SEM2: Introducing mechanics in cell and tissue modeling using coarse-grained homogeneous particle dynamics.

Modeling multiscale mechanics in shape-shifting engineered tissues, such as organoids and organs-on-chip, is both important and challenging. In fact, it is difficult to model relevant tissue-level large non-linear deformations mediated by discrete cell-level behaviors, such as migration and proliferation. One approach to solve this problem is subcellular element modeling (SEM), where ensembles of coarse-grained particles interacting via empirically defined potentials are used to model individual cells while preserving cell rheology. However, an explicit treatment of multiscale mechanics in SEM was missing. Here, we incorporated analyses and visualizations of particle level stress and strain in the open-source software SEM++ to create a new framework that we call subcellular element modeling and mechanics or SEM2. To demonstrate SEM2, we provide a detailed mechanics treatment of classical SEM simulations including single-cell creep, migration, and proliferation. We also introduce an additional force to control nuclear positioning during migration and proliferation. Finally, we show how SEM2 can be used to model proliferation in engineered cell culture platforms such as organoids and organs-on-chip. For every scenario, we present the analysis of cell emergent behaviors as offered by SEM++ and examples of stress or strain distributions that are possible with SEM2. Throughout the study, we only used first-principles literature values or parametric studies, so we left to the Discussion a qualitative comparison of our insights with recently published results. The code for SEM2 is available on GitHub at https://github.com/Synthetic-Physiology-Lab/sem2.

Aortic wall thickness in dilated ascending aorta: Comparison between tricuspid and bicuspid aortic valve.

BACKGROUND: Bicuspid aortic valve (BAV) is frequently associated with dilatation of the thoracic aorta. Peculiar anatomical, histological and mechanical changes of the aortic wall in BAV aortopathy have been hypothesized to suggest an increased risk of acute aortic complications in patients with BAV. AIM: In this study we tried to clarify any differences in the adaptability of the aortic wall to the mechanism of dilatation between patients with BAV and those with TAV. METHODS: In total, 354 samples were taken from 71 patients undergoing elective aortic surgery and divided into two groups: BAV group (n=16; 101 samples); and TAV group (n=55; 253 samples). Aortic wall thickness was measured with a dedicated caliper. The relationship between aortic wall thickness and aortic dilatation and demographic variables was evaluated cumulatively and comparatively (BAV versus TAV). In patients with more than three samples available, intrapatient variability was also studied. Finally, potential risk factors for severely reduced aortic wall thickness were also assessed. RESULTS: Analysis of preoperative characteristics revealed significant differences in patient age (54±16years for BAV and 66±11years for TAV; P=0.0011), with no differences in variables related to aortic dilatation (including phenotype). Cumulative aortic wall thickness was significantly thinner in the anterior than in the posterior wall. In the comparative analysis, aortic wall thickness was significantly thinner in patients with BAV in both the anterior and posterior regions. Furthermore, in patients with BAV, dilatation>51mm was a significant predictor of severely reduced aortic wall thickness. CONCLUSIONS: In our experience, patients with BAV aortopathy reached the cut-off for the surgical indication at an early age. Careful monitoring in patients with BAV is mandatory when aortic dilatation has reached 51mm, as it is related to significant anatomical changes.

3D Printing of Copper Using Water-Based Colloids and Reductive Sintering.

Copper was manufactured by using a low-cost 3D printing device and copper oxide water-based colloids. The proposed method avoids the use of toxic volatile solvents (used in metal-based robocasting), adopting copper oxide as a precursor of copper metal due to its lower cost and higher chemical stability. The appropriate rheological properties of the colloids have been obtained through the addition of poly-ethylene oxide-co-polypropylene-co-polyethylene oxide copolymer (Pluronic P123) and poly-acrylic acid to the suspension of the oxide in water. Mixing of the components of the colloidal suspension was performed with the same syringes used for the extrusion, avoiding any material waste. The low-temperature transition of water solutions of P123 is used to facilitate the homogenization of the colloid. The copper oxide is then converted to copper metal through a reductive sintering process, performed at 1000°C for a few hours in an atmosphere of Ar-10%H2. This approach allows the obtainment of porous copper objects (up to 20%) while retaining good mechanical properties. It could be beneficial for many applications, for example current collectors in lithium batteries.

Current progress toward isogeometric modeling of the heart biophysics.

In this paper, we review a powerful methodology to solve complex numerical simulations, known as isogeometric analysis, with a focus on applications to the biophysical modeling of the heart. We focus on the hemodynamics, modeling of the valves, cardiac tissue mechanics, and on the simulation of medical devices and treatments. For every topic, we provide an overview of the methods employed to solve the specific numerical issue entailed by the simulation. We try to cover the complete process, starting from the creation of the geometrical model up to the analysis and post-processing, highlighting the advantages and disadvantages of the methodology.

On the dielectric and mechanical characterization of tissue-mimicking breast phantoms.

Objective. In this paper, we focus on the dielectric and mechanical characterization of tissue-mimicking breast phantoms.Approach. Starting from recipes previously proposed by our research group, based on easy-to-handle, cheap and safe components (i.e. sunflower oil, deionized water, dishwashing liquid and gelatin), we produced and tested, both dielectrically and mechanically, more than 100 samples. The dielectric properties were measured from 500 MHz to 14 GHz, the Cole-Cole parameters were derived to describe the dielectric behaviour in a broader frequency range, and the results were compared with dielectric properties of human breastex vivotissues up to 50 GHz. The macroscale mechanical properties were measured by means of unconfined compression tests, and the impact of the experimental conditions (i.e. preload and test speed) on the measured Young's moduli was analysed. In addition, the mechanical contrast between healthy- and malignant-tissue-like phantoms was evaluated.Main results. The results agree with the literature in the cases in which the experimental conditions are known, demonstrating the possibility to fabricate phantoms able to mimic both dielectric and mechanical properties of breast tissues.Significance. In this work, for the first time, a range of materials reproducing all the categories of breast tissues were experimentally characterized, both from a dielectric and mechanical point of view. A large range of frequency were considered for the dielectric measurements and several combinations of experimental conditions were investigated in the context of the mechanical characterization. The proposed results can be useful in the design and testing of complementary or supplementary techniques for breast cancer detection based on micro/millimetre-waves, possibly in connection with other imaging modalities.

Finite element analysis of transcatheter aortic valve implantation: Insights on the modelling of self-expandable devices.

Computational simulations of Transcatheter Aortic Valve Implantation (TAVI) have reached a high level of complexity and accuracy for the prediction of possible implantation scenarios during the decision-making process. However, when focusing on the prosthetic device, currently different devices are available on the market which not only have different geometries, but also different material properties. The present work focuses on the calibration of Nitinol constitutive parameters of four self-expandable devices starting from experimental radial force tests on the prosthetic samples. Beside providing optimal material properties for each specific device, we also perform a patient-specific simulation, comparing the results obtained using both "literature" and calibrated parameters with the aim of investigating the impact of metallic frame parameters choice on simulation results.

Uniaxial properties of ascending aortic aneurysms in light of effective stretch.

A constitutive model that explicitly considers the gradual recruitment of collagen fibers is applied to investigate the uniaxial properties of human ascending aortic aneurysms. The model uses an effective stretch, which is a continuum scale kinematic variable measuring the true stretch of the tissue, to formulate the fiber stress. The constitutive equation contains two shape parameters characterizing the stochastic distribution of fiber waviness, and two elastic parameters accounting for, respectively, the elastic properties of ground substance and the straightened collagen fibers. The model is applied to 156 sets of uniaxial stress-stretch data obtained from 52 aneurysm samples. Major findings include (1) the uniaxial response can be well described by a quadratic strain energy function of the effective strain; (2) the ultimate stretches, when measured in terms of the effective stretch, are closely clustered around 1.1, in contrast to a much wider range in the original stretch; and (3) the ultimate stress correlates positively with the fiber stiffness. The age dependence and directional differences of constitutive parameters are also investigated. Results indicate that only the waviness depends strongly on age; no clear alterations occur in elastic parameters. Further, the fibers are wavier and stiffer in the circumferential direction than in the longitudinal direction. No other parameters exhibit significant direction difference. STATEMENT OF SIGNIFICANCE: We introduced a constitutive model which explicitly accounts for collagen fiber recruitment to investigate the uniaxial properties of human ascending aortic aneurysm tissues. Uniaxial response data from 156 specimens were considered in the study. It was found that the seemingly dissimilar response curves are, in fact, similar if we measure the deformation using an effective stretch which factors out the uncrimping deformation. The rupture stretches in terms of the effective stretch are closely packed around 1.1. And the stress-stretch curves collapse to a canonical curve after a transformation.

CoreValve vs. Sapien 3 Transcatheter Aortic Valve Replacement: A Finite Element Analysis Study.

AIM: to investigate the factors implied in the development of postoperative complications in both self-expandable and balloon-expandable transcatheter heart valves by means of finite element analysis (FEA). MATERIALS AND METHODS: FEA was integrated into CT scans to investigate two cases of postoperative device failure for valve thrombosis after the successful implantation of a CoreValve and a Sapien 3 valve. Data were then compared with two patients who had undergone uncomplicated transcatheter heart valve replacement (TAVR) with the same types of valves. RESULTS: Computational biomechanical modeling showed calcifications persisting after device expansion, not visible on the CT scan. These calcifications determined geometrical distortion and elliptical deformation of the valve predisposing to hemodynamic disturbances and potential thrombosis. Increased regional stress was also identified in correspondence to the areas of distortion with the associated paravalvular leak. CONCLUSION: the use of FEA as an adjunct to preoperative imaging might assist patient selection and procedure planning as well as help in the detection and prevention of TAVR complications.

Performance of high conformability vs. high radial force devices in the virtual treatment of TAVI patients with bicuspid aortic valve.

OBJECTIVE: Transcatheter Aortic Valve Implantation (TAVI) is a consolidated procedure showing a low operative risk and excellent long-term outcomes in patients with aortic stenosis. Patients presenting a bicuspid aortic valve (BAV) often require valve replacement due to the highly calcific nature of the aortic leaflets. However, BAV patients have usually been contraindicated for TAVI due to their complex valve anatomy. The aim of this work was to compare the performance of devices featuring high conformability (HC) against those with high radial force (HRF). METHODS: Four BAV patients undergoing TAVI were retrospectively selected. The aortic roots including the native leaflets and calcifications were reconstructed from pre-operative Computed Tomography scans. In each patient, both HC and HRF devices were virtually implanted using Finite Element Analysis simulations. After implantation, paravalvular orifice area, von Mises stress distribution, root contact area, and device eccentricity were calculated. RESULTS: Simulations showed good agreement with intraoperative imaging. In 3 out of 4 patients, the HRF device resulted in a lower paravalvular area than the HC. Stress distribution was also more homogeneously distributed in the HRF group as compared with the HC group. Despite their lower adaptability, HRF devices showed consistently higher stent-root contact area. CONCLUSION: HRF devices showed improved results with respect to HC valves after being deployed in BAV anatomies. We hypothesize that the ability to reshape the annulus is the major determinant of success in this subgroup of patients featuring highly calcified leaflets.

Outcome of transcatheter aortic valve replacement in bicuspid aortic valve stenosis with new-generation devices.

OBJECTIVES: To compare device success and paravalvular leak rates of 3 new-generation transcatheter aortic valve replacement devices in patients with bicuspid aortic valve stenosis and to test their biomechanical performance in a computer-based simulation model of aortic root with increasing ellipticity. METHODS: This retrospective multicentre study included 56 bicuspid aortic valve patients undergoing transcatheter aortic valve replacement with new-generation devices: Lotus/Lotus Edge (N = 15; 27%), Evolut-R (N = 20; 36%) and ACURATE neo (N = 21; 37%). Three virtual simulation models of aortic root with increasing index of eccentricity (0-0.25-0.5) were implemented. Stress distribution, stent-root contact area and paravalvular orifice area were computed. RESULTS: Device success was achieved in 43/56 patients (77%) with comparable rates among Lotus (87%), Evolut-R (60%) and ACURATE neo (86%; P = 0.085). Moderate paravalvular leak rate was significantly lower in the Lotus group as compared to Evolut-R group (0% vs 30%; P = 0.027) and comparable to the ACURATE neo group (0% vs 10%; P = 0.33). By index of eccentricity = 0.5, Lotus showed a uniform and symmetric pattern of stress distribution with absent paravalvular orifice area, ACURATE neo showed a mild asymmetry with small paravalvular orifice area (1.1 mm2), whereas a severely asymmetric pattern was evident with Evolut-R, resulting in a large paravalvular orifice area (12.0 mm2). CONCLUSIONS: Transcatheter aortic valve replacement in bicuspid aortic valve patients with new-generation devices showed comparable device success rates. Lotus showed moderate paravalvular leak rate comparable to that of ACURATE neo and significantly lower than Evolut-R. On simulation, Lotus and ACURATE neo showed optimal adaptability to elliptic anatomies as compared to Evolut-R.

Patient-specific computational fluid dynamics analysis of transcatheter aortic root replacement with chimney coronary grafts.

OBJECTIVES: Transcatheter aortic root repair (TARR) consists of the simultaneous endovascular replacement of the aortic valve, the root and the proximal ascending aorta. The aim of the study is to set-up a computational model of TARR to explore the impact of the endovascular procedure on the coronary circulation supported by chimney grafts. METHODS: Computed tomography of a patient with dilated ascending aorta was segmented to obtain a 3-dimensional representation of the proximal thoracic aorta, including aortic root and supra-aortic branches. Computed assisted design tools were used to modify the geometry to create the post-procedural TARR configuration featuring the main aortic endograft integrated with 2 chimney grafts for coronary circulation. Computational Fluid Dynamics simulations were run in both pre- and post-procedural configurations using a pulsatile inflow and lumped parameter models at the outflows to simulate peripheral aortic and coronary circulation. Differences in coronary flow and pressure along the cardiac cycle were evaluated. RESULTS: After the virtual implant of the TARR device with coronary grafts, the flow became more organized and less recirculation was seen in the ascending aorta. Coronary perfusion was guaranteed with negligible flow differences between pre- and post-procedural configurations. However, despite being well perfused by chimney grafts, the procedure induces an increase of the pressure drop between the coronary ostia and the ascending aorta of 8 mmHg. CONCLUSIONS: The proposed numerical simulations, in the specific case under investigation, suggest that the TARR technique maintains coronary perfusion through the chimney grafts. This study calls for experimental validation and further analyses of the impact of TARR on cardiac afterload, decrease of aortic compliance and local pressure drop induced by the coronary chimney grafts.

Bioengineering Case Study to Evaluate Complications of Adverse Anatomy of Aortic Root in Transcatheter Aortic Valve Replacement: Combining Biomechanical Modelling with CT imaging.

Gated computed tomography (CT) might not adequately predict occurrence of post-implantation transcatheter aortic valve replacement (TAVR) complications in hostile aortic root as it would require a more complex integration of morphological, functional and hemodynamical parameters. We used a computational framework based on finite element analysis (FEA) to simulate patient-specific implantation. Application of biomechanical modelling using FEA to gated-CT was able to demonstrate the relation of the device with voluminous calcification, its consequent misalignment and a significant stent deformation. Use of FEA and other advanced computed predictive modelling techniques as an adjunct to CT scan could improve our understanding of TAVR, potentially predict complications and fate of the devices after implantation and inform patient-specific treatment.

A Finite Element Analysis Study from 3D CT to Predict Transcatheter Heart Valve Thrombosis.

BACKGROUND: Transcatheter aortic valve replacement has proved its safety and effectiveness in intermediate- to high-risk and inoperable patients with severe aortic stenosis. However, despite current guideline recommendations, the use of transcatheter aortic valve replacement (TAVR) to treat severe aortic valve stenosis caused by degenerative leaflet thickening and calcification has not been widely adopted in low-risk patients. This reluctance among both cardiac surgeons and cardiologists could be due to concerns regarding clinical and subclinical valve thrombosis. Stent performance alongside increased aortic root and leaflet stresses in surgical bioprostheses has been correlated with complications such as thrombosis, migration and structural valve degeneration. MATERIALS AND METHODS: Self-expandable catheter-based aortic valve replacement (Medtronic, Minneapolis, MN, USA), which was received by patients who developed transcatheter heart valve thrombosis, was investigated using high-resolution biomodelling from computed tomography scanning. Calcific blocks were extracted from a 250 CT multi-slice image for precise three-dimensional geometry image reconstruction of the root and leaflets. RESULTS: Distortion of the stent was observed with incomplete cranial and caudal expansion of the device. The incomplete deployment of the stent was evident in the presence of uncrushed refractory bulky calcifications. This resulted in incomplete alignment of the device within the aortic root and potential dislodgment. CONCLUSION: A Finite Element Analysis (FEA) investigation can anticipate the presence of calcified refractory blocks, the deformation of the prosthetic stent and the development of paravalvular orifice, and it may prevent subclinical and clinical TAVR thrombosis. Here we clearly demonstrate that using exact geometry from high-resolution CT scans in association with FEA allows detection of persistent bulky calcifications that may contribute to thrombus formation after TAVR procedure.

Multidisciplinary preoperative simulations to optimize surgical outcomes in a challenging case of the complete double aortic arch in the adult.

BACKGROUND: Challenging surgical cases are becoming more and more frequent, making the optimization of decision making process and an accurate preoperative planning mandatory in order to improve postoperative outcomes. AIMS: Here we present an original multidisciplinary approach aimed at optimizing decision making in a peculiar case of double aortic arch (DAA) presenting in an adult patient. MATERIALS AND METHODS: Following the diagnosis of DAA, based on conventional exams, a three steps engineering simulation was adopted including: a) three-dimensional (3D) rapid prototype simulation; b) computational fluid-dynamic analysis; c) 3D virtual simulation of surgical exposure. RESULTS: Based on careful evaluation of such simulations we were able to identify optimal anatomical and functional surgical options, along with the optimal surgical approach. DISCUSSION: In peculiar clinical case, a significant step forward to optimize preoperative surgical planning could be obtained applying current available engineering techniques. CONCLUSION: We do believe that a multidisciplinary approach could become mandatory, in challenging cases, to optimize preoperative planning and outcomes.

Reversed Auxiliary Flow to Reduce Embolism Risk During TAVI: A Computational Simulation and Experimental Study.

INTRODUCTION: Endovascular treatments, such as transcatheter aortic valve implantation (TAVI), carry a risk of embolization due to debris dislodgement during various procedural steps. Although embolic filters are already available and marketed, mechanisms underlying cerebral embolism still need to be elucidated in order to further reduce cerebrovascular events. METHODS: We propose an experimental framework with an in silico duplicate allowing release of particles at the level of the aortic valve and their subsequent capture in the supra-aortic branches, simulating embolization under constant inflow and controlled hemodynamic conditions. The effect of a simple flow modulation, consisting of an auxiliary constant flow via the right subclavian artery (RSA), on the amount of particle entering the brachiocephalic trunk was investigated. Preliminary computational fluid dynamics (CFD) simulations were performed in order to assess the minimum retrograde flow-rate from RSA required to deviate particles. RESULTS: Our results show that a constant reversed auxiliary flow of 0.5 L/min from the RSA under a constant inflow of 4 L/min from the ascending aorta is able to protect the brachiocephalic trunk from particle embolisms. Both computational and experimental results also demonstrate that the distribution of the bulk flow dictates the distribution of the particles along the aortic branches. This effect has also shown to be independent of release location and flow rate. CONCLUSIONS: The present study confirms that the integration of in vitro experiments and in silico analyses allows designing and benchmarking novel solutions for cerebral embolic protection during TAVI such as the proposed embo-deviation technique based on an auxiliary retrograde flow from the right subclavian artery.

Complementary Role of the Computed Biomodelling through Finite Element Analysis and Computed Tomography for Diagnosis of Transcatheter Heart Valve Thrombosis.

INTRODUCTION: The TAVR procedure is associated with a substantial risk of thrombosis. Current guidelines recommend catheter-based aortic valve implantation for prohibitive-high-risk patients with severe aortic valve stenosis but acknowledge that the aetiology and mechanism of thrombosis are unclear. METHODS: From 2015 to 2018, 607 patients with severe aortic valve stenosis underwent either self-expandable or balloon-expandable catheter-based aortic valve implantation at our institute. A complementary study was designed to support computed tomography as a predictor of complications using an advanced biomodelling process through finite element analysis (FEA). The primary evaluation of study was the thrombosis of the valve at 12 months. RESULTS: At 12 months, 546 patients had normal valvular function. 61 patients had THVT while 6 showed thrombosis and dislodgement with deterioration to NYHA Class IV requiring rehospitalization. The FEA biomodelling revealed a strong link between solid uncrushed calcifications, delayed dislodgement of TAVR and late thrombosis. We observed an interesting phenomenon of fibrosis/calcification originating at the level of the misplaced valve, which was the primary cause of coronary obstruction. CONCLUSION: The use of cardiac CT and predictive biomodelling should be integrated into routine practice for the selection of TAVR candidates and as a predictor of negative outcomes given the lack of accurate investigations available. This would assist in effective decision-making and diagnosis especially in a high-risk cohort of patients.

Patient-specific CFD modelling in the thoracic aorta with PC-MRI-based boundary conditions: A least-square three-element Windkessel approach.

The increasing use of computational fluid dynamics for simulating blood flow in clinics demands the identification of appropriate patient-specific boundary conditions for the customization of the mathematical models. These conditions should ideally be retrieved from measurements. However, finite resolution of devices as well as other practical/ethical reasons prevent the construction of complete data sets necessary to make the mathematical problems well posed. Available data need to be completed by modelling assumptions, whose impact on the final solution has to be carefully addressed. Focusing on aortic vascular districts and related pathologies, we present here a method for efficiently and robustly prescribing phase contrast MRI-based patient-specific data as boundary conditions at the domain of interest. In particular, for the outlets, the basic idea is to obtain pressure conditions from an appropriate elaboration of available flow rates on the basis of a 3D/0D dimensionally heterogeneous modelling. The key point is that the parameters are obtained by a constrained optimization procedure. The rationale is that pressure conditions have a reduced impact on the numerical solution compared with velocity conditions, yielding a simulation framework less exposed to noise and inconsistency of the data, as well as to the arbitrariness of the underlying modelling assumptions. Numerical results confirm the reliability of the approach in comparison with other patient-specific approaches adopted in the literature.

Transcatheter Technologies for Valvular Replacement: an Update.

This report provides a brief overview of the basic principles, recent advances, and recommendations for the treatment of severe aortic stenosis with transcatheter aortic valve replacement (TAVR) in adults. Approaches that avoid neurological, cardiac and peripheral vascular complications have been developed. In addition, TAVR can be performed in intermediate- and low-risk patients. However, these procedures require specialized training and may not allow for complete resolution of the underlying issue. Even if cardiologists learn to perform the procedure and despite advancements in device technology, TAVR is still susceptible to structural valve degeneration, thrombosis and late cerebral embolization. To date, TAVR has shown no consistent advantage over surgical aortic valve replacement (SAVR) in intermediate- and low-risk patients.

Blood Flow after Endovascular Repair in the Aortic Arch: A Computational Analysis.

BACKGROUND: The benefits of thoracic endovascular aortic repair (TEVAR) have encouraged stent graft deployment more proximally in the aortic arch. This study quantifies the hemodynamic impact of TEVAR in proximal landing zone 2 on the thoracic aorta and the proximal supra-aortic branches. METHODS: Patients treated with TEVAR in proximal landing zone 2 having available preoperative and 30-day postoperative computer tomography angiography and phase-contrast magnetic resonance imaging data were retrospectively selected. Blood flow was studied using patient-specific computational fluid dynamics simulations. RESULTS: Four patients were included. Following TEVAR in proximal landing zone 2, the mean flow in the left common carotid artery (LCCA) increased almost threefold, from 0.21 (0.12-0.41) L/min to 0.61 (0.24-1.08) L/min (+294%). The surface area of the LCCA had not yet increased commensurately and therefore maximum flow velocity in the LCCA increased from 44.9 (27.0-89.3) cm/s to 72.6 (40.8-135.0) cm/s (+62%). One of the patients presented with Type Ib endoleak at 1-year follow-up. The displacement force in this patient measured 32.1 N and was directed dorsocranial, perpendicular to the distal sealing zone. There was a linear correlation between the surface area of the stent graft and the resulting displacement force (p = 0.04). CONCLUSION: TEVAR in proximal landing zone 2 alters blood flow in the supra-aortic branches, resulting in increased flow with high flow velocities in the LCCA. High displacement forces were calculated and related to stent graft migration and Type I endoleak during 1-year follow-up.