Immersed boundary-finite element model of fluid-structure interaction in the aortic root

It has long been recognized that aortic root elasticity helps to ensure efficient aortic valve closure, but our understanding of the functional importance of the elasticity and geometry of the aortic root continues to evolve as increasingly detailed in vivo imaging data become available. Herein, we describe fluid-structure interaction models of the aortic root, including the aortic valve leaflets, the sinuses of Valsalva, the aortic annulus, and the sinotubular junction, that employ a version of Peskin's immersed boundary (IB) method with a finite element (FE) description of the structural elasticity. We develop both an idealized model of the root with three-fold symmetry of the aortic sinuses and valve leaflets, and a more realistic model that accounts for the differences in the sizes of the left, right, and noncoronary sinuses and corresponding valve cusps. As in earlier work, we use fiber-based models of the valve leaflets, but this study extends earlier IB models of the aortic root by employing incompressible hyperelastic models of the mechanics of the sinuses and ascending aorta using a constitutive law fit to experimental data from human aortic root tissue. In vivo pressure loading is accounted for by a backwards displacement method that determines the unloaded configurations of the root models. Our models yield realistic cardiac output at physiological pressures, with low transvalvular pressure differences during forward flow, minimal regurgitation during valve closure, and realistic pressure loads when the valve is closed during diastole. Further, results from high-resolution computations demonstrate that IB models of the aortic valve are able to produce essentially grid-converged dynamics at practical grid spacings for the high-Reynolds number flows of the aortic root

The living aortic valve: From molecules to function.

The aortic valve lies in a unique hemodynamic environment, one characterized by a range of stresses (shear stress, bending forces, loading forces and strain) that vary in intensity and direction throughout the cardiac cycle. Yet, despite its changing environment, the aortic valve opens and closes over 100,000 times a day and, in the majority of human beings, will function normally over a lifespan of 70-90 years. Until relatively recently heart valves were considered passive structures that play no active role in the functioning of a valve, or in the maintenance of its integrity and durability. However, through clinical experience and basic research the aortic valve can now be characterized as a living, dynamic organ with the capacity to adapt to its complex mechanical and biomechanical environment through active and passive communication between its constituent parts. The clinical relevance of a living valve substitute in patients requiring aortic valve replacement has been confirmed. This highlights the importance of using tissue engineering to develop heart valve substitutes containing living cells which have the ability to assume the complex functioning of the native valve

Glycosaminoglycan Stabilization Reduces Tissue Buckling in Bioprosthetic Heart Valves

Currently, bioprosthetic heart valves are crosslinked with glutaraldehyde to prevent tissue degradation and to reduce tissue antigenicity. Glutaraldehyde forms stable crosslinks with collagen via a Schiff base reaction of the aldehyde with an amine group of the hydroxylysine/lysine in collagen. However, within a decade of implantation, 20-30% of these bioprostheses will become dysfunctional and over 50% will fail due to degeneration within 12-15 years post-operatively. Gylcosaminoglycans, a major constituent of valvular tissue, play an important role in maintaining a hydrated environment necessary for absorbing compressive loads, modulating shear stresses, and resisting tissue buckling. One of the disadvantages of glutaraldehyde crosslinking is its incomplete stabilization of GAGs, which lack the amine functionalities necessary for fixation by aldehyde addition. Previous studies have reported a greater depth of buckling in glutaraldehyde crosslinked aortic valves, one of the major causes of failure in these bioprostheses. Buckling occurs at sites of sharp bending, producing large stresses that can eventually lead to mechanical fatigue and consequent valvular degeneration. Local structural collapse occurs at these areas of tissue buckling to minimize compressive stresses, which subsequently causes a reduction in tissue length. Previous studies have reported the loss of GAGs in glutaraldehyde crosslinked porcine cusps during fixation, storage, in vitro fatigue experimentation, and in vivo subdermal implantation due to enzyme-mediated GAG degradation. Additionally, GAG loss has been observed in failed porcine bioprosthetic heart valves following clinical use. Therefore, to evaluate the potential role of GAGs in reduction of buckling in bioprosthetic heart valves, we used two 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) based crosslinking chemistries that link GAG carboxyl groups to the amine groups of proteins. Neomycin trisulfate, a hyaluronidase inhibitor, was employed to effectively stabilize the GAGs and subsequently prevent its enzymatic degradation. Previously, stabilization of valvular GAGs using neomycin trisulfate, a GAG-enzyme inhibitor, coupled with carbodiimide fixation chemistry was found to resist in vitro and in vivo enzymatic degradation of GAGs. Thus, using the above-mentioned GAG-targeted fixation strategies, we demonstrate that the retention of valvular GAGs reduces the extent of buckling in bioprosthetic heart valves, which may subsequently improve the durability of these bioprostheses

Hemodynamics and Mechanobiology of Aortic Valve Inflammation and Calcification

Cardiac valves function in a mechanically complex environment, opening and closing close to a billion times during the average human lifetime, experiencing transvalvular pressures and pulsatile and oscillatory shear stresses, as well as bending and axial stress. Although valves were originally thought to be passive pieces of tissue, recent evidence points to an intimate interplay between the hemodynamic environment and biological response of the valve. Several decades of study have been devoted to understanding these varied mechanical stimuli and how they might induce valve pathology. Here, we review efforts taken in understanding the valvular response to its mechanical milieu and key insights gained from in vitro and ex vivo whole-tissue studies in the mechanobiology of aortic valve remodeling, inflammation, and calcification

Biomechanical behavior of bioprosthetic heart valve heterograft tissues: characterization, simulation, and performance

The use of replacement heart valves continues to grow due to the increased prevalence of valvular heart disease resulting from an ageing population. Since bioprosthetic heart valves (BHVs) continue to be the preferred replacement valve, there continues to be a strong need to develop better and more reliable BHVs through and improved the general understanding of BHV failure mechanisms. The major technological hurdle for the lifespan of the BHV implant continues to be the durability of the constituent leaflet biomaterials, which if improved can lead to substantial clinical impact. In order to develop improved solutions for BHV biomaterials, it is critical to have a better understanding of the inherent biomechanical behaviors of the leaflet biomaterials, including chemical treatment technologies, the impact of repetitive mechanical loading, and the inherent failure modes. This review seeks to provide a comprehensive overview of these issues, with a focus on developing insight on the mechanisms of BHV function and failure. Additionally, this review provides a detailed summary of the computational biomechanical simulations that have been used to inform and develop a higher level of understanding of BHV tissues and their failure modes. Collectively, this information should serve as a tool not only to infer reliable and dependable prosthesis function, but also to instigate and facilitate the design of future bioprosthetic valves and clinically impact cardiology

The Mechanical Properties of Native Porcine Aortic and Pulmonary Heart Valve Leaflets

Aortic heart valves and their replacements fail in vivo for reasons that are not fullyunderstood. Mechanical evaluation and simulations of the function of native aorticvalves and their replacements have been limited to tensile and biaxial tests that seek toquantify the behavior of leaflet tissues as a homogenous whole. However, it is widelyunderstood that valvular tissues are multi-layered structures composed of collagen,elastin, and glycosaminoglycans. The mechanical behavior of these layers within intactvalve leaflet tissues and their interactions are unknown. In addition, pulmonary valveshave been used as substitutes for diseased aortic valves without any real understanding ofthe mechanical differences between the aortic and pulmonary valves. The pulmonaryvalve operates in an environment significantly different than that of the aortic valve and,thus, mechanical behavioral differences between the two valve leaflets may exist. In thisstudy, we sought to determine the mechanical properties of the porcine aortic andpulmonary valves in flexure, and to determine the mechanical relationship between theleaflet layers: the fibrosa, spongiosa, and ventricularis. This was accomplished bydeveloping a novel flexure mechanical testing device that allowed for the determinationof the flexural stiffness of the leaflet tissue was determined using Bernoulli-Eulerbending. Moreover, transmural strains were quantified and used to determine thelocation of the neutral axis to determine if differences existed in the layer properties ofthe fibrosa and ventricularis. To contrast the flexural studies, biaxial experiments werealso performed on the aortic and pulmonary valves to determine the mechanicaldifferences in the tensile behavior between the two leaflets.Results indicated that the pulmonary valve is stiffer than the aortic valve inflexure but less compliant than the aortic valve in biaxial tensile tests. The interactionsbetween the layers of the leaflets suggest an isotropic mechanical response in flexure, butdo so through mechanisms that are not fully understood. For heart valve leafletreplacement therapy, this study illustrates the biomechanical differences between theaortic and pulmonary valve leaflets and emphasizes the need to fully characterize the twoas separate but related entities. Understanding the interactions of microscopic structuressuch as collagen and elastin fibers is critical to understanding the response of the tissue asa whole and how all these elements combine to provide a functioning component of theorgan system

Platform Technologies to Advance Clinically Relevant Tissue Engineered Heart Valve Products

Diseased heart valves are commonly replaced by mechanical, bioprosthetic, or allograft heart valves. These replacements provide major improvements in cardiac function and quality of life, but have significant limitations and eventually require surgical replacement within 15-20 years. These risks are particularly prominent in pediatric patients and young adults. The field of tissue engineering and regenerative medicine, which combines scaffolds and cells, holds great promise in developing living replacement heart valves that would self-repair and grow in size along with the growing children. The long-term goal of this project is to generate living, tissue-engineered heart valves from biological scaffolds and autologous stem cells – a goal that hinges on our ability to create tissue devices that withstand mechanical stresses immediately upon implantation without posing risks of immunological rejection. We hypothesized that these valves can be generated by optimal integration of three main factors: acellular heart valve root scaffolds, autologous stem cells, and construct preconditioning in a bioreactor. Furthermore, we hypothesized that the valves would not be generated without advanced bioreactor systems for the development, conditioning, and translation to clinical practice. To reach this goal, we developed integrated platform technologies for complete aortic valve root (AVR) decellularization, stem cell seeding, and dynamic conditioning before implantation. Unique features include universal “no touch” valve-mounting devices, decellularization in a purpose-designed pulsatile perfusion system, and techniques for in vitro re-vitalization with adipose tissue-derived stem cells (hADSCs) followed by progressive conditioning in our heart valve bioreactors. Acellular porcine AVRs seeded with autologous (sheep) ADSCs were implanted in 10 sheep as right ventricle to pulmonary artery shunts with complete clamping of the pulmonary aorta. Results showed perfect decellularization of the entire porcine AVR and almost complete seeding with ADSCs. Bioreactor studies revealed stem cell pre-differentiation into cells resembling valvular interstitial cells as a response to dynamic stimulation. Animal studies with follow-ups to 12 months are ongoing. Novel customized devices and bioreactor systems are vital to the successful development of tissue engineered heart valve products, especially in preparation for clinical translation. Herein is described some of the basic equipment and expertise necessary for the successful development of tissue-engineered cardiovascular products

Quantification of leaflet flutter in bioprosthetic heart valves using fluid-structure interaction analysis

Many studies have indicated that leaflet fluttering and associated bending in biopros-thetic heart valves (BHVs) is an important criterion in determining the durability of BHVimplants. In this thesis work, a computational methodology for the flutter quantificationof BHV leaflets is presented using an immersogeometric fluid–structure interaction (FSI)framework. The proposed approach is based upon displacement tracking of the BHV leafletfree edges. Integrating over the discrete Fourier transform of free edge displacement data,the energy spectral density is computed for a measure of leaflet flutter. This methodologyseeks to improve approaches used in experimental flutter quantification through utiliza-tion of highly accurate simulation solutions and visualizations to capture a measurement ofleaflet flutter. A set of sampling cases with varying valve material thickness are generatedand FSI-based flutter quantification is performed to investigate the effect of leaflet materialthickness on the presence of flutter and bending in BHVs