Within each of the four layers of mitral valve (MV) leaflet tissues there resides a heterogeneous population of interstitial cells that maintain the structural integrity of the MV tissue via protein biosynthesis and enzymatic degradation. There is increasing evidence that tissue stress-induced MV interstitial cell (MVIC) deformations can have deleterious effects on their biosynthetic states that are potentially related to the reduction of tissue-level maintenance and to subsequent organ-level failure. To better understand the interrelationships between tissue-level loading and cellular responses, we developed the following integrated experimental-computational approach. Since in-vivo cellular deformations are not directly measurable, we quantified the in-situ layer-specific MVIC deformations for each of the four layers under a controlled biaxial tension loading device coupled to multi-photon microscopy. Next, we explored the interrelationship between the MVIC stiffness and deformation to layer-specific tissue mechanical and structural properties using a macro-micro finite element computational model. Experimental results indicated that the MVICs in the fibrosa and ventricularis layers deformed significantly more than those in the atrialis and spongiosa layers, reaching a nucleus aspect ratio of 3.3 under an estimated maximum physiological tension of 150 N/m. The simulated MVIC moduli for the four layers were found to be all within a narrow range of 4.71–5.35 kPa, suggesting that MVIC deformation is primarily controlled by each tissue layer’s respective structure and mechanical behavior rather than the intrinsic MVIC stiffness. This novel result further suggests that while the MVICs may be phenotypically and biomechanically similar throughout the leaflet, they experience layer-specific mechanical stimulatory inputs due to distinct extracellular matrix architecture and mechanical behaviors of the four MV leaflet tissue layers. This also suggests that MVICs may behave in a layer-specific manner in response to mechanical stimuli in both normal and surgically modified MVs.

Recent long-term studies showed an unsatisfactory recurrence rate of severe mitral regurgitation 3–5 years after surgical repair, suggesting that excessive tissue stresses and the resulting strain-induced tissue failure are potential etiological factors controlling the success of surgical repair for treating mitral valve (MV) diseases. We hypothesized that restoring normal MV tissue stresses in MV repair techniques would ultimately lead to improved repair durability through the restoration of MV normal homeostatic state. Therefore, we developed a micro- and macro- anatomically accurate MV finite element model by incorporating actual fiber microstructural architecture and a realistic structure-based constitutive model. We investigated MV closing behaviors, with extensive in vitro data used for validating the proposed model. Comparative and parametric studies were conducted to identify essential model fidelity and information for achieving desirable accuracy. More importantly, for the first time, the interrelationship between the local fiber ensemble behavior and the organ-level MV closing behavior was investigated using a computational simulation. These novel results indicated not only the appropriate parameter ranges, but also the importance of the microstructural tuning (i.e., straightening and re-orientation) of the collagen/elastin fiber networks at the macroscopic tissue level for facilitating the proper coaptation and natural functioning of the MV apparatus under physiological loading at the organ level. The proposed computational model would serve as a logical first step toward our long-term modeling goal—facilitating simulation-guided design of optimal surgical repair strategies for treating diseased MVs with significantly enhanced durability.

Valvular heart diseases are complex disorders, varying in pathophysiological mechanism and affected valve components. Understanding the effects of these diseases on valve functionality requires a thorough characterization of the mechanics and structure of the healthy heart valves. In this study, we performed biaxial mechanical experiments with extensive testing protocols to examine the mechanical behaviors of the mitral valve and tricuspid valve leaflets. We also investigated the effect of loading rate, testing temperatures, species (porcine versus ovine hearts), and age (juvenile vs adult ovine hearts) on the mechanical responses of the leaflet tissues. In addition, we evaluated the structure of chordae tendineae within each valve and performed histological analysis on each atrioventricular leaflet. We found all tissues displayed a characteristic nonlinear anisotropic mechanical response, with radial stretches on average 30.7% higher than circumferential stretches under equibiaxial physiological loading. Tissue mechanical responses showed consistent mechanical stiffening in response to increased loading rate and minor temperature dependence in all five atrioventricular heart valve leaflets. Moreover, our anatomical study revealed similar chordae quantities in the porcine mitral (30.5 ± 1.43 chords) and tricuspid valves (35.3 ± 2.45 chords) but significantly more chordae in the porcine than the ovine valves (p < 0.010). Our histological analyses quantified the relative thicknesses of the four distinct morphological layers in each leaflet. This study provides a comprehensive database of the mechanics and structure of the atrioventricular valves, which will be beneficial to development of subject-specific atrioventricular valve constitutive models and toward multi-scale biomechanical investigations of heart valve function to improve valvular disease treatments.

Estimation of regional tissue stresses in the functioning heart valve remains an important goal in our understanding of normal valve function and in developing novel engineered tissue strategies for valvular repair and replacement. Methods to accurately estimate regional tissue stresses are thus needed for this purpose, and in particular to develop accurate, statistically informed means to validate computational models of valve function. Moreover, there exists no currently accepted method to evaluate engineered heart valve tissues and replacement heart valve biomaterials undergoing valvular stresses in blood contact. While we have utilized mitral valve anterior leaflet valvuloplasty as an experimental approach to address this limitation, robust computational techniques to estimate implant stresses are required. In the present study, we developed a novel numerical analysis approach for estimation of the in-vivo stresses of the central region of the mitral valve anterior leaflet (MVAL) delimited by a sonocrystal transducer array. The in-vivo material properties of the MVAL were simulated using an inverse FE modeling approach based on three pseudo-hyperelastic constitutive models: the neo-Hookean, exponential-type isotropic, and full collagen-fiber mapped transversely isotropic models. A series of numerical replications with varying structural configurations were developed by incorporating measured statistical variations in MVAL local preferred fiber directions and fiber splay. These model replications were then used to investigate how known variations in the valve tissue microstructure influence the estimated ROI stresses and its variation at each time point during a cardiac cycle. Simulations were also able to include estimates of the variation in tissue stresses for an individual specimen dataset over the cardiac cycle. Of the three material models, the transversely anisotropic model produced the most accurate results, with ROI averaged stresses at the fully-loaded state of 432.6±46.5 kPa and 241.4±40.5 kPa in the radial and circumferential directions, respectively. We conclude that the present approach can provide robust instantaneous mean and variation estimates of tissue stresses of the central regions of the MVAL.

In this study, we evaluated the hypothesis that the constituent fibers follow an affine deformation kinematic model for planar collagenous tissues. Results from two experimental datasets were utilized, taken at two scales (nanometer and micrometer), using mitral valve anterior leaflet (MVAL) tissues as the representative tissue. We simulated MVAL collagen fiber network as an ensemble of undulated fibers under a generalized two-dimensional deformation state, by representing the collagen fibrils based on a planar sinusoidally shaped geometric model. The proposed approach accounted for collagen fibril amplitude, crimp period, and rotation with applied macroscopic tissue-level deformation. When compared to the small angle x-ray scattering measurements, the model fit the data well, with an r 2 ¼ 0.976. This important finding suggests that, at the homogenized tissue-level scale of~1 mm, the collagen fiber network in the MVAL deforms according to an affine kinematics model. Moreover, with respect to understanding its function, affine kinematics suggests that the constituent fibers are largely noninteracting and deform in accordance with the bulk tissue. It also suggests that the collagen fibrils are tightly bounded and deform as a single fiber-level unit. This greatly simplifies the modeling efforts at the tissue and organ levels, because affine kinematics allows a straightforward connection between the macroscopic and local fiber strains. It also suggests that the collagen and elastin fiber networks act independently of each other, with the collagen and elastin forming long fiber networks that allow for free rotations. Such freedom of rotation can greatly facilitate the observed high degree of mechanical anisotropy in the MVAL and other heart valves, which is essential to heart valve function. These apparently novel findings support modeling efforts directed toward improving our fundamental understanding of tissue biomechanics in healthy and diseased conditions.

Mechanical stress is one of the major aetiological factors underlying soft-tissue remodelling, especially for the mitral valve (MV). It has been hypothesized that altered MV tissue stress states lead to deviations from cellular homeostasis, resulting in subsequent cellular activation and extracellular matrix (ECM) remodelling. However, a quantitative link between alterations in the organlevel in vivo state and in vitro-based mechanobiology studies has yet to be made. We thus developed an integrated experimental-computational approach to elucidate MV tissue and interstitial cell responses to varying tissue strain levels. Comprehensive results at different length scales revealed that normal responses are observed only within a defined range of tissue deformations, whereas deformations outside of this range lead to hypo-and hyper-synthetic responses, evidenced by changes in a-smooth muscle actin, type I collagen, and other ECM and cell adhesion molecule regulation. We identified MV interstitial cell deformation as a key player in leaflet tissue homeostatic regulation and, as such, used it as the metric that makes the critical link between in vitro responses to simulated equivalent in vivo behaviour. Results indicated that cell responses have a delimited range of in vivo deformations that maintain a homeostatic response, suggesting that deviations from this range may lead to deleterious tissue remodelling and failure.

Little is known about how valvular tissues grow and remodel in response to altered loading. In this work, we used the pregnancy state to represent a non-pathological cardiac volume overload that distends the mitral valve (MV), using both extant and new experimental data and a modified form of our MV structural constitutive model. We determined that there was an initial period of permanent set-like deformation where no remodelling occurs, followed by a remodelling phase that resulted in near-complete restoration of homeostatic tissue-level behaviour. In addition, we observed that changes in the underlying MV interstitial cell (MVIC) geometry closely paralleled the tissue-level remodelling events, undergoing an initial passive perturbation followed by a gradual recovery to the pre-pregnant state. Collectively, these results suggest that valvular remodelling is actively mediated by average MVIC deformations (i.e. not cycle to cycle, but over a period of weeks). Moreover, tissue-level remodelling is likely to be accomplished by serial and parallel additions of fibrillar material to restore the mean homeostatic fibre stress and MVIC geometries. This finding has significant implications in efforts to understand and predict MV growth and remodelling following such events as myocardial infarction and surgical repair, which also place the valve under altered loading conditions.

Intracranial aneurysms (ICAs) are focal dilations in the brain's arteries. When left untreated, ICAs can grow to the point of rupture, accounting for 50-80% of subarachnoid hemorrhage cases. Current treatments include surgical clipping and endovascular coil embolization to block circulation into the aneurysmal space for preventing aneurysm rupture. As for endovascular embolization, patients could experience aneurysm recurrence due to an incomplete coil filling or compaction over time. The use of shape memory polymers (SMPs) in place of conventional platinum coils could provide more control and predictability for mitigating these complications. This study was focused on characterization of an aliphatic urethane-based SMP to evaluate its potential as a novel biomaterial for endovascular embolization. Twelve compositions of the SMP were synthesized and their thermomechanical properties together with the shape recovery behavior were comprehensively investigated. Our results showed that the SMPs experienced a significant decrease in storage and loss moduli as heated above their glass transition temperatures (32.3-83.2 °C), and that all SMPs were thermally stable up to 265 °C. Moreover, the SMPs exhibited both composition-dependent stress relaxation and a decrease in elastic modulus during cyclic loading. The shape recovery time was less than 11 s for all SMP compositions, which is sufficiently short for shape changing during embolization procedures. Several candidate compositions were identified, which possess a glass transition temperature above body temperature (37 °C) and below the threshold of causing tissue damage (45 °C). They also exhibit high material strength and low stress relaxation behavior, suggesting their potential applicability to endovascular embolization of ICAs.