The earliest most versions of prosthetic heart valves were taken from cadavers and implanted as aortic valve allografts (homografts). The first allograft valves were implanted in 1962 by Sir Donald Ross. Homografts proved to be clinically successful from their early days and are still used today (Lund et al., 1999). They are limited primarily by their availability and by the technical skill requirements of the surgeon. In the early days, they were preserved by storage in glycerol, but today the most widely used method is cryopreservation.

BACKGROUND AND AIM OF THE STUDY:Mitral valve chordae tendineae are an essential component for correct functioning of the human heart. The microstructural make-up of the chordae is responsible for their tensile properties, and is seen gradually to change with age. However, little is known of the maturation of chordae tendineae and their microstructure.METHODS:To examine such maturation, structural changes in chordae tendineae were studied in rats at 1, 3, 7, 15 and 30 days of postnatal life, and in adult rats. Differences in the chordae microstructure of each age group were observed using light microscopy. The collagen fibril crimp period was determined using polarized light microscopy.RESULTS:At day 1 after birth the chordae had yet to develop, and the lateral sides of the mitral valve leaflets were completely attached to the papillary muscles. Chordae developed through the formation of gaps in the leaflet tissue. From day 7 on, numerous chordae were seen. As the chordae matured, crimped collagen fibrils were formed and began to align in a longitudinally packed core with increasing density. The collagen fibril crimp period increased significantly with the age of the animal.CONCLUSION:Rat chordae tendineae have yet to develop at postnatal day 1. Morphological development and microstructural maturation of the chordae are not completed until adulthood (>30 days). A further understanding of the development of mitral valve chordae tendineae will provide insight for the use of tissue-engineered chordae in surgical repair.

Over the past five years, transcatheter valves have stimulated the attention of physicians, engineers, and investors. Transcatheter valve design and implantation techniques depart from the time-proven features of surgical valves, and this has an important impact on the safety and efficacy of prosthetic valve therapy. Herein is reviewed the performance of transcatheter valve procedures in comparison to surgical valves, together with a summary of the specific design features of several emerging transcatheter valves. How the current and future generation transcatheter valves are likely to impact on patient treatment is also explored.

BACKGROUND AND AIM OF THE STUDY:The chordae tendineae, which form an important component of the mitral valve apparatus, experience continuous cyclic loading and are thus well-adapted for effectively storing and dissipating energy. An understanding of their microstructure would be expected to shed light on the mechanism of their remarkable durability.METHODS:In these studies, porcine mitral valve chordae from freshly slaughtered pigs were used. Histological samples of Picrosirius Red-stained and Movat's pentachrome-stained chordae were examined with optical microscopy and laser scanning confocal microscopy. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to study the ultrastructure at high magnification.RESULTS:Both, optical microscopy and SEM revealed that the waviness of collagen fibers was uniform across the thickness of the chordae, with no straight fibers in the core. Wavy fibers and fiber bundles were found to be in skewed-register, rather than transverse. Collagen fiber bundles were found to undulate in a three-dimensional path, rather than the planar waveform, as reported previously. TEM showed that different types of chordae had different fibril configurations. Marginal chordae had smaller diameters but a higher fibril density than did basal and strut chordae.CONCLUSION:The configuration of collagen fibrils in the mitral valve chordae is more complex than initially thought, and different chordae have morphologies that are likely specific to their mechanical role in the mitral apparatus. These findings provide insight into possible improvements for chordal repair surgery, and form a structural basis for accurate computational modeling.

Understanding the complex relationships between microstructural organization and macromechanical function is fundamental to our knowledge of the differences between normal, diseased/injured, and healing connective tissues. The long-term success of functional tissue-engineered constructs or scaffolds may largely depend on our understanding of the structural organization of the original tissue. Although innovative techniques have been used to characterize and measure the microstructural properties of collagen fibers, a large gap remains in our knowledge of the behavior of intermediate scale (i.e., "mesostructural") groups of fiber bundles in larger tissue samples. The objective of this study was to develop a system capable of directly measuring deformations of these smaller mesostructures during application of controlled loads. A novel mesostructural testing system (MSTS) has been developed to apply controlled multiaxial loads to medium (meso-) scale tissue specimens, while directly measuring local nonuniform deformations using synchronized digital video capture and "markerless" image correlation. A novel component of the MSTS is the use of elliptically polarized light to enhance collagen fiber contrast, providing the necessary texture for accurate markerless feature tracking of local fiber deformations. In this report we describe the components of the system, its calibration and validation, and the results from two different tissues: the porcine aortic valve cusp and the bovine pericardium. Validation tests on prepared samples showed maximum error of direct strain measurement to be 0.3%. Aortic valve specimens were found to have larger inhomogeneous strains during tensile testing than bovine pericardium. Clamping effects were more pronounced for the valve specimens. A new system for direct internal strain measurement in connective tissues during application of controlled loads has been developed and validated. The results from the two different tissues show that significant inhomogeneous deformations can occur even in simple tensile testing experiments.

We present a polyconvex constitutive law for tissues of the aortic outflow tract based on a novel invariant theory for dispersed transverse isotropy. In contrast to traditional structural constitutive equations, fiber splay is treated in closed form and thus can easily handle both two- (2D) and three-dimensional (3D) fiber populations. In the 2D, single preferred-direction case, the model accurately fits biaxial data for aortic valve tissue. Extended to two preferred directions, the model accurately fits available uniaxial data for the aortic sinus and aortic wall. Modification of the fiber stress-strain law requires no re-formulation of the constitutive tangent matrix, making the model flexible for different types of soft tissues, and, in the case of 3D fiber populations, the model may be suitable for describing passive myocardium. Most importantly, the model is computationally expedient in a finite-element analysis.

Soft biological tissues are complex structures with intricate microstructure, which is usually highly anisotropic. These tissues are typically composed of multiple fiber bundles, which may have a unique orientation, defined for each single element in a large finite element mesh for modeling complex structures such as the human heart. These complex orientations can be difficult to define in an ABAQUS input deck using existing methods. In general, each change in fiber orientation requires a “new material” to be defined. Using the conventional method of defining material properties in ABAQUS is time consuming and, as a result of the large number of input constants required, is prone to errors. It is therefore deemed desirable to create a new means of material property input. The ∗∗CC Cards method presented partitions the material property data for a time-dependent, anisotropic, material response into discrete card images, and thus eliminates much of the redundant data input required by ABAQUS. This strategy is also more efficient, both computationally and from the viewpoint of user time required.

BACKGROUND:Quasilinear viscoelasticity (QLV) theory has been widely and successfully used to describe the time-dependent response of connective tissues. Difficulties remain, however, particularly in material parameter estimation and sensitivities. In this study, we introduce a new alternative: the fractional order viscoelasticity (FOV) theory, which uses a fractional order integral to describe the relaxation response. FOV implies a fractal-like tissue structure, reflecting the hierarchical arrangement of collagenous tissues.METHOD OF APPROACH:A one-dimensional (I-D) FOV reduced relaxation function was developed, replacing the QLV "box-spectrum" function with a fractional relaxation function. A direct-fit, global optimization method was used to estimate material parameters from stress relaxation tests on aortic valve tissue.RESULTS:We found that for the aortic heart valve, FOV had similar accuracy and better parameter sensitivity than QLV, particularly for the long time constant (tau2). The mean (n = 5) fractional order was 0.29, indicating that the viscoelastic response of the tissue was strongly fractal-like. RESULTS SUMMARY: mean QLV parameters were C = 0.079, tau1 = 0.004, tau2 = 76, and mean FOV parameters were beta = 0.29, tau = 0.076, and rho = 1.84.CONCLUSIONS:FOV can provide valuable new insights into tissue viscoelastic behavior Determining the fractional order can provide a new and sensitive quantitative measure for tissue comparison.

Our goal is to fabricate continuous sheets of elastin atop non-biodegradable hydrogels (hylans) containing crosslinked hyaluronan, a glycosaminoglycan. Such elastin-hyaluronan composites may be useful to tissue engineer replacements for the glycosaminoglycan- and elastin-rich layers of the native aortic valve cusp. Neonatal rat aortic smooth muscle cells were cultured atop hylan gels with micro-textured surfaces, and on plastic, and the components of the extracellular matrix (collagen, elastin) were periodically analyzed. The hylan substrates induced the cells to proliferate more rapidly and over longer time periods (approximately 4 weeks) relative to those cultured on plastic (2-3 weeks). Consequently, at all assay times, the amounts of elastin was derived from the hylan-based cell cultures was 25% or more than that derived from cells cultured on plastic. However, when elastin content was normalized to the cell DNA content, no significant differences were found in the two substrates beyond the first two weeks of culture. Conversely, at culture times greater than 2 weeks, cells cultured atop hylan gels produced amounts of collagen/nanogram of DNA that were approximately 56% less than that synthesized by cells cultured on plastic. Cells grown on hylan deposited an unusual matrix layer, rich in elastin, at the hylan-cell interface. This elastin was found to be organized into fenestrated sheets and loose elastin fibers, structures that were also isolated from the elastin matrix of the ventricularis layer of porcine aortic valve cusps. We have thus demonstrated that hylan gels are useful as substrates to induce elastin synthesis in culture to obtain structures that resemble the elastin matrix of the native aortic valve.

In this paper, we present the application of a semi-global inverse method for determining material parameters of biological tissues. The approach is based on the successive response surface method, and is illustrated by fitting constitutive parameters to two nonlinear anisotropic constitutive equations, one for aortic sinus and aortic wall, the other for aortic valve tissue. Material test data for the aortic sinus consisted of two independent orthogonal uniaxial tests. Material test data for the aortic valve was obtained from a dynamic inflation test. In each case, a numerical simulation of the experiment was performed and predictions were compared to the real data. For the uniaxial test simulation, the experimental targets were force at a measured displacement. For the inflation test, the experimental targets were the three-dimensional coordinates of material markers at a given pressure. For both sets of tissues, predictions with converged parameters showed excellent agreement with the data, and we found that the method was able to consistently identify model parameters. We believe the method will find wide application in biomedical material characterization and in diagnostic imaging.

Knowledge of strain-rate sensitivity of soft tissue viscoelastic and nonlinear elastic properties is important for accurate predictions of biomechanical behavior and for quantitative assessment of the effects of disease or surgical/pharmaceutical intervention. Soft tissues are known to exhibit mild rate sensitivity, but experimental artifacts related to testing system control can confound estimation of these effects. “Perfect” ramp-and-hold stress-relaxation tests become difficult at high strain rates because of problems related to undershoot/overshoot error and vibrations. These errors can introduce unwanted bias into parameter estimation methods that rely on idealizations of the applied ramp-and-hold displacement. To address these problems, we describe a new method for estimating quasilinear viscoelastic (QLV) parameters that directly fits the QLV constitutive model to the actual point-wise stress–time history of the test, using an adaptive grid refinement (AGR) global optimization algorithm. This new method significantly improves the accuracy and predictivity of QLV parameter estimates for heart valve tissues, compared to traditional methods that use idealized displacement data. We estimated QLV parameters for aortic valve tissue over a range of physiologic displacement rates, finding that the viscoelastic content parameter (C) increased slightly with increasing strain rate, but the fast (τ1) and slow (τ2) time constants were strain rate insensitive.

The tensile properties of mitral valve chordae tendineae derive from their structural make-up. The objectives of this study were to compare the stress relaxation properties of different types of chordae and relate their variation to structural features. Fifty chordae from eight hearts were subjected to stress relaxation tests. The percent stress relaxation and the relaxation rates were found to increase in the order of marginal, basal, and strut chordae. The water content of the three types of chordae was the same (marginal 77.1 ± 5.9%, basal 77.0 ± 3.4%, strut 78.0 ± 2.3% wet weight). The collagen, elastin, and glycosaminoglycan (GAG) content in chordae were quantified using hydroxyproline assay, fastin elastin assay, and fluorophore-assisted carbohydrate electrophoresis, respectively. Collagen content of marginal chordae was only slightly less than that of basal and strut chordae (marginal 56.6 ± 8.2%, basal 61.4 ± 5.6%, strut 63.8 ± 3.9% dry weight). There was also no significant difference in elastin content between the chordae (marginal 5.3 ± 3.2%, basal 5.4 ± 2.7%, strut 4.6 ± 1.7% dry weight). However, the concentrations of unsulfated chondroitin/dermatan sulfate, 6-sulfated chondroitin sulfate, and 4-sulfate chondroitin sulfate significantly decreased in the order of marginal, basal, and strut. The total GAG-content also decreased in the order of marginal, basal, and strut (p = 0.06). The greater amount of GAGs in marginal versus strut chordae is consistent with our previous observations that marginal chordae have a greater collagen fibril density and thus more GAG-mediated, fibril-to-fibril linkages. The greater number of proteoglycan linkages may prevent the slippage of fibrils with respect to each other, and thus reduce stress relaxation. The different viscoelastic properties of mitral valve chordae can thus be explained morphologically.

Chordae tendineae are essential to the proper function of the mitral valve. Native chordae contain a dense collagenous core and an outer elastin sheath. We have been using the principle of directed collagen gel shrinkage to fabricate tissue-engineered mitral valve chordae. Because the microstructure of biologic tissues determines their mechanical behavior, the morphology of collagen and elastin in tissue-engineered chordae should mimic that of native chordae. The objective of this study, therefore, was to examine the morphology of our tissue-engineered constructs in comparison to native chordae. A collagen-cell suspension was cast into silicon rubber wells with microporous anchors at the ends and cultured in an incubator. The anchors allowed shrinkage to occur only transverse to the long axis of the wells, thus creating highly aligned collagen fibril constructs. The collagen constructs were cultured for 8 weeks and characterized mechanically, histologically, and biochemically at different culture time points. Histologic sections showed that in all mature constructs collagen fibers were oriented parallel to the long axis of the constructs. At the edge of the tissue collagen fibers were in general straight, whereas in the middle of the tissue they were wavy. Transmission electron microscopy showed a progressive increase in the density and longitudinal orientation of collagen fibrils with culture time. Light and scanning electron microscopy showed the presence of an elastin sheath around the collagen core. Immunostaining demonstrated that smooth muscle cells differentiate during tissue development and TUNEL assay showed that cells in the interior of the constructs undergo apoptosis. This study has demonstrated that collagen-cell constructs, with material properties and microstructure similar to native mitral valve chordae, can be developed using static culture.

The traditional approach to tissue engineering has involved the seeding of cells on bioresorbable scaffolds, that, when implanted into the recipient, slowly degrade and become replaced by the target organ or tissue. This has not worked for the cardiac valves. Our approach to tissue engineering of cardiac valve tissues is to build each structural component of the heart valve cusp separately in vitro and then integrate all the components together into a composite valve structure. Collagen fiber bundles were fabricated by the method of directed collagen gel shrinkage, and clastin layered were grown on substrates of crosslinked, high molecular weight hyaluronan. Collagen fiber bundles were found to have good mechanical properties, integrated well together when cultured in apposition and elastin sheets were found to be continuous and fenestrated as in the native aortic valve. Improvements in culture technique are being continually implemented by way of dynamic culture and optimal culture conditions.

The principles of tissue engineering are being used to explore numerous applications in reconstructive surgery. Mitral valve chordae are one such potential area, as mitral valve repair is increasing in popularity and synthetic materials have not been used widely. The use of cells, combined with reconstituted type I collagen, is an attractive option for fabricating materials for the replacement of thin tendonous structures such as mitral valve chordae. We have been using the principle of directed collagen gel shrinkage to fabricate tendinous structures with good mechanical properties. In this study, our objective was to maximize the strength of the collagen constructs by choosing cell type and optimizing cell-seeding density, culture time, and initial collagen concentration. A collagen-cell suspension was cast into silicone rubber wells with microporous anchors at the ends and cultured in an incubator. The anchors allowed shrinkage to occur only transverse to the long axis of the wells, thus creating highly aligned collagenous constructs. Collagen gel contraction increased with higher cell-seeding density. The optimal value was 10(6) cells/mL. The rate of gel contraction decreased with the initial collagen concentration. Fibril density increased with culture time, as the gel contracted. After the system was optimized, the mechanical strength of the constructs increased to 1.1 MPa, a value at least an order of magnitude greater than previously published results with similar systems. This study has demonstrated that collagen-cell constructs, with material properties similar to those of native mitral valve chordae, can be developed using the principle of directed collagen gel shrinkage. These structures may have application in other areas that require small-diameter tendons.