FIELD

[0001 ] The present disclosure relates generally to prosthetic valves, and more specifically, a frame with integral sewing cuff-type prosthetic valve devices, systems, and methods.

BACKGROUND

[0002] Prosthetic heart valves have been developed that attempt to mimic the function and performance of a native valve. The prosthetic valve is typically attached to a human heart with sutures via a sewing cuff, or some other mechanical attachment means (e.g., staples).

[0003] Sewing cuffs generally comprise a toroidal member that is attached to the periphery of a prosthetic valve body to form a structure for anchoring sutures to the annulus of the heart during implantation of the prosthetic valve. Sewing cuffs commonly comprise a cloth material, such as polyester, and may also comprise a filler material such as Teflon felt or Dacron cloth. The sewing cuff may be coupled to a peripheral groove located on a lower end of the valve body by circumferential cinch-like sutures, or may be mechanically captured adjacent to a stiffening ring.

SUMMARY

[0004] Described embodiments are directed to an apparatus, system, and methods for valve replacement, such as cardiac valve replacement. More specifically, described embodiments are directed toward a frame assembly including an integral sewing cuff for use in a prosthetic valve.

[0005] In accordance with an embodiment, a prosthetic valve comprises a frame. The frame has a tubular shape with a frame inside surface and a frame outside surface opposite the frame inside surface. The prosthetic valve further comprises a fabric with fabric pores having a fabric frame portion and a sewing cuff opposite the fabric frame portion. The fabric frame portion has an elastomer present in the fabric pores. The fabric frame portion is coupled to the frame. The sewing cuff extends from the frame. A composite material is coupled to at least a portion of the fabric frame portion with the fabric frame portion disposed between the frame and the composite material. Leaflets are coupled to the frame. [0006] In accordance with an embodiment, a prosthetic valve frame assembly comprises a frame. The frame has a tubular shape with a frame inside surface and a frame outside surface opposite the frame inside surface. The prosthetic valve further comprises a fabric with fabric pores having a fabric frame portion and a sewing cuff opposite the fabric frame portion. The fabric frame portion has an elastomer present in the fabric pores. The fabric frame portion is coupled to the frame. The sewing cuff extends from the frame. A composite material is coupled to at least a portion of the fabric frame portion with the fabric frame portion disposed between the frame and the composite material.

[0007] In accordance with an embodiment of method of making a frame assembly for a prosthetic valve, a first layer of film is wrapped into a tubular form about a mandrel. A fabric having a tubular shape is provided. The fabric is partially placed over the first layer of film. A frame having a tubular shape is provided. The frame has a frame inside surface and a frame outside surface and defines a frame base and a plurality of leaflet windows. The frame is placed over the fabric that is over the first layer of film with the frame inside surface in contact with the fabric. The fabric is everted over the frame base and over the frame outside surface in contact with the frame outside surface defining a fold in the fabric with the fold extending from the frame base, the fold defining a sewing cuff. A second layer of film is wrapped over the fabric that is over the frame outside surface. The first layer of film and the second layer of film are coupled to each other, to the fabric, and to the frame.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The accompanying drawings are included to provide a further understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments described herein, and together with the description serve to explain the principles discussed in this disclosure.

[0009] FIG. 1 A is a side view of an embodiment of a prosthetic valve;

[0010] FIG. 1 B is a perspective view of the embodiment of the prosthetic valve of FIG 1 A;

[001 1 ] FIG. 1 C is an axial cross-sectional view along line C— C of the embodiment of the prosthetic valve of FIG 1 A; [0012] FIG. 2A is a representation of an embodiment of a frame unrolled to a flat orientation;

[0013] FIG. 2B is a representation of another embodiment of a frame unrolled to a flat orientation;

[0014] FIG. 3A is an axial or top view of an embodiment of a prosthetic valve in an open configuration;

[0015] FIG. 3B is an axial or top view of the embodiment of the prosthetic valve of FIG. 3A in a closed configuration;

[0016] FIG. 4 is a side view of an embodiment of a prosthetic valve within the anatomy;

[0017] FIG. 5 is a perspective view of an embodiment of an assembly mandrel; and

[0018] FIG. 6A-F are side views of stages in an example process for making a frame assembly with an integral sewing cuff, in accordance with an embodiment.

DEFINITIONS

[0019] The term leaflet as used herein in the context of prosthetic valves is a component of a one-way valve wherein the leaflet is operable to move between an open and closed position under the influence of a pressure differential. In an open position, the leaflet allows blood to flow through the prosthetic valve. In a closed position, the leaflet blocks retrograde flow through the prosthetic valve. In embodiments comprising multiple leaflets, each leaflet cooperates with at least one neighboring leaflet to block the retrograde flow of blood. The pressure differential in the blood is caused, for example, by the contraction of a ventricle or atrium of the heart, such pressure differential typically resulting from a fluid pressure building up on one side of the leaflets when closed. As the pressure on an inflow side of the prosthetic valve rises above the pressure on the outflow side of the prosthetic valve, the leaflets open and blood flows therethrough. As blood flows through the prosthetic valve into a neighboring chamber or blood vessel, the pressure on the inflow side equalizes with the pressure on the outflow side. As the pressure on the outflow side of the prosthetic valve raises above the blood pressure on the inflow side of the prosthetic valve, the leaflet returns to the closed position preventing retrograde flow of blood through the prosthetic valve. Leaflets may be comprised of biological tissue, such as bovine pericardium, or synthetic, biocompatible materials sufficiently compliant and flexible, such as a biocompatible polymer.

[0020] The term membrane as used herein refers to a sheet of material comprising a single composition, such as, but not limited to, expanded

fluoropolymer.

[0021 ] The term composite material as used herein refers to a combination of a membrane, such as, but not limited to, expanded fluoropolymer, and an elastomer, such as, but not limited to, a fluoroelastomer. The elastomer may be present within a porous structure of the membrane, coated on one or both sides of the membrane, or a combination of coated on and imbibed.

[0022] The term imbibed as used herein refers to the presence of material in the pores of a film. The process of imbibing as used herein refers to the means for depositing a material into the pores of the film. Means for imbibing may include, but are not limited to, printing, soaking, or any other suitable means for delivering materials into the pores.

[0023] The term laminate as used herein refers to an article comprising multiple layers of membrane, composite material, or other materials, such as elastomer, and combinations thereof, that are coupled together.

[0024] The term film as used herein refers to one or more of the membrane, composite material, or laminate.

[0025] The term pores generally refers to void space that may be found in a material. Pores that are found in a fabric is referred to as fabric pores. Pores that are found in fluoropolymer membrane are referred to as fluoropolymer membrane pores. Pores also refers to void spaces in which another material may be present.

[0026] The term biocompatible material as used herein generically refers to a film or a biological material, such as, but not limited to, bovine pericardium.

[0027] The term leaflet window is defined as that space that a frame defines, and from which a leaflet extends. The leaflet may extend from frame elements or adjacent to frame elements and spaced apart therefrom.

[0028] The terms native valve orifice and tissue orifice refer to an anatomical structure into which a prosthetic valve may be placed. Such anatomical structure includes, but is not limited to, a location wherein a cardiac valve may or may not have been surgically removed. It is understood that other anatomical structures that may receive a prosthetic valve include, but are not limited to, veins, arteries, ducts and shunts. Although reference is made herein to replacing a native valve with a prosthetic valve, it is understood and appreciated that a valve orifice or implant site may also refer to a location in a synthetic or biological conduit that may receive a prosthetic valve for a particular purpose, and therefore the scope of the

embodiments provided herein is not limited to native valve replacement.

[0029] The term couple as used herein is used synonymously with join, connect, attach, adhere, affix, or bond, whether directly or indirectly, and whether permanently or temporarily.

DETAILED DESCRIPTION

[0030] Persons skilled in the art will readily appreciate that various aspects of the present disclosure can be realized by any number of methods and apparatus configured to perform the intended functions. Stated differently, other methods and apparatuses can be incorporated herein to perform the intended functions. It should also be noted that the accompanying drawing figures referred to herein are not necessarily drawn to scale, but may be exaggerated to illustrate various aspects of the present disclosure, and in that regard, the drawing figures should not be construed as limiting.

[0031 ] Although the embodiments herein may be described in connection with various principles and beliefs, the described embodiments should not be bound by theory. For example, embodiments are described herein in connection with prosthetic valves, more specifically cardiac prosthetic valves. However,

embodiments within the scope of this disclosure can be applied toward any prosthetic valve or mechanism of similar structure and/or function. Furthermore, embodiments within the scope of this disclosure can be applied in non-cardiac applications.

[0032] Embodiments herein include various apparatus, systems, and methods for a prosthetic valve suitable for surgical placement, such as, but not limited to, cardiac valve replacement. The prosthetic valve is operable as a one-way valve wherein the prosthetic valve defines a valve orifice into which leaflets open to permit flow and close so as to occlude the valve orifice and prevent flow in response to differential fluid pressure.

[0033] Embodiments provided herein are related to a prosthetic valve with an integral sewing cuff that is durably attached to a frame and suitable for surgical placement. The durability of the attachment of the sewing cuff is accomplished by sandwiching a fabric between a frame and a composite material, in accordance with an embodiment. The fabric extends beyond a frame base to form a sewing cuff that is integral to the frame assembly.

[0034] As will be described below, in accordance with an embodiment, the sewing cuff facilitates tissue ingrowth while tissue ingrowth is discouraged elsewhere around the frame.

Prosthetic Valve

[0035] FIG. 1 A is a side view of a prosthetic valve 100, in accordance with an embodiment. FIG 1 B is a perspective view of the prosthetic valve 100 of FIG. 1 A, and FIG. 1 C is an axial cross-sectional view of a portion of the prosthetic valve 100 of FIG. 1 A along cut-line C--C. The prosthetic valve 100 comprises leaflets 1 22 and a frame assembly 120 with sewing cuff 1 16. The frame assembly 120 with sewing cuff 1 16 comprises a frame 1 10 with a frame inside surface 124 and a frame outside surface 1 26, a fabric 1 12 with fabric pores that is coupled to the frame 1 1 0 defining a fabric frame portion 1 14 that extends beyond the frame 1 10 to form a sewing cuff 1 16, a composite material 1 1 8 coupled to at least a portion of the fabric frame portion 1 14 such that the fabric 1 12 is between the composite material 1 1 8 and the frame 1 10.

[0036] As shown in FIG. 1 C, the fabric 1 12 and composite material 1 18 are coupled to both the frame inside surface 1 24 and frame outside surface 126 of the frame 1 10 thereby defining an inner fabric frame portion 1 28, an inner composite material 1 30, an outer fabric frame portion 132, and an outer composite material 134. In another embodiment, the fabric 1 12 and composite material 1 1 8 are coupled to only the frame inside surface 124 of the frame 1 10, defining an inner fabric frame portion 128 and an inner composite material 130. In yet another embodiment, the fabric 1 12 and composite material 1 18 are coupled to only the frame outside surface 126 of the frame 1 10, defining an outer fabric frame portion 132 and an outer composite material 134.

[0037] As shown in FIGs 1 A-1 C, the composite material 1 1 8 may be coupled to substantially all of the fabric frame portion 1 14, that is, coupled to the frame 1 1 0. The composite material 1 1 8 may further extend beyond the frame 1 1 0 into the leaflet windows 144 to form the leaflets 122. Alternatively, leaflets 1 22 may be sewn or otherwise coupled to the frame assembly 120.

Frame

[0038] Referring to FIGs. 1 A-1 C, the frame 1 1 0 is a tubular member defining a predetermined repeating pattern. The frame 1 1 0 comprises a frame first end 136 and a frame second end 138 opposite the frame first end 136. Positioned at the frame first end 136 is the frame base 140. A plurality of spaced apart frame strut elements 142 extend from the frame first end 136 to the frame second end 138 in a predetermined repeating pattern. The frame 1 10 further comprises a frame outside surface 1 26 and a frame inside surface 124 opposite the frame outside surface 126, as shown in FIG. 1 C.

[0039] The frame base 140 and frame strut elements 142 define leaflet windows 144. Each leaflet window 144 includes two leaflet window sides 146 and a leaflet window base 148. As will be described in more detail below, a biocompatible material is disposed over each of the leaflet windows 144 to form a leaflet 122. The leaflet window 144 may define any shape suitable for a particular purpose of an embodiment of a prosthetic valve 100, including, but not limited to a parabolic shape, a trapezoidal shape, and a triangular shape.

[0040] The frame 1 10 may be referred to in a general sense as a stent or a frame. The frame 1 1 0 defines any number of features and geometric shapes that facilitate support to the leaflet 1 22 and provide dimensional stability when implanted.

[0041 ] The frame 1 1 0 may comprise a cut tube or wire form, or any other element suitable for the particular purpose. The frame 1 10 may be etched, cut, laser cut, or stamped from a tube or a sheet of material, with the sheet then formed into a substantially cylindrical structure. Alternatively, an elongated material, such as a wire, bendable strip, or a series thereof, can be bent or braided and formed into a substantially cylindrical structure wherein the walls of the cylinder comprise an open framework.

[0042] The frame 1 10 can comprise any metallic or polymeric biocompatible material. For example, the frame 1 10 can comprise a material, such as, but not limited to nitinol, cobalt-nickel alloy, stainless steel, or polypropylene, acetyl homopolymer, acetyl copolymer, ePTFE, other alloys or polymers, or any other biocompatible material having adequate physical and mechanical properties to function as described herein.

[0043] FIGs. 2A-2B are side views of alternative embodiments of the frame 1 10a-1 1 0b where the frame has been cut longitudinally and laid open to better illustrate the elements of the frame.

[0044] FIG. 2A is a representation of an embodiment of a prosthetic valve 100a comprising a frame 1 1 0a that has been unrolled to a flat orientation to better illustrate the elements. The frame 1 10a is formed from a wire 145. The wire 145 is formed into a cylindrical shape that defines a plurality of U-shaped or parabola shaped leaflet windows 144a with leaflet window sides 146a that extend to the frame second end 138 and a leaflet window base 148a that is adjacent to the frame first end 1 36. The wire 145 further defines the frame base 140b at the frame first end 136.

[0045] FIG. 2B is a representation of an embodiment of a prosthetic valve 100b comprising a frame 1 1 0b that has been unrolled to a flat orientation to better illustrate the elements. The frame 1 10b comprises a plurality of spaced apart frame strut elements 142b defining substantially an isosceles triangle interconnected by another frame strut element 142b that defines the frame base 140b and defining leaflet windows 144b. Each leaflet window side 146b is defined by a side of one triangle and a side of an adjacent triangle, and wherein each leaflet window base 148b is defined by a frame strut element 142b that defines a portion of the frame base 140b. The frame second end 138 further comprises posts 152 extending from an apex of the frame strut elements 142b that define each of the isosceles triangles.

[0046] It is understood that the frame 1 1 0 may comprise any number of leaflet windows 144, and thus leaflets 122, suitable for a particular purpose, in accordance with embodiments. Frames comprising one, two, three or more leaflet windows and corresponding leaflets are anticipated.

Fabric and Sewing Cuff

[0047] In accordance with an embodiment of a prosthetic valve 100 suitable for surgical implantation, the prosthetic valve 100 further comprises a sewing cuff

1 16 about a frame outside surface 126 in accordance with an embodiment, as shown in FIGs. 1 A-1 C and FIG. 4. The sewing cuff 1 16 is operable to provide structure that receives suture for coupling the prosthetic valve 1 00 to the implant site, such as the tissue orifice. The sewing cuff 1 16 may be located circumferentially around the frame base 140 of the frame 1 10 or paravalvular, that is, extending axially from the frame base 140.

[0048] Referring again to the embodiment of FIG. 1 C, a fabric 1 12 with fabric pores is coupled to the frame inside surface 124 and the frame outside surface 1 26. Portions of the fabric 1 12 that are coupled to the frame 1 10 define fabric frame portions 1 14. The sewing cuff 1 16 is formed from fabric 1 12 material that extends beyond the frame base 140. As shown in FIG. 1 C, the fabric 1 1 2 defines a fabric first end 1 56, a fabric second end 158 opposite the fabric first end 156, and a fabric central portion 1 60 between the fabric first end 1 56 and the fabric second end 158. The fabric frame portion 1 14 comprises the fabric first end 1 56 which is coupled to the frame inside surface 124, and the fabric second end 158 which is coupled to the frame outside surface 126. The fabric central portion 160 comprises the sewing cuff 1 16, which is defined by a loop or fold of the fabric 1 12 extending beyond the frame base 140.

[0049] In an embodiment, the fabric 1 12 is coupled to substantially all of the frame inside surface 124 and substantially all of the frame outside surface 126, including the frame base 140 and the frame strut elements 142. In other

embodiments the fabric 1 1 2 is coupled to a portion of the frame inside surface 1 24 and/or a portion of the frame outside surface 126. In other embodiments, the fabric 1 1 2 is coupled to the frame 1 10 at the frame base 140 on either the frame inside surface 1 24 and/or the frame outside surface 126. The fabric 1 1 2 may further extend, wholly or partially, into the leaflet windows 144. Extension of the fabric 1 12 at least partially into the leaflet window 144 may benefit the durability of the leaflet 144 as a reinforcement or a cushion layer between the frame 1 1 0 and the leaflet material that is coupled to the leaflet window 144.

[0050] In accordance with an embodiments, the fabric frame portion 1 14 has an elastomer present in the fabric pores of the fabric 1 12; in contrast, the sewing cuff

1 1 6 does not have an elastomer present in the fabric pores of fabric 1 12. This enables the sewing cuff 1 16 to be operable to facilitate tissue ingrowth into the fabric pores, but tissue ingrowth is discouraged elsewhere around the frame assembly 120.

In another embodiment a predetermined portion of the sewing cuff 1 16 may have an elastomer present in the fabric pores of the fabric 1 12 so that tissue ingrowth is facilitated in specific regions of the sewing cuff 1 16 but not in others. [0051 ] The sewing cuff 1 16 and fabric frame portion 1 14 may comprise any suitable fabric 1 12, such as, but not limited to, double velour polyester, PTFE, ePTFE, Dacron, or any other biocompatible fabric that does not deteriorate over time. The fabric 1 12 may be knit, woven, or non-woven. The sewing cuff 1 16 may further comprise a filler 162 between fabric layers. The filler 162 material may comprise the same material as the fabric 1 12 or may be any other suitable material, including silicone. The filler 162 may be a bead of material, a base tube rolled into an O-ring, one or more layers of a knit or woven material, wraps of a fiber, or any other suitable form. In some embodiments the filler 1 62 may be injected through a needle between the layers of the fabric 1 12 that form the sewing cuff 1 16 or inserted through a seam in the fabric 1 12 that is subsequently sewn together. The sewing cuff 1 16 may be located circumferentially around a perimeter of the frame 1 10.

[0052] In some embodiments the sewing cuff 1 16 and fabric frame portion 1 14 are comprised of a single piece of fabric. In other embodiments the sewing cuff 1 16 and fabric frame portion 1 14 are comprised of two or more fabric pieces which are coupled together by sewing, use of an adhesive, or any other suitable means.

Leaflet

[0053] Referring to FIG. 1 B and 2A-B, each leaflet window 144 is provided with a biocompatible material, such as a film or bovine pericardium, which is coupled to the leaflet window sides 146 and leaflet window base 148 with the biocompatible material defining a leaflet 1 22. The shape of the leaflets 122 are defined in part by the shape of the leaflet window 144 and the leaflet free edge 154.

[0054] FIGs. 3A and 3B are top axial views of a prosthetic valve 100 in an open and closed position, respectively. When the leaflets 122 are in a fully open position, the prosthetic valve 100 presents a valve orifice 102 that is substantially circular as shown in FIG. 3A. Fluid flow is permitted through the valve orifice 102 when the leaflets 1 22 are in an open position. When the leaflets 122 are in a closed position, the prosthetic valve 100 presents a substantially occluded orifice restricting fluid flow.

Film

[0055] A film 150 is any sheet-like material that is biologically compatible and configured to couple to the frame 1 1 0, in accordance with embodiments. It is understood that the term "film" is used generically for one or more biocompatible materials suitable for a particular purpose.

[0056] In accordance with an embodiment, the biocompatible material is a film that is not of a biological source and that is sufficiently flexible and strong for the particular purpose, such as a biocompatible polymer. In an embodiment, the film comprises a biocompatible polymer that is combined with an elastomer, referred to as a composite material.

[0057] In an embodiment, the film 150 may be formed from a tubular shape to at least partially cover the frame 1 10. The film 150 can comprise one or more of a membrane, composite material, or laminate. Details of various types of film 150 are discussed below.

[0058] The biocompatible material that makes up the film can comprise any biological tissue or synthetic, biocompatible materials sufficiently compliant and flexible, such as a biocompatible polymer. In an embodiment, the film comprises a biocompatible polymer that is combined with an elastomer, referred to as a composite material. A material according to one embodiment includes a composite material comprising an expanded fluoropolymer membrane, which comprises a plurality of void spaces within a matrix of fibrils, and an elastomeric material. It should be appreciated that multiple types of fluoropolymer membranes and multiple types of elastomeric materials can be combined to form a laminate while remaining within the scope of the present disclosure. It should also be appreciated that the elastomeric material can include multiple elastomers, multiple types of non- elastomeric components, such as inorganic fillers, therapeutic agents, radiopaque markers, and the like while remaining within the scope of the present disclosure.

[0059] In accordance with an embodiment, the composite material includes an expanded fluoropolymer material made from porous ePTFE membrane, for instance as generally described in U.S. Patent No. 7,306,729 to Bacino.

[0060] The expandable fluoropolymer, used to form the expanded

fluoropolymer material described, may comprise PTFE homopolymer. In alternative embodiments, blends of PTFE, expandable modified PTFE and/or expanded copolymers of PTFE may be used. Non-limiting examples of suitable fluoropolymer materials are described in, for example, U.S. Patent No. 5,708,044, to Branca, U.S. Patent No. 6,541 ,589, to Baillie, U.S. Patent No. 7,531 ,61 1 , to Sabol et al., U.S. Patent Application No. 1 1 /906,877, to Ford, and U.S. Patent Application No.

12/41 0,050, to Xu et al.

[0061 ] The expanded fluoropolymer membrane can comprise any suitable microstructure for achieving the desired leaflet performance. In accordance with an embodiment, the expanded fluoropolymer comprises a microstructure of nodes interconnected by fibrils, such as described in U.S. Patent No. 3,953,566 to Gore defining fluoropolymer membrane pores. The fibrils radially extend from the nodes in a plurality of directions, and the membrane has a generally homogeneous structure. Membranes having this microstructure may typically exhibit a ratio of matrix tensile strength in two orthogonal directions of less than 2, and possibly less than 1 .5.

[0062] In another embodiment, the expanded fluoropolymer membrane has a microstructure of substantially only fibrils, as is generally taught by U.S. Patent No. 7,306,729, to Bacino, defining fluoropolymer membrane pores. The expanded fluoropolymer membrane having substantially only fibrils, can possess a high surface area, such as greater than 20m ² /g, or greater than 25m ² /g, and in some

embodiments can provide a highly balanced strength material having a product of matrix tensile strengths in two orthogonal directions of at least 1 .5 x 10 ⁵ MPa ² , and/or a ratio of matrix tensile strengths in two orthogonal directions of less than 4, and possibly less than 1 .5.

[0063] The expanded fluoropolymer membrane can be tailored to have any suitable thickness and mass to achieve the desired leaflet performance. By way of example, but not limited thereto, the leaflet 122 comprises an expanded

fluoropolymer membrane having a thickness of about 0.1 μηι. The expanded fluoropolymer membrane can possess a mass per area of about 1 .15 g/m ² .

Membranes according to an embodiment of the invention can have matrix tensile strengths of about 41 1 MPa in the longitudinal direction and 315 MPa in the transverse direction.

[0064] Additional materials may be incorporated into the fluoropolymer membrane pores or within the material of the membranes or in between layers of membranes to enhance desired properties of the leaflet. Composite materials described herein can be tailored to have any suitable thickness and mass to achieve the desired leaflet performance. Composite materials according to embodiments can include fluoropolymer membranes and have a thickness of about 1 .9 μηι and a mass per area of about 4.1 g/m ² . [0065] The expanded fluoropolymer membrane combined with elastomer to form a composite material provides the elements of the present disclosure with the performance attributes required for use in high-cycle flexural implant applications, such as heart valve leaflets, in various ways. For example, the addition of the elastomer can improve the fatigue performance of the leaflet by eliminating or reducing the stiffening observed with ePTFE-only materials. In addition, it may reduce the likelihood that the material will undergo permanent set deformation, such as wrinkling or creasing, that could result in compromised performance. In one embodiment, the elastomer occupies substantially all of the pore volume or space within the porous structure of the expanded fluoropolymer membrane. In another embodiment the elastomer is present in the fluoropolymer membrane pores of the at least one fluoropolymer layer. Having elastomer filling the pore volume or present in the fluoropolymer membrane pores reduces the space in which foreign materials can be undesirably incorporated into the composite. An example of such foreign material is calcium that may be drawn into the membrane from contact with the blood. If calcium becomes incorporated into the composite material, as used in a heart valve leaflet, for example, mechanical damage can occur during cycling open and closed, thus leading to the formation of holes in the leaflet and degradation in

hemodynamics.

[0066] In an embodiment, the elastomer that is combined with the ePTFE is a thermoplastic copolymer of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE), such as described in U.S. Patent No. 7,462,675 to Chang et al. In another embodiment, the elastomer is Silicone MED-4720, NuSil, Carpinteria, CA, USA.

[0067] As discussed above, the elastomer is combined with the expanded fluoropolymer membrane such that the elastomer occupies the void space or fluoropolymer membrane pores within the expanded fluoropolymer membrane to form a composite material. This filling of the fluoropolymer membrane pores of the expanded fluoropolymer membrane with elastomer can be performed by a variety of methods. In one embodiment, a method of filling the fluoropolymer membrane pores of the expanded fluoropolymer membrane includes the steps of dissolving the elastomer in a solvent suitable to create a solution with a viscosity and surface tension that is appropriate to partially or fully flow into the fluoropolymer membrane pores of the expanded fluoropolymer membrane and allow the solvent to evaporate, leaving the filler behind. [0068] In one embodiment, the composite material comprises three layers: two outer layers of ePTFE and an inner layer of a fluoroelastomer disposed therebetween. Additional fluoroelastomers can be suitable and are described in U.S. Publication No. 2004/0024448 to Chang et al.

[0069] In another embodiment, a method of filling the fluoropolymer membrane pores of the expanded fluoropolymer membrane includes the steps of delivering the filler via a dispersion to partially or fully fill the fluoropolymer membrane pores of the expanded fluoropolymer membrane.

[0070] In another embodiment, a method of filling the fluoropolymer membrane pores of the expanded fluoropolymer membrane includes the steps of bringing the porous expanded fluoropolymer membrane into contact with a sheet of the elastomer under conditions of heat and/or pressure that allow elastomer to flow into the fluoropolymer membrane pores of the expanded fluoropolymer membrane.

[0071 ] In another embodiment, a method of filling the fluoropolymer membrane pores of the expanded fluoropolymer membrane includes the steps of polymerizing the elastomer within the fluoropolymer membrane pores of the expanded fluoropolymer membrane by first filling the fluoropolymer membrane pores with a prepolymer of the elastomer and then at least partially curing the elastomer.

[0072] After reaching a minimum percent by weight of elastomer, the leaflets constructed from fluoropolymer materials or ePTFE generally performed better with increasing percentages of elastomer resulting in significantly increased cycle lives. In one embodiment, the elastomer combined with the ePTFE is a thermoplastic copolymer of tetrafluoroethylene and perfluoromethyl vinyl ether, such as described in U.S. Patent No. 7,462,675 to Chang et al., and other references that would be known to those of skill in the art. Other biocompatible polymers which can be suitable for use as a leaflet include but are not limited to the groups of urethanes, silicones(organopolysiloxanes), copolymers of silicon-urethane, styrene/isobutylene copolymers, polyisobutylene, polyethylene-co-poly(vinyl acetate), polyester copolymers, nylon copolymers, fluorinated hydrocarbon polymers and copolymers or mixtures of each of the foregoing.

Other Considerations

[0073] The prosthetic valve 100 can further comprise a bio-active agent. Bio- active agents can be coated onto a portion or the entirety of the film 150 for controlled release of the agents once the prosthetic valve 100 is implanted. The bio- active agents can include, but are not limited to, vasodilator, anti-coagulants, antiplatelet, anti-thrombogenic agents such as, but not limited to, heparin. Other bio- active agents can also include, but are not limited to agents such as, for example, anti-proliferative/antimitotic agents including natural products such as vinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D), daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP) llb/llla inhibitors and vitronectin receptor antagonists; anti-proliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines

(hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nitrosoureas

(carmustine (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); anti-proliferative/antimitotic antimetabolites such as folic acid analogs

(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2- chlorodeoxyadenosine {cladribine}); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen); anti-coagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;

antimigratory; antisecretory (breveldin); anti-inflammatory: such as adrenocortical steroids (Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a- methylprednisolone, triamcinolone, betamethasone, and dexamethasone), nonsteroidal agents (salicylic acid derivatives i.e. aspirin; para-aminophenol derivatives i.e. acetominophen; indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and

meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF);

angiotensin receptor blockers; nitric oxide donors; anti-sense oligionucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor receptor signal transduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMG co-enzyme reductase inhibitors (statins); and protease inhibitors.

Method of Making

[0074] Embodiments described herein also pertain to a method of making the embodiments of a prosthetic valve as described herein. In order to make the various embodiments, a cylindrical assembly mandrel 168 can be used. With reference to FIGs. 5, 6A-6C, the assembly mandrel 168 comprises a structural form operable to receive the frame 1 10 thereon. An embodiment of a method of making a prosthetic valve 100 comprises the steps of coupling the fabric 1 12 to the frame 1 10 with a fabric central portion 1 60 of the fabric 1 12 extending beyond the frame base 140 that will be used to form the sewing cuff 1 16 of FIG. 1 A; imbibing the fabric frame portion 1 14 with an elastomer so that the elastomer is present in the fabric pores of the fabric 1 12 while keeping the fabric central portion 160 of the fabric 1 12 that will be made into the sewing cuff 1 16 free of elastomer in the fabric pores of the fabric 1 12; thermally setting the assembly; coupling a composite material 1 18 to the fabric frame portion 1 14 such that the fabric frame portion 1 14 is between the frame 1 1 0 and the composite material 1 18.

Example

[0075] A frame assembly 120 with sewing cuff 1 16 that is integral to the frame assembly 120 was made in the following manner. The following knit fabric was obtained. A 32 TPI, 32ga 2-bar in-lay warp knit was created using 1 00 denier, round ePTFE fiber (W.L. Gore and Associates, Elkton, MD). Parallel cuts were made in the knit at 45 degrees relative to the warp direction and hand sewn into a 25 mm diameter tube using CV-4 GORE-TEX Suture (W.L. Gore and Associates, Flagstaff, AZ).

[0076] An assembly mandrel 168 was machined from aluminum in a cylindrical shape shown in perspective view in FIG. 5. The assembly mandrel 168 has a first end 170 and an opposing second end 172. Two rows of six 0.5 mm diameter vent holes 174 were drilled into the assembly mandrel 168 as shown in FIG. 5. The vent holes 174 communicate with a vent port 180.

[0077] Two layers of a sacrificial composite material comprising polyimide imbibed ePTFE film with a thickness of approximately 0.004 mm were wrapped around assembly mandrel 168. The sacrificial composite material was punctured above the vent holes 1 74.

[0078] Referring to FIG. 6A, the fabric 1 12 was an ePTFE knit tube 176. The ePTFE knit tube 1 76 was slid over the sacrificial material. Next, a 0.1 64 mm thick fluoroelastomer film was obtained. The fluoroelastomer was formulated according to the general teachings described in U.S. Patent No. 7,462,675. A 40 mm wide strip of the fluoroelastomer film 178 was wrapped on top of the knit tube 176, for a total of 1 layer, positioned relative to vent holes 174 as shown in FIG. 6A.

[0079] A frame 1 1 0 was constructed as follows. The frame 1 10 was laser machined from a length of seamless MP35N tubing with a wall thickness of 0.60 mm.

[0080] Frame 1 10 was slid over the fluoroelastomer film 178 and positioned so that the frame base 140 was approximately 1 mm from the edge of

fluoroelastomer film 178 as shown in FIG. 6B.

[0081 ] A 40 mm wide strip of the fluoroelastomer film 178 previously described in this example was wrapped on top of the frame 1 1 0 and aligned directly above the previously applied fluoroelastomer film 178, for a total of 3 additional layers.

[0082] A length of 3.2 mm diameter Gore Joint Sealant (W.L. Gore and Associates, Elkton, MD) was wrapped around the assembly mandrel, just below the frame base 140 of the frame 1 10. This material used as filler 162 will provide bulk to the sewing cuff 1 16 as shown in FIG. 6C.

[0083] The excess length of the ePTFE knit tube 176 that is extending beyond the length of the frame 1 1 0 was pulled over the filler 162 and the frame 1 10 so that it extended beyond the frame strut elements 142 of the frame 1 10.

[0084] An ePTFE CV-4 suture was tied around the assembly mandrel 1 68 and located between the frame base 140 and the filler 1 62. The suture held the knit in close contact with the frame base 140 and the filler 162.

[0085] A 40 mm wide strip of the fluoroelastomer film 178 previously described in this example was wrapped on top of the frame 1 1 0 and aligned directly above the previously applied fluoroelastomer film 178, for a total of 14 additional layers.

[0086] Two layers of the previously described sacrificial composite material were wrapped on top of the coverings on the frame 1 10. Adhesive-backed polyimide tape was used to attach the ePTFE/polyimide composite to the assembly mandrel at each end and to seal the longitudinal seam thereby creating a fabric-frame assembly.

[0087] The fabric-frame assembly was then placed inside a heated pressure chamber. A vent port 1 80 in the first end 170 of the assembly mandrel 168 was plumbed to a vacuum source. The fabric-frame assembly was then subjected to 414 KPa pressure for about 26 minutes as the temperature inside the assembly mandrel reached about 260°C.

[0088] The pressure vessel was allowed to cool to room temperature. The pressure was released and the assembly mandrel 168 was removed from the pressure vessel. The resulting bonded fabric-frame assembly was slid off of the assembly mandrel 168 and the sacrificial ePTFE/polyimide composite material was removed.

[0089] The ePTFE knit tube 1 76 (the fabric in this embodiment) and fluoroelastomer film 178 of the bonded fabric-frame assembly 1500 was trimmed to within 1 mm of the frame. The fluoroelastomer filled the fabric pores or void spaces within the ePTFE knit in proximity to frame 1 10, both on the inner fabric frame portion 128 and outer fabric frame portion 132, as shown in FIG. 1 C. The

fluoroelastomer did not fill the fabric pores within the ePTFE knit and the filler 162 in the fabric central portion 160 of the sewing cuff 1 16.

[0090] With nothing on the assembly mandrel 168, two layers of the aforementioned sacrificial composite material were wrapped around the assembly mandrel 168 as previously described. The sacrificial composite material was punctured above the vent holes 174. A sacrificial layer of stainless steel foil 1 92 was wrapped around the assembly mandrel 168, adjacent to and extending away from the row of vent holes 1 74, as shown in FIG. 6D.

[0091 ] A composite material was then prepared as follows. A membrane layer of ePTFE was manufactured according to the general teachings described in U.S.

Patent No. 7,306,729. The ePTFE membrane was tested in accordance with the methods described herein. The ePTFE membrane had a mass per area of about 1 .12g/m2, a porosity of about 52%, a thickness of about 1 .0 μηι, a bubble point of about 458 KPa, a matrix tensile strength of about 481 MPa in the longitudinal direction and about 307 MPa in the transverse direction. This membrane was imbibed with the same fluoroelastomer as described previously in this example. The fluoroelastomer was dissolved in Fluorinert Electronic Liquid FC-72, 3M, St. Paul, MN, USA in an about 3.0% concentration. The solution was coated using a die coater onto the ePTFE membrane (while being supported by a polyethylene release film) and dried in a convection oven set to about 1 10°C for about 3 minutes. The resulting composite material of ePTFE/fluoroelastomer had a mass per area of about 3.6 g/m2.

[0092] The ePTFE/fluoroelastomer composite material 1 18 was wrapped around the assembly mandrel 168 and previously applied components for a total of 5 layers. The composite material 1 18 was trimmed with a razor blade against the sacrificial stainless steel foil, approximately 1 mm from the edge of the foil. The foil and trimmed composite was removed from the assembly mandrel 1 68.

[0093] The fabric-frame assembly 190 was slid onto the assembly mandrel 168 and positioned on top of the ePTFE/fluoroelastomer composite material so that the frame base 140 aligned with the edge of the composite material 1 1 8 as shown in FIG. 6E.

[0094] Two layers of the aforementioned sacrificial composite material were wrapped around the fabric-frame assembly so that the edge of the sacrificial composite aligned with the frame base 140 and covered the sewing cuff 1 16, as shown in FIG. 6F.

[0095] Twenty-seven (27) additional layers of the ePTFE/fluoroelastomer composite material 193 were wrapped around the assembly mandrel 168, completely covering all the previously applied components as shown in FIG. 6F.

[0096] Two layers of the aforementioned sacrificial composite material were wrapped around the assembly mandrel 168 and previously applied components. Adhesive-backed polyimide tape was used to attach the ePTFE/polyimide composite to the assembly mandrel 168 at each end and to seal the longitudinal seam.

[0097] The assembly mandrel 168 with previously applied components was then placed in a pressure vessel and pressurized as described above with the exceptions that the time and temperature were about 24 minutes and 262°C, respectively. This resulting frame assembly 1 20 with the sewing cuff 1 16 that is now integral to the frame assembly 120 was allowed to cool to room temperature, removed from the pressure vessel and slid off of the assembly mandrel 168, as shown in FIG. 6F.

[0098] The ePTFE/fluoroelastomer composite material was trimmed at the base of the valve frame, revealing the sewing cuff 1 16 that is still un-imbibed with elastomer.

[0099] In subsequent steps, leaflets were attached to the leaflet windows. Testing Methods

[00100] It should be understood that although certain methods and equipment are described below, any method or equipment determined suitable by one of ordinary skill in the art may be alternatively utilized.

Mass, Thickness, and Density of ePTFE Membranes

[00101 ] Membrane samples were die cut to form rectangular sections about 2.54 cm by about 15.24 cm to measure the weight (using a Mettler-Toledo analytical balance model AG204) and thickness (using a Kafer Fz1000/30 snap gauge). Using these data, density was calculated with the following formula: p = m/(w t), in which: p = density (g/cm3), m = mass (g), w = width (cm), I = length (cm), and t = thickness (cm). The average of three measurements was reported.

Matrix Tensile Strength (MTS) of ePTFE Membranes

[00102] Tensile break load was measured using an INSTRON 122 tensile test machine equipped with flat-faced grips and a 0.445 kN load cell. The gauge length was about 5.08 cm and the cross-head speed was about 50.8 cm/min. The sample dimensions were about 2.54 cm by about 15.24 cm. For highest strength

measurements, the longer dimension of the sample was oriented in the highest strength direction. For the orthogonal MTS measurements, the larger dimension of the sample was oriented perpendicular to the highest strength direction. Each sample was weighed using a Mettler Toledo Scale Model AG204, then the thickness was measured using the Kafer FZ1000/30 snap gauge; alternatively, any suitable means for measuring thickness may be used. The samples were then tested individually on the tensile tester. Three different sections of each sample were measured. The average of the three maximum loads (i.e., peak force) measurements was reported. The longitudinal and transverse matrix tensile strengths (MTS) were calculated using the following equation: MTS= (maximum load/cross-section area) ^* (bulk density of PTFE)/ (density of the porous membrane), where the bulk density of the PTFE was taken to be about 2.2 g/cm ³ . The porosity of the specimen is accounted for by multiplying the tensile strength by the ratio of density of the polymer to the density of the specimen.

Bubble Point and Mean Flow Pore Size

[00103] Bubble point and mean flow pore size were measured according to the general teachings of ASTM F31 6-03 using a capillary flow Porometer, Model CFP 1500AEXL from Porous Materials, Inc., Ithaca NY, USA. The sample

membrane was placed into the sample chamber and wet with SilWick Silicone Fluid (available from Porous Materials Inc.) having a surface tension of about 20.1 dynes/cm. The bottom clamp of the sample chamber had an about 2.54 cm diameter hole. Using the Capwin software version 7.73.012 the following parameters were set as specified in the table below.

Parameter Set Point

Maxflow (cm ³ /m) 200000

Bublflow(cm ³ /m) 100

F/PT (old bubltime) 50

Minbpress (PSI) 0

Zerotime (seconds) 1

V2incr(cts) 10

Preginc (cts) 1

Pulse delay(seconds) 2

Maxpre (PSI) 500

Pulse width (seconds) 0.2

Mineqtime (seconds) 30

Presslew (cts) 10

Flowslew (cts) 50

Eqiter 3

Aveiter 20

Maxpdif (PSI) 0.1

Maxfdif (PSI) 50

Sartp(PSI) 1

Sartf (cm ³ /m) 500

[00104] It will be apparent to those skilled in the art that various modifications and variations can be made in the present embodiments without departing from the spirit or scope of the embodiments. Thus, it is intended that the present

embodiments cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.