Euclidean and Shape-Based Analysis of the Dynamic Mitral Annulus in Children using a Novel Open-Source Framework.

BACKGROUND: The dynamic shape of the normal adult mitral annulus has been shown to be important to mitral valve function. However, annular dynamics of the healthy mitral valve in children have yet to be explored. The aim of this study was to model and quantify the shape and major modes of variation of pediatric mitral valve annuli in four phases of the cardiac cycle using transthoracic echocardiography. METHODS: The mitral valve annuli of 100 children and young adults with normal findings on three-dimensional echocardiography were modeled in four different cardiac phases using the SlicerHeart extension for 3D Slicer. Annular metrics were quantified using SlicerHeart, and optimal normalization to body surface area was explored. Mean annular shapes and the principal components of variation were computed using custom code implemented in a new SlicerHeart module (Annulus Shape Analyzer). Shape was regressed over metrics of age and body surface area, and mean shapes for five age-stratified groups were generated. RESULTS: The ratio of annular height to commissural width of the mitral valve ("saddle shape") changed significantly throughout age for systolic phases (P < .001) but within a narrow range (median range, 0.20-0.25). Annular metrics changed statistically significantly between the diastolic and systolic phases of the cardiac cycle. Visually, the annular shape was maintained with respect to age and body surface area. Principal-component analysis revealed that the pediatric mitral annulus varies primarily in size (mode 1), ratio of annular height to commissural width (mode 2), and sphericity (mode 3). CONCLUSIONS: The saddle-shaped mitral annulus is maintained throughout childhood but varies significantly throughout the cardiac cycle. The major modes of variation in the pediatric mitral annulus are due to size, ratio of annular height to commissural width, and sphericity. The generation of age- and size-specific mitral annular shapes may inform the development of appropriately scaled absorbable or expandable mitral annuloplasty rings for children.

Bayesian Optimization-Based Inverse Finite Element Analysis for Atrioventricular Heart Valves.

Inverse finite element analysis (iFEA) of the atrioventricular heart valves (AHVs) can provide insights into the in-vivo valvular function, such as in-vivo tissue strains; however, there are several limitations in the current state-of-the-art that iFEA has not been widely employed to predict the in-vivo, patient-specific AHV leaflet mechanical responses. In this exploratory study, we propose the use of Bayesian optimization (BO) to study the AHV functional behaviors in-vivo. We analyzed the efficacy of Bayesian optimization to estimate the isotropic Lee-Sacks material coefficients in three benchmark problems: (i) an inflation test, (ii) a simplified leaflet contact model, and (iii) an idealized AHV model. Then, we applied the developed BO-iFEA framework to predict the leaflet properties for a patient-specific tricuspid valve under a congenital heart defect condition. We found that the BO could accurately construct the objective function surface compared to the one from a [Formula: see text] grid search analysis. Additionally, in all cases the proposed BO-iFEA framework yielded material parameter predictions with average element errors less than 0.02 mm/mm (normalized by the simulation-specific characteristic length). Nonetheless, the solutions were not unique due to the presence of a long-valley minima region in the objective function surfaces. Parameter sets along this valley can yield functionally equivalent outcomes (i.e., closing behavior) and are typically observed in the inverse analysis or parameter estimation for the nonlinear mechanical responses of the AHV. In this study, our key contributions include: (i) a first-of-its-kind demonstration of the BO method used for the AHV iFEA; and (ii) the evaluation of a candidate AHV in-silico modeling approach wherein the chordae could be substituted with equivalent displacement boundary conditions, rendering the better iFEA convergence and a smoother objective surface.

An investigation of how specimen dimensions affect biaxial mechanical characterizations with CellScale BioTester and constitutive modeling of porcine tricuspid valve leaflets.

Biaxial mechanical characterizations are the accepted approach to determine the mechanical response of many biological soft tissues. Although several computational and experimental studies have examined how experimental factors (e.g., clamped vs. suture mounting) affect the acquired tissue mechanical behavior, little is known about the role of specimen dimensions in data acquisition and the subsequent modeling. In this study, we combined our established mechanical characterization framework with an iterative size-reduction protocol to test the hypothesis that specimen dimensions affect the observed mechanical behavior of biaxial characterizations. Our findings indicated that there were non-significant differences in the peak equibiaxial stretches of tricuspid valve leaflets across four specimen dimensions ranging from 4.5×4.5mm to 9 × 9mm. Further analyses revealed that there were significant differences in the low-tensile modulus of the circumferential tissue direction. These differences resulted in significantly different constitutive model parameters for the Tong-Fung model between different specimen dimensions of the posterior and septal leaflets. Overall, our findings demonstrate that specimen dimensions play an important role in experimental characterizations, but not necessarily in constitutive modeling of soft tissue mechanical behavior during biaxial testing with the commercial CellScale BioTester.

The effects of leaflet material properties on the simulated function of regurgitant mitral valves.

Advances in three-dimensional imaging provide the ability to construct and analyze finite element (FE) models to evaluate the biomechanical behavior and function of atrioventricular valves. However, while obtaining patient-specific valve geometry is now possible, non-invasive measurement of patient-specific leaflet material properties remains nearly impossible. Both valve geometry and tissue properties play a significant role in governing valve dynamics, leading to the central question of whether clinically relevant insights can be attained from FE analysis of atrioventricular valves without precise knowledge of tissue properties. As such we investigated (1) the influence of tissue extensibility and (2) the effects of constitutive model parameters and leaflet thickness on simulated valve function and mechanics. We compared metrics of valve function (e.g., leaflet coaptation and regurgitant orifice area) and mechanics (e.g., stress and strain) across one normal and three regurgitant mitral valve (MV) models with common mechanisms of regurgitation (annular dilation, leaflet prolapse, leaflet tethering) of both moderate and severe degree. We developed a novel fully-automated approach to accurately quantify regurgitant orifice areas of complex valve geometries. We found that the relative ordering of the mechanical and functional metrics was maintained across a group of valves using material properties up to 15% softer than the representative adult mitral constitutive model. Our findings suggest that FE simulations can be used to qualitatively compare how differences and alterations in valve structure affect relative atrioventricular valve function even in populations where material properties are not precisely known.

The Effects of leaflet material properties on the simulated function of regurgitant mitral valves.

Advances in three-dimensional imaging provide the ability to construct and analyze finite element (FE) models to evaluate the biomechanical behavior and function of atrioventricular valves. However, while obtaining patient-specific valve geometry is now possible, non-invasive measurement of patient-specific leaflet material properties remains nearly impossible. Both valve geometry and tissue properties play a significant role in governing valve dynamics, leading to the central question of whether clinically relevant insights can be attained from FE analysis of atrioventricular valves without precise knowledge of tissue properties. As such we investigated 1) the influence of tissue extensibility and 2) the effects of constitutive model parameters and leaflet thickness on simulated valve function and mechanics. We compared metrics of valve function (e.g., leaflet coaptation and regurgitant orifice area) and mechanics (e.g., stress and strain) across one normal and three regurgitant mitral valve (MV) models with common mechanisms of regurgitation (annular dilation, leaflet prolapse, leaflet tethering) of both moderate and severe degree. We developed a novel fully-automated approach to accurately quantify regurgitant orifice areas of complex valve geometries. We found that the relative ordering of the mechanical and functional metrics was maintained across a group of valves using material properties up to 15% softer than the representative adult mitral constitutive model. Our findings suggest that FE simulations can be used to qualitatively compare how differences and alterations in valve structure affect relative atrioventricular valve function even in populations where material properties are not precisely known.

A Bayesian constitutive model selection framework for biaxial mechanical testing of planar soft tissues: Application to porcine aortic valves.

A variety of constitutive models have been developed for soft tissue mechanics. However, there is no established criterion to select a suitable model for a specific application. Although the model that best fits the experimental data can be deemed the most suitable model, this practice often can be insufficient given the inter-sample variability of experimental observations. Herein, we present a Bayesian approach to calculate the relative probabilities of constitutive models based on biaxial mechanical testing of tissue samples. Forty-six samples of porcine aortic valve tissue were tested using a biaxial stretching setup. For each sample, seven ratios of stresses along and perpendicular to the fiber direction were applied. The probabilities of eight invariant-based constitutive models were calculated based on the experimental data using the proposed model selection framework. The calculated probabilities showed that, out of the considered models and based on the information available through the utilized experimental dataset, the May-Newman model was the most probable model for the porcine aortic valve data. When the samples were further grouped into different cusp types, the May-Newman model remained the most probable for the left- and right-coronary cusps, whereas for non-coronary cusps two models were found to be equally probable: the Lee-Sacks model and the May-Newman model. This difference between cusp types was found to be associated with the first principal component analysis (PCA) mode, where this mode's amplitudes of the non-coronary and right-coronary cusps were found to be significantly different. Our results show that a PCA-based statistical model can capture significant variations in the mechanical properties of soft tissues. The presented framework is applicable to other tissue types, and has the potential to provide a structured and rational way of making simulations population-based.

Benchtop characterization of the tricuspid valve leaflet pre-strains.

The pre-strains of biological soft tissues are important when relating their in vitro and in vivo mechanical behaviors. In this study, we present the first-of-its-kind experimental characterization of the tricuspid valve leaflet pre-strains. We use 3D photogrammetry and the reproducing kernel method to calculate the pre-strains within the central 10×10 mm region of the tricuspid valve leaflets from n=8 porcine hearts. In agreement with previous pre-strain studies for heart valve leaflets, our results show that all the three tricuspid valve leaflets shrink after being explanted from the ex vivo heart. These calculated strains are leaflet-specific and the septal leaflet experiences the most compressive changes. Furthermore, the strains observed after dissection of the central 10×10 mm region of the leaflet are smaller than when the valve is explanted, suggesting that our computed pre-strains are mainly due to the release of in situ annulus and chordae connections. The leaflets are then mounted on a biaxial testing device and preconditioned using force-controlled equibiaxial loading. We show that the employed preconditioning protocol does not 100% restore the leaflet pre-strains as removed during tissue dissection, and future studies are warranted to explore alternative preconditioning methods. Finally, we compare the calculated biomechanically oriented metrics considering five stress-free reference configurations. Interestingly, the radial tissue stretches and material anisotropies are significantly smaller compared to the post-preconditioning configuration. Extensions of this work can further explore the role of this unique leaflet-specific leaflet pre-strains on in vivo valve behavior via high-fidelity in-silico models. STATEMENT OF SIGNIFICANCE: This study provides a first of its kind benchtop characterization of tricuspid valve leaflet pre-strains. We used 3D photogrammetry to reconstruct the central region of the tricuspid valve leaflets in three configurations. The associated configurational changes revealed compressive, leaflet-specific strains after dissection of the valve from its in situ environment. Interestingly, we found that biaxial preconditioning did not restore the measured pre-strains of the leaflets. Depending on the selection of the stress-free reference configuration, this led to substantial differences in the leaflet mechanics. Our findings and methodology are crucial when it comes to relating in vitro mechanical behaviors to valve function in vivo. Future studies can integrate our quantified pre-strains into in-silico simulations to get more realistic predictions about the valve function.

Ex vivo experimental characterizations for understanding the interrelationship between tissue mechanics and collagen microstructure of porcine mitral valve leaflets.

Unidirectional blood flow in the left side of the heart is regulated by the mitral valve. To better understand the mitral valve function, researchers have examined the structural and mechanical properties of the mitral valve leaflets; however, limitations of the previous studies include the use of mechanics- and structure-altering tissue modifications (e.g., optical clearing) that limit the ability to quantify the unique load-dependent reorientation and realignment of the collagen fibers as well as their interrelation with the valve tissue mechanics. Herein, we aimed to circumvent these limitations by utilizing an integrated polarized-light imaging and biaxial testing system for understanding the mechanics-microstructure interrelationship for porcine mitral valve leaflets. We further performed constitutive modeling and evaluated the accuracy of the affine fiber kinematics theory. From the tissue mechanics perspective, the posterior leaflet was more extensible in the radial direction than the anterior leaflet (14.2% difference in radial tissue stretch), while exhibiting smaller collagen and elastin moduli based on the determined constitutive model parameters. From the collagen microstructure's standpoint, the posterior leaflet had smaller increases in optical anisotropy (closely related to the degree of fiber alignment) than the anterior leaflet (32.8±7.7% vs. 50.0±19.7%). Further, the leaflets were found to possess two distinct fiber families - one family oriented along the circumferential tissue direction, and another more disperse family with a 30°-40° offset from the first fiber family. Finally, affine fiber kinematics consistently underpredicted the collagen fiber reorientations Overall, this study improved our understanding of the mitral valve leaflets that is essential for facilitating tissue-emulated valve replacement and cardiac valve modeling frameworks.

Linking the region-specific tissue microstructure to the biaxial mechanical properties of the porcine left anterior descending artery.

Coronary atherosclerosis is the main cause of death worldwide. Advancing the understanding of coronary microstructure-based mechanics is fundamental for the development of therapeutic tools and surgical procedures. Although the passive biaxial properties of the coronary arteries have been extensively explored, their regional differences and the relationship between tissue microstructure and mechanics have not been fully characterized. In this study, we characterized the passive biaxial mechanical properties and microstructural properties of the proximal, medial, and distal regions of the porcine left anterior descending artery (LADA). We also attempted to relate the biaxial stress-stretch response of the LADA and its respective birefringent responses to the polarized light for obtaining information about the load-dependent microstructural variations. We found that the LADA extensibility is reduced in the proximal-to-distal direction and that the medial region exhibits more heterogeneous mechanical behavior than the other two regions. We have also observed highly dynamic microstructural behavior where fiber families realign themselves depending on loading. In addition, we found that the microstructure of the distal region exhibited highly aligned fibers along the longitudinal axis of the artery. To verify this microstructural feature, we imaged the LADA specimens with multi-photon microscopy and observed that the adventitia microstructure transitioned from a random fiber network in the proximal region to highly aligned fibers in the distal region. Our findings could offer new perspectives for understanding coronary mechanics and aid in the development of tissue-engineered vascular grafts, which are currently limited due to their mismatch with native tissue in terms of mechanical properties and microstructural features. STATEMENT OF SIGNIFICANCE: The tissue biomechanics of coronary arteries is fundamental for the development of revascularization techniques such as coronary artery bypass. These therapeutics require a deep understanding of arterial mechanics, microstructure, and mechanobiology to prevent graft failure and reoperation. The present study characterizes the unique regional mechanical and microstructural properties of the porcine left anterior descending artery using biaxial testing, polarized-light imaging, and confocal microscopy. This comprehensive characterization provides an improved understanding of the collagen/elastin architecture in response to mechanical loads using a region-specific approach. The unique tissue properties obtained from this study will provide guidance for the selection of anastomotic sites in coronary artery bypass grafting and for the design of tissue-engineered vascular grafts.

Layer Microdissection of Tricuspid Valve Leaflets for Biaxial Mechanical Characterization and Microstructural Quantification.

The tricuspid valve (TV) regulates the unidirectional flow of unoxygenated blood from the right atrium to the right ventricle. The TV consists of three leaflets, each with unique mechanical behaviors. These variations among the three TV leaflets can be further understood by examining their four anatomical layers, which are the atrialis (A), spongiosa (S), fibrosa (F), and ventricularis (V). While these layers are present in all three TV leaflets, there are differences in their thicknesses and microstructural constituents that further influence their respective mechanical behaviors. This protocol includes four steps to elucidate the layer-specific differences: (i) characterize the mechanical and collagen fiber architectural behaviors of the intact TV leaflet, (ii) separate the composite layers (A/S and F/V) of the TV leaflet, (iii) carry out the same characterizations for the composite layers, and (iv) perform post-hoc histology assessment. This experimental framework uniquely allows the direct comparison of the intact TV tissue to each of its composite layers. As a result, detailed information regarding the microstructure and biomechanical function of the TV leaflets can be collected with this protocol. Such information can potentially be used to develop TV computational models that seek to provide guidance for the clinical treatment of TV disease.

Linking collagen fiber architecture to tissue-level biaxial mechanical behaviors of porcine semilunar heart valve cusps.

The semilunar heart valves regulate the blood flow from the ventricles to the major arteries through the opening and closing of the scallop shaped cusps. These cusps are composed of collagen fibers that act as the primary loading-bearing component. The load-dependent collagen fiber architecture has been previously examined in the existing literature; however, these studies relied on chemical clearing and tissue modifications to observe the underlying changes in response to mechanical loads. In the present study, we address this gap in knowledge by quantifying the collagen fiber orientations and alignments of the aortic and pulmonary cusps through a multi-scale, non-destructive experimental approach. This opto-mechanical approach, which combines polarized spatial frequency domain imaging and biaxial mechanical testing, provides a greater field of view (10-25mm) and faster imaging time (45-50s) than other traditional collagen imaging techniques. The birefringent response of the collagen fibers was fit with a von Mises distribution, while the biaxial mechanical testing data was implemented into a modified full structural model for further analysis. Our results showed that the semilunar heart valve cusps are more extensible in the tissue's radial direction than the circumferential direction under all the varied biaxial testing protocols, together with greater material anisotropy among the pulmonary valve cusps compared to the aortic valve cusps. The collagen fibers were shown to reorient towards the direction of the greatest applied loading and incrementally realign with the increased applied stress. The collagen fiber architecture within the aortic valve cusps were found to be more homogeneous than the pulmonary valve counterparts, reflecting the differences in the physiological environments experienced by these two semilunar heart valves. Further, the von Mises distribution fitting highlighted the presence and contribution of two distinct fiber families for each of the two semilunar heart valves. The results from this work would provide valuable insight into connecting tissue-level mechanics to the underlying collagen fiber architecture-an essential information for the future development of high-fidelity aortic/pulmonary valve computational models.

An in-silico benchmark for the tricuspid heart valve - Geometry, finite element mesh, Abaqus simulation, and result data set.

This article provides Abaqus input files and user subroutines for performing finite element simulations of the tricuspid heart valve with an idealized geometry. Additional post-processing steps to obtain a ParaView visualization file (*.vtk) of the deformed geometry are also provided to allow the readers to use the included ParaView state file (*.pvsm) for customizable visualization and evaluation of the simulation results. We expect this first-of-its-kind in-silico benchmark dataset will facilitate user-friendly simulations considering material nonlinearity, leaflet-to-leaflet contact, and large deformations. Additionally, the information included herein can be used to rapidly evaluate other novel in-silico approaches developed for simulating cardiac valve function. The benchmark can be expanded to consider more complex features of the tricuspid valve function, such as the dynamic annulus motion or the time-varying transvalvular pressure. Interested readers are referred to the companion article (Johnson et al., 2021) for an example application of this in-silico tool for isogeometric analysis of tricuspid valves.

Determination of a Strain Energy Density Function for the Tricuspid Valve Leaflets Using Constant Invariant-Based Mechanical Characterizations.

The tricuspid valve (TV) regulates the blood flow within the right side of the heart. Despite recent improvements in understanding TV mechanical and microstructural properties, limited attention has been devoted to the development of TV-specific constitutive models. The objective of this work is to use the first-of-its-kind experimental data from constant invariant-based mechanical characterizations to determine a suitable invariant-based strain energy density function (SEDF). Six specimens for each TV leaflet are characterized using constant invariant mechanical testing. The data is then fit with three candidate SEDF forms: (i) a polynomial model-the transversely isotropic version of the Mooney-Rivlin model, (ii) an exponential model, and (iii) a combined polynomial-exponential model. Similar fitting capabilities were found for the exponential and the polynomial forms (R2=0.92-0.99 versus 0.91-0.97) compared to the combined polynomial-exponential SEDF (R2=0.65-0.95). Furthermore, the polynomial form had larger Pearson's correlation coefficients than the exponential form (0.51 versus 0.30), indicating a more well-defined search space. Finally, the exponential and the combined polynomial-exponential forms had notably smaller but more eccentric model parameter's confidence regions than the polynomial form. Further evaluations of invariant decoupling revealed that the decoupling of the invariant terms within the exponential form leads to a less satisfactory performance. From these results, we conclude that the exponential form is better suited for the TV leaflets owing to its superb fitting capabilities and smaller parameter's confidence regions.

Effects of enzyme-based removal of collagen and elastin constituents on the biaxial mechanical responses of porcine atrioventricular heart valve anterior leaflets.

The leaflets of the atrioventricular heart valves (AHVs) regulate the one-directional flow of blood through a coordination of the extracellular matrix components, including the collagen fibers, elastin, and glycosaminoglycans. Dysfunction of the AHVs, such as those caused by unfavorable microstructural remodeling, lead to valvular heart diseases and improper blood flow, which can ultimately cause heart failure. In order to better understand the mechanics and remodeling of the AHV leaflets and how therapeutics can inadvertently cause adverse microstructural changes, a systematic characterization of the role of each constituent in the biomechanical properties is appropriate. Previous studies have quantified the contributions of the individual microstructural components to tissue-level behavior for the semilunar valve cusps, but not for the AHV leaflets. In this study, for the first time, we quantify the relationships between microstructure and mechanics of the AHV leaflet using a three-step experimental procedure: (i) biaxial tension and stress relaxation testing of control (untreated) porcine AHV anterior leaflet specimens; (ii) enzyme treatment to remove a portion of either the collagen or elastin constituent; and (iii) biaxial tensile and stress relaxation testing of the constituent-removed (treated) specimens. We have observed that the removal of ∼100% elastin resulted in a ∼10% decrease in the tissue extensibility with biaxial tension and a ∼10% increase in the overall stress reduction with stress relaxation. In contrast, removal of 46% of the collagen content insignificantly affected tissue extensibility with biaxial tension and significantly increased stress decay (10%) with stress relaxation. These findings provide an insight into the microstructure-mechanics relationship of the AHVs and will be beneficial for future developments and refinements of microstructurally informed constitutive models for the simulation of diseased and surgically intervened AHV function. STATEMENT OF SIGNIFICANCE: This study presents, for the first time, a thorough mechanical characterization of the atrioventricular heart valve leaflets before and after enzymatic removal of elastin and collagen. We found that the biaxial tensile properties of elastin-deficient tissues and collagen-deficient are stiffer. The fact of elastin supporting low-stress valve function and collagen as the main load-bearing component was evident in a decrease in the low-tension modulus for elastin-deficient tissues and in the high-tension modulus for collagen-deficient tissues. Our quantification and experimental technique could be useful in predicting the disease-related changes in heart valve mechanics. The information obtained from this work is valuable for refining the constitutive models that describe the essential microstructure-mechanics relationship.

Parameterization, geometric modeling, and isogeometric analysis of tricuspid valves.

Approximately 1.6 million patients in the United States are affected by tricuspid valve regurgitation, which occurs when the tricuspid valve does not close properly to prevent backward blood flow into the right atrium. Despite its critical role in proper cardiac function, the tricuspid valve has received limited research attention compared to the mitral and aortic valves on the left side of the heart. As a result, proper valvular function and the pathologies that may cause dysfunction remain poorly understood. To promote further investigations of the biomechanical behavior and response of the tricuspid valve, this work establishes a parameter-based approach that provides a template for tricuspid valve modeling and simulation. The proposed tricuspid valve parameterization presents a comprehensive description of the leaflets and the complex chordae tendineae for capturing the typical three-cusp structural deformation observed from medical data. This simulation framework develops a practical procedure for modeling tricuspid valves and offers a robust, flexible approach to analyze the performance and effectiveness of various valve configurations using isogeometric analysis. The proposed methods also establish a baseline to examine the tricuspid valve's structural deformation, perform future investigations of native valve configurations under healthy and disease conditions, and optimize prosthetic valve designs.

A pilot study on biaxial mechanical, collagen microstructural, and morphological characterizations of a resected human intracranial aneurysm tissue.

Intracranial aneurysms (ICAs) are focal dilatations that imply a weakening of the brain artery. Incidental rupture of an ICA is increasingly responsible for significant mortality and morbidity in the American's aging population. Previous studies have quantified the pressure-volume characteristics, uniaxial mechanical properties, and morphological features of human aneurysms. In this pilot study, for the first time, we comprehensively quantified the mechanical, collagen fiber microstructural, and morphological properties of one resected human posterior inferior cerebellar artery aneurysm. The tissue from the dome of a right posterior inferior cerebral aneurysm was first mechanically characterized using biaxial tension and stress relaxation tests. Then, the load-dependent collagen fiber architecture of the aneurysm tissue was quantified using an in-house polarized spatial frequency domain imaging system. Finally, optical coherence tomography and histological procedures were used to quantify the tissue's microstructural morphology. Mechanically, the tissue was shown to exhibit hysteresis, a nonlinear stress-strain response, and material anisotropy. Moreover, the unloaded collagen fiber architecture of the tissue was predominantly aligned with the testing Y-direction and rotated towards the X-direction under increasing equibiaxial loading. Furthermore, our histological analysis showed a considerable damage to the morphological integrity of the tissue, including lack of elastin, intimal thickening, and calcium deposition. This new unified characterization framework can be extended to better understand the mechanics-microstructure interrelationship of aneurysm tissues at different time points of the formation or growth. Such specimen-specific information is anticipated to provide valuable insight that may improve our current understanding of aneurysm growth and rupture potential.

Manifold learning based data-driven modeling for soft biological tissues.

Data-driven modeling directly utilizes experimental data with machine learning techniques to predict a material's response without the necessity of using phenomenological constitutive models. Although data-driven modeling presents a promising new approach, it has yet to be extended to the modeling of large-deformation biological tissues. Herein, we extend our recent local convexity data-driven (LCDD) framework (He and Chen, 2020) to model the mechanical response of a porcine heart mitral valve posterior leaflet. The predictability of the LCDD framework by using various combinations of biaxial and pure shear training protocols are investigated, and its effectiveness is compared with a full structural, phenomenological model modified from Zhang et al. (2016) and a continuum phenomenological Fung-type model (Tong and Fung, 1976). We show that the predictivity of the proposed LCDD nonlinear solver is generally less sensitive to the type of loading protocols (biaxial and pure shear) used in the data set, while more sensitive to the insufficient coverage of the experimental data when compared to the predictivity of the two selected phenomenological models. While no pre-defined functional form in the material model is necessary in LCDD, this study reinstates the importance of having sufficiently rich data coverage in the date-driven and machine learning type of approaches. It is also shown that the proposed LCDD method is an enhancement over the earlier distance-minimization data-driven (DMDD) against noisy data. This study demonstrates that when sufficient data is available, data-driven computing can be an alternative method for modeling complex biological materials.

A Pilot Study on Linking Tissue Mechanics with Load-Dependent Collagen Microstructures in Porcine Tricuspid Valve Leaflets.

The tricuspid valve (TV) is composed of three leaflets that coapt during systole to prevent deoxygenated blood from re-entering the right atrium. The connection between the TV leaflets' microstructure and the tissue-level mechanical responses has yet to be fully understood in the TV biomechanics society. This pilot study sought to examine the load-dependent collagen fiber architecture of the three TV leaflets, by employing a multiscale, combined experimental approach that utilizes tissue-level biaxial mechanical characterizations, micro-level collagen fiber quantification, and histological analysis. Our results showed that the three TV leaflets displayed greater extensibility in the tissues' radial direction than in the circumferential direction, consistently under different applied biaxial tensions. Additionally, collagen fibers reoriented towards the direction of the larger applied load, with the largest changes in the alignment of the collagen fibers under radially-dominant loading. Moreover, collagen fibers in the belly region of the TV leaflets were found to experience greater reorientations compared to the tissue region closer to the TV annulus. Furthermore, histological examinations of the TV leaflets displayed significant regional variation in constituent mass fraction, highlighting the heterogeneous collagen microstructure. The combined experimental approach presented in this work enables the connection of tissue mechanics, collagen fiber microstructure, and morphology for the TV leaflets. This experimental methodology also provides a new research platform for future developments, such as multiscale models for the TVs, and the design of bioprosthetic heart valves that could better mimic the mechanical, microstructural, and morphological characteristics of the native tricuspid valve leaflets.

A pilot in silico modeling-based study of the pathological effects on the biomechanical function of tricuspid valves.

Current clinical assessment of functional tricuspid valve regurgitation relies on metrics quantified from medical imaging modalities. Although these clinical methodologies are generally successful, the lack of detailed information about the mechanical environment of the valve presents inherent challenges for assessing tricuspid valve regurgitation. In the present study, we have developed a finite element-based in silico model of one porcine tricuspid valve (TV) geometry to investigate how various pathological conditions affect the overall biomechanical function of the TV. There were three primary observations from our results. Firstly, the results of the papillary muscle (PM) displacement study scenario indicated more pronounced changes in the TV biomechanical function. Secondly, compared to uniform annulus dilation, nonuniform dilation scenario induced more evident changes in the von Mises stresses (83.8-125.3 kPa vs 65.1-84.0 kPa) and the Green-Lagrange strains (0.52-0.58 vs 0.47-0.53) for the three TV leaflets. Finally, results from the pulmonary hypertension study scenario showed opposite trends compared to the PM displacement and annulus dilation scenarios. Furthermore, various chordae rupture scenarios were simulated, and the results showed that the chordae tendineae attached to the TV anterior and septal leaflets may be more critical to proper TV function. This in silico modeling-based study has provided a deeper insight into the tricuspid valve pathologies that may be useful, with moderate extensions, for guiding clinical decisions. NOVELTY STATEMENT: The novelties of the research are summarized below: A comprehensive in silico pilot study of how isolated functional tricuspid regurgitation pathologies and ruptured chordae tendineae would alter the tricuspid valve function; An extensive analysis of the tricuspid valve function, including mechanical quantities (eg, the von Mises stress and the Green-Lagrange strain) and clinically-relevant geometry metrics (eg, the tenting area and the coaptation height); and A developed computational modeling pipeline that can be extended to evaluate patient-specific tricuspid valve geometries and enhance the current clinical diagnosis and treatment of tricuspid regurgitation.

Mechanics of Porcine Heart Valves' Strut Chordae Tendineae Investigated as a Leaflet-Chordae-Papillary Muscle Entity.

Proper blood flow through the atrioventricular heart valves (AHVs) relies on the holistic function of the valve and subvalvular structures, and a failure of any component can lead to life-threatening heart disease. A comprehension of the mechanical characteristics of healthy valvular components is necessary for the refinement of heart valve computational models. In previous studies, the chordae tendineae have been mechanically characterized as individual structures, usually in a clamping-based approach, which may not accurately reflect the in vivo chordal interactions with the leaflet insertion and papillary muscles. In this study, we performed uniaxial mechanical testing of strut chordae tendineae of the AHVs under a unique tine-based leaflet-chordae-papillary muscle testing to observe the chordae mechanics while preserving the subvalvular component interactions. Results of this study provided insight to the disparity of chordae tissue stress-stretch responses between the mitral valve (MV) and the tricuspid valve (TV) under their respective emulated physiological loading. Specifically, strut chordae tendineae of the MV anterior leaflet had peak stretches of 1.09-1.16, while peak stretches of 1.08-1.11 were found for the TV anterior leaflet strut chordae. Constitutive parameters were also derived for the chordae tissue specimens using an Ogden model, which is useful for AHV computational model refinement. Results of this study are beneficial to the eventual improvement of treatment methods for valvular disease.