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A computational framework is developed to consider the concurrent growth and remodelling (G&R) processes occurring in the large pulmonary artery (PA) and right ventricle (RV), as well as ventricular–vascular interactions during the progression of pulmonary arterial hypertension (PAH). This computational framework couples the RV and the proximal PA in a closed-loop circulatory system that operates in a short timescale of a cardiac cycle, and evolves over a long timescale due to G&R processes in the PA and RV. The framework predicts changes in haemodynamics (e.g. 68.2% increase in mean PA pressure), RV geometry (e.g. 38% increase in RV end-diastolic volume) and PA tissue microstructure (e.g. 90% increase in collagen mass) that are consistent with clinical and experimental measurements of PAH. The framework also predicts that a reduction in RV contractility is associated with long-term RV chamber dilation, a common biomarker observed in the late-stage PAH. Sensitivity analyses on the G&R rate constants show that large PA stiffening (both short and long term) is affected by RV remodelling more than the reverse. This framework can serve as a foundation for the future development of a more predictive and comprehensive cardiovascular G&R model with realistic heart and vascular geometries.

The production, removal, and remodeling of fibrillar collagen is fundamental to arterial homeostasis, including dynamic morphological and microstructural changes that occur in response to sustained changes in blood flow and pressure under physiological conditions. These dynamic processes involve complex, coupled biological, chemical, and mechanical mechanisms that are not completely understood. Nevertheless, recent simulations using constrained mixture models with phenomenologically motivated constitutive relations have demonstrated a capability to predict salient features of the progression of certain vascular adaptations and disease processes. Collagen turnover is modeled, in part, via stress-dependent changes in collagen half-life, typically taken within the range of 10–70 days. By contrast, in this work we introduce a biochemomechanical approach to model the cellular synthesis of procollagen as well as its transition from an intermediate state of assembled microfibrils to mature cross-linked fibers, with mechano-regulated removal. The resulting model can simulate temporal changes in geometry, composition, and stress during early vascular adaptation (weeks to months) for modest changes in blood flow or pressure. It is shown that these simulations capture salient features from data presented in the literature from different animal models.

Pulmonary arterial hypertension (PAH) is associated with elevated pulmonary arterial pressure. PAH prognosis remains poor with 15% mortality rate within 1 year, even with modern clinical management. Previous clinical studies proposed wall shear stress (WSS) to be an important hemodynamic factor affecting cell mechanotransduction, growth and remodeling, and disease progress in PAH. However, WSS in vivo is typically at most 2.5 Pa and a doubt has been cast whether WSS alone can drive disease progress. Furthermore, our current understanding of PAH pathology largely comes from small animals' studies in which caliber enlargement, a hallmark of PAH in humans, is rarely reported. Therefore, a large-animal experiment on pulmonary arteries (PAs) is needed to validate whether increased pressure can induce enlargement of PAs caliber. In this study, we use an inflation testing device to characterize the mechanical behavior, both nonlinear elastic behavior and irreversible damage of porcine arteries. The parameters of elastic behavior are estimated from the inflation test at a low-pressure range before and after over-pressurization. Then, histological images are qualitatively examined for medial and adventitial layers. This study sheds light on the relevance of pressure-induced damage mechanism in human PAH. This article is protected by copyright. All rights reserved.

The intraluminal thrombus (ILT) has been shown to negatively impact the progression of the abdominal aortic aneurysms (AAAs). The formation of this thrombus layer has been connected to the local flow environment within AAAs, but the specific mechanisms leading to thrombus formation are still not fully understood. Our study investigated the association between vortical structures, near-wall hemodynamic metrics (e.g., time averaged wall shear stress (TAWSS) and oscillatory shear index (OSI)), and ILT accumulation in a longitudinal cohort of 14 AAAs (53 scans total). Vortices and hemodynamic parameters were estimated using hemodynamic simulations performed to each scan of each patient and compared to local 3D changes of ILT thickness between two consecutive scans (∆ILT). Results showed that vortices formed and remained strong and close to the lumen surface in AAAs without an ILT, while in AAAs with ILTs these detached from the lumen surface and dissipated nearby wall region where an increase in ILT thickness was observed. Although low TAWSS was observed in regions with and without ILT accumulation, an inverse correlation between ∆ILT and TAWSS was observed within the regions that experienced a thrombus growth. Our results support the idea that vortical structures might be playing a role modulating ILT accumulation into specific wall regions. Also, it submits the idea that the low TAWSS will be modulating the growth of thrombus within these preferred ILT accumulated regions. This article is protected by copyright. All rights reserved.

Pulmonary hypertension (PH) is one of the least understood and highly elusive cardiovascular conditions associated with elevated pulmonary arterial pressure. Although the disease mechanisms are not completely understood, evidence has accumulated from human and animal studies that irreversible processes of pulmonary arterial wall damage, compensated by stress-mediated growth, play critical roles in eliciting the mechanisms of disease progression. The aim of this study is to develop a thermodynamic modeling structure of the pulmonary artery to consider coupled plastic-degradation-growth irreversible processes to investigate the mechanical roles of the dissipative phenomena in the disease progression. The proposed model performs a model parameter study of plastic deformation and degradation processes coupled with dissipative growth subjected to elevated pulmonary arterial pressure and computationally generates in silico simulations of PH progression using the clinical features of PH, found in human morphological and mechanical data. The results show that considering plastic deformation can provide a much better fitting of the ex vivo inflation tests than a widely used pure hyperelastic model in higher pressure conditions. In addition, the parameter sensitivity study illustrates that arterial damage and growth cause the increased stiffness, and the full simulation (combining elastic-plastic-degradation-growth models) reveals a key postpathological recovery process of compensating vessel damage by vascular adaptation by reducing the rate of vessel dilation and mediating vascular wall stress. Finally, the simulation results of luminal enlargement, arterial thickening, and arterial stiffness for an anisotropic growth are found to be close to the values from the literature.

Translating recent advances in abdominal aortic aneurysm (AAA) growth and remodeling (G&R) knowledge into a predictive, patient-specific clinical treatment tool requires a major paradigm shift in computational modelling. The objectives of this study are to develop a prediction framework that 1) first calibrates the physical AAA G&R model using patient-specific serial computed tomography (CT) scan images, 2) predicts the expansion of an AAA in the future, and 3) quantifies the associated uncertainty in the prediction. We adopt a Bayesian calibration method to calibrate parameters in the G&R computational model and predict the magnitude of AAA expansion. The proposed Bayesian approach can take different sources of uncertainty; therefore, it is well suited to achieve our aims in predicting the AAA expansion process as well as in computing the propagated uncertainty. We demonstrate how to achieve the proposed aims by solving the formulated Bayesian calibration problems for cases with the synthetic G&R model output data and real medical patient-specific CT data. We compare and discuss the performance of predictions and computation time under different sampling cases of the model output data and patient data, both of which are simulated by the G&R computation. Furthermore, we apply our Bayesian calibration to real patient-specific serial CT data and validate our prediction. The accuracy and efficiency of the proposed method is promising, which appeals to computational and medical communities.

Objective: We propose a novel approach to predict the Abdominal Aortic Aneurysm (AAA) growth in future time, using longitudinal computer tomography (CT) scans of AAAs that are captured at different times in a patient-specific way. Methods : We adopt a formulation that considers a surface of the AAA as a manifold embedded in a scalar field over the three dimensional (3D) space. For this formulation, we develop our Dynamical Gaussian Process Implicit Surface (DGPIS) model based on observed surfaces of 3D AAAs as visible variables while the scalar fields are hidden . In particular, we use Gaussian process regression to construct the field as an observation model from CT training image data. We then learn a dynamic model to represent the evolution of the field. Finally, we derive the predicted AAA surface from the predicted field along with uncertainty quantified in future time. Results : A dataset of 7 subjects (4–7 scans) was collected and used to evaluate the proposed method by comparing its prediction Hausdorff distance errors against those of simple extrapolation. In addition, we evaluate the prediction results with respect to a conventional shape analysis technique such as Principal Component Analysis (PCA). All comparative results show the superior prediction performance of the proposed approach. Conclusion : We introduce a novel approach to predict the AAA growth and its predicted uncertainty in future time, using longitudinal CT scans in a patient-specific fashion. Significance: The capability to predict the AAA shape and its confidence region by our approach establish the potential for guiding clinicians with informed decision in conducting medical treatment and monitoring of AAAs.

Blood vessels are often subjected to axial twisting during body movement or surgery. Sustained twisting may lead to blood vessel growth and remodeling, however, it remains unclear how the extracellular matrix in the blood vessels remodel under sustained axial twisting. This study aimed to develop a computational model to simulate stress-induced growth and remodeling (GR) of thin-walled blood vessels under axial twisting. Cylindrical vessels were subjected to a step increase in axial torque while the axial stretch and lumen pressure remained constant. The vessel walls were modeled based on the constrained mixture theory given as microstructure-based discrete fiber families with isotropic matrix structure models. Simulation results demonstrated that in response to a constant twist angle loading, arterial wall thickness, mass, and twisting torque gradually increase towards a new steady state. However, the stress and mass decrease in one diagonal fiber family while increasing in the other diagonal fiber family before reaching plateaus. A novel finding was that the two helical collagen fiber families showed different growth rates and patterns during remodeling, driven by the different fiber stresses generated by the twisting, and led to non-symmetric material properties. This study sheds new light on arterial wall remodeling under axial twisting.

Microstructural changes in the pulmonary arteries associated with pulmonary arterial hypertension (PAH) is not well understood and characterized in humans. To address this issue, we developed and applied a patient-specific inverse finite element (FE) modeling framework to characterize mechanical and structural changes of the micro-constituents in the proximal pulmonary arteries using in-vivo pressure measurements and magnetic resonance images. The framework was applied using data acquired from a pediatric PAH patient and a heart transplant patient with normal pulmonary arterial pressure, which serves as control. Parameters of a constrained mixture model that are associated with the structure and mechanical properties of elastin, collagen fibers and smooth muscle cells were optimized to fit the patient-specific pressure-diameter responses of the main pulmonary artery. Based on the optimized parameters, individual stress and linearized stiffness resultants of the three tissue constituents, as well as their aggregated values, were estimated in the pulmonary artery. Aggregated stress resultant and stiffness are, respectively, 4.6 and 3.4 times higher in the PAH patient than the control subject. Stress and stiffness resultants of each tissue constituent are also higher in the PAH patient. Specifically, the mean stress resultant is highest in elastin (PAH: 69.96, control: 14.42 kPa-mm), followed by those in smooth muscle cell (PAH: 13.95, control: 4.016 kPa-mm) and collagen fibers (PAH: 13.19, control: 2.908 kPa-mm) in both the PAH patient and the control subject. This result implies that elastin may be the key load-bearing constituent in the pulmonary arteries of the PAH patient and the control subject.

Growth is a significant factor that results in deformations of tubular organs, and particular deformations associated with growth enable tubular organs to perform certain physiological functions. Configuring growth profiles that achieve particular deformation patterns is critical for analyzing potential pathological conditions and for developing corresponding clinical treatments for tubular organ dysfunctions. However, deformation-targeted growth is rarely studied. In this article, the human cervix during pregnancy is studied as an example to show how cervical thinning and dilation are generated by growth. An advanced hyperelasticity theory called morphoelasticity is employed to model the deformations, and a growth tensor is used to represent growth in three principle directions. The computational results demonstrate that both negative radial growth and positive circumferential growth facilitate thinning and dilation. Modeling such mixed growth represents an advancement beyond commonly used uniform growth inside tissues to study tubular deformations. The results reveal that complex growth may occur inside tissues to achieve certain tubular deformations. Integration of further biochemical and cellular activities that initiate and mediate such complex growth remains to be explored.

Computational Growth and Remodeling (G&R) models have been widely used to capture the pathological development of arterial diseases and have shown promise for aiding clinical diagnosis, prognosis prediction, and staging classification. However, due to the high complexity of the arterial adaptation mechanism, high-fidelity arterial G&R simulation usually takes hours or even days, which hinders its application in clinical practice. To remedy this problem, we develop a computationally efficient arterial G&R simulation framework that comprehensively combines the physics-based G&R simulations and data-driven machine learning approaches. The proposed framework greatly enhances the computational efficiency of arterial G&R simulations, thereby enabling more time-consuming arterial applications, including personalized parameter estimation and arterial disease progression prediction. In particular, we achieve significant computational cost reduction mainly through two methods: (1) constructing a Multifidelity Surrogate (MFS) to approximate multifidelity G&R simulations by using a cokriging approach and (2) developing a novel iterative optimization algorithm for personalized parameter estimation. The proposed framework is demonstrated by estimating G&R model parameters and predicting individual aneurysm growth using follow-up CT images of Abdominal Aortic Aneurysms (AAAs) from 21 patients. Results show that the personalized parameters are satisfactorily estimated and the growth of AAAs is predicted within the clinically relevant time frame, i.e., less than 2 h, without a loss of accuracy.

ObjectiveThe maximum diameter measurement of an abdominal aortic aneurysm (AAA), which depends on orthogonal and axial cross-sections or maximally inscribed spheres within the AAA, plays a significant role in the clinical decision making process. This study aims to build a large dataset of morphological parameters from longitudinal CT scans and analyze their correlations. Furthermore, this work explores the existence of a “master curve” of AAA growth, and tests which parameters serve to enhance its predictability for clinical use.Methods106 CT scan images from 25 Korean AAA patients were retrospectively obtained. We subsequently computed morphological parameters, growth rates, and pair-wise correlations, and attempted to enhance the predictability of the growth for high-risk aneurysms using non-linear curve fitting and least-square minimization.ResultsAn exponential AAA growth model was fitted to the maximum spherical diameter, as the best representative of the growth among all parameters (r-square: 0.985) and correctly predicted to 74 of 79 scans based on a 95% confidence interval. AAA volume expansion rateswere highly correlated (r=0.80) with thrombus accumulation rates.ConclusionsThe exponential growth model using spherical diameter provides useful information about progression of aneurysm size and enables AAA growth rate extrapolation during a given surveillance period.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization., Author summary We provide the first full presentation in the literature of CRIMSON, the Cardiovascular Integrated Modelling and Simulation Package. CRIMSON consists of a graphical user interface desktop computer program for creating geometric models of blood vessels from medical imaging scans, specifying parameters such as the stiffness of the artery walls, the resistance of connected vessels which are not visible on the scans, and determining the appropriate parameters for all aspects of the model. CRIMSON additionally consists of the Flowsolver, a high-performance computing package which simulates the flow of blood through the models created in the graphical user interface. Whilst several packages which can simulate blood flow exist, most target general fluid simulations, and this lack of specialisation means that blood flow simulation is harder to perform, and can require ad hoc (and potentially scientifically-limiting) workflow decisions. CRIMSON’s specialisation deals with these problems, as well as presenting a number of unique features which are unavailable elsewhere.

Coronary autoregulation is a short-term response manifested by a relatively constant flow over a wide range of perfusion pressures for a given metabolic state. This phenomenon is thought to be facilitated through a combination of mechanisms, including myogenic, shear dependent, and metabolic controls. The study of coronary autoregulation is challenging due to the coupled nature of the mechanisms and their differential effects through the coronary tree. In this paper, we developed a novel framework to study coronary autoregulation based on the constrained mixture theory. This structurally-motivated autoregulation model required calibration of anatomical and structural parameters of coronary trees via a homeostatic optimization approach using extensive literature data. Autoregulation was then simulated for two different coronary trees: subepicardial and subendocardial. The structurally calibrated model reproduced available baseline hemodynamics and autoregulation data for each coronary tree. The autoregulation analysis showed that the diameter of the intermediate and small arterioles varies the most in response to changes in perfusion pressure. Finally, we demonstrated the utility of the model in two application examples: 1) response to drops in epicardial pressure, and 2) response to drug infusion in the coronary arteries. The proposed structurally-motivated model could be extended to study long-term growth and remodeling in the coronary circulation in response to hypertension, atherosclerosis, etc.Key pointsCoronary autoregulation is defined as the capability of the coronary circulation to maintain the blood supply to the heart over a range of perfusion pressures. This phenomenon is facilitated through intrinsic mechanisms that control the vascular resistance by regulating the mechanical function of smooth muscle cells. Understanding the mechanisms involved in coronary autoregulation is one of the most fundamental questions in coronary physiology.This paper presents a structurally-motivated coronary autoregulation model that uses a nonlinear continuum mechanics approach to account for the morphometry and vessel wall composition in two coronary trees in the subepicardial and subendocardial layers.The model is calibrated against diverse experimental data from literature and is used to study heterogeneous autoregulatory response in the coronary trees. This model drastically differs from previous models, which relied on lumped parameter model formulations, and is suited to the study of long-term pathophysiological growth and remodeling phenomena in coronary vessels.

Objective To investigate the relationship between the characteristics of intraluminal thrombus (ILT) with abdominal aortic aneurysm (AAA) expansion. Methods This retrospective clinical study applied homogeneous multistate continuous-time Markov chain models to longitudinal computed tomography (CT) data from Korean patients with AAA. Four AAA states were considered (early, mild, severe, fatal) and the maximal thickness of the ILT (maxILT), the fraction of the wall area covered by the ILT (areafrac) and the fraction of ILT volume (volfrac) were used as covariates. Results The analysis reviewed longitudinal CT images from 26 patients. Based on likelihood-ratio statistics, the areafrac was the most significant biomarker and maxILT was the second most significant. In addition, within AAAs that developed an ILT layer, the analysis found that the AAA expands relatively quickly during the early stage but the rate of expansion reduces once the AAA has reached a larger size. Conclusion The results recommend surgical intervention when a patient has an areafrac more than 60%. Although this recommendation should be considered with caution given the limited sample size, physicians can use the proposed model as a tool to find such recommendations with their own data.

An abdominal aortic aneurysm (AAA) is a gradual enlargement of the aorta that can cause a life-threatening event when a rupture occurs. Aneurysmal geometry has been proved to be a critical factor in determining when to surgically treat AAAs, but, it is challenging to predict the patient-specific evolution of an AAA with biomechanical or statistical models. The recent success of deep learning in biomedical engineering shows promise for predictive medicine. However, a deep learning model requires a large dataset, which limits its application to the prediction of the patient-specific AAA expansion. In order to cope with the limited medical follow-up dataset of AAAs, a novel technique combining a physical computational model with a deep learning model is introduced to predict the evolution of AAAs. First, a vascular Growth and Remodeling (G&R) computational model, which is able to capture the variations of actual patient AAA geometries, is employed to generate a limited in silico dataset. Second, the Probabilistic Collocation Method (PCM) is employed to reproduce a large in silico dataset by approximating the G&R simulation outputs. A Deep Belief Network (DBN) is then trained to provide fast predictions of patient-specific AAA expansion, using both in silico data and patients' follow-up data. Follow-up Computer Tomography (CT) scan images from 20 patients are employed to demonstrate the effectiveness and the feasibility of the proposed model. The test results show that the DBN is able to predict the enlargements of AAAs with an average relative error of 3.1%, which outperforms the classical mixed-effect model by 65%.

Objective For small abdominal aortic aneurysms (AAAs), a regular follow-up examination is recommended every 12 months for AAAs of 30–39 mm and every six months for AAAs of 40–55 mm. Follow-up diameters can determine if a patient follows the common growth model of the population. However, the rapid expansion of an AAA, often associated with higher rupture risk, may be overlooked even though it requires surgical intervention. Therefore, the prognosis of abdominal aortic aneurysm growth is clinically important for planning treatment. This study aims to build enhanced Bayesian inference methods to predict maximum aneurysm diameter. Methods 106 CT scans from 25 Korean AAA patients were retrospectively obtained. A two-step approach based on Bayesian calibration was used, and an exponential abdominal aortic aneurysm growth model (population-based) was specified according to each individual patient's growth (patient-specific) and morphologic characteristics of the aneurysm sac (enhanced). The distribution estimates were obtained using a Markov Chain Monte Carlo (MCMC) sampler. Results The follow-up diameters were predicted satisfactorily (i.e. the true follow-up diameter was in the 95% prediction interval) for 79% of the scans using the population-based growth model, and 83% of the scans using the patient-specific growth model. Among the evaluated geometric measurements, centerline tortuosity was a significant (p = 0.0002) predictor of growth for AAAs with accelerated and stable expansion rates. Using the enhanced prediction model, 86% of follow-up scans were predicted satisfactorily. The average prediction errors of population-based, patient-specific, and enhanced models were ±2.67, ±2.61 and ± 2.79 mm, respectively. Conclusion A computational framework using patient-oriented growth models provides useful tools for per-patient basis treatment and enables better prediction of AAA growth.

Recent studies suggest that cells routinely probe their mechanical environments and that this mechanosensitive behavior regulates some of their cellular activities. The finite elasticity theory of small-on-large deformation (SoL) has been shown to be effective in interpreting the mechanosensitive behavior of cells on a substrate that has been subjected to a prior large static stretch before the culturing of the cells. Small on large deformation is the superposition of a small deformation onto a prior large deformation that serves as the new reference configuration. This article aims to refine SoL theory to develop a theoretical framework for improved physical interpretation of mechanosensing. Given the initial large deformation in SoL, the stress generated by the small deformation is linearized, and the linearized elasticity tensor is taken to be a significant factor facilitating prediction of cellular behavior. The pre-stretch is shown to produce direction-based, effective elastic moduli for cellular mechanosensing. The utility of this SoL theory is illustrated by culturing of two different cell types grown on uniaxially pre-stretched surfaces that induce changes to the cell orientation and behavior.

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevated pulmonary arterial (PA) pressure. While several computational hemodynamic models of the pulmonary vasculature have been developed to understand PAH, they are lacking in some aspects, such as the vessel wall deformation and its lack of calibration against measurements in humans. Here, we describe a computational modeling framework that addresses these limitations. Specifically, computational models describing the coupling of hemodynamics and vessel wall mechanics in the pulmonary vasculature of a PAH patient and a normal subject were developed. Model parameters, consisting of linearized stiffness E of the large vessels and Windkessel parameters for each outflow branch, were calibrated against in vivo measurements of pressure, flow and vessel wall deformation obtained, respectively, from right-heart catheterization, phase-contrast and cine magnetic resonance images. Calibrated stiffness E of the proximal PA was 2.0 and 0.5 MPa for the PAH and normal models, respectively. Calibrated total compliance C T and resistance R T of the distal vessels were, respectively, 0.32 ml/mmHg and 11.3 mmHg∗min/l for the PAH model, and 2.93 ml/mmHg and 2.6 mmHg∗min/l for the normal model. These results were consistent with previous findings that the pulmonary vasculature is stiffer with more constricted distal vessels in PAH patients. Individual effects on PA pressure due to remodeling of the distal and proximal compartments of the pulmonary vasculature were also investigated in a sensitivity analysis. The analysis suggests that the remodeling of distal vasculature contributes more to the increase in PA pressure than the remodeling of proximal vasculature.

In the study on emergency treatment of massive hemorrhage, it is important to investigate the duration of inflation time in resuscitative endovascular balloon occlusion of aorta (REBOA). REBOA temporarily controls bleeding and maintains the blood pressure while causing side effects to the other organs. To elucidate the side effects of REBOA on the main organs and establish their clinical criteria, both mechanical behavior and clinical examination of each organ tissue must be characterized based on the operation time. Particularly, two rate-dependent mechanical tests (tensile and compression tests) and tissue blood tests (blood urea nitrogen, creatinine, aspartate aminotransferase, and lactate tests) of the kidney, liver, and duodenum tissues were examined according to the inflation time of REBOA. Finally, it was demonstrated that the characteristic of the soft tissue by the loading rate was maintained even in the ischemic tissue. In addition, based on the presented results, it was confirmed that the inflation time of REBOA have an effect on the variation in properties of several organ tissues.

Nerve regeneration after spinal cord injury requires proper axon alignment to bridge the lesion site and myelination to achieve functional recovery. Significant effort has been invested in developing engineering approaches to induce axon alignment with less focus on myelination. Topological features, such as aligned fibers and channels, have been shown to induce axon alignment, but do not enhance axon thickness. We previously demonstrated that surface anisotropy generated through mechanical prestretch induced mesenchymal stem cells to align in the direction of prestretch. In this study, we demonstrate that static prestretch-induced anisotropy promotes dorsal root ganglion (DRG) neurons to extend thicker axon aggregates along the stretched direction and form aligned fascicular-like axon tracts. Moreover, Schwann cells, when cocultured with DRG neurons on the prestretched surface colocalized with the aligned axons and expressed P0 protein, are indicative of myelination of the aligned axons, thereby demonstrating that prestretch-induced surface anisotropy is beneficial in enhancing axon alignment, growth, and myelination.

While it has long been recognized that bi-directional interaction between the heart and the vasculature plays a critical role in the proper functioning of the cardiovascular system, a comprehensive study of this interaction has largely been hampered by a lack of modeling framework capable of simultaneously accommodating high-resolution models of the heart and vasculature. Here, we address this issue and present a computational modeling framework that couples finite element (FE) models of the left ventricle (LV) and aorta to elucidate ventricular - arterial coupling in the systemic circulation. We show in a baseline simulation that the framework predictions of (1) LV pressure - volume loop, (2) aorta pressure - diameter relationship, (3) pressure - waveforms of the aorta, LV and left atrium (LA) over the cardiac cycle are consistent with the physiological measurements found in healthy human. To develop insights of ventricular-arterial interactions, the framework was then used to simulate how alterations in the geometrical or, material parameter(s) of the aorta affect the LV and vice versa. We show that changing the geometry and microstructure of the aorta model in the framework led to changes in the functional behaviors of both LV and aorta that are consistent with experimental observations. On the other hand, changing contractility and passive stiffness of the LV model in the framework also produced changes in both the LV and aorta functional behaviors that are consistent with physiology principles.