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This manuscript presents a novel formulation for a linear elastic model of a heterogeneous arterial section undergoing uniform pressure in a quasi-static regime. The novelties are twofold. First, an elastic bed support on the external boundary (elastic bed boundary condition) replaces the classical Dirichlet boundary condition (i.e., blocking displacements at arbitrarily selected nodes) for elastic solids to ensure a solvable problem. In addition, this modeling approach can be used to effectively account for the effect of the surrounding material on the vessel. Secondly, to study many geometrical configurations corresponding to different patients, we devise an unfitted strategy based on the Immersed Boundary (IB) framework. It allows using the same (background) mesh for all possible configurations both to describe the geometrical features of the cross-section (using level sets) and to compute the solution of the mechanical problem. Results on coronary arterial sections from realistic segmented images demonstrate that the proposed unfitted IB-based approach provides results equivalent to the standard finite elements (FE) for the same number of active degrees of freedom with an average difference in the displacement field of less than 0.5%. However, the proposed methodology does not require the use of a different mesh for every configuration. Thus, it is paving the way for dimensionality reduction.

Introduction: Glaucoma, a leading cause of blindness worldwide, is primarily caused by elevated intraocular pressure (IOP). Accurate and reliable IOP measurements are the key to diagnose the pathology in time and to provide for effective treatment strategies. The currently available methods for measuring IOP include contact and non contact tonometers (NCT), which estimate IOP based on the corneal deformation caused by an external load, that in the case of NCT is an air pulse. The deformation of the cornea during the tonometry is the result of the coupling between the IOP, the mechanical properties of the corneal tissue, the corneal thickness, and the external force applied. Therefore, there is the need to decouple the four contributions to estimate the IOP more reliably.Methods: This paper aims to propose a new methodology to estimate the IOP based on the analysis of the mechanical work performed by the air jet and by the IOP during the NCT test. A numerical eye model is presented, initially deformed by the action of a falling mass to study the energy balance. Subsequently, Fluid-Structure Interaction (FSI) simulations are conducted to simulate the action of Corvis ST.Results and discussion: The new IOP estimation procedure is proposed based on the results of the simulations. The methodology is centred on the analysis of the time of maximum apex velocity rather than the point of first applanation leading to a new IOP estimation not influenced by the geometrical and mechanical corneal factors.

The development of in silico trials based on high-fidelity simulations of clinical procedures requires the availability of large cohorts of three-dimensional (3D) patient-specific anatomy models, which are often hard to collect due to limited availability and/or accessibility and imaging quality. Statistical shape modeling (SSM) allows one to identify the main modes of shape variation and to generate new samples based on the variability observed in a training dataset. In this work, a method for the automatic 3D reconstruction of vascular anatomies based on SSM is used for the generation of a virtual cohort of cerebrovascular models suitable for computational simulations, useful for in silico stroke trials. Starting from 88 cerebrovascular anatomies segmented from stroke patients’ images, an SSM algorithm was developed to generate a virtual population of 100 vascular anatomies, defined by centerlines and diameters. An acceptance criterion was defined based on geometric parameters, resulting in the acceptance of 83 generated anatomies. The 3D reconstruction method was validated by reconstructing a cerebrovascular phantom lumen and comparing the result with an STL geometry obtained from a computed tomography scan. In conclusion, the final 3D models of the generated anatomies show that the proposed methodology can produce a reliable cohort of cerebral arteries.

Understanding the corneal mechanical properties has great importance in the study of corneal pathologies and the prediction of refractive surgery outcomes. Non-Contact Tonometry (NCT) is a non-invasive diagnostic tool intended to characterize the corneal tissue response in vivo by applying a defined air-pulse. The biomarkers inferred from this test can only be considered as indicators of the global biomechanical behaviour rather than the intrinsic biomechanical properties of the corneal tissue. A possibility to isolate the mechanical response of the corneal tissue is the use of an inverse finite element method, which is based on accurate and reliable modelling. Since a detailed methodology is still missing in the literature, this paper aims to construct a high-fidelity finite-element model of an idealized 3D eye for in silico NCT. A fluid-structure interaction (FSI) simulation is developed to virtually apply a defined air-pulse to a 3D idealized eye model comprising cornea, limbus, sclera, lens and humors. Then, a sensitivity analysis is performed to examine the influence of the intraocular pressure (IOP) and the structural material parameters on three biomarkers associated with corneal deformation. The analysis reveals the requirements for the in silico study linked to the correct reproduction of three main aspects: the air pressure over the cornea, the biomechanical properties of the tissues, and the IOP. The adoption of an FSI simulation is crucial to capture the correct air pressure profile over the cornea as a consequence of the air-jet. Regarding the parts of the eye, an anisotropic material should be used for the cornea. An important component is the sclera: the stiffer the sclera, the lower the corneal deformation due to the air-puff. Finally, the fluid-like behavior of the humors should be considered in order to account for the correct variation of the IOP during the test which will, otherwise, remain constant. The development of a strong FSI tool amenable to model coupled structures and fluids provides the basis to find the biomechanical properties of the corneal tissue in vivo.

Abstract Smart biomaterials are increasingly being used to control stem cell fate in vitro by the recapitulation of the native niche microenvironment. By integrating experimental measurements with numerical models, we show that in mesenchymal stem cells grown inside a 3D synthetic niche both nuclear transport of a myogenic factor and the passive nuclear diffusion of a smaller inert protein are reduced. Our results also suggest that cell morphology modulates nuclear proteins import through a partition of the nuclear envelope surface, which is a thin but extremely permeable annular portion in cells cultured on 2D substrates. Therefore, our results support the hypothesis that in stem cell differentiation, the nuclear import of gene-regulating transcription factors is controlled by a strain-dependent nuclear envelope permeability, probably related to the reorganization of stretch-activated nuclear pore complexes.

The widespread incidence of cardiovascular diseases and associated mortality and morbidity, along with the advent of powerful computational resources, have fostered an extensive research in computational modeling of vascular pathophysiology field and promoted in-silico models as a support for biomedical research. Given the multiscale nature of biological systems, the integration of phenomena at different spatial and temporal scales has emerged to be essential in capturing mechanobiological mechanisms underlying vascular adaptation processes. In this regard, agent-based models have demonstrated to successfully embed the systems biology principles and capture the emergent behavior of cellular systems under different pathophysiological conditions. Furthermore, through their modular structure, agent-based models are suitable to be integrated with continuum-based models within a multiscale framework that can link the molecular pathways to the cell and tissue levels. This can allow improving existing therapies and/or developing new therapeutic strategies. The present review examines the multiscale computational frameworks of vascular adaptation with an emphasis on the integration of agent-based approaches with continuum models to describe vascular pathophysiology in a systems biology perspective. The state-of-the-art highlights the current gaps and limitations in the field, thus shedding light on new areas to be explored that may become the future research focus. The inclusion of molecular intracellular pathways (e.g., genomics or proteomics) within the multiscale agent-based modeling frameworks will certainly provide a great contribution to the promising personalized medicine. Efforts will be also needed to address the challenges encountered for the verification, uncertainty quantification, calibration and validation of these multiscale frameworks.

The bicuspid aortic valve (BAV) is a common and heterogeneous congenital heart abnormality that is often complicated by aortic stenosis. Although initially developed for tricuspid aortic valves (TAV), transcatheter aortic valve replacement (TAVR) devices are increasingly applied to the treatment of BAV stenosis. It is known that patient-device relationship between TAVR and BAV are not equivalent to those observed in TAV but the nature of these differences are not well understood. We sought to better understand the patient-device relationships between TAVR devices and the two most common morphologies of BAV. We performed finite element simulation of TAVR deployment into three cases of idealized aortic anatomies (TAV, Sievers 0 BAV, Sievers 1 BAV), derived from patient-specific measurements. Valve leaflet von Mises stress at the aortic commissures differed by valve configuration over a ten-fold range (TAV: 0.55 MPa, Sievers 0: 6.64 MPa, and Sievers 1: 4.19 MPa). First principle stress on the aortic wall was greater in Sievers 1 (0.316 MPa) and Sievers 0 BAV (0.137 MPa) compared to TAV (0.056 MPa). TAVR placement in Sievers 1 BAV demonstrated significant device asymmetric alignment, with 1.09 mm of displacement between the center of the device measured at the annulus and at the leaflet free edge. This orifice displacement was marginal in TAV (0.33 mm) and even lower in Sievers 0 BAV (0.23 mm). BAV TAVR, depending on the subtype involved, may encounter disparate combinations of device under expansion and asymmetry compared to TAV deployment. Understanding the impacts of BAV morphology on patient-device relationships can help improve device selection, patient eligibility, and the overall safety of TAVR in BAV.

(1) Background: in silico models are increasingly relied upon to study the mechanisms of atrial fibrillation. Due to the complexity associated with atrial models, cellular variability is often ignored. Recent studies have shown that cellular variability may have a larger impact on electrophysiological behaviour than previously expected. This paper compares two methods for AF remodelling using regional populations. (2) Methods: using 200,000 action potentials, experimental data was used to calibrate healthy atrial regional populations with two cellular models. AF remodelling was applied by directly adjusting maximum channel conductances. AF remodelling was also applied through adjusting biomarkers. The methods were compared upon replication of experimental data. (3) Results: compared to the percentage method, the biomarker approach resulted in smaller changes. RMP, APD20, APD50, and APD90 were changed in the percentage method by up to 11%, 500%, 50%, and 60%, respectively. In the biomarker approach, RMP, APD20, APD50, and APD90 were changed by up to 4.5%, 132%, 50%, and 35%, respectively. (4) Conclusion: applying AF remodelling through biomarker-based clustering resulted in channel conductance changes that were consistent with experimental data, while maintaining the highly non-linear relationships between channel conductances and biomarkers. Directly changing conductances in the healthy regional populations impacted the non-linear relationships and resulted in non-physiological APD20 and APD50 values.