Improving early detection of keratoconus by Non Contact Tonometry. A computational study and new biomarkers proposal.

Keratoconus is a progressive ocular disorder affecting the corneal tissue, leading to irregular astigmatism and decreased visual acuity. The architectural organization of corneal tissue is altered in keratoconus, however, data from ex vivo testing of biomechanical properties of keratoconic corneas are limited and it is unclear how their results relate to true mechanical properties in vivo. This study explores the mechanical properties of keratoconic corneas through numerical simulations of non-contact tonometry (NCT) reproducing the clinical test of the Corvis ST device. Three sensitivity analyses were conducted to assess the impact of corneal material properties, size, and location of the pathological area on NCT results. Additionally, novel asymmetry-based indices were proposed to better characterize corneal deformations and improve the diagnosis of keratoconus. Our results show that the weakening of corneal material properties leads to increased deformation amplitude and altered biomechanical response. Furthermore, asymmetry indices offer valuable information for locating the pathological tissue. These findings suggest that adjusting the Corvis ST operation, such as a camera rotation, could enhance keratoconus detection and provide insights into the relative position of the affected area. Future research could explore the application of these indices in detecting early-stage keratoconus and assessing the fellow eye's risk for developing the pathology.

On the necessity to include arterial pre-stress in patient-specific simulations of minimally invasive procedures.

Transcatheter aortic valve implantation (TAVI) and thoracic endovascular aortic repair (TEVAR) are minimally invasive procedures for treating aortic valves and diseases. Finite element simulations have proven to be valuable tools in predicting device-related complications. In the literature, the inclusion of aortic pre-stress has not been widely investigated. It plays a crucial role in determining the biomechanical response of the vessel and the device-tissue interaction. This study aims at demonstrating how and when to include the aortic pre-stress in patient-specific TAVI and TEVAR simulations. A percutaneous aortic valve and a stent-graft were implanted in aortic models reconstructed from patient-specific CT scans. Two scenarios for each patient were compared, i.e., including and neglecting the wall pre-stress. The neglection of pre-stress underestimates the contact pressure of 48% and 55%, the aorta stresses of 162% and 157%, the aorta strains of 77% and 21% for TAVI and TEVAR models, respectively. The stent stresses are higher than 48% with the pre-stressed aorta in TAVI simulations; while, similar results are obtained in TEVAR cases. The distance between the device and the aorta is similar with and without pre-stress. The inclusion of the aortic wall pre-stress has the capability to give a better representation of the biomechanical behavior of the arterial tissues and the implanted device. It is suggested to include this effect in patient-specific simulations replicating the procedures.

Microcatheter tracking in thrombectomy procedures: A finite-element simulation study.

BACKGROUND AND OBJECTIVE: Mechanical thrombectomy is a minimally invasive procedure that aims at removing the occluding thrombus from the vasculature of acute ischemic stroke patients. Thrombectomy success and failure can be studied using in-silico thrombectomy models. Such models require realistic modeling steps to be effective. We here present a new approach to model microcatheter tracking during thrombectomy. METHODS: For 3 patient-specific vessel geometries, we performed finite-element simulations of the microcatheter tracking (1) following the vessel centerline (centerline method) and (2) as a one-step insertion simulation, where the microcatheter tip was advanced along the vessel centerline while its body was free to interact with the vessel wall (tip-dragging method). Qualitative validation of the two tracking methods was performed with the patient's digital subtraction angiography (DSA) images. In addition, we compared simulated thrombectomy outcomes (successful vs unsuccessful thrombus retrieval) and maximum principal stresses on the thrombus between the centerline and tip-dragging method. RESULTS: Qualitative comparison with the DSA images showed that the tip-dragging method more realistically resembles the patient-specific microcatheter-tracking scenario, where the microcatheter approaches the vessel walls. Although the simulated thrombectomy outcomes were similar in terms of thrombus retrieval, the thrombus stress fields (and the associated fragmentation of the thrombus) were strongly different between the two methods, with local differences in the maximum principal stress curves up to 84%. CONCLUSIONS: Microcatheter positioning with respect to the vessel affects the stress fields of the thrombus during retrieval, and therefore, may influence thrombus fragmentation and retrieval in-silico thrombectomy.

On the need of a scale-dependent material characterization to describe the mechanical behavior of 3D printed Ti6Al4V custom prostheses using finite element models.

Additive manufacturing is widely used in the orthopaedic industry for the high freedom and flexibility in the design and production of personalized custom implants made of Ti6Al4V. Within this context, finite element modeling of 3D printed prostheses is a robust tool both to guide the design phase and to support clinical evaluations, possibly virtually describing the in-vivo behavior of the implant. Given realistic scenarios, a suitable description of the overall implant's mechanical behavior is unavoidable. Considering typical custom prostheses' designs (i.e. acetabular and hemipelvis implants), complex designs involving solid and/or trabeculated parts, and material distribution at different scales hinder a high-fidelity modeling of the prostheses. Moreover, uncertainties in the production and in the material characterization of small parts approaching the accuracy limit of the additive manufacturing technology still exist. While recent works suggest that the mechanical properties of thin 3D-printed parts may be peculiarly affected by specific processing parameters (i.e. powder grain size, printing orientation, samples' thickness) as compared to conventional Ti6Al4V alloy, the current numerical models make gross simplifications in describing the complex material behavior of each part at different scales. The present study focuses on two patient-specific acetabular and hemipelvis prostheses, with the aim of experimentally characterizing and numerically describing the dependency of the mechanical behavior of 3D printed parts on their peculiar scale, therefore, overcoming one major limitation of current numerical models. Coupling experimental activities with finite element analyses, the authors initially characterized 3D printed Ti6Al4V dog-bone samples at different scales, representative of the main material components of the investigated prostheses. Afterwards, the authors implemented the characterized material behaviors into finite element models to compare the implications of adopting scale-dependent vs. conventional scaleindependent approaches in predicting the experimental mechanical behavior of the prostheses in terms of their overall stiffness and the local strain distribution. The material characterization results highlighted the need for a scale-dependent reduction of the elastic modulus for thin samples compared to the conventional Ti6Al4V, which is fundamental to properly describe the overall stiffness and local strain distribution on the prostheses. The presented works demonstrate how an appropriate material characterization and a scale-dependent material description is needed to develop reliable FE models of 3D printed implants characterized by a complex material distribution at different scales.

Applicability assessment for in-silico patient-specific TEVAR procedures.

Thoracic Endovascular Aortic Repair (TEVAR) is a minimally invasive technique to treat thoracic aorta pathologies and consists of placing a self-expandable stent-graft into the pathological region to restore the vessel lumen and recreate a more physiological condition. Exhaustive computational models, namely the finite element analysis, can be implemented to reproduce the clinical procedure. In this context, numerical models, if used for clinical applications, must be reliable and the simulation credibility should be proved to predict clinical procedure outcomes or to build in-silico clinical trials. This work aims first at applying a previously validated TEVAR methodology to a patient-specific case. Then, defining the TEVAR procedure performed on a patient population as the context of use, the overall applicability of the TEVAR modeling is assessed to demonstrate the reliability of the model itself following a step-by-step method based on the ASME V&V40 protocol. Validation evidence sources are identified for the specific context of use and adopted to demonstrate the applicability of the numerical procedure, thereby answering a question of interest that evaluates the deployed stent-graft configuration in the vessel.

A finite element model of the embryonic zebrafish heart electrophysiology.

BACKGROUND AND OBJECTIVE: In the last 30 years, a growing interest has involved the study of zebrafish thanks to its physiological characteristics similar to those of humans. The aim of the following work is to create an electrophysiological computational model of the zebrafish heart and lay the foundation for the development of an in-silico model of the zebrafish heart that will allow to study the correlation between pathologies and drug administration with the main electrophysiological parameters as the ECG signal. METHODS: The model considers a whole body and the two chambers of three days post fertilization (3 dpf) zebrafish. A four-variable phenomenological action potential model describes the action potential of different heart regions. Tissue conductivity was calibrated to reproduce the experimentally described activation sequence. RESULTS: The model is able to correctly reproduce the activation sequence and times found in literature, with activation of the atrium and ventricle that correspond to 36 and 59 ms, respectively, and a delay of 14 ms caused by the presence of the atrioventricular band (AV band). Moreover, the obtained in-silico ECG reflects the main characteristics of the zebrafish ECG in good agreement with experimental records, a P-wave with a duration of approximately the total atrial activation, followed by a QRS complex of approximately 109 ms corresponding to ventricle activation. CONCLUSIONS: The model allows the assessment of the main electrophysiological parameters in terms of activation sequence and timing, reproducing monopolar and bipolar ECG signals in line with experimental data. Coupling the proposed model with an electrophysiological detailed action potential model of zebrafish will represent a significant breakthrough toward the development of an in-silico zebrafish heart.

A detailed methodology to model the Non Contact Tonometry: a Fluid Structure Interaction study.

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.

Cardiac cells stimulated with an axial current-like waveform reproduce electrophysiological properties of tissue fibers.

BACKGROUND AND OBJECTIVE: In silico electrophysiological models are generally validated by comparing simulated results with experimental data. When dealing with single-cell and tissue scales simultaneously, as occurs frequently during model development and calibration, the effects of inter-cellular coupling should be considered to ensure the trustworthiness of model predictions. The hypothesis of this paper is that the cell-tissue mismatch can be reduced by incorporating the effects of conduction into the single-cell stimulation current. METHODS: Five different stimulation waveforms were applied to the human ventricular O'Hara-Rudy cell model. The waveforms included the commonly used monophasic and biphasic (symmetric and asymmetric) pulses, a triangular waveform and a newly proposed asymmetric waveform (stimulation A) that resembles the transmembrane current associated with AP conduction in tissue. A comparison between single-cell and fiber simulated results was established by computing the relative difference between the values of AP-derived properties at different scales, and by evaluating the differences in the contributions of ionic conductances to each evaluated property. As a proof of the benefit, we investigated multi-scale differences in the simulation of the effects induced by dofetilide, a selective IKr blocker with high torsadogenic risk, on ventricular repolarization at different pacing rates. RESULTS: Out of the five tested stimulation waveforms, stimulation A produced the closest correspondence between cell and tissue simulations in terms of AP properties at steady-state and under dynamic pacing and of ionic contributors to those AP properties. Also, stimulation A reproduced the effects of dofetilide better than the other alternative waveforms, mirroring the 'beat-skipping' behavior observed at fast pacing rates in experiments with human tissue. CONCLUSIONS: The proposed stimulation current waveform accounts for inter-cellular coupling effects by mimicking cell excitation during AP conduction. The proposed waveform improves the correspondence between simulation scales, which could improve the trustworthiness of single-cell simulations without adding computational cost.

Cellular heterogeneity and repolarisation across the atria: an in silico study.

Mechanisms of atrial fibrillation and the susceptibility to reentries can be impacted by the repolarization across the atria. Studies into atrial fibrillation ignore cell-to-cell heterogeneity due to electrotonic coupling. Recent studies show that cellular variability may have a larger impact on electrophysiological behaviour than assumed. This paper aims to determine the impact of cellular heterogeneity on the repolarization phase across the AF remodelled atria. Using a population of models approach, 10 anatomically identical atrial models were created to include cellular heterogeneity. Atrial models were compared with an equivalent homogenous model. Activation, APD90, and repolarization maps were used to compare models. The impact of electrotonic coupling in the tissue was determined through a comparison of RMP, APD20, APD50, APD90, and triangulation between regional atrial tissue and the single cell populations. After calibration, cellular heterogeneity does not impact atrial depolarization. Repolarization patterns were significantly impacted by cellular heterogeneity, with the APD90 across the LA increasing due to heterogeneity and the reverse occurring in the RA. Electrotonic coupling caused a reduction in variability across all biomarkers but did not fully remove variability. Electrotonic coupling resulted in an increase in APD20 and APD50, and reduced triangulation compared to isolated cell populations. Heterogeneity also caused a reduction in triangulation compared with regionally homogeneous atria.

Combined stent-retriever and aspiration intra-arterial thrombectomy performance for fragmentable blood clots: A proof-of-concept computational study.

Mechanical thrombectomy (MT) treatment of acute ischemic stroke (AIS) patients typically involves use of stent retrievers or aspiration catheters alone or in combination. For in silico trials of AIS patients, it is crucial to incorporate the possibility of thrombus fragmentation during the intervention. This study focuses on two aspects of the thrombectomy simulation: i) Thrombus fragmentation on the basis of a failure model calibrated with experimental tests on clot analogs; ii) the combined stent-retriever and aspiration catheter MT procedure is modeled by adding both the proximal balloon guide catheter and the distal access catheter. The adopted failure criterion is based on maximum principal stress threshold value. If elements of the thrombus exceed this criterion during the retrieval simulation, then they are deleted from the calculation. Comparison with in-vitro tests indicates that the simulation correctly reproduces the procedures predicting thrombus fragmentation in the case of red blood cells rich thrombi, whereas non-fragmentation is predicted for fibrin-rich thrombi. Modeling of balloon guide catheter prevents clot fragments' embolization to further distal territories during MT procedure.

Self-expandable stent for thrombus removal modeling: Solid or beam finite elements?

BACKGROUND: The performance of self-expandable stents is being increasingly studied by means of finite-element analysis. As for peripheral stents, transcatheter valves and stent-grafts, there are numerous computational studies for setting up a proper model, this information is missing for stent-retrievers used in the procedure of thrombus removal in cerebral arteries. It is well known that the selection of the appropriate finite-element dimensions (topology) and formulations (typology) is a fundamental step to set up accurate and reliable computational simulations. In this context, a thorough verification analysis is here proposed, aimed at investigating how the different element typologies and topologies - available to model a stent-retriever - affect simulation results. METHOD: Hexahedral and beam element formulations were analyzed first individually by virtually replicating a crimping test on the device, and then by replicating the thrombectomy procedure aiming at removing a thrombus from a cerebral vessel. In particular, three discretization refinements for each element type and different element formulations including both full and reduced integration were investigated and compared in terms of the resultant radial force of the stent and the stress field generated in the thrombus. RESULTS: The sensitivity analysis on the element formulation performed with the crimping simulations allowed the identification of the optimal setting for each element family. Both setting lead to similar results in terms of stent performance in the virtual thrombectomy and should be used in future studies simulating the mechanical thrombectomy with stent-retrievers. CONCLUSIONS: The carried out virtual thrombectomy procedures confirmed that the beam element formulation results were sufficiently accurate to model the radial force and the performance of the stent-retriever during the procedure. For different self-expandable stents, hexahedral formulation could be essential in stress analysis.

Validation and Verification of High-Fidelity Simulations of Thoracic Stent-Graft Implantation.

Thoracic Endovascular Aortic Repair (TEVAR) is the preferred treatment option for thoracic aortic pathologies and consists of inserting a self-expandable stent-graft into the pathological region to restore the lumen. Computational models play a significant role in procedural planning and must be reliable. For this reason, in this work, high-fidelity Finite Element (FE) simulations are developed to model thoracic stent-grafts. Experimental crimp/release tests are performed to calibrate stent-grafts material parameters. Stent pre-stress is included in the stent-graft model. A new methodology for replicating device insertion and deployment with explicit FE simulations is proposed. To validate this simulation, the stent-graft is experimentally released into a 3D rigid aortic phantom with physiological anatomy and inspected in a computed tomography (CT) scan at different time points during deployment with an ad-hoc set-up. A verification analysis of the adopted modeling features compared to the literature is performed. With the proposed methodology the error with respect to the CT is on average 0.92 ± 0.64%, while it is higher when literature models are adopted (on average 4.77 ± 1.83%). The presented FE tool is versatile and customizable for different commercial devices and applicable to patient-specific analyses.

Multiscale Computational Modeling of Vascular Adaptation: A Systems Biology Approach Using Agent-Based Models.

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.

A computational optimization study of a self-expandable transcatheter aortic valve.

Developing an efficient stent frame for transcatheter aortic valves (TAV) needs thorough investigation in different design and functional aspects. In recent years, most TAV studies have focused on their clinical performance, leaflet design, and durability. Although several optimization studies on peripheral stents exist, the TAV stents have different functional requirements and need to be explicitly studied. The aim of this study is to develop a cost-effective optimization framework to find the optimal TAV stent design made of Ni-Ti alloy. The proposed framework focuses on minimizing the maximum strain occurring in the stent during crimping, making use of a simplified model of the stent to reduce computational cost. The effect of the strut cross-section of the stent, i.e., width and thickness, and the number and geometry of the repeating units of the stent (both influencing the cell size) on the maximum strain is investigated. Three-dimensional simulations of the crimping process are used to verify the validity of the simplified representation of the stent, and the radial force has been calculated for further evaluation. The results suggest the key role of the number of cells (repeating units) and strut width on the maximum strain and, consequently, on the stent design. The difference in terms of the maximum strain between the simplified and the 3D model was less than 5%, confirming the validity of the adopted modeling strategy and the robustness of the framework to improve the TAV stent designs through a simple, cost-effective, and reliable procedure.

The first virtual patient-specific thrombectomy procedure.

Treatment of acute ischemic stroke has been recently improved with the introduction of endovascular mechanical thrombectomy, a minimally invasive procedure able to remove a clot using aspiration devices and/or stent-retrievers. Despite the promising and encouraging results, improvements to the procedure and to the stent design are the focus of the recent efforts. Computational studies can pave the road to these improvements, providing their ability to describe and accurately reproduce a real procedure. A patient with ischemic stroke due to intracranial large vessel occlusion was selected and after the creation of the cerebral vasculature from computed tomography images and a histologic analysis to determine the clot composition, the entire thrombectomy procedure was virtually replicated. As in the real situation, the computational replica showed that two attempts were necessary to remove the clot, as a result of the position of the stent retriever with respect to the clot. Furthermore, the results indicated that clot fragmentation did not occur as the deformations were mainly in a compressive state without the possibility for clot cracks to propagate. The accurate representation of the procedure can be used as an important step for operative optimization planning and future improvements of stent designs.

Applicability analysis to evaluate credibility of an in silico thrombectomy procedure.

Intra-arterial thrombectomy is a minimally invasive procedure in which an obstructing thrombus (clot) is removed using a minimally-invasive device: a stent-retriever. The stent-retriever is first deployed, and then the thrombus is removed during stent-retriever retraction. This procedure can be simulated using a detailed computational model. However, to be useful for an in silico trial in a clinical setting, model credibility should be demonstrated. The aim of this work is to apply a credibility process for the validation phases to the thrombectomy procedure in order to deem it credible for use in an in silico trial. Validation evidence is proposed for the identified context of use and then used to build credibility to the numerical model. Applicability of the proposed model is justified and assessed using a rigorous step-by-step method based on the ASME V&V40 protocol.

Understanding TAVR device expansion as it relates to morphology of the bicuspid aortic valve: A simulation study.

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.

Applicability assessment of a stent-retriever thrombectomy finite-element model.

An acute ischaemic stroke appears when a blood clot blocks the blood flow in a cerebral artery. Intra-arterial thrombectomy, a mini-invasive procedure based on stent technology, is a mechanical available treatment to extract the clot and restore the blood circulation. After stent deployment, the clot, trapped in the stent struts, is pulled along with the stent towards a receiving catheter. Recent clinical trials have confirmed the effectiveness and safety of mechanical thrombectomy. However, the procedure requires further investigation. The aim of this study is the development of a numerical finite-element-based model of the thrombectomy procedure. In vitro thrombectomy tests are performed in different vessel geometries and one simulation for each test is carried out to verify the accuracy and reliability of the proposed numerical model. The results of the simulations confirm the efficacy of the model to replicate all the experimental setups. Clot stress and strain fields from the numerical analysis, which vary depending on the geometric features of the vessel, could be used to evaluate the possible fragmentation of the clot during the procedure. The proposed in vitro/in silico comparison aims at assessing the applicability of the numerical model and at providing validation evidence for the specific in vivo thrombectomy outcomes prediction.

In silico approaches for transcatheter aortic valve replacement inspection.

Introduction: Increasing applications of transcatheter aortic valve replacement (TAVR) to treat high- or medium-risk patients with aortic diseases have been proposed in recent years. Despite its increasing use, many influential factors are still to be understood. Furthermore, innovative applications of TAVR such as in bicuspid aortic valves or in low-risk patients are emerging in clinical use. Numerical analyses are increasingly used to reproduce clinical treatments. The future trends in this area are foreseen for in silico trials and personalized medicine. Areas covered: This review paper analyzes the recent years (Jan 2018 - Aug 2020) of in silico studies simulating the behavior of transcatheter aortic valves with emphasis on the addressed clinical question and the used modeling strategies. The manuscripts are firstly classified based on their clinical hypothesis. A second classification is based on the adopted modeling approach in terms of patient domain, device modeling, and inclusion or exclusion of the fluid domain. Expert opinion: The TAVR can be virtually performed in numerous vessel geometries and with different devices. This versatility allows a rapid evaluation of the feasibility of different implantation approaches for specific patients, and patient populations, resulting in faster and safer introduction or optimization of new treatments or devices.

Effect of myofibril architecture on the active contraction of dystrophic muscle. A mathematical model.

Duchenne muscular dystrophy (DMD) is a muscle degenerative disease caused by a mutation in the dystrophin gene. The lack of dystrophin leads to persistent inflammation, degeneration/regeneration cycles of muscle fibers, Ca2＋ dysregulation, incompletely regenerated fibers, necrosis, fibrotic tissue replacement, and alterations in the fiber ultrastructure i.e., myofibril misalignment and branched fibers. This work aims to develop a comprehensive chemo-mechanical model of muscle-skeletal tissue accounting for dispersion in myofibrillar orientations, in addition to the disorders in sarcomere pattern and the fiber branching. The model results confirm a significant correlation between the myofibrillar dispersion and the reduction of isometric force in the dystrophic muscle and indicate that the reduction of contraction velocity in the dystrophic muscle seems to be associated with the local disorders in the sarcomere patterns of the myofibrils. Also, the implemented model can predict the force-velocity response to both concentric and eccentric loading. The resulting model represents an original approach to account for defects in the muscle ultrastructure caused by pathologies as DMD.