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Collagen fiber disruption occurs independent of calcification in clinically explanted bioprosthetic heart valves
Abstract
The durability of bioprosthetic heart valves (BHV) is severely limited by tissue deterioration, manifested as calcification and mechanical damage to the extracellular matrix. Extensive research on mineralization mechanisms has led to prevention strategies, but little work has been done on understanding the mechanisms of noncalcific matrix damage. The present study tested the hypothesis that calcification-independent damage to the valvular structural matrix mediated by mechanical factors occurs in clinical implants and could contribute to porcine aortic BHV structural failure. We correlated quantitative assessment of collagen fiber orientation and structural integrity by small angle light scattering (SALS) with morphologic analysis in 14 porcine aortic valve bioprostheses removed from patients for structural deterioration following 5-20 years of function. Calcification of the explants varied from 0 (none) to 1+ (minimal) to 4+ (extensive), as assessed radiographically. SALS tests were performed over entire excised cusps using a 0.254-mm spaced grid, and the resultant structural information used to generate maps of the local collagen fiber damage that were compared with sites of calcific deposits. All 42 cusps showed clear evidence of substantial noncalcific structural damage. In 29 cusps that were calcified, structural damage was consistently spatially distinct from the calcification deposits, generally in a distribution similar to that noted in porcine BHV subjected to in vitro durability testing. Our results suggest a mechanism of noncalcific degradation dependent on cuspal mechanics that could contribute to porcine aortic BHV failure.
... The most popular replacement heart valves continue to be the 'bioprosthetic' heart valves (BHV), and are typically fabricated from glutaraldehyde-crosslinked pericardial xenograft tissue biomaterials (XTBs) sutured to a rigid or semi-flexible stent [1,2]. While these devices continue to benefit many patients in the short term, failure due to fatigue induced structural deterioration along with tissue mineralization continue to be the central issues limiting their durability [3,4]. Currently, the BHV durability is assessed through costly and time-consuming in-vitro accelerated wear testing (AWT) and pre-clinical animal model-based evaluations. ...
... Importantly, it has been noted that both calcific and structural damage processes can occur in parallel or independently [3,4]. Structural damage has been found to occur in areas of the valve that were not affected by calcification and are subject to high mechanical forces, suggesting that mechanical fatigue can independently contribute to structural deterioration of the valve [3,4,22,23,24,25]. ...
... Importantly, it has been noted that both calcific and structural damage processes can occur in parallel or independently [3,4]. Structural damage has been found to occur in areas of the valve that were not affected by calcification and are subject to high mechanical forces, suggesting that mechanical fatigue can independently contribute to structural deterioration of the valve [3,4,22,23,24,25]. ...
Currently, the most common replacement heart valve design is the `bioprosthetic' heart valve (BHV), which has important advantages in that it does not require permanent anti-coagulation therapy, operates noiselessly, and has blood flow characteristics similar to the native valve. BHVs are typically fabricated from glutaraldehyde-crosslinked pericardial xenograft tissue biomaterials (XTBs) attached to a rigid, semi-flexible, or fully collapsible stent in the case of the increasingly popular transcutaneous aortic valve replacement (TAVR). While current TAVR assessments are positive, clinical results to date are generally limited to $<$2 years. Since TAVR leaflets are constructed using thinner XTBs, their mechanical demands are substantially greater than surgical BHV due to the increased stresses during in vivo operation, potentially resulting in decreased durability. Given the functional complexity of heart valve operation, in-silico predictive simulations clearly have potential to greatly improve the TAVR development process. As such simulations must start with accurate material models, we have developed a novel time-evolving constitutive model for pericardial xenograft tissue biomaterials (XTB) utilized in BHV (doi: 10.1016/j.jmbbm.2017.07.013). This model was able to simulate the observed tissue plasticity effects that occur in approximately in the first two years of in vivo function (50 million cycles). In the present work, we implemented this model into a complete simulation pipeline to predict the BHV time evolving geometry to 50 million cycles. The pipeline was implemented within an isogeometric finite element formulation that directly integrated our established BHV NURBS-based geometry (doi: 10.1007/s00466-015-1166-x). Simulations of successive loading cycles indicated continual changes in leaflet shape, as indicated by spatially varying increases in leaflet curvature. While the simulation model assumed an initial uniform fiber orientation distribution, anisotropic regional changes in leaflet tissue plastic strain induced a complex changes in regional fiber orientation. We have previously noted in our time-evolving constitutive model that the increases in collagen fiber recruitment with cyclic loading placed an upper bound on plastic strain levels. This effect was manifested by restricting further changes in leaflet geometry past 50 million cycles. Such phenomena was accurately captured in the valve-level simulations due to the use of a tissue-level structural-based modeling approach. Changes in basic leaflet dimensions agreed well with extant experimental studies. As a whole, the results of the present study indicate the complexity of BHV responses to cyclic loading, including changes in leaflet shape and internal fibrous structure. It should be noted that the later effect also influences changes in local mechanical behavior (i.e. changes in leaflet anisotropic tissue stress-strain relationship) due to internal fibrous structure resulting from plastic strains. Such mechanism-based simulations can help pave the way towards the application of sophisticated simulation technologies in the development of replacement heart valve technology. ABSTRACT Currently, the most common replacement heart valve design is the 'bioprosthetic' heart valve (BHV), which has important advantages in that it does not require permanent anti-coagulation therapy, operates noiselessly, and has blood flow characteristics similar to the native valve. BHVs are typically fabricated from glutaraldehyde-crosslinked pericardial xenograft tissue biomaterials (XTBs) attached to a rigid, semi-flexible, or fully collapsible stent in the case of the increasingly popular transcutaneous aortic valve replacement (TAVR). While current TAVR assessments are positive, clinical results to date are generally limited to <2 years. Since TAVR leaflets are constructed using thinner XTBs, their mechanical demands are substantially greater than surgical BHV due to the increased stresses during in vivo operation, potentially resulting in decreased durability. Given the functional complexity of heart valve operation, in-silico predictive simulations clearly have potential to greatly improve the TAVR development process. As such simulations must start with accurate material models, we have developed a novel time-evolving constitutive model for pericardial xenograft tissue biomaterials (XTB) utilized in BHV (doi: 10.1016/j.jmbbm.2017.07.013). This model was able to simulate the observed tissue plasticity effects that occur in approximately in the first two years of in vivo function (50 million cycles). In the present work, we implemented this model into a complete simulation pipeline to predict the BHV time evolving geometry to 50 million cycles. The pipeline was implemented within an isogeometric finite element formulation that directly integrated our established BHV NURBS-based geometry (doi: 10.1007/s00466-015-1166-x). Simulations of successive loading cycles indicated continual changes in leaflet shape, as indicated by spatially varying increases in leaflet curvature. While the simulation model assumed an initial uniform fiber orientation distribution, anisotropic regional changes in leaflet tissue plastic strain induced a complex changes in regional fiber orientation. We have previously noted in our time-evolving constitutive model that the increases in collagen fiber recruitment with cyclic loading placed an upper bound on plastic strain levels. This effect was manifested by restricting further changes in leaflet geometry past 50 million cycles. Such phenomena was accurately captured in the valve-level simulations due to the use of a tissue-level structural-based modeling approach. Changes in basic leaflet dimensions agreed well with extant experimental studies. As a whole, the results of the present study indicate the complexity of BHV responses to cyclic loading, including changes in leaflet shape and internal fibrous structure. It should be noted that the later effect also influences changes in local mechanical behavior (i.e. changes in leaflet anisotropic tissue stress-strain relationship) due to internal fibrous structure resulting from plastic strains. Such mechanism-based simulations can help pave the way towards the application of sophisticated simulation technologies in the development of replacement heart valve technology. 2
... 55 Mechanical stress is a key factor in the initial development and aggravation of any type of calcification. 56 Thus, a close correlation between areas of high mechanical stress and calcification has been established. 57 Mechanical stress has been reported to cause abnormal calcification 58 by inducing fiber disruption and separation and then by opening small cavities 59 that are predisposed to initial local lipid accumulations before secondary calcifications. ...
... Tears can develop secondary anarchic calcification that provokes cusp tears through mechanical traction and secondary valvular cusp incompetence 5,56 or secondary collagen degradation leading to tissue fragility and a greater likelihood of tears. 56 The most common sites for calcium deposits are 2 regions of high stress (ie, cusp commissural/basal areas), 5,83 and calcification is present a long time before the apparition of tears in these areas. ...
... Tears can develop secondary anarchic calcification that provokes cusp tears through mechanical traction and secondary valvular cusp incompetence 5,56 or secondary collagen degradation leading to tissue fragility and a greater likelihood of tears. 56 The most common sites for calcium deposits are 2 regions of high stress (ie, cusp commissural/basal areas), 5,83 and calcification is present a long time before the apparition of tears in these areas. 5,84 The site for collagen alteration is different, being located in the central fibrosa, 5 an area in which delayed tears and perforations mainly develop. ...
Background
Pigs/bovines share common antigens with humans: α‐Gal, present in all pigs/bovines close to the human B‐antigen; and AH‐histo‐blood‐group antigen, identical to human AH‐antigen and present only in some animals. We investigate the possible impact of patients’ ABO blood group on bioprosthesis structural valve degeneration (SVD) through calcification/pannus/tears/perforations for patients ≤60 years at implantation.
Methods and Results
This was a single‐center study (Paris, France) that included all degenerative bioprostheses explanted between 1985 and 1998, mostly porcine bioprostheses (Carpentier‐Edwards second/third porcine bioprostheses) and some bovine bioprostheses. For the period 1998 to 2014, only porcine bioprostheses with longevity ≥13 years were included (total follow‐up ≥29 years). Except for blood groups, important predictive factors for SVD were prospectively collected (age at implantation/longevity/number/site/sex/SVD types) and analyzed using logistic regression. All variables were available for 500 explanted porcine bioprostheses. By multivariate analyses, the A group was associated with an increased risk of: tears (odds ratio[OR], 1.61; P=0.026); pannus (OR, 1.5; P=0.054), pannus with tears (OR, 1.73; P=0.037), and tendency for lower risk of: calcifications (OR, 0.63; P=0.087) or isolated calcification (OR, 0.67; P=0.17). A‐antigen was associated with lower risk of perforations (OR 0.56; P=0.087). B‐group patients had an increased risk of: perforations (OR, 1.73; P=0.043); having a pannus that was calcified (OR, 3.0, P=0.025). B‐antigen was associated with a propensity for calcifications in general (OR, 1.34; P=0.25).
Conclusions
Patient’s ABO blood group is associated with specific SVD types. We hypothesize that carbohydrate antigens, which may or may not be common to patient and animal bioprosthetic tissue, will determine a patient’s specific immunoreactivity with respect to xenograft tissue and thus bioprosthesis outcome in terms of SVD.
... In addition to various blocking agents, several crosslinking agents have been evaluated for use in BHV processing, including phytic acid [89], polyepoxy compounds [90,91], and carbodiimide [92,93]. In all these methods, as well as with glutaraldehyde crosslinked BHV, the implanted bioprosthesis functions as a dead tissue prone to calcification and disruption of the collagen fibers, with no repair [94]. In contrast, the method studied above for humanization of porcine tendon bioprostheses may allow for reconstruction of the porcine BHV into a viable, autologous valve that functions permanently, as it undergoes repair by infiltrating fibroblasts. ...
... Hypothetically, stentless porcine BHV, which undergo humanization may further enable their use in children, in whom humanized porcine BHV may increase in size with the growth of patients. In addition, the use of porcine BHV that humanizes may solve in all age groups the current problem of leaflet sagging, because of disruption of crosslinked collagen fibers [94]. The live recipient's fibroblasts in the humanized BHV will provide intact collagen fibers to replace disrupted fibers. ...
This review describes the first studies on successful conversion of porcine soft-tissue bioprostheses into viable permanently functional tissue in humans. This process includes gradual degradation of the porcine tissue, with concomitant neo-vascularization and reconstruction of the implanted bioprosthesis with human cells and extracellular matrix. Such a reconstruction process is referred to in this review as “humanization”. Humanization was achieved with porcine bone-patellar-tendon-bone (BTB), replacing torn anterior-cruciate-ligament (ACL) in patients. In addition to its possible use in orthopedic surgery, it is suggested that this humanization method should be studied as a possible mechanism for converting implanted porcine bioprosthetic heart-valves (BHV) into viable tissue valves in young patients. Presently, these patients are only implanted with mechanical heart-valves, which require constant anticoagulation therapy. The processing of porcine bioprostheses, which enables humanization, includes elimination of α-gal epitopes and partial (incomplete) crosslinking with glutaraldehyde. Studies on implantation of porcine BTB bioprostheses indicated that enzymatic elimination of α-gal epitopes prevents subsequent accelerated destruction of implanted tissues by the natural anti-Gal antibody, whereas the partial crosslinking by glutaraldehyde molecules results in their function as “speed bumps” that slow the infiltration of macrophages. Anti-non gal antibodies produced against porcine antigens in implanted bioprostheses recruit macrophages, which infiltrate at a pace that enables slow degradation of the porcine tissue, neo-vascularization, and infiltration of fibroblasts. These fibroblasts align with the porcine collagen-fibers scaffold, secrete their collagen-fibers and other extracellular-matrix (ECM) components, and gradually replace porcine tissues degraded by macrophages with autologous functional viable tissue. Porcine BTB implanted in patients completes humanization into autologous ACL within ~2 years. The similarities in cells and ECM comprising heart-valves and tendons, raises the possibility that porcine BHV undergoing a similar processing, may also undergo humanization, resulting in formation of an autologous, viable, permanently functional, non-calcifying heart-valves.
... SEM analysis established that significant degradation of collagen architecture occurs due to mechanical wear near the free edges similar to that reported in earlier studies. 27,29 Figure 7a illustrates the layers of the pericardium. Typically, in heart valves with bovine pericardial leaflets, the leaflets are oriented in the valve such that the fibrous pericardium forms the inflow side of the valve (Figs. ...
... 37 Valve performance can be affected by leaflet deformation 25 resulting in leaflet sagging or stretching (as observed in this study), wrinkling or folding, 12,40 or pinwheeling (clockwise/anticlockwise twisting of the leaflets around the valve's central axis). 25 Valve deformation can cause abnormal leaflet coaptation leading to increased regurgitation and turbulence, delamination and alteration of collagen structure leading to leaflet tearing, 11,13,15,16,29 and calcification. 3,12,33 Our previous work showed that valve noncircularity results in inhomogeneous distribution of stresses between the leaflets 9 ; the experimental data in this paper on varying leaflet deformations further describe the leaflet damage modes and reduction in valve durability due to fatigue. ...
After implantation of a transcatheter bioprosthetic heart valve its original circular circumference may become distorted, which can lead to changes in leaflet coaptation and leaflets that are stretched or sagging. This may lead to early structural deterioration of the valve as seen in some explanted transcatheter heart valves. Our in vitro study evaluates the effect of leaflet deformations seen in elliptical configurations on the damage patterns of the leaflets, with circular valve deformation as the control. Bovine pericardial tissue heart valves were subjected to accelerated wear testing under both circular (N = 2) and elliptical (N = 4) configurations. The elliptical configurations were created by placing the valve inside custom-made elliptical holders, which caused the leaflets to sag or stretch. The hydrodynamic performance of the valves was monitored and high resolution images were acquired to evaluate leaflet damage patterns over time. In the elliptically deformed valves, sagging leaflets experienced more damage from wear compared to stretched leaflets; the undistorted leaflets of the circular valves experienced the least leaflet damage. Free-edge thinning and tearing were the primary modes of damage in the sagging leaflets. Belly region thinning was seen in the undistorted and stretched leaflets. Leaflet and fabric tears at the commissures were seen in all valve configurations. Free-edge tearing and commissure tears were the leading cause of valve hydrodynamic incompetence. Our study shows that mechanical wear affects heart valve pericardial leaflets differently based on whether they are undistorted, stretched, or sagging in a valve configuration. Sagging leaflets are more likely to be subjected to free-edge tear than stretched or undistorted leaflets. Reducing leaflet stress at the free edge of non-circular valve configurations should be an important factor to consider in the design and/or deployment of transcatheter bioprosthetic heart valves to improve their long-term performance.
... The microstructural changes of soft tissues under cyclic stretches have been extensively studied for tendons, ligaments, cartilages, and valvular tissues (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). For example, cyclic stretches cause kink, rupture, and slip of collagen fibrils in tendons (47,56,57) and reduce crimps of collagen fibers in valvular tissues (53,55). ...
Bovine pericardium (BP) has been used as leaflets of prosthetic heart valves. The leaflets are sutured on metallic stents and can survive 400 million flaps (~10-year life span), unaffected by the suture holes. This flaw-insensitive fatigue resistance is unmatched by synthetic leaflets. We show that the endurance strength of BP under cyclic stretch is insensitive to cuts as long as 1 centimeter, about two orders of magnitude longer than that of a thermoplastic polyurethane (TPU). The flaw-insensitive fatigue resistance of BP results from the high strength of collagen fibers and soft matrix between them. When BP is stretched, the soft matrix enables a collagen fiber to transmit tension over a long length. The energy in the long length dissipates when the fiber breaks. We demonstrate that a BP leaflet greatly outperforms a TPU leaflet. It is hoped that these findings will aid the development of soft materials for flaw-insensitive fatigue resistance.
... On the contrary, bioprosthetic heart valves have improved central blood flow due to their bio-mimicking trileaflet design and do not require anticoagulant therapy. However, these bioprosthetic heart valves also have some drawbacks, including limited durability due to leaflet calcification, leaflet tearing, fatigue damage, and tissue failure [14][15][16][17]. Therefore, 10 to 20 percent of homograft bioprostheses and 30 percent of heterograft bioprostheses fail within 10 to 15 years of implantation and require replacement [18][19][20]. ...
According to rough estimates, one in every 125 newborns born in the United States has a congenital cardiac abnormality that must be repaired. With the recent development of new biomaterials and innovative treatment methods, percutaneous cardiac valve replacement has been considered as an alternative to surgical procedures. While percutaneous heart valve replacement is a relatively new procedure with a few commercially available devices, the devices are not sufficiently low-profile, and do not grow with the child. To address this issue, a novel low-profile growing percutaneous pediatric heart valve frame made of two types of unique metallic biomaterials (supere lastic nitinol and biodegradable iron) has been developed through this study. The developed pediatric heart valve frame has an innovative mechanism that will expand its diameter by disconnecting biodegradable metals, enabling the growth of the device with the surrounding tissue in the cardiac space. The thermally treated iron wires show stable and gradual degradation characteristics, showing approximately 7.66% for both wires treated under 350 and 450 °C. Polymer-coated wires show a degradation range of 4.96 to 5.55% depending on the type of coating. Degradation test results show the predicted 9–23 months of degradation depending on the type of surface treatment (e.g., thermal treatment, polymer coating), which is a suitable range when compared with the theoretical arterial vessel remodeling process period in the human vascular system. Radial forces calculated by finite element analysis and measured by mechanical testing matched well, showing 5–6 N with a 20% diameter reduction considering the deployed valve frame in the heart. Biocompatibility study results demonstrated superior cell viability in thermally treated iron wires after 3 days of cell culture and showed rarely found platelets on the surface after 3-h blood exposure tests. Prototype devices were successfully fabricated using optimized advanced joining processes for dissimilar metallic materials such as nitinol and iron. This study represents the first demonstration of self-expanding and biodegradable percutaneous heart valve frames for pediatric patients that grow with a child.
... Due to Glut only crosslinked adjacent amino groups to stabilize collagen fibers, while other key ECM components, such as GAGs and elastin, cannot be stably preserved after implantation. The destruction of the integrity of extracellular matrix (ECM) leads to calcification or biomechanical property damage (Sacks and Schoen, 2002;Mirnajafi et al., 2006). It should also be noted that calcification could accelerate degeneration of tissue. ...
The bioprosthetic heart valves (BHVs) are the best option for the treatment of valvular heart disease. Glutaraldehyde (Glut) is commonly used as the golden standard reagent for the crosslinking of BHVs. However, the obvious defects of Glut, including residual aldehyde toxicity, degradation and calcification, increase the probability of valve failure in vivo and motivated the exploration of alternatives. Thus, the aim of this study is to develop a non-glutaraldehyde hybrid cross-linking method composed of Neomycin Trisulfate, Polyethylene glycol diglycidyl ether and Tannic acid as a substitute for Glut, which was proven to reduce calcification, degradation, inflammation of the biomaterial. Evaluations of the crosslinked bovine pericardial included histological and ultrastructural characterization, biomechanical performance, biocompatibility and structural stability test, and in vivo anti-inflammation and anti-calcification assay by subcutaneous implantation in juvenile Sprague Dawley rats. The results revealed that the hybrid crosslinked bovine pericardial were superior to Glut crosslinked biomaterial in terms of better hydrophilicity, thermodynamics stability, hemocompatibility and cytocompatibility, higher Young’s Modulus, better stability and resistance to enzymatic hydrolysis, and lower inflammation, degradation and calcification levels in subcutaneous implants. Considering all above performances, it indicates that the hybrid cross-linking method is appropriate to replace Glut as the method for BHV preparation, and particularly this hybrid crosslinked biomaterials may be a promising candidate for next-generation BHVs.
... Therefore, extremely high pressures may be needed to achieve a sufficient result which may in turn increase the risk of harm for the respective patient. 32 In addition, the Trifecta has been described as being prone to coronary obstruction during ViV treatment which may be further enhanced by dilatation of the valve. 33 Hypothetically, the acute-delta change in geometry may cause higher risk, than gradual deformation even in higher atm. ...
Objectives:
The aim of this study was to investigate the degree of functional improvement of a transcatheter heart valve (THV) for valve-in-valve after bioprosthetic valve fracture (BVF) of three small surgical aortic valve bioprostheses (SAVBP) using high-pressure balloon aortic valvuloplasty (HP-BAV) under standardized ex-vivo-conditions.
Methods:
A THV 26 mm (Evolut R) and SAVBP 21 mm (Perimount Magna Ease, Trifecta, and Epic supra [n = 4] were used. Mean pressure gradient (MPG), effective orifice area (EOA), geometric orifice area (GOA), minimal internal diameter (MID), and pinwheeling index (PWI) were analyzed before and after HP-BAV of the SAVBP using a noncompliant balloon. Fracturing of the SAVBP was done before implantation of the THV and the balloon pressures at the point of fracture were recorded.
Results:
The Magna Ease and Epic fractured at balloon pressures of 18 and 8 atm, respectively. The Trifecta did not fracture up to a balloon pressure of 30 atm but was dilated. HP-BAV led to increased THV expansion as evident by straightened coaptation lines of the Evolut R 26 mm with reduced PWI, increased MID, and increased GOA in all 21 mm SAVBP. Evolut R showed significantly lower MPG and higher EOA as ViV in all prostheses after HP-BAV (p < 0.001). MPG and EOA of Evolut R differed regarding the SAVBP. Evolut R presented the lowest MPG and highest EOA in Magna Ease and the highest MPG and lowest EOA in Epic supra.
Conclusions:
The degree of function improvement of the same THV as ViV after HP-BAV depends on the surgical valve model. Functional improvement can also be achieved without valve fracture.
... However, it has been shown that the mechanical fatigue and resulting collagen fiber damage may be a key mechanism in calcification and device failure and that fixed tissue demonstrates reduced resistance to mechanical fatigue compared to unfixed tissue [7,8]. Furthermore, it has also been shown that delamination of the collagen fiber layers not necessarily breakage of the fibers themselves is the main mode of failure [9,10]. As a result, a study by Anssari-Benam et al. identified that changes in the microstructure from glutaraldehyde fixation change the fiber interface shear and critical length which suggest reduced durability [11]. ...
Decellularized pericardial tissue is a strong candidate for a TEHV material as ECM is present to guide cellular infiltration and fixed porcine and bovine pericardial tissue have existing use in bioprosthetic heart valves. In this work, we compare the mechanical and microstructural properties of decellularized-sterilized (DS) porcine, bovine, and bison pericardial tissues with respect to use as a TEHV. H&E staining was used to verify removal of cellular content post-decellularization and to evaluate collagen fiber structure. Additionally, uniaxial and biaxial tension testing were used to compare mechanical performance and, for the latter, acquire constitutive model parameters for subsequent finite element (FE) modeling. H&E staining revealed complete removal of cellular content and good collagen fiber structure. Tensile testing showed comparable mechanical strength between the three DS pericardial tissues and considerably stronger mechanical properties compared to native tissues. Bovine and bison DS pericardial tissues showed the strongest mechanical performance in the FE models with bison demonstrating the overall best mechanical characteristics. The increased thickness of bovine and bison tissues coupled with the strong mechanical behavior and ECM structure indicates that these materials will be resistant to damage until sufficient cellular infiltration has occurred such that damaged tissue can be repaired.Graphical abstract
... As they are unable to replicate physiological flow conditions and lifelong anticoagulation, their utility in this field is limited. Tissue-based prostheses have replaced them, and their weaker durability is challenging (157)(158)(159). Polymeric leaflets for heart valve prostheses can overcome the limitations of both mechanical and tissue-based prostheses (160). ...
Increasing attention to hygiene and health care has led to the development of biomedical and biomedical material applications. Various biomedical applications have been created from polymers due to their swift development. Polyurethanes (PUs) have several important biomedical applications. The most advanced biomedical applications—including responses to stimuli, drug delivery, scaffolding, prosthesis development, and wound dressing—have determined the importance of PUs and PU nanocomposites. Also, preparation of smart and responsive PUs can improve their biomedical applications. The next generation of PU biomedical applications belongs to smart, benign, biocompatible, and durable PUs, with appropriate physicochemical properties.
... 21 Histological examination of explanted porcine bioprosthetic valves have shown free-edge tears in the absence of calcification at points that experience the highest localised mechanical forces. 22,23 Tears are associated with collagen fibre degradation. As such successive iterations of the pericardial valve have attempted to minimise mechanical sheer stress on the valve leaflets whilst simultaneously ensuring optimal haemodynamic performance. ...
It is now 50 years since the development of the first pericardial valve in 1971. In this time significant progress has been made in refining valve design aimed at improving the longevity of the prostheses. This article reviews the current literature regarding the longevity of pericardial heart valves in the aortic position. Side by side comparisons of freedom from structural valve degeneration are made for the valves most commonly used in clinical practice today, including stented, stentless, and sutureless valves. Strategies to reduce structural valve degeneration are also discussed including methods of tissue fixation and anti‐calcification, ways to minimise mechanical stress on the valve, and the role of patient prosthesis mismatch.
... Conversely, other studies suggest that mechanical damage and calcification are two completely independent degenerative mechanisms in BHV leaflets [ 18 , 19 ]. It is also important to note that these studies have been conducted on both porcine aortic valve and bovine pericardial leaflets, which have markedly different microstructures [15][16][17][18][19] . ...
In cases of aortic stenosis, bioprosthetic heart valves (BHVs), with glutaraldehyde-fixed bovine pericardium leaflets (GLBP), are often implanted to replace the native diseased valve. Widespread use of BHVs, however, is restricted due to inadequate long-term durability, owing specifically to premature leaflet failure. Mechanical fatigue damage and calcification remain the primary leaflet failure modes, where glutaraldehyde treatment is known to accelerate calcification. The literature in this area is limited, with some studies suggesting mechanical damage increases calcification and others that they are independent degenerative mechanisms. In this study, specimens which were non-destructively pre-sorted according to collagen fibre architecture and uniaxially cyclically loaded until failure or 1 million cycles, were placed in an in-vitro calcification solution. The weakest specimen group (those with fibres aligned perpendicular to the load) had statistically significantly higher volumes of calcification when compared to those with a high fatigue life. Moreover, SEM imaging revealed that ruptured and damaged fibres presented calcium binding sites; resulting in 4 times more calcification in fractured samples in comparison to those which did not fail by fatigue. To the authors' knowledge, this study quantifies for the first time, that mechanical damage drives calcification in commercial-grade GLBP and that calcification varies spatially according to localised damage levels. These findings illustrate that not only is calcification of GLBP exacerbated by fatigue damage, but that both failure phenomena are underpinned by the collagen fibre organisation. Consequently, controlling for GLBP collagen fibre architecture in leaflets could minimise the progression of these primary failure modes in patient BHVs. Statement of significance: Mechanical damage and calcification are the primary premature failure modes of glutaraldehyde-fixed bovine pericardial (GLBP) leaflets in bioprosthetic heart valves. In this study, commercial-grade GLBP specimens which were uniaxially cyclically loaded to failure or 1 million cycles, were placed in an in vitro calcification solution. MicroCT and SEM analysis showed that localised calcification levels varied spatially according to damage, where ruptured fibres offered additional calcium binding sites. Furthermore, specimens with a statistically significant lower fatigue life were associated with statistically significant higher calcification. This study revealed that mechanical damage drives calcification of GLBP. Non-destructive pre-screening of collagen fibres demonstrated that both the fatigue life and calcification potential of commercial-grade GLBP, are underpinned by the collagen fibre architecture.
... Localization to the central region of the cusp (the most prominent site of collagen architecture disruption in failed BHVs 57 ) suggests an important association between mechanical stress, oxidative damage, and BHV failure. Indeed, all explanted cusps demonstrated a lower degree of collagen fiber alignment in the vicinity of the nodulus of Arantii, accompanied frequently by a band extending from the nodulus down toward the basal attachment; the same result was achieved also in in vitro tests, 57 suggesting the change in leaflet curvature during the cardiac cycle gives rise to bending stresses, shearing, or buckling. Notably, calcium concentrations alone did not necessarily predict implant duration, suggesting that oxidized amino acids may play a significant role in a calcium-independent mechanism of BHV SVD. 25 Christian et al 58 investigated the effects of oxidative stress on bovine BHVs using clinical pathologic BHV explants as well as experimental models: increased levels of the oxidized amino acids such as ortho-tyrosine, meta-tyrosine, and di-tyrosine were present in explanted valves compared with nonimplanted BHV. ...
Bioprosthetic heart valves (BHVs) largely circumvent the need for long‐term anticoagulation compared with mechanical valves but are increasingly susceptible to deterioration and reduced durability with reoperation rates of ≈10% and 30% at 10 and 15 years, respectively. Structural valve degeneration is a common, unpreventable, and untreatable consequence of BHV implantation and is frequently characterized by leaflet calcification. However, 25% of BHV reoperations attributed to structural valve degeneration occur with minimal leaflet mineralization. This review discusses the noncalcific mechanisms of BHV structural valve degeneration, highlighting the putative roles and pathophysiological relationships between protein infiltration, glycation, oxidative and mechanical stress, and inflammation and the structural consequences for surgical and transcatheter BHVs.
... The literature in this area is both limited and contradictory where some studies propose that mechanical damage induces and accelerates tissue calcification [11]- [13]. However, other studies suggest that these are two completely independent mechanisms in BHV leaflets [14], [15]. It is also important to note that these studies have been conducted on both porcine aortic valve and bovine pericardial leaflets, which have markedly different microstructures [11]- [15]. ...
In cases of aortic stenosis, bioprosthetic heart valves (BHVs), with leaflets made from glutaraldehyde fixed bovine pericardium (GLBP), are often implanted to replace the native diseased valve. Widespread use of these devices, however, is restricted due to inadequate long-term durability owing specifically to premature leaflet failure. Mechanical fatigue damage and calcification remain the primary leaflet failure modes, where glutaraldehyde treatment is known to accelerate calcification. The literature in this area is limited, with some studies suggesting mechanical damage increases calcification and others that they are independent degenerative mechanisms. In this study, specimens which were non-destructively pre-sorted according to collagen fibre architecture and then uniaxially cyclically loaded until failure or 1 million cycles, were placed in an in-vitro calcification solution. Measurements of percentage volume calcification demonstrated that the weakest specimen group (those with fibres aligned perpendicular to the load) had statistically significantly higher volumes of calcification when compared to those with a high fatigue life. Moreover, SEM imaging revealed that ruptured and damaged fibres presented binding sites for calcium to attach; resulting in more than 4 times the volume of calcification in fractured samples when compared to those which did not fail by fatigue. To the authors’ knowledge, this study quantifies for the first time, that mechanical damage drives calcification in commercial-grade GLBP and that this calcification varies spatially according to localised levels of damage. These findings illustrate that not only is calcification potential in GLBP exacerbated by fatigue damage, but that both failure phenomena are underpinned by the unloaded collagen fibre organisation. Consequently, controlling for GLBP collagen fibre architecture in leaflets could minimise the progression of these prevalent primary failure modes in patient BHVs.
... Even though BHVs offer less risk of blood damage and less invasive employment strategies, they fail to provide similar longevity to the MHVs. The lifetime of the BHVs varies from 10 to 15 years (Applegate et al., 2017;Hoffmann et al., 2008), resulting mostly from structural deterioration due to calcification or damage due to fatigue (Manji et al., 2012;Rodriguez-Gabella et al., 2017;Sacks and Schoen, 2002;Siddiqui et al., 2009;Singhal et al., 2013). ...
Valvular diseases, such as aortic stenosis, are considered a common condition in the US. In severe cases, either mechanical or prosthetic heart valves are employed to replace the diseased native valve. The prosthetic heart valve has been a focal point for researchers to gain a better understanding of the mechanics, which will lead to improved longevity. In this study, our objective was to evaluate the effect of fundamental curves on the geometric orifice area and the coaptation area by implementing a two-level Taguchi Orthogonal Array (OA) design (Analysis of Variance (ANOVA) technique) and the interaction plots to investigate the individual contributions. The leaflet geometry was represented with the attachment curve, the free edge, and the belly curve. A total of three varying control coordinates were used to form different leaflet surfaces. With two different biocompatible polymers, 16 finite element models were prepared. Each model was subjected to time-varying transvalvular pressure. The results showed that the control coordinate for the belly curve has the highest impact on the coaptation area of the valve models with higher average 100% modulus. The geometric orifice area was affected by both control points of the attachment curve and the belly curve. A similar effect was also observed for the valve models with lower average 100% modulus.
... Most biological tissues are comprised of networks of collagen fibers embedded in a ground substance and can be regarded as fiber reinforced composites. Similar to engineering fiber-reinforced composites ( Daum et al., 2019;Dong et al., 2014;Häsä and Pinho, 2019;Puck and Schürmann, 2002 ), biological tissues also encounter mechanical failures, with fatigue failure being identified as one of the primary factors limiting the durability of such medical devices ( Sacks, 2001 ;Sacks and Schoen, 2002 ). For instance, bioprosthetic valves often could fail within 10 years after implantation and as soon as 5 years in younger patients ( Lawford et al., 1987 ;Schoen and Levy, 1999 ). ...
Biologically-derived and chemically-treated collagenous tissues such as glutaraldehyde-treated bovine pericardium (GLBP) are widely used in many medical applications. The long-term cyclic loading-induced tissue fatigue damage has been identified as one of the primary factors limiting the durability of such medical devices and an in-depth understanding of the fatigue behaviors of biological tissues is critical to increase device durability. However, a limited number of fatigue damage experiments were performed on biological tissues due to complexity and time-consuming nature of such fatigue experiments. Consequently, accurate constitutive models for fatigue damage are also lacking. In this study, we performed a rigorous fatigue experiment on GLBP tissues. The stress, strain and permanent set at a maximum of 8 different fatigue cycles, up to 15 million cycles, were obtained, which demonstrated a nonlinear stress softening and a nonlinear permanent set accumulation. Based on the experimental data, we developed a novel residual stiffness-based fatigue model. The fatigue model considers the fatigue-induced reduction of initial stiffness and stiffening effect, in contrast to our previous damage-based model that only considered the fatigue-induced reduction of the initial stiffness. Moreover, a new constitutive relation was proposed to describe how the fatigue life (the cycle number at failure) depends on the equivalent strain, analogous to the stress versus fatigue life (S-N) curve for traditional engineering material. The new fatigue model can characterize the stress softening and nonlinear permanent set effects when referring to the pre-fatigued configuration. It can also describe the nonlinear stress stiffening effect when referring to the post-fatigued configuration. The model predictions are in good agreement with the experiment. The experimental results and the novel model could be applied to fatigue analyses of medical devices to improve the durability.
... These are used for both established surgical and more novel percutaneous valve designs [3][4][5][6]. However, the durability of BHVs remains limited, mostly due to structural deterioration caused by fatigue and tissue mineralization [7][8][9][10]. Due to the limited lifetime of BHVs, patients may require multiple replacement surgeries, which can cause an increased rate of complications, particularly in elderly patients with comorbidities. ...
The transcatheter aortic valve replacement (TAVR) has emerged as a minimally invasive alternative to surgical treatments of valvular heart disease. TAVR offers many advantages, however, the safe anchoring of the transcatheter heart valve (THV) in the patients anatomy is key to a successful procedure. In this paper, we develop and apply a novel immersogeometric fluid-structure interaction (FSI) framework for the modeling and simulation of the TAVR procedure to study the anchoring ability of the THV. To account for physiological realism, methods are proposed to model and couple the main components of the system, including the arterial wall, blood flow, valve leaflets, skirt, and frame. The THV is first crimped and deployed into an idealized ascending aorta. During the FSI simulation, the radial outward force and friction force between the aortic wall and the THV frame are examined over the entire cardiac cycle. The ratio between these two forces is computed and compared with the experimentally estimated coefficient of friction to study the likelihood of valve migration.
... Studies have shown that the regions of tearing in bioprosthetic heart valves correlate with the regions of high tensile and bending stresses [12,13]. Stress concentrations within the leaflet can either directly accelerate tissue structural fatigue damage or initiate calcification by causing structural disintegration, enabling multiple calcification pathways that lead to valve failure [14,15]. Although the details of the process are unclear, it is widely accepted that the valve designs that reduce leaflet stresses are likely to give improved performance in longterm applications. ...
In this study, a Bayesian optimization based computational framework is developed to investigate the design of transcatheter aortic valve (TAV) leaflets and to optimize leaflet geometry such that its peak stress under the blood pressure of 120 mmHg is reduced. A generic TAV model is parametrized by mathematical equations describing its 2D shape and its 3D stent-leaflet assembly line. Material properties previously obtained for bovine (BP) and porcine pericardium (PP) via a combination of flexural and biaxial tensile testing were incorporated into the finite element (FE) model of TAV. A Bayesian optimization approach was employed to investigate about 1000 leaflet designs for each material under the nominal circular deployment and physiological loading conditions. The optimal parameter values of the TAV model were obtained, corresponding to leaflet shapes that can reduce the peak stress by 16.7% in BP and 18.0% in PP, compared with that from the initial generic TAV model. Furthermore, it was observed that while peak stresses tend to concentrate near the stent-leaflet attachment edge, optimized geometries benefit from more uniform stress distributions in the leaflet circumferential direction. Our analysis also showed that increasing leaflet contact area redistributes peak stresses to the belly region contributing to peak stress reduction. The results from this study may inspire new TAV designs that can have better durability.
... Bioprosthetic degeneration results from calcification, tissue degeneration, or a combination of the two. Non-calcified leaflet degeneration has been documented as a result of microstructural deterioration and consequent mechanical property changes (22,23). In addition, stress concentration and increased deformation are believed to trigger calcification process (24,25). ...
Background:
Transcatheter aortic valve replacement (TAVR) has recently been shown to be equivalent to surgical aortic valve replacement (SAVR) in intermediate-risk patients. As TAVR expands towards the traditionally SAVR population, TAVR versus SAVR durability becomes increasingly important. While the durability of TAVR is unknown, valve design - particularly with regards to leaflet stress - impacts on valve durability. Although leaflet stress cannot be measured directly, it can be determined using finite element modeling, with such models requiring the mechanical properties of the leaflets. Balloon-expandable TAVR involves the use of bovine pericardial leaflets treated in the same manner as surgical bioprosthetic leaflets. The study aim was to determine the leaflet mechanical properties of Carpentier-Edwards bioprostheses for future TAVR and SAVR computational models.
Methods:
A total of 35 leaflets were excised from 12 Carpentier-Edwards Model 3000TFX Perimount Magna aortic bioprostheses (21 mm, 23 mm, and 25 mm) and subjected to displacement-controlled equibiaxial stretch testing. The stress-strain data acquired were fitted to a Fung constitutive model to describe the material properties in circumferential and radial directions. Leaflet stiffness was calculated at specified physiological stress, corresponding to zero pressure, systemic pressure, and between zero and systemic pressure.
Results:
The 21-mm bioprostheses had significantly thinner leaflets than the larger bioprostheses. A non-linear stress-strain relationship was observed in all leaflets along the circumferential and radial directions. No significant difference in leaflet stiffness at systemic pressure, or between zero and systemic pressure, was found among the three bioprosthesis sizes. However, the leaflets from the 23 mm bioprosthesis were significantly more compliant than those of the 21 mm and 25 mm bioprostheses at zero pressure in the circumferential direction. No differences were observed in leaflet stiffness in circumferential versus radial directions.
Conclusions:
The bovine pericardial leaflets from Carpentier-Edwards Perimount Magna bioprostheses showed no differences in material properties among different valve sizes at systemic pressure. The thinner 21 mm leaflets did not show any corresponding differences in leaflet stiffness, which suggests that the thinner TAV leaflets may have a similar stiffness to their thicker SAV counterparts.
... Healthy leaflets imply homeostasis, with subpopulations of valvular interstitial cells (VICs) catabolizing damaged collagen and the same or other VICs mediating de novo collagen synthesis (Merryman et al. 2007; Rabkin-Aikawa et al. 2004;van der Kamp and Nauta 1979). By contrast, disruption, depletion, or excess accretions of collagens are hallmarks of various valvular diseases (Rabkin et al. 2001;Sacks and Schoen 2002;Cole et al. 1984;Banerjee et al. 2014;Lacerda et al. 2012), likely manifesting as both causes and effects of disrupted mechanotransduction across the macro to micro length scales. These two sides of the remodeling coin beg the question: what are the signals that instruct VICs to turnover collagen? ...
Collagen is at the heart of any and all questions concerning semilunar valvular leaflet composition, structure, and function. Whether during development, physiological homeostasis, or pathological degeneration, it is the structural-mechanical state of the heart valve leaflet collagen network that ultimately confers valvular function, and the difference between health and disease. In the current study, the effects of physiologically relevant strain states on collagen catabolism are investigated in porcine aortic and pulmonary valve leaflets. Application of bacterial collagenase to the tissues which acts to simulate collagen degradation by endogenous matrix metalloproteinases, biaxial stress relaxation, and histology are all used to serve as measures of functional and compositional collagen catabolism. Current stress-relaxation results are used in conjunction with previous equibiaxial testing to confirm that a mechanism exists to prevent collagen catabolism when stretched at physiologically relevant strain states. Collectively, these in vitro results indicate that biaxial strain states are capable of impacting the susceptibility of valvular collagens to catabolism, and that at physiological strain states, a protective mechanism exists to effectively block collagen catabolism. The results of the study will be broadly applicable to clarify the roles of tissue microarchitecture and load transmission in a variety of other developmental, homeostatic, or pathogenic tissue processes such as tumor growth, embryogenesis, thrombi formation, and atherogenesis.
... Anti-calcifying agents are also effective (117). However, ECM disorganization and degradation remains the ultimate limiting factor in durability (118). ...
Cardiovascular calcification is an independent risk factor and an established predictor of adverse cardiovascular events. Despite concomitant factors leading to atherosclerosis and heart valve disease (VHD), the latter has been identified as an independent pathological entity. Calcific aortic valve stenosis is the most common form of VDH resulting of either congenital malformations or senile “degeneration.” About 2% of the population over 65 years is affected by aortic valve stenosis which represents a major cause of morbidity and mortality in the elderly. A multifactorial, complex and active heterotopic bone-like formation process, including extracellular matrix remodeling, osteogenesis and angiogenesis, drives heart valve “degeneration” and calcification, finally causing left ventricle outflow obstruction. Surgical heart valve replacement is the current therapeutic option for those patients diagnosed with severe VHD representing more than 20% of all cardiac surgeries nowadays. Tissue Engineering of Heart Valves (TEHV) is emerging as a valuable alternative for definitive treatment of VHD and promises to overcome either the chronic oral anticoagulation or the time-dependent deterioration and reintervention of current mechanical or biological prosthesis, respectively. Among the plethora of approaches and stablished techniques for TEHV, utilization of different cell sources may confer of additional properties, desirable and not, which need to be considered before moving from the bench to the bedside. This review aims to provide a critical appraisal of current knowledge about calcific VHD and to discuss the pros and cons of the main cell sources tested in studies addressing in vitro TEHV.
... Additionally, it is estimated that during systole, stresses in particular regions of the leaflet can reach up to 3.17 MPa, with peak stresses of 1.17 MPa observed in the diastolic phase (Abbasi et al., 2016). BHVs are prone to early failure, with data in the literature clearly indicating that the durability of these devices has not yet been optimised (Sacks and Schoen, 2002;Vyavahare et al., https://doi.org/10.1016/j.jmbbm.2018.09.038 Received 24 April 2018Received in revised form 29 August 2018;Accepted 24 September 20181999Vesely, 2003;Li and Sun, 2017;Siddiqui et al., 2009). ...
The durability of bovine pericardium leaflets employed in bioprosthetic heart valves (BHVs) can significantly limit the longevity of heart valve prostheses. Collagen fibres are the dominant load bearing component of bovine pericardium, however fibre architecture within leaflet geometries is not explicitly controlled in the manufacture of commercial devices. Thus, the purpose of this study was to ascertain the influence of pre-determined collagen fibre orientation and dispersion on the mechanical performance of bovine pericardium. Three tissue groups were tested in uniaxial tension: cross-fibre tissue (XD); highly dispersed fibre-orientations (HD); or preferred-fibre tissue (PD). Both the XD and PD tissue were tested under cyclic loading at 1.5 Hz and a stress range of 2.7 MPa. The results of the static tensile experiments illustrated that collagen fibre orientation and degree of alignment significantly influenced the material's response, whereby, there was a statistically significant decrease in material properties between the XD groups and both the PD and HD groups for ultimate tensile strength and stiffness (p < 0.01). Furthermore, HD tissue had a stiffness of approximately 58% of the PD group, and XD tissue had a stiffness of approximately 18% of the PD group. The dynamic behaviour of the XD and PD groups was extremely distinct; for example a Weibull analysis indicated that the 50% probability of failure in specimens with fibres orientated perpendicular (XD) to the loading direction occurred at 375 cycles. Due to this failure, XD specimens survived on average less than 20% of the cycles completed by those in which fibres were aligned along the loading direction (PD). The results from this study indicate that fibre architecture is a significant factor in determining static strength and fatigue life in bovine pericardium, and thus must be incorporated in the design process to improve future device durability.
... Moreover, a severely impaired collagen crimp structure of the FC valves with a crimp altitude decrease of 2.4-fold and a 2.2-fold increase in the crimp period, indicated long-term failure and loss of biomechanical sustainability. The loss of the characteristic crimp structure of collagen Type I in the fibrosa has previously been associated with reduced flexural rigidity of tissue valves [29]. In contrast to FC leaflets, native-like matrix structures in the IFC leaflets were detected after explantation. ...
Objectives:
Frozen cryopreservation (FC) with the vapour phase of liquid nitrogen storage (-135°C) is a standard biobank technique to preserve allogeneic heart valves to enable a preferable allograft valve replacement in clinical settings. However, their long-term function is limited by immune responses, inflammation and structural degeneration. Ice-free cryopreserved (IFC) valves with warmer storage possibilities at -80°C showed better matrix preservation and decreased immunological response in preliminary short-term in vivo studies. Our study aimed to assess the prolonged performance of IFC allografts in an orthotopic pulmonary sheep model.
Methods:
FC (n = 6) and IFC (n = 6) allografts were transplanted into juvenile Merino sheep. After 12 months of implantation, functionality testing via 2-dimensional echocardiography and histological analyses was performed. In addition, multiphoton autofluorescence imaging and Raman microspectroscopy analysis were applied to qualitatively and quantitatively assess the matrix integrity of the leaflets.
Results:
Six animals from the FC group and 5 animals from the IFC group were included in the analysis. Histological explant analysis showed early inflammation in the FC valves, whereas sustainable, fully functional, devitalized acellular IFC grafts were obtained. IFC valves showed excellent haemodynamic data with fewer gradients, no pulmonary regurgitation, no calcification and acellularity. Structural remodelling of the leaflet matrix structure was only detected in FC-treated tissue, whereas IFC valves maintained matrix integrity comparable to that of native controls. The collagen crimp period and amplitude and elastin structure were significantly different in the FC valve cusps compared to IFC and native cusps. Collagen fibres in the FC valves were less aligned and straightened.
Conclusions:
IFC heart valves with good haemodynamic function, reduced immunogenicity and preserved matrix structures have the potential to overcome the known limitations of the clinically applied FC valve.
... Glutaraldehyde (GLUT)-based cross-linking has been studied and used in industry for many years [8,15,16]. However, GLUT-cross-linked BHVs usually failed within 10 years [17][18][19]. ...
Calcification is one of the main causes for bioprosthetic heart valves (BHVs)’ failure. Reported strategies to improve BHVs’ anti-calcification properties only target some of risk factors for calcification. In the current study, we demonstrated dopamine-modified alginate coating served as a protected layer for BHVs’ anti-calcification. Alginate coating was characterized by infrared spectroscopic analysis, ultraviolet spectrophotometer, and water contact angle test. By both high-calcium and high-phosphorus in vitro calcification model and rat subdermal implant in vivo calcification model, our results showed alginate-coated BHVs’ have greatly improved BHVs’ anti-calcification performance due to constant ionic exchange of calcium and sodium. Besides, alginate-coated BHVs did not change BHVs’ mechanical strength and tissue’s shrink temperature. This was the first proof-of-concept study to verify that alginate coating would be a novel method for BHVs’ anti-calcification.
... Heparin, as the most widely used anticoagulant, has been successfully used in biomodification to prevent platelet aggregation and thrombogenesis (20,21). Collagen is one of the extracellular matrix proteins, which is beneficial for promoting cell attachment, spreading, differentiation, and valve mechanical movement (22)(23)(24). Heparin is a highly sulfated glycosaminoglycan (GAG) capable of storing and releasing growth factors. Several proteins contain heparin-binding domains, resulting in a strong interaction between this polysaccharide and the extracellular matrix components involved in cell adhesion, proliferation, and osteogenic differentiation. ...
Expanded polytetrafluoroethylene (ePTFE) prosthetic valves have been widely used in clinical applications in Asian countries. However, these valves still have limits with regard to thrombosis, neointimal hyperplasia, restenosis, and valvar vegetation. The achievement of in situ endothelialization on implant materials is a promising way to overcome those limits. Here, heparin/collagen multilayers were fabricated on ePTFE films via a layer‐by‐layer (LBL) self‐assembly technique, and then, the endothelial cell (EC) adhesive peptide sequence Arg‐Glu‐Asp‐Val (REDV) was immobilized on the multilayers. After modification with the heparin/collagen multilayers with or without REDV peptide, less platelet activation and aggregation were observed, the blood coagulation time was increased, and the hemolysis rate was decreased compared to that on pristine ePTFE films. The REDV‐functionalized ePTFE films positively impacted early EC adhesion, later cell proliferation and cell activity. The EC barrier was confirmed to be successfully achieved on the functionalized ePTFE film surface in vitro. The successful assembly of the REDV‐functionalized heparin/collagen multilayer on ePTFE films improved the blood compatibility, anticoagulant properties, and cell compatibility of the films in vitro, and thus, represents a candidate approach for applications requiring quick in situ endothelialization in vivo.
... Buna benzer sorunlar kriyoprezervasyonlu hemogreft kapaklarda da görülmütür. [27,28] Doku mühendisli¤i yaklaımları kalp kapakçık üretimi için de cazip hale gelmektedir. Biyomekanik olarak uygun, dayanıklı, elastik kalp kapakçıkların üretiminde doku iskeleleri de göz önüne bulundurulmaktadır. ...
Currently, cardiovascular diseases are among the most common causes of death in adults, with high mortality rates. The treatment of cardiovascular diseases is limited by factors such as donor deficiency and immunological tolerance. On the face of it, studies on person-specific treatment methods are rapidly taking place. Tissue engineering studies are accelerating with the developments in biomaterials science and existing cell studies and appli- cations. Tissue engineering approach in tissue damage treatment and cardiovascular applications also pioneer in terms of clinical applications. In this review, we explain, ongoing tissue applications and preclinical studies in cardiomyocyte and heart valve models treatment are described.
15 Aortic valve (AV) disease is a common valvular lesion in the United States, present in about 16 5% of the population at age 65 with increasing prevalence with advancing age. While current 17 replacement heart valves have extended life for many, their long term use remains hampered by 18 limited durability. Non-surgical treatments for AV disease do not yet exist, in large part because Large animal models, long used to assess replacement AV devices, cannot yet reproduce AV dis-23 ease processes. As an important alternative mouse animal models are attractive for their ability 24 to perform genetic studies of the AV disease processes and test potential pharmaceutical treat-25 ments. While mouse models have been used for cellular and genetic studies of AV disease, their 26 small size and fast heart rates have hindered their use for tissue-and organ-level studies. We 27 have recently developed a novel ex vivo micro-CT based methodology to 3D reconstruct murine 28 heart valves and estimate the leaflet mechanical behaviors (Feng, et al. Scientific Reports 13.1 29 (2023): 12852.). In the present study, we extended our approach to 3D reconstruction of the in 30 vivo functional murine AV (mAV) geometry using high-frequency four-dimensional ultrasound 31 (4DUS). From the resulting 4DUS images we digitized the mAV mid-surface coordinates in the 32 fully closed and fully opened states. We then utilized matched high-resolution µCT images of 33 ex vivo mouse mAV to develop mAV NURBS based geometric model. We then fitted the mAV 34 geometric model to the in vivo data to reconstruct the 3D in vivo mAV geometry in the closed 35 and open states in n=3 mAV. Results demonstrated high fidelity geometric results. To our knowl-36 edge, this is the first time such reconstruction was ever achieved. This robust assessment of in 37 vivo mAV leaflet kinematics in 3D opens up the possibility for longitudinal characterization of 38 murine models that develop aortic valve disease. 39 2
Background
It is unknown whether bioprostheses used for transcatheter aortic valve implantation will have similar long-term durability as those used for surgical aortic valve replacement. Repetitive mechanical stress applied to the valve leaflets, particularly during diastole, is the main determinant of structural valve deterioration. Leaflet mechanical stress cannot be measured in vivo. The objective of this in vitro/in silico study was thus to compare the magnitude and regional distribution of leaflet mechanical stress in old vs new generations of self-expanding (SE) vs balloon expandable (BE) transcatheter heart valves (THVs).
Methods
A double activation simulator was used for in vitro testing of two generations of SE THV (Medtronic CoreValve 26 mm and EVOLUT PRO 26 mm) and two generations of BE THV (Edwards SAPIEN 23 mm vs SAPIEN-3 23 mm). These THVs were implanted within a 21-mm aortic annulus. A noncontact system based on stereophotogammetry and digital image correlation with high spatial and temporal resolution (2000 img/sec) was used to visualize the valve leaflet motion and perform the three-dimensional analysis. A finite element model of the valve was developed, and the leaflet deformation obtained from the digital image correlation analysis was applied to the finite element model to calculate local leaflet mechanical stress during diastole.
Results
The maximum von Mises leaflet stress was higher in early vs new THV generation (p < 0.05) and in BE vs SE THV (p < 0.05): early generation BE: 2.48 vs SE: 1.40 MPa; new generation BE: 1.68 vs SE: 1.07 MPa. For both types of THV, the highest values of leaflet stress were primarily observed in the upper leaflet edge near the commissures and to a lesser extent in the mid-portion of the leaflet body, which is the area where structural leaflet deterioration most often occurs in vivo.
Conclusions
The results of this in vitro/in silico study suggest that: i) Newer generations of THVs have ∼30% lower leaflet mechanical stress than the early generations; ii) For a given generation, SE THVs have lower leaflet mechanical stress than BE THVs. Further studies are needed to determine if these differences between new vs early THV generations and between SE vs BE THVs will translate into significant differences in long-term valve durability in vivo.
Development of tissue engineered scaffolds for cardiac valve replacement is nearing clinical translation. While much work has been done to characterize mechanical behavior of native and bioprosthetic valves, and incorporate those data into models improving valve design, similar work for degradable valve scaffolds is lacking. This is particularly important given the implications mechanics have on short-term survival and long-term remodeling. As such, this study aimed to characterize spatially-resolved strain profiles on the leaflets of degradable polymeric valve scaffolds, manipulating common design features such as material stiffness by blending poly(carbonate urethane)urea with stiffer polymers, and geometric configuration, modeled after either a clinically-used valve design (Mk1 design) or an anatomically "optimized" design (Mk2 design). It was shown that material stiffness plays a significant role in overall valve performance, with the stiffest valve groups showing asymmetric and incomplete opening during systole. However, the geometric configuration had a significantly greater effect on valve performance as well as strain magnitude and distribution. Major findings in the strain maps included systolic strains having overall higher strain magnitudes than diastole, and peak radial-direction strain concentrations in the base region of Mk1 valves during systole, with a significant mitigation of radial strain in Mk2 valves. The high tunability of tissue engineered scaffolds is a great advantage for valve design, and the results reported here indicate that design parameters have significant and unequal impact on valve performance and mechanics.
The use of numerical methods to simulate native and prosthetic heart valves will likely continue to expand. These tools, combined with new anatomical data, tissue mechanical properties, and methods for failure prediction enable computational analysts to simulate heart valve prostheses more accurately. To truly advance the field of simulation for prosthetic heart valves, one needs the development of data and methods to assist in addressing the project goals. This chapter will discuss some of the current application as they relate to cardiac valves, i.e., the types of studies that can assist in the translation of mechanical loads predicted by FEA to physiologic effects on the vessels, valve leaflets, and ultimately the patients.
Purpose: Bioprosthetic Heart Valves (BHVs) are currently in widespread use with promising outcomes. Computational modeling provides a framework for quantitatively describing BHVs in the preclinical phase. To obtain reliable solutions in computational modeling, it is essential to consider accurate leaflet properties such as mechanical properties and density. Bovine pericardium (BP) is widely used as BHV leaflets. Previous computational studies assume BP density to be close to the density of water or blood. However, BP leaflets undergo multiple treatments such as fixation and anti-calcification. The present study aims to measure the density of the BP used in BHVs and determine its effect on leaflet stress distribution. Methods: We determined the density of eight square BP samples laser cut from Edwards BP patches. The weight of specimens was measured using an A&D Analytical Balance, and volume was measured by high-resolution imaging. Finite element models of a BHV similar to PERIMOUNT Magna were developed in ABAQUS. Results: The average density value of the BP samples was 1410 kg/m3. In the acceleration phase of a cardiac cycle, the maximum stress value reached 1.89 MPa for a density value of 1410 kg/m3 , and 2.47 MPa for a density of 1000 kg/m3(30.7% difference). In the deceleration, the maximum stress value reached 713 and 669 kPa, respectively. Conclusion: Stress distribution and deformation of BHV leaflets are dependent upon the magnitude of density. Ascertaining an accurate value for the density of BHV leaflets is essential for computational models.
Congenital heart diseases (CHDs) frequently impact the right ventricular outflow tract, resulting in a significant incidence of pulmonary valve replacement in the pediatric population. While contemporary pediatric pulmonary valve replacements (PPVRs) allow satisfactory patient survival, their biocompatibility and durability remain suboptimal and repeat operations are commonplace, especially for very young patients. This places enormous physical, financial, and psychological burdens on patients and their parents, highlighting an urgent clinical need for better PPVRs. An important reason for the clinical failure of PPVRs is biofouling, which instigates various adverse biological responses such as thrombosis and infection, promoting research into various antifouling chemistries that may find utility in PPVR materials. Another significant contributor is the inevitability of somatic growth in pediatric patients, causing structural discrepancies between the patient and PPVR, stimulating the development of various growth‐accommodating heart valve prototypes. This review offers an interdisciplinary perspective on these challenges by exploring clinical experiences, physiological understandings, and bioengineering technologies that may contribute to device development. It thus aims to provide an insight into the design requirements of next‐generation PPVRs to advance clinical outcomes and promote patient quality of life.
Significant valvular heart disease left untreated can have serious life-threatening consequences and given the lack of effective medical therapies and the evolution of valve-related devices, cardiac valve replacement and repair procedures are now performed frequently. Patients with heart valve disease gain significant survival and quality-of-life improvements with valve replacement. This chapter summarizes the pathologic anatomy and clinicopathological considerations in valve replacement and repair surgery, encompassing pathology associated with substitute valves and their repair as well as other pertinent cardiac and noncardiac pathology. It provides the reader with a broad overview and approach to the analysis of different prosthetic heart valves that may be encountered as surgical pathology or autopsy specimens (and potentially in a research setting). Discussion of the following related areas provides additional context: (1) surgical considerations and outcomes, (2) description of valve replacement devices, (3) approach to evaluating postsurgical hearts and substitute valves as pathological specimens, (4) transcatheter valve implantation, and (5) ongoing research and development. Attention is also given to pathologic considerations related to minimally invasive and repair procedures on cardiac valves.
Bakterielle Nanocellulose (BNC) hat sich in den letzten Jahren zu einem innovativen Biomaterial für den Einsatz in der Implantattechnologie entwickelt. Das faserartige Biomaterial wird von Bakterien direkt synthetisiert und zeichnet sich durch eine intrinsische, mechanische Stabilität und Biokompatibilität aus. Aufbauend auf ersten Ergebnissen in Tierstudien, welche die grundsätzliche Eignung der BNC als Implantatwerkstoff belegen, steht das Biomaterial bakterielle Nanocellulose als Neuheit in der Implantattechnologie im Mittelpunkt dieser Dissertation. Für den Einsatz der BNC in Implantaten ist das Verhalten bei mechanischer Beanspruchung von vorrangigem Interesse. Die Mikrostruktur faserartiger Biomaterialien ist sehr komplex und die mechanischen Eigenschaften der BNC sind bisher nicht vollständig verstanden. Daher wird in dieser Dissertation die mechanische Integrität des Fasernetzwerkes bei verschiedenen Belastungsarten analysiert. Neben einem umfassenden Verständnis des Materialverhaltens bei mechanischer Beanspruchung, steht zudem eine gezielte Beeinflussung der mechanischen Eigenschaften im Fokus der Forschungsarbeit. Dazu werden hygroskopische Substanzen (Glycerin, Polyethylenglykol) in das Fasernetzwerk eingebracht, sodass die mechanische Kraftantwort der BNC bei Belastung systematisch verändert wird. Darauf aufbauend wird der Einsatz des innovativen Biomaterials bei ausgewählten, kardiovaskulären Implantaten untersucht. Neben der Erstellung methodischer Konzepte, werden innovative Prozesse entwickelt und funktionsfähige Prototypen hergestellt. Die Entwicklung eines Bioreaktors ermöglicht die Synthese einer dreidimensional geformten BNC. Damit werden erstmals Prototypen von Gefäßprothesen und Stentgrafts mit einer Membran aus BNC sowie eine dreidimensionale, nahtlose Gewebekomponente aus BNC für Transkatheter-Aortenklappenprothesen hergestellt. Des Weiteren wird ein innovatives Konzept zur Herstellung lokal quellfähiger BNC entwickelt, die der Prävention potentieller paravalvulärer Leckagen bei minimalinvasiv implantierbaren Herzklappenprothesen dient. Die Anwendung dieses Konzeptes bei Aortenklappenprothesen erfolgt abschließend durch die Herstellung eines Prototyps mit einer lokal quellfähigen Gewebekomponente aus BNC.
Enzymatically degradable hydrogels were designed for the 3D culture of valvular interstitial cells (VICs), and through the incorporation of various functionalities, we aimed to investigate the role of the tissue microenvironment in promoting the osteogenic properties of VICs and matrix mineralization. Specifically, porcine VICs were encapsulated in a poly(ethylene glycol) hydrogel crosslinked with a matrix metalloproteinase (MMP)-degradable crosslinker (KCGPQG↓IWGQCK) and formed via a thiol-ene photoclick reaction in the presence or absence of collagen type I to promote matrix mineralization. VIC-laden hydrogels were treated with osteogenic medium for up to 15 days, and the osteogenic response was characterized by the expression of RUNX2 as an early marker of an osteoblast-like phenotype, osteocalcin (OCN) as a marker of a mature osteoblast-like phenotype, and vimentin (VIM) as a marker of the fibroblast phenotype. In addition, matrix mineralization was characterized histologically with Von Kossa stain for calcium phosphate. Osteogenic response was further characterized biochemically with calcium assays, and physically via optical density measurements. When the osteogenic medium was supplemented with calcium chloride, OCN expression was upregulated and mineralization was discernable at 12 days of culture. Finally, this platform was used to screen various drug therapeutics that were assessed for their efficacy in preventing mineralization using optical density as a higher throughput readout. Collectively, these results suggest that matrix composition has a key role in supporting mineralization deposition within diseased valve tissue.
Bioprosthetic heart valves (BHVs) are implanted in aortic valve stenosis patients to replace the native, dysfunctional valve. Yet, the long-term performance of the glutaraldehyde-fixed bovine pericardium (GLBP) leaflets is known to reduce device durability. The aim of this study was to investigate a type of commercial-grade GLBP which has been over-looked in the literature to date; that of high collagen fibre dispersion (HD). Under uniaxial cyclic loading conditions, it was observed that the fatigue behaviour of HD GLBP was substantially equivalent to GLBP in which the fibres are highly aligned along the loading direction. It was also found that HD GLBP had a statistically significant 9.5% higher collagen content when compared to GLBP with highly aligned collagen fibres. The variability in diseased BHV delivery sites results in unpredictable and complex loading patterns across leaflets in vivo. This study presents the possibility of a shift from the traditional choice of circumferentially aligned GLBP leaflets, to that of high fibre dispersion arrangements. Characterised by its high fatigue life and increased collagen content, in addition to multiple fibre orientations, GLBP of high fibre dispersion may provide better patient outcomes under the multi-directional loading to which BHV leaflets are subjected in vivo.
Bioprostheses, composed of chemically treated animal tissue and termed heterografts or xenografts, are the most widely used type of substitute heart valve. Their major limitation is structural degeneration caused by calcification. Calcification following implantation occurs in a tissue made vulnerable to calcification by the chemical treatment and physical changes induced during valve fabrication and their consequences following implantation. Data from clinical valve explants and subdermal and circulatory experiments in animal models have elucidated the pathophysiology, earliest events, and determinants of this significant clinical problem. The primary mechanism of calcification appears to result from exposure of a susceptible substrate (with phosphoester-containing devitalized cells and cell fragments) to extracellular fluid rich in calcium. The key drivers are (1) biochemical environment, (2) implant structure and chemistry, both of which are prerequisite to calcification, and (3) mechanical stress, which accelerates site-specific mineralization. Therefore, the primary approaches to inhibiting the fundamental process of calcification target the processes involved in the nucleation of calcific deposits and thus have sought to remove cell-based phospholipids or otherwise alter the substrate.
Ectopic or dystrophic calcification promotes premature implant and medical device failure. This chapter summarizes the various mechanisms of calcification proposed in the literature in the context of a medical device or biomaterial implantation into the human body, with particular emphasis on cardiovascular biomaterials, specifically heart valve replacements. It discusses the relevant history of the design decisions that evolved heart valve replacement materials. It also describes various ways researchers have investigated methods to mitigate calcification by modifying the biomaterial. The chapter concludes with a practical guide for choosing materials and test methods, and design considerations for medical devices that are prone to calcification.
Transthoracic echocardiography (TTE) is widely used as a pre-operative screening tool. It can provide extensive information about cardiac function and underlying pathology, which could influence decisions regarding surgery. This patient was referred for TTE as part of the pre-op screening, as he had a biological prosthetic aortic valve. This was a rare case where misleading TTE measurements inadvertently led to the patient being referred for transcatheter aortic valve replacement (TAVR), which delayed non-cardiac surgery.
Routine pre-op TTE in a district hospital showed severely increased gradients compared to the previous year, so the patient was referred to a tertiary centre for TAVR. However peri-operative trans-oesophageal echocardiography (TOE) showed lower gradients and satisfactory valve area. The cause of high gradients at the time of pre-op screening was retrospectively attributed to profound anaemia present at the time. When the anaemia was corrected, the prosthetic valve gradients reduced to levels similar to the previous year. This case reiterates the fact that Echocardiographers should be familiar with haemodynamic factors that could affect the validity of Doppler measurements that use Bernoulli’s equation and the continuity principle. This report also looks at how echocardiographers can mitigate the effects of non-valvar factors.
Heart valve disease is a significant medical problem worldwide. Treatment for end-stage disease is heart valve replacement, but both mechanical and bioprosthetic replacement heart valves suffer from significant limitations. Promising alternatives to currently available replacement heart valves are being developed using the principles of tissue engineering. Significant progress has been made in the development of a tissue engineered heart valve (TEHV) substitute, including the characterization and development of various different cell sources and cell seeding techniques, advancements in natural and polymer matrix and scaffold design, and the creation of bioreactors, which are biomimetic devices used to modulate the in vitro development of tissue engineered neotissue through the application of biochemical and biomechanical stimuli. This chapter addresses the need for a tissue engineered alternative to current heart valve replacement options and reviews past and ongoing work in the field. The basics of heart valve structure, function, and disease are presented and followed by a review of investigations leading to the development of a TEHV, including the critical challenges that remain.
Bioprosthetic materials based on mammalian pericardium tissue are the gold standard in reconstructive surgery. Their application range covers repair of rectovaginal septum defects, abdominoplastics, urethroplasty, duraplastics, maxillofacial, ophthalmic, thoracic and cardiovascular reconstruction, etc. However, a number of factors contribute to the success of their integration into the host tissue including structural organization, mechanical strength, biocompatibility, immunogenicity, surface chemistry, and biodegradability. In order to improve the material's properties, various strategies are developed, such as decellularization, crosslinking, and detoxification. In this review, the existing issues and long-term achievements in the development of bioprosthetic materials based on the mammalian pericardium tissue, aimed at a wide-spectrum application in reconstructive surgery are analyzed. The basic technical approaches to preparation of biocompatible forms providing continuous functioning, optimization of biomechanical and functional properties, and clinical applicability are described.
Abstract
The review describes the milestones in the development of bioprosthetic materials based on mammalian pericardium tissue. The basic technical approaches to preparation of biocompatible forms including decellularization, crosslinking, detoxification, and application range of pericardial biomeshes in reconstructive surgery are discussed.
Transcatheter aortic valve replacement (TAVR) is an established treatment for patients with severe symptomatic aortic stenosis. It is known and recognized that leaflet geometry has a key role in structural and hemodynamic performance of bioprosthetic heart valves. Excessive mechanical stress on the leaflets will lead to accelerated tissue degeneration and diminished long-term valve durability. The goal of this study was to develop an automatic optimization framework by means of commercially available software packages to reduce maximum stress value of transcatheter aortic valve (TAV) leaflets. Leaflet design was parameterized by 2 s-order non-uniform rational B-splines (NURBS) curves and particle swarm optimization method was used to examine the optimization design space. Optimized leaflet geometry for 23-mm and 26-mm TAVs were obtained under dynamic physiological loading condition. Leaflet stress distributions of the optimized TAV geometries were compared with two commercially available bioprostheses (i) Carpentier-Edwards PERIMOUNT Magna surgical bioprosthesis and (ii) Edwards SAPIEN 3 transcatheter heart valve. A considerable reduction in the maximum in-plane principal stress was observed in the optimized TAV geometries compared to the commercially available bioprostheses. The optimization results underline the opportunity to improve leaflet design in the next generation of TAVs to potentially increase long-term durability of transcatheter heart valves.
Transcatheter aortic valves (TAV) are symmetrically designed, but they are often not deployed inside cylindrical conduits with circular cross-sectional areas. Many TAV patients have heavily calcified aortic valves, which often result in deformed prosthesis geometries after deployment. We investigated the effects of deformed valve annulus configurations on a surgical bioprosthetic valve as a model for TAV. We studied valve leaflet motions, stresses and strains, and analogue hydrodynamic measures (using geometric methods), via finite element modeling. Two categories of annular deformations were created to approximate clinical observations: 1) non-circular annulus with valve area conserved, and 2) under-expansion (reduced area) compared to circular annulus. We found that under-expansion had more impact on increasing stenosis than non-circularity, and that non-circularity had more impact on increasing regurgitation than under-expansion. We found durability predictors (stress/strain) to be highest in commissure regions of non-circular configurations. This study adds more evidence for considering the clinical impacts of TAV deformation on acute and long-term valve performance in the design and testing phase of device development.
For the past 50+ years, the heart valve replacement (HVR) industry has gone through multiple growth phases in terms of innovation and market growth, and is now a formidable submarket of the cardiovascular medical device space. HVRs started off as small, compact simplistic devices made from synthetic parts. Now, these archaic prototypes have evolved into a diverse product offering from a multitude of small to large healthcare firms that range from completely synthetic materials to crosslinked tissue-based HVRs to new research being performed to investigate engineered tissue valves. These innovative leaps in technology and growth in commerce would not have been possible without the collaboration of multidisciplinary investigators unified through their passion in pursuing one goal—a superior healthcare option that resulted in a better quality of life for individuals throughout the world needing a new heart valve. Everything from biomaterial design to micro/macro-biomechanics to build computational modeling to optimize valve design has been utilized to create the current product line and are currently still in use as our metrics and methods get more advanced to innovate the future of heart valves as well as cardiovascular device technology. The future of HVRs rests on academia and industry coming together to move technology forward to provide patients in dire need of a more durable HVR device. Therefore, the rest of the content covered in this book is a comprehensive review of current art and models in existence to design an effective HVR in the efforts of empowering individuals wishing to bring healthcare options to a patient segment in dire need of change. The following chapter will cover past and current approaches in designing and fabricating HVR materials, current performance of HVRs, material design considerations of next generation materials, and major research interests in the next generation of HVR materials. The rest of this publication will cover approaches in properly leveraging this base biomaterial in valve-specific design to innovate a more effective HVR.
Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular morbidity and mortality, and its prevalence is expected to increase in the aging population of the developed world. Currently, no noninvasive therapeutic strategies exist to prevent or treat CAVD. Though the advent of new valve replacement technologies have improved clinical outcomes, these techniques remain suboptimal for the two populations most at risk for valvular complications—pediatric and elderly patients. Recent advances in basic research have shown that CAVD arises through active cellular mechanisms, offering hope that drugs can be developed to target relevant pathways and provide new clinical options for CAVD patients. Translating these benchtop discoveries to clinical realities, however, will require both a holistic understanding of how targetable cellular level processes affect valve tissue function and the ability to identify early CAVD development in patients. This chapter addresses this translation by reviewing the current state of CAVD research and the ongoing efforts to meet the clinical need.
Valvular heart diseases lead to over 300,000 heart valve replacements worldwide each year. Commercially available bioprosthetic heart valves (BHVs) are mostly made from porcine or bovine pericardiums which were crosslinked by glutaraldehyde (GLUT). However, valve failures can occur within 10 years due to progressive degradation and calcification. GLUT could crosslink collagen but it fails to stabilize elastin. In this current study, we developed a new BHVs preparation strategy named as "GLUT/TE/LOXL/EGCG" that utilizes exogenous tropoelastin (TE)/lysyl oxidase (LOXL) and epigallocatechin gallate (EGCG) to increase the elastin content as well as the stabilization of elastin. The feeding ratios of tropoelastin and lysyl oxidase were optimized. The contents of desmosine and insoluble elastin, biomechanics, cytotoxicity, hemocompatibility, in vivo componential stability and anti-calcification potential were characterized. Pericardiums with increased elastin content had improved the mechanical properties. GLUT/TE/LOXL/EGCG-treated pericardiums had similar cytotoxicity and coagulation properties compared to GLUT and GLUT/EGCG control. We demonstrated that GLUT/TE/LOXL/EGCG-treated pericardiums had high amount of insoluble elastin in 90 days' rat subdermal implantation model, and better resistance for calcification. This new tropoelastin and lysyl oxidase treatments strategy would be a promising method to make BHVs which have better structural stability and anti-calcification properties.
Valvular heart diseases lead to over 300,000 heart valve replacements worldwide each year. Bioprosthetic heart valves (BHVs), derived from glutaraldehyde (GLUT) crosslinked porcine or bovine pericardium, are often used. However, valve failure can occur within 12–15 years due to progressive degradation and/or calcification. Being innovated by previous amino reagent studies used for GLUT detoxification and carbodiimide [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EDC] chemistry, in this study, we developed a new fabrication method that utilizes exogenous amino donor arginine or lysine carbodiimide combined treatments to better stabilize the extracellular matrix of porcine pericardium. The carboxyl group density, amine content, differential scanning calorimetry, collagenase and elastase degradation, calcification by rat subdermal implantation, cytotoxicity, and platelet adhesion were characterized. We demonstrated that exogenous amino donor carbodiimide combined treatment for pericardiums had better resistance to elastase degradation (1.63 ± 0.11% and 1.44 ± 0.24% in arginine or lysine versus 3.68 ± 0.16% and 3.04 ± 0.11% in GLUT and GLUT/EDC control) and calcification (0.624 ± 0.193 and 0.637 ± 0.213 Ca µg/mg tissue in arginine or lysine versus 1.610 ± 0.124 and 1.512 ± 0.075 Ca µg/mg tissue in GLUT and GLUT/EDC control). This new strategy combined arginine or lysine and carbodiimide crosslinking would be a promising method to produce more robust BHVs with better structural stability and anticalcification property.
Background:
In order to accommodate transcatheter valves to miniaturized catheters, the leaflet thickness must be reduced to a value which is typically less than that of surgical bioprostheses. The study aim was to use finite-element simulations to determine the impact of the thickness reduction on stress and strain distribution.
Methods:
A 23 mm transcatheter aortic valve (TAV) was modelled based on the Edwards SAPIEN XT (Edwards Lifesciences, Irvine, CA, USA). Finite-element (FE) analysis was performed using the ABAQUS/Explicit solver. An ensemble-averaged transvalvular pressure waveform measured from in-vitro tests conducted in a pulse duplicator was applied to the leaflets. Through a parametric study, uniform TAV leaflet thickness was reduced from 0.5 to 0.18 mm.
Results:
By reducing leaflet thickness, significantly higher stress values were found in the leaflet's fixed edge during systole, and in the commissures during diastole. Through dynamic FE simulations, the highest stress values were found during systole in the leaflet fixed edge. In contrast, at the peak of diastole high-stress regions were mainly observed in the commissures. The peak stress was increased by 178% and 507% within the leaflets after reducing the thickness of 0.5 mm to 0.18 mm at the peak of systole and diastole, respectively.
Conclusions:
The study results indicated that, the smaller the leaflet thickness, the higher the maximum principal stress. Increased mechanical stress on TAV leaflets may lead to accelerated tissue degeneration. By using a thinner leaflet, TAV durability may not atch with that of surgical bioprostheses.
Bioprosthetic heart valves fail as the result of two simultaneous processes: structural deterioration and calcification. Leaflet deterioration and perforation have been correlated with regions of highest stress in the tissue. The failures have long been assumed to be due to simple mechanical fatigue of the collagen fibre architecture; however, we have hypothesized that local stresses-and particularly dynamic stresses-accelerate local proteolysis, leading to tissue failure. This study addresses that hypothesis. Using a novel, custom-built microtensile culture system, strips of bovine pericardium were subjected to static and dynamic loads while being exposed to solutions of microbial collagenase or trypsin (a non-specific proteolytic enzyme). The time to extend to 30% strain (defined here as time to failure) was recorded. After failure, the percentage of collagen solubilized was calculated based on the amount of hydroxyproline present in solution. All data were analyzed by analysis of variance (ANOVA). In collagenase, exposure to static load significantly decreased the time to failure (P < 0.002) due to increased mean rate of collagen solubilization. Importantly, specimens exposed to collagenase and dynamic load failed faster than those exposed to collagenase under the same average static load (P = 0.02). In trypsin, by contrast, static load never led to failure and produced only minimal degradation. Under dynamic load, however, specimens exposed to collagenase, trypsin, and even Tris/CaCl2 buffer solution, all failed. Only samples exposed to Hanks' physiological solution did not fail. Failure of the specimens exposed to trypsin and Tris/CaCl2 suggests that the non-collagenous components and the calcium-dependent proteolytic enzymes present in pericardial tissue may play roles in the pathogenesis of bioprosthetic heart valve degeneration.
Bioprosthetic heart valves removed 76 to 150 months after implantation were morphologically investigated to
correlate structural alterations with clinical failure modes. Traditional morphologic methods of evaluating
valvular heterografts, such as microradiography and electron microscopy, were complemented by undecalcified ground sections, a new technique for analyzing the distribution of mineral deposits. Apart from well-investigated mechanisms that accelerate tissue degeneration, our observations point to additional facts: (1) phagocytosis of collagen fibrils and elastic material by macrophages and foreign body giant cells in areas near tears and perforations and (2) initial calcification indicated by delicate crystals in the intercellular space arranged in close relation to the periodicity of the cross-striation pattern of collagen fibrils. The present report not only calls attention to degenerative changes that are enhanced by mechanical stress but also underlines phagocytosis as animportant mechanism in the destruction of bioprosthetic heart valves.
Substitute heart valves composed of human or animal tissues have been used since the early 1960s, when aortic valves obtained fresh from human cadavers were transplanted to other individuals as allografts. Today, tissue valves are used in 40% or more of valve replacements worldwide, predominantly as stented porcine aortic valves (PAV) and bovine pericardial valves (BPV) preserved by glutaraldehyde (GLUT) (collectively termed bioprostheses). The principal disadvantage of tissue valves is progressive calcific and noncalcific deterioration, limiting durability. Native heart valves (typified by the aortic valve) are cellular and layered, with regional specializations of the extracellular matrix (ECM). These elements facilitate marked repetitive changes in shape and dimension throughout the cardiac cycle, effective stress transfer to the adjacent aortic wall, and ongoing repair of injury incurred during normal function. Although GLUT bioprostheses mimic natural aortic valve structure (a) their cells are nonviable and thereby incapable of normal turnover or remodeling ECM proteins; (b) their cuspal microstructure is locked into a configuration which is at best characteristic of one phase of the cardiac cycle (usually diastole); and (c) their mechanical properties are markedly different from those of natural aortic valve cusps. Consequently, tissue valves suffer a high rate of progressive and age-dependent structural valve deterioration resulting in stenosis or regurgitation (>50% of PAV overall fail within 10–15 years; the failure rate is nearly 100% in 5 years in those <35 years old but only 10% in 10 years in those >65). Two distinct processes—intrinsic calcification and noncalcific degradation of the ECM—account for structural valve deterioration. Calcification is a direct consequence of the inability of the nonviable cells of the GLUT-preserved tissue to maintain normally low intracellular calcium. Consequently, nucleation of calcium-phosphate crystals occurs at the phospholipid-rich membranes and their remnants. Collagen and elastin also calcify. Tissue valve mineralization has complex host, implant, and mechanical determinants. Noncalcific degradation in the absence of physiological repair mechanisms of the valvular structural matrix is increasingly being appreciated as a critical yet independent mechanism of valve deterioration. These degradation mechanisms are largely rationalized on the basis of the changes to natural valves when they are fabricated into a tissue valve (mentioned above), and the subsequent interactions with the physiologic environment that are induced following implantation. The “Holy Grail” is a nonobstructive, nonthrombogenic tissue valve which will last the lifetime of the patient (and potentially grow in maturing recipients). There is considerable activity in basic research, industrial development, and clinical investigation to improve tissue valves. Particularly exciting in concept, yet early in practice is tissue engineering, a technique in which an anatomically appropriate construct containing cells seeded on a resorbable scaffold is fabricated in vitro, then implanted. Remodeling in vivo, stimulated and guided by appropriate biological signals incorporated into the construct, is intended to recapitulate normal functional architecture. © 1999 John Wiley & Sons, Inc. J Biomed Mater Res, 47, 439–465, 1999.
We undertook this study to establish a more quantitative understanding of the microstructural response of the aortic valve cusp to pressure loading. Fresh porcine aortic valves were fixed at transvalvular pressures ranging from 0 mmHg to 90 mmHg, and small-angle light scattering (SALS) was used to quantify the gross fiber structure of the valve cusps. At all pressures the fiber-preferred directions coursed along the circumferential direction. Increasing transvalvular pressure induced the greatest changes in fiber alignment between 0 and 1 mmHg, with no detectable change past 4 mmHg. When the fibrosa and ventricularis layers of the cusps were re-scanned separately, the fibrosa layer revealed a higher degree of orientation while the ventricularis was more randomly oriented. The degree of fiber orientation for both layers became more similar once the transvalvular pressure exceeded 4 mmHg, and the layers were almost indistinguishable by 60 mmHg. It is possible that, in addition to retracting the aortic cusp during systole, the ventricularis mechanically may contribute to the diastolic cuspal stiffness at high transvalvular pressures, which may help to prevent over distention of the cusp. Our results suggest a complex, highly heterogeneous structural response to transvalvular pressure on a fiber level that will have to be duplicated in future bioprosthetic heart valve designs. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 41, 131–141, 1998.
The use of bioprosthetic valves fabricated from fixed heterograft tissue (porcine aortic valves or bovine pericardium) in heart valve replacement surgery is limited because of calcification-related failures. The mechanism of calcification of bioprosthetic valves is quite complex and has a variety of determinants, including host factors, tissue fixation conditions, and mechanical effects. Currently, there is no effective therapy to prevent calcification in clinical settings. This article reviews a variety of anticalcification strategies that are under investigation either in advanced animal models or in clinical trials. Bisphosphonates, such as ethan hydroxybisphosphonate (EHBP), inhibit calcium phosphate crystal formation. However, because of their systemic toxicity, they are used as either tissue treatments or polymeric site-specific delivery systems. Detergent treatment, such as sodium dodecyl sulfate (SDS), extracts almost all phospholipids from bioprosthetic heart valve cuspal tissue. Procedures, such as amino oleic acid pretreatment, inhibit calcium uptake. Polyurethane trileaflet valves, investigated as alternatives to bioprosthetic or mechanical valve prostheses, undergo intrinsic and thrombus-related calcification and degradation. Calcification- and thrombus-resistant polyurethanes synthesized in our laboratory by covalent linking of EHBP or heparin (either in bulk or on surface) by unique polyepoxidation chemistry are attractive candidates for further research. Tissue-engineered heart valves may have an important place in the future.
Copyright © 1997 Elsevier Science Inc. All rights reserved.
Scanning and transmission electron microscopic studies were made of (1) 12 glutaraldehyde-treated porcine valvular heterografts that had been implanted in patients for 2 days to 76 months; (2) 3 unimplanted commercially processed porcine aortic valves; and (3) 1 unprocessed porcine aortic valve. Comparison of unprocessed porcine valves and unimplanted commercially processed valves showed loss of endothelium and acid mucopolysaccharides during preimplantation processing. Short-term (less than 2 months) changes after implantation consisted of insudation of plasma proteins, penetration of erythrocytes into surface crevices, formation of a thin surface layer of fibrin, and deposition of macrophages, giant cells and a few platelets. Longer-term (more than 2 months) changes were proportional to the time interval after implantation and consisted of progressive disruption of collagen, erosion of the valve surfaces, formation of aggregates of platelets and accumulation of lipid. The surfaces of the leaflets did not become covered with endothelium or with a fibrous sheath. Calcific deposits were found in one valve and bacterial organisms in another. Thus, progressive breakdown of collagen appears to be a critical factor in determining the long-term durability of glutaraldehyde-treated porcine valvular heterografts.
Static tensile tests and accelerated fatigue tests were used to investigate the mechanical durability of glutaraldehyde preserved bovine and porcine mitral tissue with a view to gaining some understanding of the long-term functional behaviour of preserved heterografts. As well as there being a reduction in the tissue compliance following fixation, the effects of cyclic loading over a wide range of peak stresses were to reduce further the tissue compliance. Fatigue induced structural changes leading finally to gross disruption of the collagen fibre array were observed using optical and electron microscopy.
Bioprosthetic heart valves removed 76 to 150 months after implantation were morphologically investigated to correlate structural alterations with clinical failure modes. Traditional morphologic methods of evaluating valvular heterografts, such as microradiography and electron microscopy, were complemented by undecalcified ground sections, a new technique for analyzing the distribution of mineral deposits. Apart from well-investigated mechanisms that accelerate tissue degeneration, our observations point to additional facts: (1) phagocytosis of collagen fibrils and elastic material by macrophages and foreign body giant cells in areas near tears and perforations and (2) initial calcification indicated by delicate crystals in the intercellular space arranged in close relation to the periodicity of the cross-striation pattern of collagen fibrils. The present report not only calls attention to degenerative changes that are enhanced by mechanical stress but also underlines phagocytosis as an important mechanism in the destruction of bioprosthetic heart valves.
The aim of this study was to determine whether second-generation porcine bioprostheses, glutaraldehyde fixed at pressures said to be less than 4 mm Hg, exhibit more natural leaflet material properties than earlier valves fixed at 80 to 100 mm Hg. Biaxial mechanical testing techniques were used to compare Carpentier-Edwards SAV, St. Jude Medical BioImplant, Hancock II, and Medtronic Intact bioprostheses (12 leaflets from four valves in each case) with fresh porcine aortic valves and high pressure-fixed Carpentier-Edwards 6625 bioprostheses (14 leaflets from five valves in each case). The circumferential extensibility of leaflets from Medtronic Intact bioprostheses and from fresh porcine aortic valves were not significantly different (p greater than 0.05), whereas leaflets from the other second-generation valves tested and from Carpentier-Edwards 6625 valves were highly inextensible in the circumferential direction. The radial material properties of leaflets from all bioprostheses differed from those of fresh porcine aortic valves, which were very extensible with a high pretransitional compliance. The radial extensibility and compliance of Hancock II, St. Jude Medical BioImplant, and Carpentier-Edwards 6625 leaflets were not significantly different (p greater than 0.05). In the radial direction, Carpentier-Edwards SAV and Medtronic Intact valve leaflets were substantially more extensible than Carpentier-Edwards 6625 leaflets (p less than 0.01), whereas Medtronic Intact leaflets were more compliant than all other bioprostheses. These data demonstrate (1) that second-generation porcine bioprosthetic valves do not necessarily exhibit more natural leaflet material properties than earlier high pressure-fixed xenografts and (2) that Medtronic Intact valve leaflets have material properties most closely approximating the fresh porcine aortic valve.
Although heart valve bioprostheses provide a normal quality of life, their durability is still of great concern. Their durability failure is defined as "degeneration," which is considered to be a consequence of metabolic factors. In this study, we demonstrate that mechanical and design factors can also be responsible for bioprosthesis failure. Large numbers of porcine and pericardial bioprostheses were tested in a fatigue-testing system in which the test conditions were proved to be reproducible and accurate by a laser Doppler anemometer. The results have allowed us to define causes of failure, previously insufficiently stressed, in each type of valve tested. There is a clear difference in factors influencing tissue disruption between porcine and pericardial valves. We have compared these in vitro results with in vivo clinical findings. The main inferences are as follows: (1) Bioprostheses rupture and fail in the same fashion in both in vitro and in vivo studies. (2) Mechanical and design factors are involved in tissue failure. (3) The in vitro/in vivo durability ratio is not 1:1. This ratio depends on the test conditions. (4) Pericardial valves fail because of damage during closure, whereas porcine valves are damaged during both opening and closing (mostly opening) because of design features. (5) Once one cusp fails and prolapses, the other cusps will fail in an accelerated fashion. (6) In vitro durability of 100 X 10(6) cycles can be considered excellent and is an achievable goal. (7) Variability is the key impediment to predicting the durability of bioprostheses. Valves can fail within 2 to 3 million cycles or can last more than 100 million cycles. Similarly, bioprostheses may require explantation within a few months or can last 10 to 13 years in patients. (8) Fatigue testing is an excellent and valuable tool to elucidate the mechanical factors responsible for this variability.
Current reports indicate that collagen fiber disruption resulting from cyclic leaflet bending is a factor determining long-term durability of bioprosthetic heart valves. Examination of the opening characteristics of porcine xenografts has shown two areas of high bending curvature that correlate well with sites of leaflet tearing. These are at the free edge and near the attachment of the leaflets to the aortic root. To determine the potential effects of sharp bends in leaflet material, we examined 15 strips each of fresh and glutaraldehyde-treated porcine aortic valve tissue. Leaflet strips were bent to curvatures of 0.18 mm-1 to 6.67 mm-1, histologically processed, sectioned, and examined under a light microscope. We observed severe compressive buckling in the samples taken from bioprosthetic valves but little in the fresh-tissue samples. At physiological curvatures (less than 0.28 mm-1), no buckling occurred in the fresh tissue; at high bending curvatures (2.0 mm-1), the depth of buckling observed in the treated tissue was 100% greater than that in the fresh. We believe that porcine xenograft failure is related to compressive buckling of the aldehyde-treated tissue and is mediated by the systematic breaking of collagen fibers at the site of buckling. We suggest that alternative valve designs and preservation techniques be employed to prevent such abnormal leaflet deformations.
Bioprosthetic valve calcification is usually assessed pathologically by gross inspection, radiographic studies, and histologic examination. Quantitation of mineral content by chemical assay has not been reported for failed clinical valves removed from adults. In this study, calcium determination by atomic absorption spectroscopy was done on 52 removed porcine valves after routine pathologic examination, including specimen radiography done by a standard technique. Specimens included 31 valves with calcific primary tissue failure, two calcified (but not overtly dysfunctional) valves removed simultaneously with failed valves, 14 nondeteriorated valves obtained at reoperation or autopsy after long-term implantation, and five valves removed within 1 month after insertion. Chemically determined mineral content varied widely among patients and duration of function. Valves with calcific failure had 113 +/- 68 micrograms/mg calcium overall (mean +/- SD) after 36 to 156 months (mean 87) of function. Almost all dysfunctional porcine valves with radiographically demonstrated calcific deposits had greater than 34 and 67 micrograms/mg calcium for mitral and aortic valves, respectively. Nondeteriorated valves (implanted 8 to 145 months, mean 57) had 5 +/- 6 micrograms/mg calcium. Failed aortic valves had more calcium than failed mitral valves and valves with calcific stenosis more than valves with regurgitation caused by calcification with tearing. Correlation of semiquantitative radiographic grading with chemically determined valve mineral was good, indicating that radiographic assessment of calcification may be used reliably for clinical comparisons between valves.
Calcification, the major cause of bioprosthetic heart valve failures, is a serious clinical problem with uncertain pathogenesis. The objectives of the present study were to define the progressive chemical and morphologic sequence of mineralization in glutaraldehyde-treated porcine aortic valve cusps implanted subcutaneously in rats and to compare the pathology and pathophysiology of calcification in subcutaneous implants with that of orthotopic valve replacements in calves. Cusps were implanted subcutaneously in 3-week-old rats for 24 hours to 18 weeks. Cuspal calcium was 114 +/- 18 micrograms/mg of dry weight (mean +/- SEM) at day 21 and 218 +/- 6 at day 56 of implantation and unchanged thereafter. The earliest mineral deposits, noted at 48 hours, were associated with devitalized porcine connective tissue cells, but by 7 days, mineral deposits also involved collagen bundles. Scanning electron microscopy with energy-dispersive x-ray analysis demonstrated predominant accumulation in the spongiosa with a spongiosa to fibrosa energy-dispersive x-ray analysis count ratio of calcium of 15 at 21 days. In stent-mounted glutaraldehyde-preserved porcine valves implanted in five calves as mitral replacements for 69 to 142 days, cuspal calcium was 86 micrograms/mg (mean) (range 47 to 128). Calf implants also had cell oriented and collagen calcification predominating in the valvar spongiosa. In both rat subcutaneous and calf mitral valve models, early diffuse calcific microcrystals evolved into confluent nodules that disrupted tissue architecture. It is concluded that calcification of glutaraldehyde-preserved porcine aortic valves implanted subcutaneously in rats begins within 48 hours, earliest deposits are localized to residual porcine connective tissue cells, but latter deposits also involve collagen fibrils, mineralization is most prominent in the spongiosa, the pathology of calcification in rat subcutaneous implants and calf mitral replacements is comparable, suggesting a common pathophysiology, and calcific nodule formation most likely initiates clinical features.
The details of heart valve prosthesis-associated problems are not widely known. This study investigated the etiologies of the failures of 91 valves, 33 mechanical prostheses and 58 bioprostheses, obtained at reoperation (83) or autopsy (eight) at the Brigham and Women's Hospital during the 42-month period from mid- 1980 through 1983, one to 264 months (mean, 72 months) after valve replacement. Analysis was by gross, histologic, radiographic, and microbiologic examination, as well as review of clinical records. Overall causes of failure included paravalvular leak (15 per cent), thrombosis (7 per cent), tissue overgrowth (8 per cent), degeneration or mechanical failure (43 per cent), and endocarditis (19 per cent). Endocarditis and paravalvular leak were equally frequent with mechanical prostheses and bioprostheses. In addition, thrombosis (18 per cent), tissue overgrowth (21 per cent), and structural failure (12 per cent) were all important failure modes for mechanical prostheses. Sterile degeneration was the overwhelming cause of failure for bioprostheses, accounting for the failure of 35 of 58 (60 per cent) of those recovered. Sterile degeneration took several forms: calcification, with or without cuspal tears (27 cases, 47 per cent of bioprostheses; mean, 77 months, range, 44 to 108 months) and cuspal defects without calcification (eight cases, 14 per cent; mean, 59 months, range, eight to 122 months). In general, calcification increased with time after implantation, but the propensity for the mineralization of bioprostheses varied widely among patients. Four torn valves that had been in place for more than six years had radiographically undetectable calcific deposits. The results of this study indicate that paravalvular leak and endocarditis are frequent causes of failure for all valve types. No clear failure mode predominates with mechanical valve prostheses, although some designs have specific inherent limitations. In contrast, degeneration, especially that related to mineralization, is the most important cause of the late failure of contemporary bioprostheses.
Bioprosthetic cardiac valve calcification is a frequent complication after long-term valve replacement. In this study the authors sought to examine the biologic determinants of this type of dystrophic calcification using subcutaneous implants of glutaraldehyde-preserved porcine aortic valve leaflets (GPVs) in rats. GPVs and clinical valvular bioprostheses were prepared identically. Retrieved implants were examined for calcification and the deposition of osteocalcin (OC), a vitamin K-dependent, bone-derived protein, that is found in other dystrophic and ectopic calcifications. GPVs implanted in 3-week-old rats calcified progressively (GPV Ca2+, 122.9 +/- 6.0 micrograms/mg) after 21 days, with mineral deposition occurring in a morphologic pattern comparable to that noted in clinical retrievals. Calcified GPVs accumulated osteocalcin (OC, 183.4 +/- 19.4 ng/mg); Nonpreserved porcine aortic leaflet implants did not calcify (Ca2+ + 5.6 +/- 1.0 micrograms/mg). Millipore diffusion chamber (0.45-mu pore size enclosed GPV implants accumulated calcium and adsorbed osteocalcin despite the absence of attached host cells. GPVs implanted for 21 days in 8-month-old rats calcified less (GPV Ca2+, 22.4 +/- 5.0 micrograms/mg) than did GPVs implanted in 3-week-old rats (see above). High-dose warfarin therapy (80 mg/kg) did not alter GPV calcification (GPV Ca2+, 39.6 +/- 2.9 micrograms/mg) in 72-hour subcutaneous implants in 3-week-old male rats, compared with control rats (GPV Ca2+, 40.8 +/- 4.8 micrograms/mg).
Leaflet tissue specimens prepared from porcine aortic valves treated with glutaraldehyde at low and high pressures have been subjected to 0.45 x 10(9) accelerated fatigue cycles in Ringer's solution. The waveform or crimped property of the collagen fibres in the leaflet tissue is an essential requirement for its ability to resist localized deformation during repeated flexure. High pressure glutaraldehyde fixation of the whole valve eliminated the crimp structure and resulted in the formation of localized kink sites in the tissue specimen during repeated flexure. Eleven separate sites of serious tissue disruption were observed in the three fatigue specimens obtained from the high pressure-treated valve. In contrast to this only one site of serious disruption was observed in the three fatigue specimens obtained from the low pressure-treated valve. Here fixation preserved the fully crimped morphology of the collagen. It is expected that the long-term mechanical durability of glutaraldehyde treated aortic valves can be substantially increased if careful consideration is given to the pressure at which initial fixation is carried out.
Calcification of bioprostheses used for heart valve replacement is a serious problem, since it causes bioprosthetic dysfunction. In vivo, bioprostheses are subjected to large mechanical stresses during each cardiac cycle. We investigated whether stresses play a major role in calcification of bioprostheses. Previous studies of Carpentier-Edwards porcine, Hancock porcine, and Ionescu-Shiley pericardial bioprostheses indicated that the highest stresses occurred in the areas of greatest flexion of the leaflet. In porcine bioprostheses, stresses were greater in the commissural region than at the base, and were compressive on the aortic surface of the leaflet. The pericardial tissue showed shear deformation in the zone of flexion. In the present study, the three types of bioprostheses were implanted in the aortic position in calves to investigate the development, location, and distribution of calcification. Visual, radiographic, and histologic techniques were used. All bioprostheses showed calcification which began in the area of leaflet flexion. In porcine bioprostheses, calcification occurred earlier in the commissural region than at the base. The earliest calcific deposits were localized within collagen cords on the aortic surface of the leaflets. In pericardial bioprostheses, calcification occurred at multiple foci along the zone of leaflet flexion and was located between and within layers of collagen along planes parallel to the leaflet surface. Hence calcification in all bioprostheses began in the areas of greatest stress. In porcine bioprostheses, calcification was present where collagen fibers are likely to have been damaged by compressive stresses. In pericardial bioprostheses, calcification was found along the planes of shear where structural integrity is likely to have been disrupted by the sliding of individual layers of collagen over each other. It is concluded that mechanical stresses initiate calcification by damaging the structural integrity of the leaflet tissue. Therefore, calcification of bioprostheses can be inhibited by reducing functional stresses through the modification of design and tissue properties to duplicate those of the natural aortic valve.
This paper describes a theoretical and experimental approach to the analysis of the deformations of a thin biological tissue. A biological tissue undergoes complex deformations during which normal and shearing strains are produced. These strains can be very large and yet be within the elastic range of the material. The procedure described is demonstrated for the pericardium used in making bioprosthetic heart valves. It is observed that the pericardium exhibits a directional property in which the shearing deformations occur in one direction but not in the opposite direction. By the application of the proposed method, modes of deformation can be determined and modes of failure predicted.
Rupture of the fibrous cap of the atherosclerotic plaque is a key event that predisposes to coronary thrombosis, leading to acute coronary syndromes. Recent studies have shown that the fibrous caps of vulnerable and ruptured atherosclerotic plaques have reduced collagen and glycosaminoglycan content in association with an increased macrophage density and a reduced smooth muscle cell density. Since collagen breakdown in the fibrous caps may contribute to a thinning and weakening of the cap, increasing its vulnerability to rupture, we tested the hypothesis that monocyte-derived macrophages, by producing matrix-degrading metalloproteinases (MMPs), could induce collagen breakdown in human atherosclerotic fibrous caps.
Monocytes were isolated from human blood by Ficoll-Paque density gradient and allowed to grow in cell culture until phenotypic and staining characteristics indicated transformation into macrophages (4 to 7 days). Fibrous caps were dissected from human aortic or carotid plaques and incubated for 48 hours with macrophages in serum-free medium without (n = 21) and with (n = 10) an MMP inhibitor or with cell- and serum-free medium only (n = 9). Hydroxyproline released in the culture medium was measured by a spectrophotometric method and used as evidence of collagen breakdown in the fibrous caps. Immunocytochemistry with specific monoclonal antibodies was used to identify expression of MMP-1 (interstitial collagenase) and MMP-2 (72-kD gelatinase) in cell culture, and zymography was used to detect MMP activity in the culture supernatant. The amount of hydroxyproline released was significantly greater when fibrous caps were incubated with macrophages than when incubated with cell-free medium (0.4 +/- 0.16 micrograms.mL-1.mg-1 versus 0.02 +/- 0.03 micrograms.mL-1.mg-1 of tissue; P < .04 by Mann-Whitney test). There was no hydroxyproline release when fibrous caps were incubated with macrophages in the presence of an MMP inhibitor. Immunocytochemistry demonstrated MMP-1 and MMP-2 expression by macrophages between days 4 and 7, and zymography confirmed the presence of MMP-2 activity in the supernatant.
In this study, human monocyte-derived macrophages were shown to induce collagen breakdown in fibrous caps of human atherosclerotic plaques associated with cellular expression and zymographic evidence of MMP activity; no evidence of collagen breakdown was found in the presence of an MMP inhibitor. These findings support the hypothesis that increased macrophage density and/or activation in the atherosclerotic plaque may induce collagen breakdown in the fibrous cap by secreting MMPs and possibly other proteases, thus contributing to vulnerability to plaque rupture.
Porcine bioprosthesis were treated with 0.625% glutaraldehyde and stabilized under changing pressure from 4 to 30 mmHg. Bovine pericardium and 12 biovalves (of age between 14 days and 80 months) after implantation in the human body were investigated (7 porcine PB and 5 pericardial bioprosthesis--PCB). Circumferential and radial strips from porcine aortic valve leaflets, bovine pericardium and bioprosthetic leaflets were studied in light, transmitting and scanning electron microscopy. Uniaxial load tests were carried out to examine the deformability and strength of these tissues. Microscopic examination of the biovalves revealed that the PB and PCB tissue retained its original architecture, but with alterations in detailed structure. The collagen bundles stuck together with vacuolization between them. There were some areas of the collagen structure fragmentation which could lead to complete necrosis. Eighty months after implantation in patients, the PCB became more extensible and its ultimate strain increases 2.5 times. Ultimate stress decreases in the radial direction from 9.43 to 2.88 MPa, and in the circumferential direction from 9.43 to 6.44 MPa. Forty-eight months after implantation, PB tissue's ultimate stress decreases in the circumferential direction from 4.06 to 1.99 MPa. At the same time ultimate strain increases from 13 to 22%. This study is to improve the methods of tissue stabilization in 0.625% glutaraldehyde solution for the first 48 h at cyclic, changing construction of biovalves soft supporting stent after 48 h.
All types of contemporary cardiac valve substitutes suffer deficiencies and complications that limit their success. Mechanical and bioprosthetic valves are intrinsically obstructive, especially in small sizes. Mechanical valves are associated with thromboembolic problems; the chronic anticoagulation used in virtually all mechanical valve recipients causes hemorrhage in some. Calcification limits the success of porcine and pericardial bioprostheses, allograft valves, and the yet experimental trileaflet polymeric prostheses. The predominant mechanism of calcification in porcine, pericardial, and allograft valves is cell mediated, being nucleated at the membranes and in organelles of the transplanted cells. In polymeric leaflet valves, calcification is both extrinsic (in adherent thrombus) and intrinsic (subsurface and acellular in the solid elastomer). Nevertheless, except for a few notable exceptions, contemporary mechanical valves are durable. Other important potential complications of prosthetic and bioprosthetic valves include paravalvular leak, endocarditis, or extrinsic interference with function. Moreover, aortic valvular allografts undergo progressive noncalcific degeneration, tearing, sagging, and/or retraction. Studies of retrieved long-term cryopreserved allograft explants demonstrate severe degeneration, with distortion of normal architectural detail, loss of endothelial and deep connective tissue cells, and variable inflammatory cellularity. Thus, they are morphologically nonviable valves, whose structural basis for function seems primarily related to the largely preserved collagen, and they are unlikely to have the capacity to grow, remodel, or exhibit active metabolic functions. Since calcification intrinsic to the cusps is the major pathologic process necessitating bioprosthetic valve reoperations, efforts to prevent formation of mineral deposits are active.(ABSTRACT TRUNCATED AT 250 WORDS)
The presence and activity of proteolytic enzymes has been investigated in vitro on soluble and insoluble preparations obtained from both unimplanted and implanted glutaraldehyde-treated bovine parietal pericardium. Using detection by colorimetric techniques, soluble preparations were shown to hydrolyze enzyme substrates that are characteristic for trypsin-like proteases, cathepsin-like proteases, and collagenase. As detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in gradient gels and gel filtration on Sepharose CL-6B, insoluble (pellet) preparations degraded denatured type I collagen in a time-dependent pattern, producing low-molecular-weight fragments. These activities were partially inhibited by phenylmethylsulfonyl fluoride, N-ethyl maleimide, soybean trypsin inhibitor, para-chloromercuribenzoic acid, or ethylenediaminetetraacetic acid, suggesting the presence of a heterogeneous enzymatic mixture. Insoluble preparations incubated with pure pericardial dermatan sulfate proteoglycan detached the glycosaminoglycan chains from their core protein carrier, producing a digestion pattern similar to Cathepsin C. These findings demonstrate the presence of active proteases in glutaraldehyde-fixed bovine pericardium per se and in explanted pericardial bioprosthetic cardiac valves, an additional factor that might contribute to intrinsic extracellular matrix degeneration in pericardial bioprosthetic devices.
The mechanism of structural failure of bioprosthetic valves is still not clearly understood. This study was undertaken to assess pure leaflet tear as a mode of failure in porcine and pericardial bioprostheses.
Of 246 bioprosthetic valves (109 porcine, 137 pericardial) implanted between 1975 and 1991, 101 had to be explanted and served as the study population.
The reasons for valve failure were calcific degeneration in 73, pure tear in 12, and endocarditis in 10. Six other patients had a perivalvar leak. The mean age at operation was 32 years. Freedom from degeneration at 10 years was 45 +/- 7% and from pure tear it was 92 +/- 2%. The hazard functions were strikingly different, as that for degeneration showed a progressive increase while that for pure tear peaked at six years post-implant. The mean age of the patients with pure tear was 41 years and for degeneration it was 24 years (p = 0.00001). The reasons for the difference in hazard function are discussed. The characteristic clinical features of pure tear allow clinical diagnosis in the majority of patients.
Pure tear is the result of uneven tissue loading with tearing occurring at sites of maximal stress. The four possible mechanisms in pericardial valves are (a) intense stress concentration at the top of the stent post (commissure); (b) compression stress below the top of the post; (c) abrasion stress in tissue mounted outside the frame; and (d) increased bending stresses on leaflet opening. In stent-mounted porcine valves, pure tear is related to incorrect mounting or to increased bending stresses.
A new morphologic method is described for the simultaneous quantitation of porcine aortic valve collagen crimp length and the assessment of biomechanical properties. This method utilizes the simultaneous real-time video recording of collagen crimp morphology and acquisition of crimp length data through the combination of polarized light microscopy and morphometry. We felt that the development of this method was warranted, due to the fundamental role played by collagen in porcine aortic valve performance. The development of this method involved the design and fabrication of a uniaxial microtensile stage, suitable for mounting on a standard microscope stage. The validation of our test method was accomplished by a comparison of untreated and glutaraldehydetreated porcine aortic valve leaflet tissue, because the biomechanical and morphologic characteristics of the native and fixed aortic valve have been extensively studied. The method described in this communication enables the collection of morphologic and biomechanical data from a single tissue specimen, eliminating the need for independent studies of multiple specimens. Furthermore, this method obviates the need for making assumptions, which may be difficult to verify, concerning the homogeneity of different test specimens with respect to their morphology and corresponding mechanical response to different experimental conditions.
The planar fibrous connective tissues of the body are composed of a dense extracellular network of collagen and elastin fibers embedded in a ground matrix, and thus can be thought of as biocomposites. Thus, the quantification of fiber architecture is an important step in developing an understanding of the mechanics of planar tissues in health and disease. We have used small angle light scattering (SALS) to map the gross fiber orientation of several soft membrane connective tissues. However, the device and analysis methods used in these studies required extensive manual intervention and were unsuitable for large-scale fiber architectural mapping studies. We have developed an improved SALS device that allows for rapid data acquisition, automated high spatial resolution specimen positioning, and new analysis methods suitable for large-scale mapping studies. Extensive validation experiments revealed that the SALS device can accurately measure fiber orientation for up to a tissue thickness of at least 500 microns to an angular resolution of approximately 1 degree and a spatial resolution of +/-254 microns. To demonstrate the new device's capabilities, structural measurements from porcine aortic valve leaflets are presented. Results indicate that the new SALS device provides an accurate method for rapid quantification of the gross fiber structure of planar connective tissues.
Use of bovine pericardium as an engineered biomaterial in the fabrication of bioprosthetic heart valves is limited, in part, by substantial intra- and intersac variations in its fibrous structure. To quantitatively assess this variability, we determined the fiber architecture of 20 whole BP sacs. Each sac was mounted on a prolate spheroidal mold, cleared and preserved in 100% glycerol, then sectioned into four equisized quadrants. This preparation method allowed for accurate intersac comparisons and minimized tissue distortions. The fiber architecture was evaluated by small-angle light scattering (SALS) using a 2.54-mm rectilinear grid resulting in approximately 1200 SALS measurements per quadrant, along with tissue thickness measured at 55 locations per quadrant. The fiber architecture was described in terms of fiber preferred directions, degree of orientation, and asymmetry of the fiber angular distribution. The BP sac fiber architecture demonstrated substantial intra- and intersac variability, with local fiber preferred directions changing by as much as 90 degrees within approximately 5 mm. Overall, most sacs revealed potential selection areas in the apex region characterized by a high degree of orientation, high uniformity in fiber preferred directions, and uniform tissue thickness. However, the size, location, and fiber orientation of these potential selection areas varied sufficiently from sac-to-sac to question whether anatomic location alone is sufficient for consistent localization of regions of high structural uniformity suitable for improved BHV design.
We undertook this study to establish a more quantitative understanding of the microstructural response of the aortic valve cusp to pressure loading. Fresh porcine aortic valves were fixed at transvalvular pressures ranging from 0 mmHg to 90 mmHg, and small-angle light scattering (SALS) was used to quantify the gross fiber structure of the valve cusps. At all pressures the fiber-preferred directions coursed along the circumferential direction. Increasing transvalvular pressure induced the greatest changes in fiber alignment between 0 and 1 mmHg, with no detectable change past 4 mmHg. When the fibrosa and ventricularis layers of the cusps were re-scanned separately, the fibrosa layer revealed a higher degree of orientation while the ventricularis was more randomly oriented. The degree of fiber orientation for both layers became more similar once the transvalvular pressure exceeded 4 mmHg, and the layers were almost indistinguishable by 60 mmHg. It is possible that, in addition to retracting the aortic cusp during systole, the ventricularis mechanically may contribute to the diastolic cuspal stiffness at high transvalvular pressures, which may help to prevent over distention of the cusp. Our results suggest a complex, highly heterogeneous structural response to transvalvular pressure on a fiber level that will have to be duplicated in future bioprosthetic heart valve designs.
We undertook the following study to quantitatively assess the changes in porcine bioprosthetic heart valve (PBHV) fiber architecture to increasing levels of fatigue damage using an in vitro accelerated test model. PBHVs were subjected to 0-500 million test cycles at 16 Hz, and small-angle light scattering (SALS) was used to quantify the gross fiber structure of the cusps. The degree of gross fiber alignment remained essentially constant from 0 to 500 million cycles over the entire cusp. Increasing fiber orientation randomness, indicative of local damage, was observed only in the vicinity of the nodulus of Arantii after 50 million cycles. The SALS data from the damaged regions suggested shearing between fiber layers, which may be part of the failure process and accelerates valve failure. Histological analysis revealed a relatively intact gross fiber structure with the collagen fiber crimp remaining, although delamination and de-registration of the crimp was also observed. Accelerated tested PBHVs also demonstrated a pronounced 'sagging', which began at the earliest cycle number tested (1.4 million cycles) and whose rate decreased logarithmically with cycle number. Results of this study suggest that PBHV cusps can alter their shape without any visually apparent material yielding or fiber failure under continual cyclic loading. Further, while most of the 4 mmHg pressure fixed PBHV's gross fiber architecture remains unchanged after 500 million cycles of accelerated testing, localized accumulated fiber damage can occur on a sub-visual structural level as early as 50 million cycles.
Structural valve deterioration of bioprostheses is mainly caused by progressive calcification. It has not yet been convincingly demonstrated whether pericardial or porcine bioprostheses are more prone to calcification.
A previously described in vitro test protocol consisting of non-destructive holographic interferometry, which permits quantitative deformation analysis of heart valves and accelerated dynamic calcification in vitro was used to evaluate five stented pericardial bioprostheses of different sizes and design (three or two leaflets) from one manufacturer. The extent of calcification was assessed after up to 20 x 10(6) cycles in the valve tester by microradiography, and areas of calcification were compared by holographic interferometry using computerized image processing. Calcification was confirmed by EDX-analysis and Von Kossa staining. Results were compared with in vitro testing of 25 porcine bioprostheses from different manufacturers.
The tested pericardial bioprostheses had an individual distribution of mechanical stresses detectable by holographic interferometry, which resulted in different calcification of valve leaflets. A strong correlation between calcification and stress distribution was found (correspondence of affected areas: 82.3 +/- 10.1%, r = 0.97). Variability in calcification and stress distribution, respectively, of pericardial valves compared well with our findings for porcine prostheses. Overall, the extent of leaflet calcification was not statistically different for pericardial and porcine bioprostheses (p = 0.21).
The biological material of bioprostheses (pericardial versus porcine) does not seem to be the crucial factor in the calcification process. Mechanical stresses detectable by holographic interferometry have a more pronounced impact and predict calcification of individual prostheses, at least in the in vitro setting.
The mechanisms underlying the failure of porcine bioprosthetic aortic heart valves are not well understood. One possible explanation is that delaminations of the layered leaflet structure occur through flexion, leading to calcification and further delaminations, and finally resulting in valve failure. We investigated the changes in flexural rigidity of the belly of aortic valve cusps subjected to accelerated durability testing. We used three-point bending wherein a load was applied to the center of each specimen by a thin stainless steel bar calibrated to a known load-displacement relationship. Ten circumferential and 15 radial specimens from valves fatigued to 0, 50, 100, and 200 million cycles were flexed both with and against the curvature of the cusp. Linear beam theory was applied as a means to compare the relative bending stiffness between groups. Although specimens aligned to the circumferential direction were stiffer when bent against the cuspal curvature, the radial oriented specimens exhibited no bending directional dependence. Both the radial and circumferential specimens experienced a significant decrease in the bending stiffness with an increased number of accelerated test cycles. Overall, our results suggest that it is the fibrosa that experiences the greatest loss of stiffness with mechanically induced fatigue damage.
Several recent studies attempted to classify plaques as those prone to cause clinical manifestations (vulnerable, atheromatous plaques) or those less frequently associated with acute thrombotic complication (stable, fibrous plaques). Defining the cellular and molecular mechanisms that underlie these morphological features remains a challenge. Because interstitial forms of collagen determine the biomechanical strength of the atherosclerotic lesion, this study investigated expression of the collagen-degrading matrix metalloproteinase (MMP) interstitial collagenase-3 (MMP-13) and the previously studied MMP-1 in human atheroma and used a novel technique to test the hypothesis that collagenolysis in atheromatous lesions exceeds that in fibrous human atherosclerotic lesions.
Human carotid atherosclerotic plaques, similar in size, were separated by conventional morphological characteristics into fibrous (n=10) and atheromatous (n=10) lesions. Immunohistochemical and Western blot analysis demonstrated increased levels of MMP-1 and MMP-13 in atheromatous versus fibrous plaques. In addition, collagenase-cleaved type I collagen, demonstrated by a novel cleavage-specific antibody, colocalized with MMP-1- and MMP-13-positive macrophages. Macrophages, rather than endothelial or smooth muscle cells, expressed MMP-13 and MMP-1 on stimulation in vitro. Furthermore, Western blot analysis demonstrated loss of interstitial collagen type I and increased collagenolysis in atheromatous versus fibrous lesions. Finally, atheromatous plaques contained higher levels of proinflammatory cytokines, activators of MMPs.
This report demonstrates that atheromatous rather than fibrous plaques might be prone to rupture due to increased collagenolysis associated with macrophages, probably mediated by the interstitial collagenases MMP-1 and MMP-13.
Bioprosthetic heart valve (BPHV) degeneration, characterized by extracellular matrix deterioration, remodeling, and calcification, is an important clinical problem accounting for thousands of surgeries annually. Here we report for the first time, in a series of in vitro accelerated fatigue studies (5-500 million cycles) with glutaraldehyde fixed porcine aortic valve bioprostheses, that the mechanical function of cardiac valve cusps caused progressive damage to the molecular structure of type I collagen as assessed by Fourier transform IR spectroscopy (FTIR). The cyclic fatigue caused a progressive loss of helicity of the bioprosthetic cuspal collagen, which was evident from FTIR spectral changes in the amide I carbonyl stretching region. Furthermore, cardiac valve fatigue in these studies also led to loss of glycosaminoglycans (GAGs) from the cuspal extracellular matrix. The GAG levels in glutaraldehyde crosslinked porcine aortic valve cusps were 65.2 +/- 8.66 microg uronic acid/10 mg of dry weight for control and 7.91 +/- 1.1 microg uronic acid/10 mg of dry weight for 10-300 million cycled cusps. Together, these molecular changes contribute to a significant gradual decrease in cuspal bending strength as documented in a biomechanical bending assay measuring three point deformation. We conclude that fatigue-induced damage to type I collagen and loss of GAGs are major contributing factors to material degeneration in bioprosthetic cardiac valve deterioration.
Substitute heart valves composed of human or animal tissues have been used since the early 1960s, when aortic valves obtained fresh from human cadavers were transplanted to other individuals as allografts. Today, tissue valves are used in 40% or more of valve replacements worldwide, predominantly as stented porcine aortic valves (PAV) and bovine pericardial valves (BPV) preserved by glutaraldehyde (GLUT) (collectively termed bioprostheses). The principal disadvantage of tissue valves is progressive calcific and noncalcific deterioration, limiting durability. Native heart valves (typified by the aortic valve) are cellular and layered, with regional specializations of the extracellular matrix (ECM). These elements facilitate marked repetitive changes in shape and dimension throughout the cardiac cycle, effective stress transfer to the adjacent aortic wall, and ongoing repair of injury incurred during normal function. Although GLUT bioprostheses mimic natural aortic valve structure (a) their cells are nonviable and thereby incapable of normal turnover or remodeling ECM proteins; (b) their cuspal microstructure is locked into a configuration which is at best characteristic of one phase of the cardiac cycle (usually diastole); and (c) their mechanical properties are markedly different from those of natural aortic valve cusps. Consequently, tissue valves suffer a high rate of progressive and age-dependent structural valve deterioration resulting in stenosis or regurgitation (>50% of PAV overall fail within 10-15 years; the failure rate is nearly 100% in 5 years in those <35 years old but only 10% in 10 years in those >65). Two distinct processes-intrinsic calcification and noncalcific degradation of the ECM-account for structural valve deterioration. Calcification is a direct consequence of the inability of the nonviable cells of the GLUT-preserved tissue to maintain normally low intracellular calcium. Consequently, nucleation of calcium-phosphate crystals occurs at the phospholipid-rich membranes and their remnants. Collagen and elastin also calcify. Tissue valve mineralization has complex host, implant, and mechanical determinants. Noncalcific degradation in the absence of physiological repair mechanisms of the valvular structural matrix is increasingly being appreciated as a critical yet independent mechanism of valve deterioration. These degradation mechanisms are largely rationalized on the basis of the changes to natural valves when they are fabricated into a tissue valve (mentioned above), and the subsequent interactions with the physiologic environment that are induced following implantation. The "Holy Grail" is a nonobstructive, nonthrombogenic tissue valve which will last the lifetime of the patient (and potentially grow in maturing recipients). There is considerable activity in basic research, industrial development, and clinical investigation to improve tissue valves. Particularly exciting in concept, yet early in practice is tissue engineering, a technique in which an anatomically appropriate construct containing cells seeded on a resorbable scaffold is fabricated in vitro, then implanted. Remodeling in vivo, stimulated and guided by appropriate biological signals incorporated into the construct, is intended to recapitulate normal functional architecture.
We examined 67 explanted Medtronic Freestyle (MF) valves of 0 to 1,490 days of implantation from 66 patients, including 9 full-root, 17 root inclusion, and 41 subcoronary implants derived from a multicenter trial composed of 1,100 patients at 27 centers worldwide (58 valves) and other removed specimens (9 valves). Macroscopic, radiographic and histological examination was performed to establish clinicopathological correlations in retrieved MF stentless aortic bioprostheses. Indications for 30 explants obtained at reoperation were perioperative technical (1 bleeding, 3 iatrogenic valve damage), endocarditis (11), sterile perivalvular leak (4), valve stenosis (1) regurgitation (3), fistula (2), or degeneration (2 cuspal tears, 1 cusp separation). Autopsy specimens were obtained after valve-related (9), non-valve-related (22), or perioperative death (6). Most non-valve-related deaths were cardiac. Valve-related deaths included endocarditis (4), paravalvular leak (1), thrombus (2), subannular occlusion (1), and tamponade (1). No excessive pannus was present. Macroscopic valve thrombosis was noted in two subcoronary implants of 180 and 279 days' duration. Histological analysis on all valves of more than 10 days implant duration or with macroscopic abnormality revealed variable but progressive flattening of the valve cusps; focal, plaquelike unorganized mural thrombus; cuspal fluid insudation; and generalized, nonspecific degenerative changes typical of explanted porcine valves. Aortic wall calcification was seen in two explants of 47 and 49 months' duration, the later with associated cuspal tear. Cusp mineralization was limited to infected valves. No excessive inflammation or fibrosis at the host-device interface was noted. Pathological findings were generally similar to those seen in clinically used glutaraldehyde-fixed xenografts. Potential pathology related to stentless design including pannus, aortic wall calcification, and host-tissue interaction were not clinically significant. Nevertheless, examination of many explanted valves at extended intervals and ongoing clinical data are needed to confirm the long-term efficacy, safety, and characteristic modes of failure of stentless bioprostheses.
We have formulated the first constitutive model to describe the complete measured planar biaxial stress-strain relationship of the native and glutaraldehyde-treated aortic valve cusp using a structurally guided approach. When applied to native, zero-pressure fixed, and low-pressure fixed cusps, only three parameters were needed to simulate fully the highly anisotropic, and nonlinear in-plane biaxial mechanical behavior. Differences in the behavior of the native and zero- and low-pressure fixed cusps were found to be primarily due to changes in the effective fiber stress-strain behavior. Further, the model was able to account for the effects of small (< 10 deg) misalignments in the cuspal specimens with respect to the biaxial test axes that increased the accuracy of the model material parameters. Although based upon a simplified cuspal structure, the model underscored the role of the angular orientation of the fibers that completely accounted for extreme mechanical anisotropy and pronounced axial coupling. Knowledge of the mechanics of the aortic cusp derived from this model may aid in the understanding of fatigue damage in bioprosthetic heart valves and, potentially, lay the groundwork for the design of tissue-engineered scaffolds for replacement heart valves.
Primary tissue failure, which is mainly caused by calcification, is still the limiting factor in the long-term outcome of heart valve bioprostheses. Even though the precise nature of this process is not fully understood, in vitro tests have been developed to reproduce and predict calcification for individual bioprostheses.
In vitro calcification testing was performed by using an accelerated pulsatile valve tester which was adapted for testing stented as well as stentless bioprostheses with physiological fluid dynamics. A total of 84 bioprostheses (porcine, pericardial and stentless porcine of different manufacturers) were cyclically loaded at a test rate of 300/min at 37 degrees C within a rapid calcification fluid with CaxP = 130(mg/dl)2 at pH 7.4. Calcification was assessed by microradiography after 12 x 10(6) cycles. In a previous step, holographic interferometry was performed to identify irregularities of valve leaflets in order to predict later calcification. Selected specimens of calcified bioprostheses underwent histology, transmission (TEM) and scanning (SEM) electron microscopy. Tissue mineralization was investigated by coupling SEM, electron microprobe analysis (EMPA) and X-ray powder diffraction (XRPD) methods.
For all tested bioprostheses, a significant calcification was achieved within 4 to 6 weeks of ongoing testing, and the degree of calcification increased with time. A significant correlation between calcification and leaflet irregularities (detected by holographic interferometry) was found (r = 0.80, p = 0.001). Calcification varied between individual bioprostheses, and significant differences were detected for different groups (calculated as percentage of total leaflet area, mean +/- SD): porcine stented (37.3 +/- 12.0%), bovine stented (23.0 +/- 8.9%), porcine stentless (16.2 +/- 7.6%). Histological and ultrastructural investigation showed intrinsic calcification involving both the spongiosa and fibrosa with collagen fibrils, interfibrillar spaces and cells as early sites of calcification. There was clear evidence of apatite crystallization, and observations made with in vitro calcification were quite similar to those occurring with in vivo implanted bioprostheses.
In vitro tests can reproduce intrinsic calcification of bioprostheses even in the absence of viable biologic host factors. Moreover, degree and sites of calcification have become predictable. This enables the development and evaluation of bioprostheses with reduction of animal experiments. From our results obtained with a broad range of available bioprostheses, stented bovine and stentless porcine valves seem to be superior to conventional stented porcine bioprostheses with regard to leaflet calcification.
Porcine bioprosthetic valves have excellent hemodynamics and do not require anticoagulation, but have limited durability. Cusp tearing is a major cause of bioprosthetic valve failure. It has been suggested that the mechanism of bioprosthetic valve failure is stiffening by calcification, which leads to elevated stresses and secondary collagen fiber damage and leaflet tearing. This thesis was tested in explanted porcine bioprostheses.
A total of 60 explanted porcine bioprosthetic valves was tested mechanically, and 15 explanted valves were examined grossly and histologically. Circumferentially and radially oriented samples of cusp tissue were tested uniaxially in a materials testing machine and compared with five controls.
Mean (+/-SD) duration of implantation was 10.9+/-5.6 years. Circumferential specimens from explants were less extensible than controls (11.0+/-5.5% versus 24.5+/-2.8% strain, p <0.001), and failed at lower tensions (973+/-733 versus 3075+/-911 N/m, p = 0.001) and at lower strains (21.2+/-8.1% versus 47.3+/-7.1% strain, p <0.001). Radial specimens from explants were less extensible (28.7+/-6.8% versus 39.2+/-5.9% strain, p = 0.002) and failed at lower strains (60.3+/-17.3% versus 112.2+/-24.9% strain, p <0.001) than the controls. The stiffness of the explants was unchanged from controls in both circumferential and radial samples. There were no differences between explants and controls in radial and circumferential stiffness, and in radial failure strength. Calcification was mild and diffuse in most of the tested samples. Tears were found in areas without calcific deposits, along with breaks in collagen fiber bundles.
These results do not support the thesis that calcification stiffens glutaraldehyde-fixed porcine bioprostheses, except when the entire cusp is transformed into a solid mass of mineral. Rather, leaflet tears may develop as a result of accumulated mechanical damage that is independent of calcification.
Characterization of the mechanisms of degeneration of porcine bioprosthetic heart valves (BHV) during long-term cyclic loading is required for predicting and ultimately preventing their failure. Isolation of purely mechanical effects from host biological ones is a necessary first step in understanding the fatigue process as a whole. Thus, in this review we focus on mechanical factors alone as a means of isolating their role in altering biomechanical properties and ultimately their contribution to the fatigue damage process. Mechanical evaluations included tension controlled biaxial, 3-point flexural, and uniaxial failure tests performed on cuspal tissue following 0, 50, 100, 200, and 300 x 10(6) in vitro accelerated test cycles. Overall, biaxial mechanical results indicate a decreasing radial extensibility that can be explained by stiffening of the effective collagen fiber network as well as a small decrease in the splay of the collagen fibers. Moreover, these results suggest that the loss in flexural rigidity with fatigue that we have previously measured (ASAIO 1999; 45:59-63) may not be because of loss of collagen stiffness alone, but also to fiber debonding and degradation of the amorphous extracellular matrix. We discuss the implications of these results that point toward the development of chemical-treatment methods that seek to maintain the integrity of the amorphous extracellular matrix to ultimately extend BHV long-term durability.
Zero transvalvular pressure fixation is thought to improve porcine bioprosthetic heart valve (BHV) durability by preserving the collagen fiber architecture of the native tissue, and thereby native mechanical properties. However, it is not known if the native mechanical properties are stable during long-term valve operation and thus provide additional durability. To address this question, we examined the biaxial mechanical properties of porcine BHV fixed at 0 and 4mmHg transvalvular pressure following 0, 1 x 10(6), 50 x 10(6), and 200 x 10(6) in vitro accelerated test cycles. At 0 cycles, the extensibility and degree of axial cross-coupling of the zero-pressure-fixed cusps were higher than those of the low-pressure-fixed cusps. Furthermore, extensibility of the zero-pressure-fixed tissue decreased between 1 x 10(6) and 50 x 10(6) cycles, approaching that of the low-pressure-fixed tissue, whose extensibility was unchanged over 0-200 x 10(6) cycles. The decrease in extensibility of the zero-pressure-fixed tissue between 1 x 10(6) and 50 x 10(6) cycles may be attributable to the ability of its collagen fibers to undergo larger changes in orientation and crimp with cyclic loading. These observations suggest that the collagen fiber architecture of the 0-mmHg-fixed porcine BHV, although locked in place by chemical fixation, may not be maintained over a sufficient number of cycles to be clinically beneficial. This study further underscores that chemically treated collagen fibers can undergo conformational changes under long-term cyclic loading not associated with damage.
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