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

A study of chemically treated pericardia to manufacture the leaflets of percutaneous heart valves : biomechanical analyses and modelisation

Contexte: En raison de l'utilisation répandue des valvules cardiaques aortiques prothétiques, il est extrêmement important d'en étudier la biofonctionnalité, la biodurabilité et la biocompatibilité. Les valves mécaniques ont une excellente durabilité. Cependant, en raison des traitements anticoagulants, il existe des risques de thromboembolique et hémorragique. Les valves polymériques ont une faible résistance à la calcification et à la thrombose. À cet égard, les valves biologiques sont préférables. Plus récemment, les chirurgiens et les cardiologues ont développe à l'implantation de valves aortiques percutanées, plutôt qu’à la chirurgie ouverte pour traiter les patients âgés et fragiles. Cependant, la durabilité des bioprothèses soulève toujours des questions reliées au sertissage et l’expansion lors de l'implantation. Comme la performance des bioprothèses dépend de l'architecture et du comportement mécanique du tissu sélectionné, il est nécessaire de sélectionner le tissu le plus approprié pour fabriquer ces prothèses. Objectifs: Il s’agit d’identifier le tissu le plus approprié avec la plus longue durabilité pour fabriquer des valvules cardiaques en comparant les propriétés mécaniques et histologiques des péricardes équin, porcin et d’âne par rapport à celles du péricarde bovin et des feuillets de la valve aortique humaine. Hypothèse: La durabilité des valves cardiaques bioprothétiques est largement déterminée par les caractéristiques histologiques et mécaniques des tissus des feuillets. Par conséquent, la sélection du péricarde selon sa structure histologique et ses propriétés mécaniques permettra d’augmenter la durée de vie de ces prothèses. Méthodologie: 1. Étude des structures de collagène des tissus sélectionnés. 2. Étude des propriétés mécaniques des tissus et évaluation de leur durabilité avec différents tests mécaniques. 3. Extraction des propriétés hyperélastiques et viscoélastiques biaxiales à l'aide des modèles appropriés. 4. Application du modèles d'éléments finis est appliqué en utilisant les propriétés mécaniques extraites pour évaluer la déhiscence possible de la valve et le stress sous la charge physiologique. Résultats: Le péricarde d’âne et le péricarde équin ont démontré une architecture ondulée de faisceaux de collagène semblable à celle du péricarde bovin. L’architecture ondulée du péricarde peut convenir aux valves aortiques transcutanées car elles sont moins susceptibles d'être délaminées lors du sertissage. Selon des tests mécaniques, les pourcentages de relaxation des différents péricardes équin (16%), âne (28%) et bovin (21%) étaient supérieurs à ceux du péricarde porcin (11%) et similaires aux feuillets valvulaires aortiques humains natifs (21%). En particulier, le péricarde porcin a démontré un comportement plus rigide (module d'élasticité plus élevé), basé sur sa plus grande amplitude d'énergie de déformation et la pente moyenne des courbes contrainte-étirement. Ce tissu était également moins extensible que les deux autres péricardes et les feuillets humains, en raison de sa souche aréale inférieure. En général, les propriétés mécaniques du péricarde d’âne sont plus proches des feuillets valvulaires humains. De plus, le modèle âne n'a induit que des régions localisées à faible stress pendant les phases systolique et diastolique du cycle cardiaque. En outre, une diminution des contraintes mécaniques sur les feuillets bioprothétiques devrait contribuer à réduire la dégénérescence des tissus et augmenter la durabilité à long terme de la valve. Conclusion: D'après nos observations, les spécimens péricardiques se sont comportés comme des tissus anisotropes et non linéaires - bien caractérisés par des modèles constitutifs. Les résultats indiquent que le péricarde d'âne est mécaniquement et histologiquement plus approprié pour la fabrication de prothèses valvulaires cardiaques que le péricarde bovin. Les résultats de cette étude peuvent être utilisés dans la conception et la fabrication de valvules cardiaques bioprothétiques percutanéei.Background: Due to the widespread use of prosthetic aortic heart valves, investigating these prostheses in terms of biofunctionality, biodurability and biocompatibility is of considerable importance. Mechanical heart valves (MHVs) have excellent durability; however, due to the long-term use of anticoagulants, thromboembolism and hemorrhage remain a possibility. Polymeric valves have a low resistance to calcification and thromboembolism. In this respect, biological valves are preferred. In recent years, surgeons and cardiologists have also used transcatheter aortic valve implantation (TAVI) due to its superiority over the open-heart surgery to treat elderly and frail patients. However, the long-term durability of the commercially available bioprosthesesstill raises questions related to crimping and ballooning at the implantation. The function and performance of the bioprostheses depend on the collagen architecture and mechanical behaviors of the pericardial tissue. Therefore, it is necessary to select the most appropriate pericardia to manufacture these prostheses. Objectives: To identify the most appropriate tissue with a long durability to make bioprosthetic heart valves by analyzing the mechanical and histological properties of the equine, porcine, and donkey pericardia, with respect to those of the bovine pericardium and human aortic valve leaflets. Hypothesis: The long term durability of bioprosthetic heart valves is largely determined by the leaflet tissues. Consequently, selecting the pericardium based on its adequate mechanical property and histological structure will increase the lifetime of these prostheses. Methodologies: 1. Histological analysis was performed to investigate the collagen structures of the selected tissues. 2. Different mechanical tests (uniaxial tests, biaxial tests, and stress relaxation tests) were performed to determine the mechanical properties of the tissues and to evaluate their durability. 3. The biaxial hyperelastic and viscoelastic properties of the selected tissues were extracted using the appropriate models. 4. The finite element model was applied using the extracted mechanical properties to evaluate valve dehiscence and stress under physiological loadings. Results: The donkey and equine pericardia showed a wavy collagen bundle architecture similar to the bovine pericardium. The wavy pericardia may be suitable for the transcatheter aortic valves (TAVs) because they are less likely to be delaminated during crimping. According to the mechanical tests, the relaxation percentages of the equine (16%), donkey (28%), and bovine (21%) pericardia were greater than that of the porcine (11%) pericardium and similar to that of the native human aortic valve leaflets (21%). In particular, the porcine pericardium exhibited a stiffer behavior (higher elastic modulus), based on its greater strain energy magnitude and the average slope of stress-stretch curves. This tissue was also less distensible than the other two pericardia and the native leaflets, due to its lower areal strain. In general, among the pericardia analyzed, the mechanical properties of the donkey pericardium are closer to that of the native leaflets. Furthermore, the donkey model showed low stress regions during the systolic and diastolic phases of the cardiac cycle. Such decreased mechanical stress in the bioprosthetic leaflets should reduce tissue degeneration and increase the long-term durability of the valve. Conclusion: Based on the observations, the pericardial specimens behaved as anisotropic and nonlinear tissues, and their mechanical behaviors were very well characterized by the constitutive models. The results indicate that, compared to the bovine pericardium, the donkey pericardium is mechanically and histologically more appropriate to manufacture heart valve prostheses. Therefore, this study contributes to our understanding of the difference in animal pericardia with respect to human heart leaflets, which is very useful for the design and manufacture of the percutaneous bioprosthetic heart valves

ECM STABILIZATION STRATEGIES FOR BIOPROSTHETIC HEART VALVES FOR IMPROVED DURABILITY

Abstract Approximately 85,000 heart valve replacement surgeries are performed every year in United States and about 300,000 surgeries worldwide. It is estimated that half of them are mechanical valve replacements and the other half bioprosthetic valve replacements. The use of bioprosthetic heart valves is slowly increasing. Bioprosthetic heart valves are made from porcine aortic valves or bovine pericardium. Commercially these bioprostheses are currently crosslinked using glutaraldehyde (GLUT) to prevent tissue degradation and reduce tissue antigenicity. GLUT crosslinks these bioprostheses by stabilizing the collagen present in the tissue via a Schiff base reaction of the aldehyde with the hydroxylysine / lysine residues of collagen. However, Glut crosslinked BHVs fail due to structural dysfunction or calcification and need second replacements. 10 years after surgery, 20-30% of these valves become dysfunctional, and more than 50% of them fail between 12 - 15 years postoperatively. GLUT is known to be a good fixative for the collagenous component of the heart valves. However, GLUT is known to cause cytotoxicity and it is one of the causes of calcification of BHVs. Several alternative fixatives have been researched for BHV stabilization. Physical methods of crosslinking include ultraviolet irradiation and dye mediated photo-oxidation (PhotoFix®, Carbomedics, Austin, TX). Alternative chemical fixatives include stabilization using epoxy compounds, diphenylphosphorylazide, acyl azides, cyanamide, diisocyanates, diglycidyl ether, polyethylene glycol (PEG), carbodiimide (Ultifix®, Medtronic, Minneapolis, MN), diamine bridges, triglycidylamine, sodium metaperiodate, reuterin and genepin. They have shown significantly lower calcification of BHVs, however none of the above mentioned crosslinker is proven successful in long-term clinical studies. Glutaraldehyde is still the only major crosslinker used for clinically used BHVs. Glycosaminoglycans (GAGs) and elastin the other two major components of heart valves apart from collagen are not stabilized by GLUT fixation. It has been shown that GAGs are lost during harvesting, fixation, storage, in vitro cyclic fatigue and after in vivo animal implantation. Clinically explanted BHVs also show GAG depletion. GAGs are an important component of the valves and they maintain a hydrated environment in the valves and help in absorbing compressive and shear stresses acting on the valve and resisting local tissue buckling. It has been hypothesized that loss of these important matrix elements might result in the accelerated degeneration of BHVs. Furthermore, fixation of these components in the valves may help in the better biomechanics of the valves and also improve in vivo durability of the valves. Better extracellular matrix (ECM) stabilization to prevent degeneration will determine the long-term success and durability of these valves. Crosslikers such as carbodiimide, triglycidylamine, and sodium metaperiodate were tried as GAG-targeted fixatives; however, they were unable to completely inhibit the enzyme mediated degradation of GAGs. The focus of this study is on using neomycin trisulfate, a hyaluronidase inhibitor, along with GAG-targeted fixative carbodiimide for stabilizing the GAGs present in the valves. Systematic approach is used in our studies to determine the tissue GAG content, resistance to enzymatic GAG degradation, collagen and elastin stability, in vitro cyclic fatigue, in vivo calcification, effect on biomechanical properties of valves as well as combination with anti-calcification treatments to prevent both degeneration and calcification. We show that neomycin based chemistry significantly stabilize GAGs in the BHVs against GAG degrading enzymes and such fixation would improve long-term durability of the prosthesis

Micromechanical Simulations of Heart Valve Tissues

Heart valve disease is generally treated by surgical replacement with either a mechanical or bioprosthetic valve. While prosthetic valves perform remarkably well, having significantly reduced patient mortality since their inception in 1960, each type exhibits specific drawbacks. Specifically, thrombosis and anticoagulation in the case of mechanical valves; calcific and fatigue-related degeneration in bioprosthetic heart valve (BHV). In attempt to improve the durability of BHV, recent studies have focused on quantifying the biomechanical interactions between the organ, tissue, and cellular-level components in native heart valve and BHV tissues. Such data is considered fundamental to designing improved BHV, and ultimately may be useful in the design of tissue engineered heart valves (TEHV).The goals of this research were two-fold: (1) to simulate layer-specific mechanical property changes incurred by the porcine BHV with fatigue, and (2) to simulate the cellular-level deformation of valve interstitial cells (VIC) nuclei under organ-level transvalvular pressures. For the first goal, parametric studies were conducted to isolate the effective modulii of the individual layers using finite element simulations of native and BHV tissues in flexure. The finite element simulations isolated fatigue-related changes in the overall effective modulus of BHV tissues specifically to the collagen-rich fibrosa layer. These results may be useful in designing improved BHV, as novel fixatives and fixation methods may have the capacity to target specific layers of the BHV tissue. For the second goal, cellular-level VIC nuclei deformations were quantified experimentally by analyzing images of histological sections prepared from native porcine aortic valves subjected to transvalvular pressures. Finite element simulations were conducted to quantify the relationship between organ-level transvalvular pressure, concomitant tissue-level strain, and ultimate cellular-level VIC nuclei deformation. The cellular-level image analysis studies uncovered layer-specific, positive relationships between VIC nuclei deformations and transvalvular pressure. These data were found to correlate with previously published data on the associated collagen fiber architecture, providing insight into the tissue-to-cellular level mechanical coupling predicted by the finite element simulations. These results may be useful in designing TEHV, as evidence suggests that the secretion and organization of extracellular matrix (ECM) (e.g., collagen) by the constituent cells of a TEHV can be modulated by mechanical deformation.To the best of our knowledge, the simulations presented herein represent the first attempt to quantify layer-specific changes in porcine BHV tissue mechanical properties with fatigue. Moreover, we report the first information on the cellular-level deformation of VIC nuclei under transvalvular pressures, including experimental analysis of the native porcine aortic valve, as well as rigorous finite element simulations. These micromechanical simulations thus offer new data on the biomechanical behavior of heart valve tissues, and may contribute to the design of improved BHV and TEHV

Effects of collagen orientation on the medium-term fatigue response of heart valve biomaterials

Worldwide 275,000 diseased heart valves are replaced annually and approximately 50% are bioprosthetic heart valves (BHV). BHV are fabricated from biologically derived tissues chemically modified to reduce immunogenecity and improve durability. BHV are nonviable, non-renewing biomaterials that undergo progressive degenerative changes in-vivo resulting in durability issues, which can be due to both calcific and non-calcific mechanisms. In-vitro durability testing of intact valves up to 200x106 cycles is used to assess BHV durability. In-vitro durability testing confounds characterization and modeling of fatigue. Thus there is a need for elucidation of the underlying mechanisms in the BHV response to repeated cyclic loading (RCL), independent of BHV design. In this study, the effects of collagen orientation on the medium-term (up to 50x106 cycles) BHV RCL response was investigated. Glutaraldehyde treated bovine pericardium were subjected to cyclic tensile loading to stress levels of 500±50 kPa at a frequency of 22 Hz. Two specimen groups were examined, with the preferred collagen fiber direction parallel (PD) and perpendicular (XD) to the direction of loading. Small angle light scattering (SALS) was used to assess the degree of fiber reorientation of the BHV collagenous network after 0 and 50x106 cycles. After 0, 20x106 and 50x106 cycles, specimens were subjected to biaxial mechanical testing and Fourier transform IR spectroscopy (FT-IR) was performed to assess molecular level changes to collagen . In addition, and the collagen fiber crimp period was also measured. Substantial permanent set effects were observed in both groups. In the perpendicular group, the areal stretch, which is a measure of overall tissue compliance, increased significantly while in the parallel group the areal stretch decreased significantly after 50x106 cycles. After 50x106 cycles, SALS measurements revealed that in the perpendicular group, the collagenous fibers became less aligned and in the parallel group, the collagen fibers became more highly aligned. The only significant changes in collagen crimp were an increase in collage crimp period from 23.46±1.39 mm (at 0 cycles) to 28.14±0.84 mm after 20x106 cycles in the parallel group. FT-IR spectra indicated that RCL of both of the groups lead to collagen conformational changes and early denaturation after 20x106 cycles. The results of this study suggest that 1) collagen orientation plays a critical role in BHV fatigue response, and 2) chemical fixation technologies that allow greater fiber mobility under functional stresses yet without permanent set effects may yield more durable materials

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

Calcification Of Bovine Pericardial Aortic Heart Valves

Heart valve disease is prevalent among Canadian population and worldwide; and for failing valves, the ultimate solution is valve replacement surgery. Bovine pericardial tissue is commonly used as a biomaterial to fabricate bioprosthetic heart valves (BHVs), however calcification of the soft tissue is an ongoing concern for its long-term performance. Calcification ultimately results in device failure due to regurgitation, stenosis, or both, which is caused by stiffening, tearing and rupturing of the tissue valve leaflets. This project investigates parameters related to bovine pericardial heart valve calcification. Three in vitro methods of calcium quantification in soft tissue were assessed using bovine pericardium (BP) – all three methods proved to be interchangeable with reliable results. We investigated the use of dimethyl sulfoxide (DMSO) and sodium dodecyl sulfate (SDS) as mediums to effectively remove cell membrane phospholipid debris in efforts to inhibit or decrease calcification - calcium reduction of approximately 50% was achieved with the use of DMSO. Lastly, we microscopically examined fresh and glutaraldehyde (GA) treated BP to examine the inherent forms of calcium present – calcium sites associated with sulfur were discovered, which have not been reported in literature. These insights could lead to significant advances in BHVs

Design of a cyclic pressure bioreactor for the ex vivo study of aortic heart valve mechanobiology

The differentiation of myosin into the respective heavy chain isoforms has shown a correlation with high mechanical stress. Aortic valve myosin expression has been reported; however, the characterization of the pressure response has yet to be fully developed. Thus, a cyclic pressure bioreactor was developed to elucidate the á/â-myosin heavy chain (MHC) expression in aortic valve leaflets subject to physiological and pathological transvalvular pressure loads. The pressure bioreactor achieved the desired pressure modulation via LabVIEW controlled solenoid valves. Results showed á/â-MHC expression on the fibrosal endothelium and minimal dispersal in the subendothelium, indicating the presence of smooth muscle cells. Endothelial layer denudation was evident with time progression while protein expression was limited to sites of excision or injury, indicating a causal relationship with high shear stress. In conclusion, á/â-MHC expression is limited by endothelium detachment and lack of smooth muscle cells, possibly on account of insufficient mechanical stimuli