes. Interestingly, we identified a set of sites that can be considered as biomarkers for Preksha meditation improvements at the genome level.

In-Silico and In-Vitro Analysis of the Novel Hybrid Comprehensive Stage II Operation for Single Ventricle Circulation.

Single ventricle (SV) anomalies account for one-fourth of all congenital heart disease cases. The existing palliative treatment for this anomaly achieves a survival rate of only 50%. To reduce the trauma associated with surgical management, the hybrid comprehensive stage II (HCSII) operation was designed as an alternative for a select subset of SV patients with the adequate antegrade aortic flow. This study aims to provide better insight into the hemodynamics of HCSII patients utilizing a multiscale Computational Fluid Dynamics (CFD) model and a mock flow loop (MFL). Both 3D-0D loosely coupled CFD and MFL models have been tuned to match baseline hemodynamic parameters obtained from patient-specific catheterization data. The hemodynamic findings from clinical data closely match the in-vitro and in-silico measurements and show a strong correlation (r = 0.9). The geometrical modification applied to the models had little effect on the oxygen delivery. Similarly, the particle residence time study reveals that particles injected in the main pulmonary artery (MPA) have successfully ejected within one cardiac cycle, and no pathological flows were observed.

Parametric investigation of an injection-jet self-powered Fontan circulation.

Approximately [Formula: see text] babies are born with only one functioning ventricle and the Fontan is the third and, ideally final staged palliative operation for these patients. This altered circulation is prone to failure with survival rates below [Formula: see text] into adulthood. Chronically elevated inferior vena cava (IVC) pressure is implicated as one cause of the mortality and morbidity in this population. An injection jet shunt (IJS) drawing blood-flow directly from the aortic arch to significantly lower IVC pressure is proposed. A computer-generated 3D model of a 2-4 year old patient with a fenestrated Fontan and a cardiac output of 2.3 L/min was generated. The detailed 3D pulsatile hemodynamics are resolved in a zero-dimensional lumped parameter network tightly-coupled to a 3D computational fluid dynamics model accounting for non-Newtonian blood rheology and resolving turbulence using large eddy simulation. IVC pressure and systemic oxygen saturation were tracked for various IJS-assisted Fontan configurations, altering design parameters such as shunt and fenestration diameters and locations. A baseline "failing" Fontan with a 4 mm fenestration was tuned to have an elevated IVC pressure (+ 17.8 mmHg). Enlargement of the fenestration to 8 mm resulted in a 3 mmHg IVC pressure drop but an unacceptable reduction in systemic oxygen saturation below 80%. Addition of an IJS with a 2 mm nozzle and minor volume load to the ventricle improved the IVC pressure drop to 3.2 mmHg while increasing systemic oxygen saturation above 80%. The salutary effects of the IJS to effectively lower IVC pressure while retaining acceptable levels of oxygen saturation are successfully demonstrated.

In-silico analysis of outflow graft implantation orientation and cerebral thromboembolism incidence for full LVAD support.

We investigate tailoring cannula implantation angles of left ventricle assist devices (LVAD) to reduce cerebral embolism risk for full LVAD support. We resolve pulsatile hemodynamics with a multi-scale computational fluid dynamics model coupled to a Lagrangian scheme tracking 2-5 mm particles for three cannula implantations. Blood is modeled as non-Newtonian. Cerebral flow distribution is altered depending on anastomosis angle and comparison of means embolization rates between steady and unsteady flow models show that unsteady modeling is more accurate even in the full LVAD support case. Intermediate angle implantation yields lowest cerebral embolization incidence of 11% vs 29% for normal and 36% for shallow implantation.

Computational Fluid Dynamics Study of Cerebral Thromboembolism Risk in Ventricular Assist Device Patients: Effects of Pulsatility and Thrombus Origin.

This study investigates the hypothesis that by surgically manipulating the outflow graft (OG) implantation during ventricle assist device placement, it may be possible to reduce the risk of cerebral embolism. We investigate this hypothesis using a computational approach on a patient-specific basis under fully pulsatile hemodynamics with a multiscale computational fluid dynamics model incorporating a coupled Eulerian-Lagrangian scheme that effectively tracks emboli in the fluid domain. Blood is modeled as a non-Newtonian fluid based on the hematocrit level. Preliminary flow analysis shows that depending on the anastomosis angle the left ventricular assist device (LVAD) can enhance the flow to the cerebral circulation by nearly 31%. Z-test results suggest that unsteady-flow modeling ought to be an integral part of any cardiovascular simulation with residual ventricular function. Assuming unsteady-flow conditions, a shallow LVAD outflow graft anastomosis angle is the most optimal if thrombi are released from the aortic-root reducing cerebral embolization incidence to 15.5% and from the ventricle to 17%, while a more pronounced anastomosis angle becomes advantageous when particles originate from the LVAD with an embolization rate of 16.9%. Overall, computations suggest that a pronounced LVAD anastomosis angle is the better implementation. Unsteady modeling is shown to be necessary for the presence of significant antegrade aortic-root flow which induces cyclical flow patterns due to residual pulsatility. On the other hand, depending on thrombus origin and ventricular assist devices (VAD) anastomosis angle there is a strong tradeoff in embolization rates.

Computational fluid dynamics investigation of the novel hybrid comprehensive stage II operation.

Background: The hybrid comprehensive stage 2 (HCS2) procedure is a novel palliative operation applicable to a select subset of single ventricle patients with adequate native antegrade aortic flow to the upper body. Flow to the descending aorta, through the pulmonary outlet and ductal arch, is influenced by a stented intrapulmonary baffle connecting the branch pulmonary arteries. We used computational fluid dynamics (CFD) to elucidate the hemodynamic characteristics of this reconstruction. Methods: We used multiscale CFD analysis of a synthetic, patient-derived HCS2 anatomic configuration with unsteady laminar flow conditions and a non-Newtonian blood model to quantify the resultant hemodynamics. The 3-dimensional CFD model was coupled to a 0-dimensional lumped parameter model of the peripheral circulation to determine the required boundary conditions. Results: For the specific anatomy studied, the intrapulmonary baffle did not obstruct flow from the pulmonary trunk to ductal arch as long as the distance between the anterior pulmonary artery wall and baffle wall exceeded ∼7 mm. Vortex shedding off of the baffle wall did not develop, because of the short distance to the ductal arch. The stented baffle experienced significantly uneven "inward" loading from the systemic side. Pulmonary outlet flow separation distal to the baffle produced a low-speed recirculation region. Conclusions: Hemodynamic patterns in this complex anatomy are generally favorable. Low flow recirculation could be mitigated by preoperative shape optimization. Calculated inward stresses on the pulmonary baffle can be used in the future to study baffle stent deformation, which is expected to be small.

Patient-Specific Multi-Scale Model Analysis of Hemodynamics Following the Hybrid Norwood Procedure for Hypoplastic Left Heart Syndrome: Effects of Reverse Blalock-Taussig Shunt Diameter.

INTRODUCTION: The hybrid Norwood (HN) is a relatively new first stage palliative procedure for neonates with hypoplastic left heart syndrome, in which a sustainable uni-ventricular circulation is established in a less invasive manner than with the standard Norwood procedure. A computational multiscale model of the circulation following the HN procedure was used to obtain detailed hemodynamics. Implementation of a reverse-BT shunt (RBTS), a synthetic bypass from the main pulmonary to the innominate artery placed to counteract aortic arch stenosis, and its effects on local and global hemodynamics were studied. METHODS: A post-op patient-derived anatomy of the HN procedure was utilized with varying degrees of distal arch obstruction, or stenosis, (nominal and 90% lumenal area reduction) and varying RBTS diameters (3.0, 3.5, 4.0 mm). A closed lumped parameter model (LPM) for the proximal and peripheral circulations was coupled to a 3D computational fluid dynamics (CFD) model in order to obtain converged flow fields for analysis. RESULTS: CFD analyses of patient-derived anatomic configurations demonstrated consistent trends of vascular bed perfusion, vorticity, oscillatory shear index and wall shear stress levels. In the models with severe stenosis, implementation of the RBTS resulted in a restoration of arterial perfusion to near-nominal levels regardless of the shunt diameter. Shunt flow velocity, vorticity, and overall wall shear stress levels decreased with increasing shunt diameter, while shunt flow and systemic oxygen delivery increased with increased shunt diameter. In the absence of distal arch stenosis, large (4.0 mm) grafts may risk thrombosis due to low velocities and flow patterns. CONCLUSION: Among the three graft sizes, the best option seems to be the 3.5 mm RBTS which provides a more organized flow similar to that of the 3.0 mm configuration with lower levels of wall shear stress. As such, in the setting of this study and for comparable HN physiologies our results suggest that: (1) the 4.0 mm shunt is a generous shunt diameter choice that may be problematic particularly when implemented prophylactically in the absence of stenosis, and (2) the 3.5 mm shunt may be a more suitable alternative since it exhibits more favorable hemodynamics at lower levels of wall shear stress.

Patient-specific multiscale computational fluid dynamics assessment of embolization rates in the hybrid Norwood: effects of size and placement of the reverse Blalock-Taussig shunt.

The hybrid Norwood operation is performed to treat hypoplastic left heart syndrome. Distal arch obstruction may compromise flow to the brain. In a variant of this procedure, a synthetic graft (reverse Blalock-Taussig shunt) is placed between the pulmonary trunk and innominate artery to improve upper torso blood flow. Thrombi originating in the graft may embolize to the brain. In this study, we used computational fluid dynamics and particle tracking to investigate the patterns of particle embolization as a function of the anatomic position of the reverse Blalock-Taussig shunt. The degree of distal arch obstruction and position of particle origin influence embolization probabilities to the cerebral arteries. Cerebral embolization probabilities can be reduced by as much as 20% by optimizing graft position, for a given arch geometry, degree of distal arch obstruction, and particle origin. There is a tradeoff, however, between cerebral pulmonary and coronary embolization probabilities.

Computational Investigation of a Self-Powered Fontan Circulation.

Children born with anatomic or functional "single ventricle" must progress through two or more major operations to sustain life. This management sequence culminates in the total cavopulmonary connection, or "Fontan" operation. A consequence of the "Fontan circulation", however, is elevated central venous pressure and inadequate ventricular preload, which contribute to continued morbidity. We propose a solution to these problems by increasing pulmonary blood flow using an "injection jet" (IJS) in which the source of blood flow and energy is the ventricle itself. The IJS has the unique property of lowering venous pressure while enhancing pulmonary blood flow and ventricular preload. We report preliminary results of an analysis of this circulation using a tightly-coupled, multi-scale computational fluid dynamics model. Our calculations show that, constraining the excess volume load to the ventricle at 50% (pulmonary to systemic flow ratio of 1.5), an optimally configured IJS can lower venous pressure by 3 mmHg while increasing systemic oxygen delivery. Even this small decrease in venous pressure may have substantial clinical impact on the Fontan patient. These findings support the potential for a straightforward surgical modification to decrease venous pressure, and perhaps improve clinical outcome in selected patients.