Abstract:
A polymeric valve which may include a heart valve, and also may include a trileaflet heart valve includes a stent having a base and a plurality of outwardly extending posts from the base and equidistant from each other. A plurality of leaflets each connected to a corresponding one of the posts at one end, and each of the leaflets connected to the base. Each of the leaflets having an operative end opposite the end connected to the post, and the operative ends of the leaflets being biased in a closed position such that the operative ends abut each other. The operative ends are configured to rhythmically open and close in relation to each other, and the leaflets include multiple cross sectional thicknesses at different portions of the leaflets.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 61/546,832 filed on Oct. 13, 2011, the entire contents of which are incorporated herein by reference. 
    
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     This invention was made with government support under grant number EB012487 awarded by the National Institute of Health. The government has certain rights in the invention. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention generally relates to implantable prosthetic devices, and more particularly, the present invention relates to an implantable prosthetic heart valve and a method for manufacturing thereof. 
     2. Description of Related Art 
     Replacement valves in a patient and in machines for mimicking valves in a patient are known in the medical field. For example, valvular heart disease (VHD) remains a significant public health issue affecting 1-2% of Americans with an estimated 2-4% of people over the age of 65 suffering from aortic valve stenosis. Currently, when extensive heart valve damage has occurred in a patient&#39;s heart, for example from heart disease or a birth defect, one remedy is to replace the heart valve surgically. Current treatment includes open-heart surgical replacement of the diseased valve with either mechanical or tissue prosthetic heart valves (PHV). The replacement heart valve may be an artificial device or an animal tissue valve (e.g., bovine pericardium or porcine aortic valve). For example, one type of heart valve which has been the subject of replacement valves are aortic valves. Presently, artificial (mechanical) heart valves are not as prevalently used as animal tissue valves. One reason is artificial valves such as polymer PHVs are unsatisfactorily susceptible to damage caused by stresses from flexing and operation during use, i.e., material fatigue. Since 1960, various devices and techniques have been used for replacement valves and delivery or implantation of the valve. 
     Referring to  FIGS. 1-3 , a prior art trileaflet heart valve  10  includes three leaflets  14 ,  16 ,  18 , and a stent structure  20  having three posts  22 . The stent structure  20  supports a multilayer composite polymeric membrane that is a flat sheet membrane sewn into the shape of three leaflets  14 ,  16 ,  18 , each having a uniform thickness. The one-piece multilayer composite polymeric membrane of the leaflets  14 ,  16 ,  18  is composed of a porous polymeric structure (e.g. a knit, weave, braid) sandwiched between two outer polymer layers. An example of such a one-piece multilayer composite polymeric membrane and heart valve as described is US Patent Application publication 2007/0118210 (pub. date May 24, 2007), Ser. No. 11/561,069, filed on Nov. 17, 2006. 
     One disadvantage of the above prior art heart valve is undesirable stress wear on the leaflets results in fatigue of the leaflets. The polymer in the prior art was a thermoplastic elastomer with low tensile strength and was prone to significant creep. The embedded mesh was designed to add strength. However, in animal testing the polymer creep exposed the underlying mesh to blood and caused an adverse reaction. Further, the above heart valve requires a multilayer composite approach that is undesirably complex to manufacture and expensive. It also does not allow for fine tuning of the leaflet thickness to improve flexibility and durability. A disadvantage of using animal tissue in replacement heart valves is that chemically fixed animal tissue valves require animal tissue sourcing, handling, processing, sterilization and packaging. Further, other disadvantages from current heart valve implantation are present from the risk to a patient receiving animal tissue heart valves, that is the implanting of xenografts, because of the differences in tissue degeneration, or tissue lifespan, between species of animals and humans, and also the possibility of transfer of diseases from the animal to a human. Also, the durability of animal tissue valves is highly dependent upon the application and the health and age of the patient. There has therefore been a long felt need in the industry for a valve, and particularly a heart valve to remedy the disadvantages described above. Additionally, mechanical valves require lifelong anticoagulant drug therapy which includes significant risk of bleeding and stroke. Polymeric trileaflet valves may eliminate the disadvantages of current heart valve prosthetics. 
     SUMMARY OF THE INVENTION 
     It would be desirable to provide a valve for use in heart valve replacement that eliminates the need for animal tissue sourcing, handling, processing, sterilization and packaging, and thereby eliminates any risks to patients involved in implanting xenografts. Further, it would be desirable to provide a replacement valve of increased durability which is not dependent on the health and age of the patient. It would further be advantageous to provide a polymeric heart valve, which can decrease the costs for heart valve replacement. Also, a need exists in the art for a prosthetic valve, and for example, specifically a trileaflet valve, which has improved durability and is less susceptible to fatigue stress. Also, a need exists for the reduction or elimination for the need for anticoagulant drug therapy in prosthetic heart valve recipients. Further, it would be desirable for a prosthetic valve to include a polymer PHVs which combines improved durability with low thrombogenicity. 
     In an aspect of the invention, a polymeric valve which may include a heart valve, and also may include a trileaflet heart valve includes a stent having a base and a plurality of outwardly extending posts from the base and equidistant from each other. A plurality of leaflets each connected to a corresponding one of the posts at one end, and each of the leaflets connected to the base. Each of the leaflets having an operative end opposite the end connected to the post, and the operative ends of the leaflets being biased in a closed position such that the operative ends abut each other. The operative ends are configured to rhythmically open and close in relation to each other, and the leaflets include multiple cross sectional thicknesses at different portions of the leaflets for optimized flexibility and durability. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other objects, features and advantages of the present invention will become apparent from the following detailed description of illustrative embodiments thereof, which is to be read in connection with the accompanying drawings. The various features of the drawings are not to scale as the illustrations are for clarity in facilitating one skilled in the art in understanding the invention in conjunction with the detailed description. This patent application (or patent) contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. In the drawings: 
         FIG. 1  is an isometric view of a prior art trileaflet heart valve; 
         FIG. 2  is an isometric view of a leaflet of the prior art valve shown in  FIG. 1  depicting the curvature of the leaflet; 
         FIG. 3  is an isometric view of the prior art heart valve shown in  FIG. 1 ; 
         FIG. 4  is an isometric view of a trileaflet heart valve according to an embodiment of the invention; 
         FIG. 5  is a perspective view of a leaflet of the heart valve shown in  FIG. 4  depicting the curvature of the leaflet; 
         FIG. 6  is a cross-sectional view of the center of a leaflet showing representative dimensions of the thicknesses of the leaflet along an operative end of the leaflet; 
         FIG. 6A  is a side elevational view of another embodiment of a leaflet as compared to  FIG. 6 , showing thicknesses of the leaflet along an operative end of the leaflet; 
         FIG. 6B  is a side elevational view of another embodiment of a leaflet as compared to  FIGS. 6 and 6A , showing thicknesses of the leaflet along an operative end of the leaflet; 
         FIG. 6C  is a side elevational view of another embodiment of a leaflet showing thicknesses of the leaflet along an operative end of the leaflet; 
         FIG. 7A  is a top view of two of the leaflets of the valve shown in  FIG. 4 ; 
         FIG. 7B  is an isometric view of the stent shown in  FIG. 4 ; 
         FIG. 7C  is isometric view of another embodiment of a stent having post inclined outwardly; 
         FIG. 8  is an isometric view of the heart valve shown in  FIG. 4 ; and 
         FIGS. 9-21  are color diagrams of embodiment of valves according to the present invention compared to prior art valves depicting stress effects on the leaflets using different colors via finite element analysis using accurate material models based upon valve material uniaxial tensile tests with red being high stress. 
         FIG. 22  is a graph showing bulk human platelet activation measurements. Polymer xSIBS valve v. Carpientier-Edwards Perimount Magna tissue valve (benchmark ‘gold standard’ tissue valve). 
         FIG. 23  is an isometric view of the reinforcing frame. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Referring to  FIGS. 4-6 , an embodiment according to the invention of a trileaflet heart valve  100  is shown. The heart valve  100  includes three leaflets  104 ,  106 ,  108 . The heart valve further includes a stent  110  having a circular base  112  and three posts  114  extending outwardly from the base  112 . The posts  114  are each offset from vertical by 1 mm making an inlet orifice of the valve 19 mm ID, and an outlet orifice 21 mm of the valve. This increases the effective orifice area and reduces the stresses in the leaflets. 
     A bottom ridge  113  of the base extends circumferentially around the base  112  forming the hemispherical bottom ridge  113 . The posts  114  are positioned in spaced relation to each other to provide a wide stent orifice. The post positioning in the present invention improves hemodynamics as a result of the widened orifice of the stent. The heart valve  100  is designed to mimic the native aortic valve in form and function. The posts  114  include a substantially rectangular top portion  115  which has rounded edges. The heart valve stent  110  has rounded edges for improved hemodynamics, which includes the area at the top of the posts, and the upper edge along the perimeter of the stent. 
     The heart valve  100  leaflets  104 ,  106 ,  108  and the stent  110  are injection molded as a single part. The leaflets are composed of a singular material, and not constructed from a composite of materials. In one embodiment of the invention, valves are molded from custom designed molds using a vacuum oven and hot-press for injection molding. Computer aided design (CAD) software may be used to create solid models of valve prototypes and valve molds. A left heart simulator (LHS) can be used for accurate hydrodynamic assessment of the heart valve for meeting FDA standards. An accelerated life cycle tester can be used for durability assessment of the heart valves, such as from Vivitro Labs. Such a machine can simulate 5 years of use in 4 months at 20 Hz. A digital particle image velocimetry (DPIV) system can be used for the validation of numerical blood analog flow results from the LHS. Full prototype platelet activation can be measured in a small volume flow loop (left ventricular assist) device. 
     The valve  100  diameter is variable based upon patient valve dimensions. The valve  100  may be manufactured in several sizes for a specific patient fit. It is understood that the valve  100  can be manufactured to fit in all nominal human aortic valve positions, in the range of approximately 15-27 mm tissue annulus diameter (TAD). Further, the valve  100  diameter and all other dimensions are proportionally variable based upon patient aortic root dimensions. Thus, all the dimensions of the valve of the present disclosure, may proportionally vary when a different valve size is needed and manufactured, e.g., the leaflets thickness tapering dimensions (which results in cross sectional dimensions shown in  FIGS. 6, 6A, 6B, 6C ), will proportionally vary according to the size of the valve, as well as the length and width dimensions of the leaflets and other parts and sections of the valve. 
     In another embodiment of the invention, the valve stent  110  may have a metal reinforcing frame  200  embedded for added stiffness where needed. Acceptable types of metal for reinforcing the stent may include, for example, stainless steel. In an alternate embodiment, the reinforcing frame  200  can be fabricated from a biologically compatible material or composite that provides the rigidity of e.g. stainless steel. 
     The material of the valve is a polymer that has not been previously applied to prosthetic heart valves. The polymer may enhance durability and hemocompatibility over chemically fixed animal tissue and competitive polymers. The polymer useful in the manufacture of the valve of the invention is a formulation provided by Innovia®, LLC Miami, Fla. that is a thermally cross-linkable formulation of their thermoplastic elastomer-poly(styrene-isobutylene-styrene) or SIBS. SIBS has physical properties that overlap polyurethane and silicone rubber. SIBS has been shown to be hydrolytically, enzymatically, and oxidatively stable in vivo. The infusible and insoluble cross-linkable thermoset formulation is called xSIBS. It is believed that xSIBS has enhanced durability over SIBS because the cross-linking of the polymer chains adds strength and reduces or eliminates creep (time dependent change in strain under a constant load below the yield stress). Altering the ratio of SIBS constituents, styrene and isobutylene, will alter the hardness or softness of the material. In one embodiment, xSIBS may include about 22% styrene. Other polymers may also be applicable in the heart valve of the present invention. 
     The valve leaflets  104 ,  106 ,  108  are designed with a customized variable thickness (discussed in greater detail below) for the reduction of high stress concentrations, and with maximized flexibility. Regions of expected high stress are thickened, that is they have a larger cross section or thickness measurement. Regions of expected lower stress are thinned, that is they have a smaller cross section or thickness. Thereby, the leaflets achieve an optimized stress distribution. The result of the customized variable thicknesses of the leaflets is improved hemodynamics and high durability. The enhanced hemodynamics of the valve  100  result in a lower thrombogenic potential. Embodiments of the valve according to the present invention are shown in  FIGS. 4, and 8 . 
     Referring to  FIGS. 5 and 6 , an operative end  120  of one of the leaflets is depicted wherein the multiple thicknesses of portions of the leaflet are shown. The operative end  120  includes an edge with a cross sectional area that provides thickness measurements for the related portion of the leaflet. The operative end  120  generally corresponds to the operative end of leaflet  106  as can be seen in comparison to the valve is  FIG. 4 . The portions  122 ,  134  of the end  120  are at the upper most and lower most portions of the end  120 . For example, in one embodiment of the invention, the thicknesses of portions of the leaflet are as follows below. The thicknesses of the portions  122 ,  134  are in the range of 0.1 mm to 0.35 mm, and may be about 0.25 mm. The thicknesses of portions  122 ,  134  may be from 0.2 to 0.25 mm with a plus or minus variation of 0.1 mm. A reference point  132  (representing a longitudinal axis passing through the center of the valve  100 ) is about 9.5 mm from the upper end  122  of the operative end  120 , and the reference point  132  is about 13 mm from the lower edge  134  of the operative end  120 . From top to bottom, portion  124  of the operative edge is about 0.18 mm thick; portion  126  is about 0.20 mm thick; portion  128  is about 0.25 mm thick; and portion  130  is about 0.18 mm thick. The thicknesses of the operative end  120  regarding portions  126 ,  128 ,  130 , may be varied in thickness by plus or minus 0.1 mm from the above thicknesses. The leaflets  104 ,  106 ,  108  are curved. Leaflets  104 ,  108  are concave in the same direction so as to fit together as shown in  FIG. 4 . Leaflet  106  is concave in a complimentary direction to leaflet  104 . 
     In another embodiment of the invention, the leaflets may have a flat profile. A flat profile provides a larger coaptation surface for improved mating of surfaces, which may reduce regurgitation. 
     Referring to  FIG. 6A , the operative end  120  of on of the leaflets is depicted wherein another embodiment of the multiple thicknesses of portions of the leaflet are shown. As in  FIG. 6 , the portions  122 ,  134  of the end  120  are at the upper most and lower most portions of the end  120 . The thicknesses of the portions  122 ,  134  may be about 0.15 mm. A post point  132  (representing the post  114  placement in  FIG. 6 ) is about 9 mm from the upper end  122  of the operative end  120 , and the post point  132  is about 12 mm from the lower edge  134  of the operative end  120 . From top to bottom, portion  124  of the operative edge is about 0.08 mm thick; portion  126  is about 0.10 mm thick; portion  128  is about 0.15 mm thick; and portion  130  is about 0.08 mm thick. 
     Referring to  FIG. 6B , the operative end  120  of on of the leaflets is depicted wherein another embodiment of the multiple thicknesses of portions of the leaflet are shown. As in  FIG. 6 , the portions  122 ,  134  of the end  120  are at the upper most and lower most portions of the end  120 . The thicknesses of the portions  122 ,  134  may be about 0.35 mm. A post point  132  (representing the post  114  placement in  FIG. 6 ) is about 9 mm from the upper end  122  of the operative end  120 , and the post point  132  is about 12 mm from the lower edge  134  of the operative end  120 . From top to bottom, portion  124  of the operative edge is about 0.28 mm thick; portion  126  is about 0.30 mm thick; portion  128  is about 0.35 mm thick; and portion  130  is about 0.28 mm thick. 
     Referring to  FIG. 6C , the operative end  120  of on of the leaflets is depicted wherein another embodiment of the multiple thicknesses of portions of the leaflet are shown. As in  FIG. 6 , the portions  122 ,  134  of the end  120  are at the upper most and lower most portions of the end  120 . The thicknesses of the portions  122 ,  134  may be about 0.2 mm. A post point  132  (representing the post  114  placement in  FIG. 6 ) is about 9 mm from the upper end  122  of the operative end  120 , and the post point  132  is about 12 mm from the lower edge  134  of the operative end  120 . From top to bottom, portion  124  of the operative edge is about 0.20 mm thick; portion  126  is about 0.25 mm thick; portion  128  is about 0.30 mm thick; and portion  130  is about 0.20 mm thick. 
     Referring to  FIG. 7A , shows leaflets  104 ,  108 , with leaflet  104  having a 60 degree angle  115  from a midline of the leaflets to an edge of the leaflet  104 .  FIG. 7B  shows an embodiment of a stent  110  with illustrative dimensions. A dimension  154  from top of the stent  110  to the top of the post  114  is about 10 mm. Dimension  152  is from a vertical outer wall of the post  114  to a reference line inside the valve  100  depicted by reference geometry  156 . Dimension  164  is about 16 mm and extends between the post dimensions, including dimension  152 , following the reference geometry  156 . Radius  160  shows an approximately 5 mm radial dimension from a post to the top of the stent  110  along a valley portion  158  between two posts  114 . 
     Referring to  FIG. 7C , an alternative embodiment of a stent  110 A portion of a valve according to the invention includes posts  114  being offset from a vertical axis  174 , such that the posts extend outwardly from the vertical axis  174  and at an obtuse angle in relation to the base of the stent  110 A. Vertical axis  172  passes through the center of the stent, and is shown for reference. 
     The heart valve of the present disclosure can be surgically implanted in the patient via open heart surgery. Alternatively, the valve may replace a valve in the patient using a catheter delivery system, such as transcatheter valve implantation. An example of a catheter delivery system is disclosed in PCT Application number PCT/US2009/035121, international filing date of Feb. 25, 2009, publication number WO/2009/111241. 
     The heart valve  100  may also be used in a valve in an artificial heart, as well as for traditional open-heart valve implantation of a heart valve replacement in a patient. The heart valve  100  may also be used in an artificial heart, or in other pulsatile mechanical circulatory support devices (e.g., a left ventricular assist device). 
     Thereby, the present invention provides optimized leaflet thickness (geometry), and a improved valve stent geometry. The combination of the leaflet geometry, stent geometry, and polymer characteristics provides greater valve stent flexibility, and leaflet durability, resulting in improved leaflet thrombogenicity. 
     A design methodology includes a design, evaluation, and optimization method, which may be called Device Thrombogenicity Emulator (DTE). DTE includes using a combination of state-of-the-art numerical and experimental methods to virtually assess hemodynamics, and then experimentally verify those results with bench top platelet activation studies. An example of an optimizing methodology applicable to the present invention is described in a paper entitled, “Device Thrombogenicity Emulator (DTE)—Design Optimization Methodology for Cardiovascular Devices: A study in two bileaflet MHV designs”; by Xenos et al.; published in the Journal of Biomechanics, 2010. In the DTE method, it is understood that platelets are annucleate cells that contribute to the formation of blood clots. When they are activated by disturbed blood flow, such as that created by implanted devices, they become sticky and clump together which can lead to stroke or death. The DTE method employs two-phase (fluid and particles) computational fluid dynamics in which is simulated blood flow with the addition of thousands of platelet sized particles. Then, the DTE method calculates the stress accumulation on the particles as they pass through the device and extracts dynamic stress history waveforms from selected “hot-spot” regions of high shear stress suspected to cause platelet activation. The dynamic stress history waveforms can be emulated in a Hemodynamic Shearing Device (HSD). A chromogenic assay may be used to measure thrombin generation, which is a key marker of the platelet activation state. Additionally, finite element analysis may be used to perform fluid-structure interaction studies to generate information about the structural stress developed in relation to blood flow. All of this information is fed into the design process and can be repeated iteratively until the design is optimized. All numerical work may be three-dimensional using the latest material models, including performing uniaxial tensile testing of xSIBS for input into numerical material models. 
       FIGS. 9 and 11  show the prior art valve stent with uniform thickness leaflets. Optimized variable thickness leaflets according to the invention are shown in  FIG. 10 . In  FIGS. 9 and 10  shown simulations which were conducted with identical material models and mesh densities in order to ascertain the effects of the changes in leaflet geometry. By comparison,  FIG. 10  shows reduced stress concentrations and magnitudes. In  FIG. 11 , the material model was changed to reflect the prior art composite leaflet design, while in  FIG. 10  the material model reflected the new xSIBS. The comparison of  FIGS. 10 and 11  shows the combined effects of material and geometry changes. The result is that the modified leaflet geometry made from xSIBS produced lower stresses.  FIGS. 12-15  represent mesh dependency studies and show consistent stress patterns over different mesh densities in the prior art stent geometry with both uniform thickness composite leaflets and new customized thickness leaflets with corresponding material models, both prior composite and new xSIBS.  FIGS. 16, 17  show the effects of a flexible stent on the stress distribution in the leaflets using the prior art stent geometry with both uniform thickness composite leaflets in  FIG. 16  with a prior art composite material, compared to customized thickness leaflets with corresponding material models of the present invention of  FIG. 17 , with xSIBS material. A flexible stent made of xSIBS produced low stresses. 
     Valves shown in  FIGS. 18 and 19  depict a comparison of stent design changes. The stent shown in  FIG. 18  incorporates some of the features of the present disclosure, and new stent geometries are shown in stent of  FIG. 19 . Both the valves shown in  FIGS. 18 and 19  have customized thickness leaflets and the xSIBS material model. The new stent design (geometries) shown in  FIG. 19  produced lower stresses in the leaflets. 
       FIGS. 20 and 21  show a comparison of stent design changes wherein the stent shown in  FIG. 20 . Both the stents shown in  FIGS. 20 and 21  include customized thickness leaflet and the xSIBS material according to the present invention. The leaflets of the valves are in semi-open valve positions. The stent design according to the present invention produced lower stresses in the leaflets. All numerical results in  FIGS. 9-21  are shown with identical stress scales. 
     While the present invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that changes in forms and details may be made without departing from the spirit and scope of the present application. It is therefore intended that the present invention not be limited to the exact forms and details described and illustrated herein, but falls within the scope of the appended claims. 
     EXAMPLE 
     Platelet thrombin generation rates were measured using a platelet activation state (PAS) assay. Results were compared measurements conducted with 21 mm Carpentier-Edwards Perimount Magna tissue valves mounted in the pulsatile LVAD and to a negative control, in which the LVAD was run without valves. 
     Bulk Human Platelet Activation Measurements 
     Platelet activation of the valves was measured using 120 ml of blood. A Berlin pulsatile left ventricular assist device (LVAD) was used to recirculate 250 ml of solution containing freshly isolated human platelets at a concentration of 20,000/μl in platelet buffer. The system held two identical valves mounted inside custom designed valve holders oriented in opposite directions. The inflow and outflow ports were connected with a compliance reservoir. The pump rate was set to 90 BPM with a stroke volume of 65 ml, corresponding to a cardiac output (CO) of 5.85 l/min. The systole/diastole ratio was set to 0.375. The recirculation test was run for 30 min with samples taken in duplicate every 10 min. Platelet thrombin generation rates were measured using our platelet activation state (PAS) assay. Results were compared to previous measurements (n=6) conducted with 21 mm Carpentier-Edwards Perimount Magna tissue valves mounted in the same LVAD and to a negative control, in which the LVAD was run without valves. One-way ANOVA statistics were performed on the platelet activation rates (PAR)—the slope of the PAS measured over the 30 min. recirculation experiments, calculated from a linear best fit curve for each experiment with significance level α=0.05. 
     There was no significant statistical difference between the platelet activation rates (PAR) of the tissue valve (PAR=0.0005 min −1 ) and the xSIBS valve (PAR=0.0008 min −1 ), although the xSIBS valve exhibited a trend of a slightly higher PAR. Both valves PAR&#39;s were significantly different from the control (p&lt;0.05). This indicates that the optimized xSIBS valve may not require anticoagulants since the tissue valves used for comparison do not cause clinically significant thrombosis.