Biology subjects

Marsden, A. L.

Publications and source records attributed to Marsden, A. L..

11 recordsLinked to original sources

bioRxiv2026

Rapid simulation of organ-scale oxygen transport for tissue ischemia prediction

A densely vascularized tissue can still be starved of oxygen. Tissue oxygenation depends heavily on vessel arrangement, blood flow distributions, and cellular metabolism. Resolving these effects from individual constituent vessels to whole organs has historically been computationally prohibitive. We introduce the Cardiovascular Analysis and Simulation of Circulatory Advection, Diffusion, and Exchange (CASCADE) toolkit, which makes vessel-resolved oxygen transport tractable at the organ scale through a novel screened Green's-function formulation. On laptop-class hardware, CASCADE simulates networks containing thousands of vessels in under one second and a full biventricular human heart model in about two minutes. We validate spatial oxygen and cell-survival predictions against experiments in perfused engineered tissues and matched finite-element simulations. In engineered tissues, sweeps across thousands of network designs and physiological conditions reveal when vessel density, oxygen supply, or network architecture limits viability, establishing design rules for sustaining thick constructs. In a human heart model, CASCADE translates coronary occlusion, anemia, polycythemia, and hypoxemia into distinct myocardial oxygenation patterns, revealing where oxygen delivery fails and how much tissue is at risk.

bioengineering↗

bioRxiv2026

A Continuum of Atrial Peristalsis Initiates the Bicuspid to Quadricuspid Valve Transition

How chamber-specific hemodynamic shear forces coordinate the spatial and temporal patterning of cardiac valves remains poorly understood. The zebrafish atrioventricular (AV) valve transitions from 2-cusp to 4-cusp at 14 days post-fertilization (dpf) through commissural remodeling, differential cell proliferation, and chondrogenic matrix secretion. Orthogonal valvular axes are present at 25 hpf (hours), preceding endocardial cushion formation. AV canal remodeling aligns the shear stress with leaflet formation at 48 hpf and 14 dpf. At 28 hpf, the ventricle develops functional syncytium, while the atrial peristalsis remains and is necessary for the Klf2a-Snai1b signaling in Notch-negative and ccm1-positive endocardial cells. Without atrial contraction, the 2-to 4-cusp transition (86.7%) fails to occur. In the absence of ventricular contraction and relaxation, the formation of the first pair of leaflets (100%) does not initiate. As a corollary, we demonstrate that KLF4/SNAI1 expression at the commissure is conserved in the mammalian AV 2- to 4-cushion transition.

developmental biology↗

bioRxiv2025

Personalized biventricular mechanics and sensitivity to model morphology

AO_SCPLOWBSTRACTC_SCPLOWWe present a computational framework for constructing patient-specific models of cardiac mechanics based on standard clinical data, including electrocardiogram (ECG), cuff blood pressure, and electrocardiography-gated computed tomography angiography (CTA) imaging. The model is coupled to a closed-loop lumped parameter network (LPN) circulatory model and incorporates rule-based fiber architecture, as well as spatially varying epicardial boundary conditions to approximate surrounding tissue support. Model parameters are personalized through a multistep procedure that sequentially tunes circulatory dynamics, passive mechanics, and active contraction. The resulting personalized BiV model closely matches clinical pressure and volume measurements and reasonably agrees with image-based myocardial deformation. To assess the impact of anatomical model choice, we compare the BiV model to two commonly-used simplifications: a truncated BiV (t-BiV) model cut at the basal plane and a left ventricle-only (LV) model. For these models, we also evaluate their sensitivity to plausible variations in boundary conditions and contractile strength. With all other inputs held fixed, the LV model exhibits similar global pressure/volume behavior, despite moderate differences in regional deformation. In contrast, the t-BiV model produces substantial differences in both global function and local myocardial mechanics. These results suggest that while LV-only models may be sufficient for biomechanical studies, truncation at the basal plane strongly impacts model outputs and should be used with caution.

bioengineering↗

bioRxiv2024

Optimized Biomechanical Design of a Pulsatile Fontan Conduit for Congenital Heart Palliation

The evolution of palliative surgical procedures for children born with congenital heart defects has proven remarkably successful in extending life, but the resulting non-physiological circulation predisposes to myriad sequelae that compromise quality of life and overall life span. Among these procedures, standard-of-care Fontan completion surgery bypasses the nonfunctional ventricle and provides steady flow of deoxygenated blood to the lungs via a synthetic conduit that typically connects the inferior vena cava to a pulmonary artery. This altered circulation reduces cardiac output, elevates central venous pressures, and possibly contributes to adverse remodeling of the pulmonary vessels. There is, therefore, strong motivation to develop a next generation Fontan conduit capable of serving as a sub-pulmonic pulsatile pump, and there are now several reports of initial attempts. None of these studies have been driven by biomechanical considerations, however, and none have achieved the desired functionality. We thus present a novel analytical framework to improve design and guide fabrication by focusing on the microstructure and material properties of the contractile myofibers and associated passive matrix. Our optimized designs simultaneously ensure desired levels of stroke volume, ejection fraction, and pressure generation given constraints on Frank-Starling myofiber contraction and the limited space within the thoracic cavity of a three-to four-year-old child. This analysis also highlights the need to minimize any associated axial force or torque generation that a pulsatile conduit could transmit to the host vessels at the requisite anastomoses.

bioengineering↗

bioRxiv2024

Assessing the Impact of Valve Sizing and Orientation on Bioprosthetic Pulmonary Valve Hemodynamics Using In Vitro 4D-Flow MRI

PurposePulmonary valve replacement (PVR) using bioprosthetic valves is a common procedure performed in patients with repaired Tetralogy of Fallot and other conditions, but these valves frequently become dysfunctional within 15 years of implantation. Since PVR is often performed in adolescence, valves are typically oversized to account for somatic growth. However, the contribution of oversizing to early valve failure are not clearly understood. The purpose of this study was to explore the impact of valve sizing and orientation on local hemodynamics and valve performance. MethodsDifferent valve sizes were represented by changing the cardiac output through a 25 mm bioprosthetic valve implanted in an idealized 3D-printed model of the right ventricular outflow tract (RVOT). The local hemodynamics at three valve sizes and two valve orientations were assessed using 4D-Flow MRI and high-speed camera imaging. ResultsNoticeable differences in jet asymmetry, the amount of recirculation, leaflet opening patterns, as well as the size and location of reversed flow regions were observed with varying valve sizes. Rotation of the valve resulted in drastic differences in reversed flow regions, but not forward flow. ConclusionFlow features observed in the oversized valve in this study have previously been correlated with calcification, hemolysis, and leaflet fatigue. Therefore, valve oversizing can negatively impact local hemodynamics and leaflet performance.

bioengineering↗

bioRxiv2024

High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

Pathological high shear stress (HSS, 100 dyn/cm2) is generated in distal pulmonary arteries (PA) (100-500 m) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm2). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Kruppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.

cell biology↗

bioRxiv2023

Longitudinal Investigation of Aortic Dissection in Mice with Computational Fluid Dynamics

Patients with aortic dissection require lifelong surveillance to monitor disease progression and detect late adverse events such as aneurysmal dilation, malperfusion or refractory pain. The variety and complexity of aortic dissection have so far eluded definitive predictions of occurrence and timing of late adverse events. The search for early indicators of late adverse events has been based mostly on morphologic features, and one commonly observed risk factor is partial thrombosis of the false lumen. While the effect of partial thrombosis on disease progression is incompletely understood, hemodynamic factors, including low velocity or stagnant flow, are likely to play a role. In this study we investigated the progression of false lumen intramural thrombus formation in four mice with angiotensin IIinduced aortic dissection. Based on 3D B-mode ultrasound images, we created segmentations of the diseased aorta including the true lumen, false lumen, and thrombus. These geometries were then used to run computational fluid dynamic simulations with subject-specific boundary conditions. Each mouse was followed for seven days and 4-5 longitudinal image datasets were acquired for each animal. We found that false lumina with a single entry tear tend to have smaller mean relative velocities, and at the same time are subject to a larger false lumen thrombus ratio. Likewise, regions of low velocity correlated with regions of elevated endothelial cell activation potential and higher particle residence times. These findings support the hypothesis that flow stagnation is the predominant hemodynamic factor that results in a large thrombus ratio in false lumina, particularly those with a single entry tear. Additional work will be needed to further explore the intricacies of these complex experimental vascular lesions and how the hemodynamic conditions compare to human aortic dissections.

bioengineering↗

bioRxiv2023

A Computational Growth and Remodeling Framework for Adaptive and Maladaptive Pulmonary Arterial Hemodynamics

Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step towards predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

bioengineering↗

bioRxiv2023

Hemodynamics in Patients with Aortic Coarctation: A Comparison of in vivo 4D-Flow MRI and FSI Simulation

The analysis of quantitative hemodynamics provides information for the diagnosis and treatment planning in patients with aortic coarctation (CoA). Patient-specific computational fluid dynamics (CFD) simulations reveal detailed hemodynamic information, but their agreement with the clinical standard 4D-Flow magnetic resonance imaging (MRI) needs to be characterized. This work directly compares in vivo CFD fluid-structure interaction (FSI) simulations against 4D-Flow MRI in patients with CoA (N=5). 4D-Flow MRI-derived flow waveforms and cuff blood pressure measurements were used to tune the boundary conditions for the FSI simulations. Flow rates from 4D-Flow MRI and FSI were compared at cross-sections in the ascending aorta (AAo), CoA and descending aorta (DAo). Qualitative comparisons showed an overall agreement of flow patterns in the aorta between the two methods. The R2 values for the flow waveforms in the AAo, CoA, and DAo were 0.97, 0.84 and 0.81 respectively, representing a strong correlation between 4DFlow MRI measurements and FSI results. This work characterizes the use of patient-specific FSI simulations in quantifying and analyzing CoA hemodynamics to inform CoA treatment planning.

bioengineering↗

bioRxiv2021

Blood flow modeling reveals improved collateral artery performance during mammalian heart regeneration

Collateral arteries are a vessel subtype that bridges two artery branches, forming a natural bypass that can deliver blood flow downstream of an occlusion. These bridges in the human heart are associated with better outcomes during coronary artery disease. We recently found that their rapid development in neonates supports heart regeneration, while the non-regenerative adult heart displays slow and minimal collateralization. Thus, inducing robust collateral artery networks could serve as viable treatment for cardiac ischemia, but reaching this goal requires more knowledge on their developmental mechanisms and functional capabilities. Here, we use whole-organ imaging and 3D computational fluid dynamics (CFD) modeling to identify the spatial architecture of and predict blood flow through collaterals in neonate and adult hearts. We found that neonate collaterals are more numerous, larger in diameter, and, even when similar in size/number, are predicted to more effectively re-perfuse an occluded coronary network when compared to adults. CFD analysis revealed that collaterals perform better in neonates because of decreased differential pressures along their coronary artery tree. Furthermore, testing of various collateral configurations indicated that larger, more proximal collaterals are more beneficial than many smaller ones, identifying a target architecture for therapeutic interventions. Morphometric analysis revealed how the coronary artery network expands during postnatal growth. Vessel diameters do not scale with cardiac muscle growth. Instead, the coronary tree expands solely by adding additional branches of a set length, a burst of which occurs during murine puberty. Finally, we compared mouse structural and functional data to human hearts. Surprisingly, fetal human hearts possessed a very large number of small, but mature, smooth muscle cell covered collaterals while angiogram data indicated adult patients with chronic coronary occlusions contained at least two. Comparing size ratios with modeled mouse data suggested low re-perfusion capabilities of the embryonic collaterals but higher functional benefits of those in diseased adults. Our unique interdisciplinary approach allowed us to quantify the functional significance of collateral arteries during heart regeneration and repair-a critical step towards realizing their therapeutic potential.

bioengineering↗

bioRxiv2021

Computational Simulation of 4-D Micro-Circular Network in Zebrafish Tail Amputation and Regeneration

Wall shear stress (WSS) in the micro-vasculature contributes to biomechanical cues that regulate mechanotransduction underlying vascular development, regeneration, and homeostasis. We hereby elucidate the interplay between hemodynamic shear forces and luminal remodeling in response to vascular injury and regeneration in the zebrafish model of tail amputation. Using the transgenic Tg(fli1:eGFP; Gata1:ds-red) line, we were able to track the enhanced green-fluorescent protein (eGFP)-labeled endothelial lining of the 3-D microvasculature for post-image segmentation and reconstruction of fluid domain for computational fluid dynamics (CFD) simulation. At 1 day post amputation (dpa), dorsal aorta (DA) and posterior cardinal vein (PCV) were severed, and vasoconstriction developed in the dorsal longitudinal anastomotic vessel (DLAV) with a concomitant increase in WSS in the segmental vessels (SV) proximal to the amputation site and a decrease in WSS in SVs distal to amputation. Simultaneously, we observed angiogenesis commencing at the tips of the amputated DLAV and PCV where WSS was minimal in the absence of blood flow. At 2 dpa, vasodilation occurred in a pair of SVs proximal to amputation, resulting in increased flow rate and WSS, whereas in the SVs distal to amputation, WSS normalized to the baseline. At 3 dpa, the flow rate in the arterial SV proximal to amputation continued to rise and merged with DLAV that formed a new loop with PCV. Thus, our CFD modeling uncovered a well-coordinated micro-vascular adaptation process following tail amputation, accompanied by the rise and fall of WSS and dynamic changes in flow rate during vascular regeneration.

bioengineering↗