US20150122687A1 - Bioprosthetic heart valves having adaptive seals to minimize paravalvular leakage - Google Patents

Abstract

A packaged bioprosthetic heart valve comprising a bioprosthetic heart valve, an adaptive seal and a package. The bioprosthetic heart valve comprises an at least partially dehydrated biological tissue leaflet structure coupled to a supporting frame. The bioprosthetic heart valve has a periphery, an inflow portion, and an outflow portion. The adaptive seal is coupled to the bioprosthetic heart valve around at least a portion of the periphery. The adaptive seal comprises an expandable material that expands after exposure to an initiating condition. The bioprosthetic heart valve and the adaptive seal is stored and contained within the package, which does not contain a liquid storage solution in contact with the bioprosthetic heart valve and the adaptive seal.

Description

CROSS-REFERENCE TO RELATED APPLICATION
• This application claims the benefit of U.S. Patent Application No. 61/900,827, filed Nov. 6, 2013, the entire disclosure of which is incorporated by reference.
FIELD OF THE INVENTION
• The invention relates to a heart valve prosthesis and, more particularly, to a heart valve prosthesis having an adaptive seal that minimizes perivalvular leakage following implantation.
BACKGROUND
• Perivalvular leakage (PVL) is a complication that is related to the replacement of heart valves. It occurs when blood flows through a channel or gap between the structure of an implanted valve and the cardiac or arterial tissue due to a lack of appropriate sealing.
• Intimate apposition of replacement heart valves and the surrounding cardiac or arterial walls seals the valve and minimizes PVL. In certain cases, however, a seal cannot be achieved, leaving irregular gaps of different sizes and shapes between the valve and the cardiac or arterial walls. This may result from inadequate sizing, incomplete expansion of the valve, an irregularly deformed valve, or highly eccentric or irregular calcification pattern on the leaflets or valve annulus.
• PVL has been shown to greatly affect the clinical outcome of transcatheter aortic valve replacement procedures, and the severity of perivalvular leakage has been correlated with patient mortality. What is therefore needed is a replacement bioprosthetic heart valve which permits a conforming engagement or fit with the surrounding cardiac or arterial wall so as to substantially fill in the gaps or channels that often result in PVL.
BRIEF SUMMARY
• Bioprosthetic heart valves having the adaptive seals described herein are preferably valves which comprise a biological tissue that has been treated so as to not require storage in liquid preservative solutions. While mechanical heart valves are capable of being stored in a dry state, valves having biological tissue typically require storage in liquid preservative solutions. Storage in liquid preservative solutions introduces a host of challenges for valves which include adaptive seals, particularly for those which are activated to expand upon exposure to liquid.
• Significant advantages are provided by the bioprosthetic heart valves disclosed herein, in which the biological tissue is treated so as to permit dry storage of the valves without a liquid storage solution. The adaptive seals can be exposed on the heart valve without requiring encapsulation or a barrier from the environment, as would be required if the valves were to be stored in a liquid preservation solution. To that end, the adaptive seals can simply comprise the expandable material exposed or contained within a permeable or semi-permeable material that permits fluid to come into contact with the expandable material, while supporting or containing the expandable material. In a preferred embodiment, the replacement heart valve or the adaptive seal is not selectively encapsulated by a non-permeable barrier.
• The simplicity of being able to provide an adaptive seal structure, without selective encapsulation, provides significant advantages over prior art heart valves in which the selective encapsulation of the adaptive seal in a liquid storage solution is a necessity. The selective encapsulation methods of the prior art are required to permit the tissue portion of the valve to be in contact with the liquid storage solution while at the same time segregating the adaptive seal portion from the liquid storage solution. If the adaptive seal is not selectively encapsulated from the liquid storage solution, it will expand and render the heart valve unusable.
• The bioprosthetic heart valves contemplated within this disclosure can be any implantable heart valve which preferably comprises a biological tissue. Such valves include transcatheter valves, surgical valves, minimally-invasive valves, and the like. The biological tissue can be derived from animal sources, preferably, from pericardial tissue, and most preferably, from bovine pericardial tissue. The biological tissue is used to form the leaflets of the heart valve and is mounted to a supporting frame or stent to form a bioprosthetic heart valve. Because the valves are stored dry, the biological tissues are treated so as to preserve their pliability and flexibility in a dry state, e.g., without storage in a liquid storage solution.
• The terms “dry” or “dehydrated”, as used herein, are understood to include residual moisture or humidity from the ambient environment and is intended to mean that the valves are not immersed in, or in contact with, a liquid or a storage solution.
• In one embodiment, a method for manufacturing a bioprosthetic heart valve is described. The method comprises providing a bioprosthetic heart valve comprising a biological tissue that has been treated with a treatment solution comprising a polyhydric alcohol, the bioprosthetic heart valve having a periphery, an inflow portion and an outflow portion. The method further comprises coupling an adaptive seal to the bioprosthetic heart valve, the adaptive seal comprising an expandable material that expands after exposure to an initiating condition. The method further comprises packaging the bioprosthetic heart valve and the coupled adaptive seal in a package that does not contain a liquid storage solution in contact with the bioprosthetic heart valve and the coupled adaptive seal. In a preferred embodiment, the adaptive seal is not further encapsulated, segregated or enclosed from the biological tissue.
• In accordance with a first aspect of the embodiment, the polyhydric alcohol is glycerol.
• In accordance with a second aspect of the embodiment, the biological tissue is at least partially dehydrated following treatment with the treatment solution.
• In accordance with a third aspect of the embodiment, the adaptive seal is a hydrophilic polymer or a hydrogel-coated wire.
• In accordance with a fourth aspect of the embodiment, the hydrophilic polymer or the hydrogel-coated wire comprises a biodegradable cross-linker. Expansion of the adaptive seal is delayed for a period of time after exposure to the initiating condition.
• In accordance with a fifth aspect of the embodiment, the initiating condition is one or more selected from the group consisting of: a change in temperature, a change in the electrical field, a change in the magnetic field, a change in the chemical environment, a change in pH, and contact with a liquid.
• In accordance with a sixth aspect of the embodiment, the expandable material expands longitudinally, radially, or both longitudinally and radially relative to the bioprosthetic heart valve after exposure to the initiating condition.
• In accordance with a seventh aspect of the embodiment, the bioprosthetic heart valve comprises a stent and the coupling comprises coating the stent with the adaptive seal or coupling patches within open cells defined by the stent.
• In another embodiment, a packaged bioprosthetic heart valve is provided. The packaged bioprosthetic heart valve comprises a bioprosthetic heart valve, an adaptive seal coupled to the bioprosthetic heart valve, and a sealed package containing the bioprosthetic heart valve and the adaptive seal. The bioprosthetic heart valve comprises a dehydrated biological tissue leaflet structure coupled to a supporting frame, the bioprosthetic heart valve having a periphery, an inflow portion, and an outflow portion. The adaptive seal comprises an expandable material that expands after exposure to an initiating condition. The sealed package containing the bioprosthetic heart valve and the adaptive seal does not contain a liquid storage solution in contact with the bioprosthetic heart valve and the adaptive seal.
• In accordance with a first aspect of the embodiment, the adaptive seal is a hydrophilic polymer or a hydrogel-coated wire.
• In accordance with a second aspect of the embodiment, the adaptive seal is a hydrogel comprising a biodegradable cross-linker and expansion of the adaptive seal is delayed for a period of time after exposure to the initiating condition.
• In accordance with a third aspect of the embodiment, the adaptive seal is a hydrogel-coated wire comprising a shape memory metal, the hydrogel-coated wire changing from a first configuration to a second configuration upon reaching or exceeding a transformation temperature.
• In accordance with a fourth aspect of the embodiment, in the first configuration, the hydrogel-coated wire has one of a straight or a coiled configuration and in the second configuration, the hydrogel-coated wire has the other of the straight or coiled configuration.
• In accordance with a fifth aspect of the embodiment, the adaptive seal is coupled to the bioprosthetic heart valve at a spaced distance from both of the inflow and outflow portions.
• In accordance with a sixth aspect of the embodiment, the adaptive seal is provided circumferentially about the bioprosthetic heart valve.
• In accordance with a seventh aspect of the embodiment, the bioprosthetic heart valve further comprises a sewing ring and the adaptive seal is coupled to and exposed from the sewing ring or contained within the sewing ring.
• In accordance with an eighth aspect of the embodiment, the supporting frame is a stent comprising a plurality of struts and open cells.
• In accordance with a ninth aspect of the embodiment, the adaptive seal is coupled to one or more struts of the supporting frame.
• In accordance with a tenth aspect of the embodiment, the adaptive seal forms one of a coating on at least a portion of the stent.
• In accordance with an eleventh aspect of the embodiment, the adaptive seal is provided as patches disposed within the open cells defined by the stent.
• Other objects, features and advantages of the described preferred embodiments will become apparent to those skilled in the art from the following detailed description. It is to be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
BRIEF DESCRIPTION OF THE DRAWINGS
• Illustrative embodiments of the present disclosure are described herein with reference to the accompanying drawings, in which:
• FIG. 1A is a side view of an embodiment of an implanted bioprosthetic heart valve with an adaptive seal in a substantially unexpanded state. The arterial walls are cut away to show the gaps between the implanted bioprosthetic heart valve and the arterial walls.
• FIG. 1B is a plan view of the outflow portion of the implanted bioprosthetic heart valve ofFIG. 1A showing the adaptive seal in a substantially unexpanded state within the arterial walls.
• FIG. 2A is a side view of the implanted bioprosthetic heart valve with the adaptive seal in a substantially expanded state. The arterial walls are cut away to show the adaptive seal expanded to fill at least some of the gaps between the implanted bioprosthetic heart valve and the arterial wall.
• FIG. 2B is a plan view of the outflow portion of the implanted bioprosthetic heart valve showing the adaptive seal in a substantially expanded state, with the arterial walls cut away to reveal the implanted bioprosthetic heart valve.
• FIG. 3A is a perspective view of the outflow portion of another embodiment of a bioprosthetic heart valve with the adaptive seal located about the periphery of the sewing ring.
• FIG. 3B is a perspective view of the inflow portion of the bioprosthetic heart valve ofFIG. 3A.
• FIGS. 4A-4B are perspective views of an embodiment of a bioprosthetic heart valve in a collapsed and an expanded state, respectively.
• FIGS. 4C-4D are perspective views of another embodiment of a bioprosthetic heart valve in a collapsed and an expanded state, respectively.
• FIGS. 4E-4F are perspective views of a further embodiment of a bioprosthetic heart valve in a collapsed and an expanded state, respectively.
• FIG. 5A is an exploded perspective view of a further embodiment of a bioprosthetic heart valve showing the tissue valve portion and the stented sealing cloth.
• FIG. 5B is a perspective view of the bioprosthetic heart valve ofFIG. 5A in which the tissue valve portion and the stented sealing cloth are assembled together.
• FIGS. 6A-6C are broken plan views of an embodiment of an expandable bioprosthetic heart valve and its delivery system in the various stages from a collapsed delivery configuration with the adaptive seal being adjacent the delivery system (FIG. 6A), an intermediate configuration with the adaptive seal is positioned around the bioprosthetic heart valve (FIG. 6B) and an expanded configuration, ready for full expansion of the adaptive seal (FIG. 6C).
• FIGS. 7A-7C are broken plan views of another embodiment of an expandable bioprosthetic heart valve and its delivery system in the various stages from a collapsed delivery configuration with the adaptive seal being adjacent the delivery system (FIG. 7A), an intermediate configuration with the adaptive seal is positioned around the bioprosthetic heart valve (FIG. 7B) and an expanded configuration, ready for full expansion of the adaptive seal (FIG. 7C).
• FIGS. 8A-8C are broken plan views of an expandable bioprosthetic heart valve and its delivery system in the various stages from a collapsed delivery configuration with the adaptive seal being adjacent the delivery system (FIG. 8A), an intermediate configuration with the adaptive seal is positioned around the bioprosthetic heart valve (FIG. 8B) and an expanded configuration, ready for full expansion of the adaptive seal (FIG. 8C).
• Like numerals refer to like parts throughout the several views of the drawings.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
• Specific, non-limiting embodiments of the present invention will now be described with reference to the drawings. It should be understood that such embodiments are by way of example only and merely illustrative of but a small number of embodiments within the scope of the present invention. Various changes and modifications obvious to one skilled in the art to which the present invention pertains are deemed to be within the spirit, scope and contemplation of the present invention as further defined in the appended claims.
• FIGS. 1A and 1B depict atranscatheter heart valve100 that has been expanded and implanted within anarterial wall1. Thetranscatheter heart valve100 generally comprises a biologicaltissue leaflet structure110 that is coupled to an expandable frame orstent120. It is understood that thestent120 can either be self-expanding or balloon-expandable. Theheart valve100 further comprises aninflow portion102, anoutflow portion104 and askirt125 that is coupled to thestent120, preferably by sutures, and located proximate theinflow portion102.
• The external peripheral surface of theheart valve100 is shown to be in discontinuous engagement with the inner surface of thearterial wall1 as shown by the gaps orvoids2 between them. These gaps result because the inner surface of thearterial wall1 is typically an irregular surface. To provide a conforming fit or engagement between theheart valve100 and the inner surface of thearterial wall1, anadaptive seal130 is provided around the external peripheral surface of theheart valve100. Theadaptive seal130 preferably comprises an expandable or swellable material, such as hydrogels (e.g., zwitterionic hydrogels), super absorbent polymers (SAPs), elastomeric materials or other swellable or absorbent polymer or elastomeric materials. Preferably, theadaptive seal130 does not comprise silicone or other lubricious materials or polymers that would potentially cause the implantedvalve100 to slip or dislodge from its initial site of implantation.
• Theadaptive seal130 can be coupled to the outer periphery of thestent120, as shown inFIGS. 1A and 1B, by adhesives or by one or more sutures. As can be seen inFIGS. 1-2, thestent120 further defines a plurality of open spaces or cells. Thus, theadaptive seal130 can also be provided as a plurality of discrete patches that can be disposed within selected ones of the plurality of open spaces or cells defined by thestent120.
• As shown inFIGS. 1A and 1B, theadaptive seal130 has a substantially unexpanded length (A1-A1,FIG. 1A) and a substantially unexpanded radial thickness (B1-B1,FIG. 1B) upon initial implantation. Because theadaptive seal130 will expand both along its length and radial thickness, it is preferably positioned around theheart valve100 at a sufficient distance away from both theinflow portion102 andoutflow portion104 such that the fully expandedadaptive seal130 does not extend beyond thestent120. In addition, theadaptive seal130 is constructed such that inward radial expansion into the lumen of the heart valve is limited, if not prevented. Thus, expansion of theadaptive seal130 is preferably limited to the area between the outer periphery of thestent120 and thearterial wall1.
• FIGS. 2A and 2B depict thetranscatheter heart valve100 ofFIGS. 1A and 1B in which theadaptive seal130 has expanded after exposure to an initiating condition. Expansion of theadaptive seal130 takes place in a conforming, non-rigid manner and theadaptive seal130 preferably expands in directions of least resistance, e.g., into the spaces orgaps2 between thestent120 and thearterial wall1. In other words, the expansion of theadaptive seal130 takes place to a greater degree in areas where there are larger gaps between thestent120 and thearterial wall1 and to a lesser degree in areas where thegaps2 are smaller. Theadaptive seal130 preferably expands along one or both of its longitudinal length (A2-A2,FIG. 2A) and its radial thickness (B2-B2,FIG. 2B). In the embodiment depicted herein, theadaptive seal130 is shown to have not expanded radially inward from thestent120 and thus will not interfere with the blood flow through thevalve100.
• In a preferred embodiment, theadaptive seal130 comprises a hydrogel material. The hydrogel can be provided as a colloidal gel, such as a hydrocolloid, a coating, a film, or a foam, or it can be provided on a substrate, such as on a cloth or about a shape memory metal or metal coil. While the embodiments depicted inFIGS. 1A and 1B depict theadaptive seal130 as a strip of material that is affixed to the outer periphery of thestent120, it is understood that thestent120 can be directly coated with a hydrogel material. Thus, in one preferred embodiment, thestent120 is coated or dipped in a hydrogel solution, then allowed to dry before it is coupled to the biological tissue to form a heart valve.
• In a preferred embodiment, theadaptive seal130 comprises a substrate and an expandable material, such as hydrogels, such as zwitterionic hydrogels, SAPs, elastomeric materials or other swellable or absorbent polymer or elastomeric material disposed on the substrate. The substrate can be an impermeable material, such as a film (e.g., a MYLAR® polyester film), or it can be permeable material, such as a densely-woven cloth. In either case, the substrate is expandable, elastically or otherwise, such that it can be wrapped around the external periphery of the heart valve in a collapsed state and expand as the heart valve is deployed to an expanded state. In embodiments where the hydrogel material is disposed on an inelastic material, such as a metal film or coil, the inelastic material assumes a particular geometry (e.g., folded, coiled, etc.) that permits expansion.
• Additionally, the substrate is preferably positioned outwardly of thestent120 and between thestent120 and the hydrogel material. In the embodiment depicted inFIGS. 1A-1B and2A-2B, the main function of the substrate is to prevent the hydrogel material from expanding radially inward and thus to limit the expansion of the hydrogel material in a radially outward direction along B2-B2 as depicted inFIG. 2B. Thus, in embodiments where a densely-woven cloth is used, it is preferred that the densely-woven cloth, when stretched around the circumference of a fully-expanded valve, does not permit the hydrogel material to migrate through the cloth and into the internal lumen of thestent120. In a preferred embodiment in which theadaptive seal130 is provided on a substrate, theadaptive seal130 preferably expands only radially outwardly of theheart valve100.
• A hydrogel is generally understood to refer to a polymer or other material that expands or swells in response to an initiating condition, such as changes in temperature, electrical field, magnetic field, chemical environment, pH, and/or phase changes, for example, contact with a liquid. In a preferred embodiment, the adaptive seal does not comprise, or is not, a silicone polymer or other lubricous material. One type of hydrogel is a hydrophilic polymer which physically expands or swells when it contacts and absorbs a liquid, such as water. The extent of the physical expansion or swelling by a hydrophilic polymer is typically limited by the covalent or physical cross-links that oppose the absorption of water once the hydrogel reaches an equilibrium swelling state. Thus, the extent of expansion may be designed or tuned to preferred dimensions based on chemically modifying these crosslinkages. Hydrophilic polymers are highly absorbent and possess a degree of flexibility that is very similar to natural tissue due to their substantial water content.
• Examples of hydrophilic polymers, e.g., hydrogels, include, but are not limited to, poly(ethylene oxide), poly(hydroxyethyl methacrylate), poly(vinyl alcohol), polyacrylamide, poly(vinylpyrrolidone), poly(ethyloxazoline), poly(propylene oxide), poly(ethylene glycol)poloxamines, polyacrylamide, hydroxypropylmethacrylate (HPMA), poly(ethylene glycol), polymethacrylate, poly(methyl methacrylate)polylactic acid, carboxymethyl cellulose, hydroxyethyl cellulose, methylhydroxypropyl cellulose, polysucrose, hyaluronate, chondroitin sulfate, dextran, alginate, chitosan, gelatin, and derivatives, mixtures, and copolymers thereof.
• Hydrogels can be sensitive to stimuli and respond to changes in the surrounding environment, e.g., an initiating condition, such as changes in temperature, electrical field, magnetic field, chemical environment, pH, and/or phase changes, for example, contact with a liquid. The hydrogels contemplated for use in connection with bioprosthetic heart valves, as described herein, are initially provided in the contracted state and expand or swell only after exposure to an initiating condition. The rate and extent of swelling of the hydrogel can be configured by chemically modifying the hydrogel. For example, where it is desired to control or delay the start or the rate of swelling or expansion of the hydrogel upon exposure to the initiating condition, the hydrogel can be crosslinked with cross-linkers that degrade in response to being exposed to the same or a different initiating condition that causes the hydrogel to expand or swell.
• Thus, in a preferred embodiment the rate and extent of expansion of the hydrogel is controlled and fine-tuned by chemically modifying the hydrogel or by incorporating degradable cross-linkers. In a preferred embodiment, the adaptive seal is or comprises a delayed-swelling hydrogel which will not expand for a period of time after exposure to an initiating condition. This period of time is preferably at least 1 minute, more preferably at least 2 minutes, and most preferably at least 5 minutes. The delayed-swelling hydrogel can be produced by incorporating biodegradable cross-linkers in the hydrogel polymer to generate a delayed swelling hydrogel. Once the hydrogel is exposed to an initiating condition, the biodegradable cross-linkers can degrade at a desired rate to permit swelling at a corresponding rate after an initial exposure to the initiating condition. The cross-linkers can be selected to slowly degrade upon exposure to a physiological fluid, such as blood. As the cross-linkers degrade, the hydrogel will expand and swell.
• While the rate of hydrogel expansion can be controlled, it is understood that the hydrogel preferably reaches its full expansion, e.g., an equilibrium state, within a period of time to permit the implanting physician to confirm the absence of PVL of the implanted heart valve. In a preferred embodiment, the adaptive seal reaches its full expansion within 5 hours of implantation, preferably within 1 hour of implantation, and most preferably within 15 minutes of implantation. Thus, the biodegradable cross-linkers of the hydrogel are preferably completely degraded or severed within 5 hours, preferably within 1 hour, and most preferably within 15 minutes of exposure to the initiating condition.
• FIGS. 3A and 3B depict asurgical heart valve200 comprising a biologicaltissue leaflet structure210 comprising three flexible leaflets and aframe220 comprising three commissure posts. Asewing ring225 defines the inflow portion of thevalve200 and is used to attach thevalve200 to the valve annulus. Thesewing ring225 can be circular or scalloped. Thesewing ring225 defines a suture-permeable cuff made of an inner body of silicone covered with a permeable or semi-permeable material or fabric.
• In the embodiment depicted inFIGS. 3A and 3B, theadaptive seal230 is preferably a hydrogel which is exposed and coupled externally about the circumferential edge of thesewing ring225 to provide conforming engagement between thesewing ring225 and the inner surface of the annulus where the valve is implanted (not shown). Theadaptive seal230 can also be provided inside thesewing ring225, with a permeable or semi-permeable fabric covering being made of a material having sufficient elasticity to permit swelling and expansion of theadaptive seal230 within thesewing ring225. Alternatively, theadaptive seal230 can also be provided as a hydrogel coating on thesewing ring225 as a result of dipping the material or fabric constituting the sewing ring into a hydrogel solution. In the embodiment depicted inFIGS. 3A and 3B, theadaptive seal230 comprises a hydrogel material that is disposed on a wire that is wrapped around thesewing ring225 and preferably secured onto the sewing ring by adhesives or by sutures. Because thevalve200 is surgically implanted and does not require thevalve200 to be crimped or collapsed, the substrate for the hydrogel material is not required to be expandable or elastic.
• FIGS. 4A and 4B depict an embodiment of atranscatheter heart valve300 which comprises anadaptive seal330aof a different configuration from the one depicted inFIGS. 1-2. Theheart valve300 comprises abiological tissue leaflet310 attached to astent320. Theheart valve300 is further depicted as comprising a hydrogel-coatedwire330asurrounding the periphery of thestent320. The hydrogel-coatedwire330a, by virtue of its geometry, comprising a plurality of loops, will permit expansion of theheart valve300 for implantation. One or more hydro-gel coated wires can be used on the valve.
• The hydrogel-coatedwire330ais formed as a plurality of loops. When theheart valve300 is in its compressed or unexpanded configuration, as depicted inFIG. 4A, the hydrogel-coatedwire330acomprises a plurality of larger loops. When theheart valve300 is in its expanded configuration, as depicted inFIG. 4B, the loops reduce in size significantly. The presence of the loops provides a degree of flexibility for radial expansion of theheart valve300.
• Suitable hydrogel-coated wires include Azur Peripheral HYDROCOIL® (MicroVention Terumo, Inc., Aliso Viejo, Calif.), which is a platinum coil with an expandable poly(acrylamide-co-acrylic acid) hydrogel and overcoiled with a stretched platinum coil. An advantage of using the hydrogel-coatedwire330ais that it stays substantially close to thestent320 in both the expanded and the compressed states such that it does not significantly add material bulk. This permits the fabrication of transcatheter heart valves having substantially narrower delivery profiles than would be expected when such valves include a PVL skirt, for example.
• In a preferred embodiment, at least one end of the hydrogel-coated wires is attached to thestent320 by crimping. In another preferred embodiment, the hydrogel-coated wires are crimped in one, two, three, or four locations along thestent320. As depicted inFIGS. 4A and 4B, the hydrogel-coatedwire330ais positioned around the entire circumference of the heart valve at a distance from both theinflow end302 and theoutflow end304. In a preferred embodiment, the hydrogel-coatedwire330aundergoes limited expansion within the first 3 minutes, and fully expands within 20 minutes.
• WhileFIGS. 4A and 4B depict theadaptive seal330ataking the form of a hydrogel-coated wire, it is understood that theadaptive seal330acan also be provided as a hydrogel coating on thestent320. In accordance with one aspect of this embodiment, thestent320 can be dipped in or spray coated with a hydrogel solution and allowed to dry prior to assembling thestent320 with thetissue leaflet310.
• FIGS. 4C and 4D depict theheart valve300 in which the hydrogel-coatedwire330bis provided in two different configurations. When thevalve300 is in a compressed state, as depicted inFIG. 4C, the hydrogel-coatedwire330bis provided in a first configuration, in which the hydrogel-coatedwire330bis tightly coiled. When the valve is in an expanded state, as depicted inFIG. 4D, the hydrogel-coatedwire330bis provided in a second configuration, in which the hydrogel-coatedwire330bis substantially straight. The hydrogel-coatedwire330bcan comprise a shape memory metal, such as Nitinol, such that it takes on the substantially straight configuration upon being heated to a particular temperature, preferably in the range of about 24-37° C. The temperature at which a shape memory metal, such as Nitinol, will change configurations can be fine-tuned by altering the profile of the shape memory metal. Alternatively, the hydrogel-coatedwire330bcan be a non-metal wire that is elastically stretchable between the first and second configurations. It is understood that where an elastic wire is used, the elastic wire does not cause significant compression of thestent320 in an expanded state.
• FIGS. 4E and 4F depict theheart valve300 in which the hydrogel-coatedwire330cis provided as a straight wire that encircles or is coiled around the outer external periphery of theheart valve300. In the preferred embodiment depicted inFIGS. 4E and 4F, the hydrogel-coatedwire330chas a length that permits it to be coiled around the entire outer circumference of the compressed valve (FIG. 4E) more than once. Preferably, only one end of the hydrogel-coatedwire330cis affixed to thestent320 by crimping. The other free end of the hydrogel-coatedwire330cis permitted to move in relation to thevalve300 as it is expanded to the fully-expanded state (FIG. 4F). In a preferred embodiment, the hydrogel-coatedwire330chas a length that permits it to be coiled around the heart valve in its fully-expanded state at least once, if not twice. One advantage provided by the hydrogel-coatedwire330cinFIGS. 4E-4F is that it will add, to a lesser event, to the delivery profile of thecompressed heart valve300.
• FIGS. 5A and 5B depict an embodiment of areplacement heart valve400 which can be implanted using minimally-invasive techniques. Theheart valve400 comprises abiological tissue410 coupled to a supportingframe420 comprising three commissure posts, asewing ring425 and aframe stent430 comprising a cloth covered anchoring frame. Theframe stent430 can be balloon expanded after implantation and is characterized as providing a greater area of engagement between theheart valve400 and the arterial or cardiac walls. Theframe stent430 therefore is believed to reduce the incidence of PVL of the implantedheart valve400. In a preferred embodiment, theframe stent430 or the cloth material constituting theframe stent430 can be coated with the adaptive seal or hydrogel material. In another preferred embodiment, the adaptive seal or hydrogel material can be contained within the cloth material of theframe stent430.
• One advantage afforded by thereplacement heart valve400 is that the manufacturing of the valve portion consisting of thebiological tissue410, the supportingframe420 and thesewing ring425 can be done separately from the manufacture of the cloth-coveredframe stent430 to constitute the adaptive seal. In the embodiment depicted inFIGS. 5A and 5B, the cloth coveredframe stent430 is dipped in or sprayed with a hydrogel solution prior to assembly with the valve portion. Alternatively, the hydrogel material can be provided within the cloth coveredframe stent430, provided that the cloth is sufficiently elastic to permit expansion by the hydrogel material contained therein. Once the valve portion and theframe stent430 are separately prepared, the two can be assembled together.
• FIGS. 6A-6C depict an expandablebioprosthetic heart valve600 and itsdelivery system602 in the various stages from a collapsed delivery configuration with theadaptive seal610 being adjacent the delivery system, as depicted inFIG. 6A, an intermediate configuration with theadaptive seal610 is positioned around thebioprosthetic heart valve600, as depicted inFIG. 6B, and an expanded configuration, in which theheart valve600 is fully expanded and theadaptive seal610 being disposed around theheart valve600, as depicted inFIG. 6C. In a preferred embodiment, theadaptive seal610 depicted inFIGS. 6A through 6C is a hydrogel-coated wire.
• Expandable bioprosthetic heart valves are known in the art and the illustratedheart valve600 illustrated inFIGS. 6A through 6C is representative of a number of such valves which can be converted from a narrow constructed configuration to a wider expanded configuration. Typically, the valves are balloon expanded into position at a target annulus after having been advanced through the vasculature, although self-expanding valves are also known. The most common delivery routes commence at the femoral or carotid arteries, though other more direct routes through chest ports are also known. One such expandable prosthetic heart valve is the Edwards SAPIEN® or SAPIEN XT® Transcatheter Heart Valve available from Edwards Lifesciences of Irvine, Calif. The Edwards SAPIEN® valve can be placed either through a transfemoral or transapical approach.
• Thedelivery system602 includes anelongated catheter604 having anexpansion balloon646 near a distal end thereof. Thebioprosthetic heart valve600 mounts around theballoon646 and is expanded thereby. The system further includesproximal connectors608 for delivery of balloon inflation fluid, passage of a guide wire, or other such functions. In the exemplary embodiment, thebioprosthetic heart valve600 includes a plurality of balloon expandable struts in between three axially-oriented commissure bars605. Bioprosthetic tissue mounts within the framework created by the struts and bars605, such as with supplementary fabric.
• In most cases, it is desirable to reduce the delivery profile of the collapsed delivery configuration as depicted inFIG. 6A. One way of achieving a reduced delivery profile is to provide theadaptive seal610 such that it does not initially encircle or wrap the collapsedbioprosthetic heart valve600 but instead is allowed to trail along the elongated catheter in a first delivery configuration. In a preferred embodiment, the collapsed delivery configuration depicted inFIG. 6A is provided within a sheath (not shown). Reducing the delivery profile of the collapsed delivery configuration will permit a reduced French size for the corresponding sheath.
• As the delivery system is inserted into the vasculature of the patient's body, both thebioprosthetic heart valve600 and theadaptive seal610 will be exposed to blood and other bodily fluids. As explained above, it is undesirable for theadaptive seal610 to swell or expand substantially, if at all, immediately upon exposure to blood because such expansion will interfere with the ability to deliver thebioprosthetic heart valve600 through the patient's vasculature and to advance thevalve600 out of the delivery sheath. Thus, in a preferred embodiment, theadaptive seal610 is chemically tuned such that it will respond to one or a plurality of initiating conditions, such as, for example, exposure to liquid and an additional condition, such as pH, temperature, a change in the electrical or magnetic field, or a change in the chemical environment, after a predetermined period of time of such exposure. In another embodiment, theadaptive seal610 will include a biodegradable cross-linker which degrades at a predetermined rate upon exposure to an initiating condition.
• Once thebioprosthetic heart valve600 is delivered proximate to the intended site of implantation, the sheath is removed. Upon removal of the sheath and before significant expansion of theheart valve600, theadaptive seal610 coils or wraps around the external periphery of theheart valve600 in a second configuration. Theadaptive seal610 can be comprised of a hydrogel material disposed on either a shape memory metal or other material that is configured to elastically wrap around theheart valve600 once it is exposed from the sheath. In a preferred embodiment, the length of theadaptive seal610 is longer than the circumference of the fully-expandedvalve600 such that a portion of theadaptive seal610 overlaps. In this manner, gaps between the two ends of theadaptive seal610 can be avoided.
• As indicated above, theadaptive seal610 preferably comprises a shape-memory material or metal, such as Nitinol, which is coated with a hydrogel and which is configured to coil around the outer circumference of thevalve600 based reaching or exceeding a transformation temperature. In a preferred embodiment, the transformation temperature is between about 24-25° C., about 25-26° C., about 26-27° C., about 27-28° C., about 28-29° C., about 29-30° C., about 30-31° C., about 31-32° C., about 32-33° C., about 33-34° C., about 34-35° C., about 35-36° C., and about 36-37° C. In embodiments where thevalve600 comprises a self-expanding stent made of shape-memory material or metal, the transformation temperature for the stent is higher than the transformation temperature for theadaptive seal610 so as to ensure that theadaptive seal610 coils around thevalve600 before thevalve600 begins to expand or is substantially or fully expanded.
• FIG. 6C depicts thebioprosthetic heart valve600 in a fully-expanded configuration with theadaptive seal610 being disposed around the circumference of thevalve600. In a particularly preferred embodiment, theadaptive seal610 does not swell or expand until after it assumes a fully expanded configuration as depicted inFIG. 6C.
• FIGS. 7A-7C depict the expandablebioprosthetic heart valve600 having a hydrogel-coatedwire610ataking on different configurations that similarly permit a smaller delivery profile. The hydrogel-coatedwire610ais provided in a first delivery configuration as a straight wire, as depicted inFIG. 7A. This permits the compressedbioprosthetic heart valve600 and itsdelivery system602 to fit within a sheath having a reduced delivery profile. Once the sheath (not shown) is removed, the hydrogel-coatedwire610atakes on a second configuration, in which it is both coiled and wrapped around the outer periphery of theheart valve600 at least two times (FIG. 7B), and a third configuration, in which the hydrogel-coatedwire610aremains in a coiled configuration but is wrapped around the outer periphery of theheart valve600 only once (FIG. 7C).
• FIGS. 8A-8C depict the expandablebioprosthetic heart valve600 having a hydrogel-coatedwire610btaking on another alternate configuration permitting a smaller delivery profile. The hydrogel-coatedwire610bis provided in a first delivery configuration as a straight wire, as depicted inFIG. 8A. This permits the compressedbioprosthetic heart valve600 and itsdelivery system602 to fit within a sheath having a reduced delivery profile. Once the sheath (not shown) is removed, the hydrogel-coatedwire610btakes on a second configuration, in which it is wrapped around the outer periphery of the heart valve600 (FIGS. 8B and 8C). Again, the length of the hydrogel-coatedwire610bis provided such that it encircles the external periphery of the compressed valve a plurality of times, preferably at least 2, 3, or 4 times (FIG. 8B). As the hydrogel-coatedwire610bis coupled to the stent at only one end, theheart valve600 is permitted to expand radially in its fully expanded state (FIG. 8C).
• With respect to the embodiments depicted inFIGS. 6-8, it is understood that theheart valve600 can be packaged in a collapsed delivery configuration with the adaptive seal being positioned adjacent thedelivery system602 as depicted inFIG. 6A,7A or8A. This allows theheart valve600 to be provided to the implanting physician in a substantially ready-to-use condition out of the package.
• As indicated above, the biological tissues suitable for the heart valves described herein are treated so as to permit storage without a liquid preservative solution, e.g., dry storage. To that end, the biological tissue can be contacted or immersed in a treatment solution comprising a polyhydric alcohol or polyol, preferably a glycerol. The glycerol can be provided in an aqueous, non-aqueous or a substantially non-aqueous solution. In a preferred embodiment, the non-aqueous solution (the solvent is not water) or the substantially non-aqueous solution is an alcoholic solution. In a preferred embodiment, the alcoholic solution comprises one or a combination of lower alcohols, preferably C₁-C₃alcohols. The biological tissue following treatment with the treatment solution is dehydrated or substantially dehydrated. In a preferred embodiment, the water content of the biological tissue following treatment with the treatment solution is reduced at least about 10%, preferably at least about 25%, preferably at least about 50%, preferably at least about 75%, preferably at least about 80%, and preferably at least about 90%.
• The time of contact between the biological tissue and the treatment solution depends on the thickness and type of tissue. Once the biological tissue has been sufficiently exposed to the treatment solution, the tissue is removed from the solution and exposed to ambient air or an inert environment (e.g., nitrogen), at standard room temperature and humidity so as not to adversely affect tissue properties. Preferably, the drying is performed in a clean room or in a laminar flow bench at ambient room conditions for about 1 to 4 hours. In a preferred embodiment, the treatment solution is a solution of glycerol and a C₁-C₃alcohol, wherein the treatment solution comprises about 60-95% by volume glycerol. Suitable treatment for the biological tissues are described in U.S. Pat. No. 8,007,992, issued Aug. 30, 2011, to Edwards Lifesciences Corp., the entire contents of which are incorporated herein by reference as if fully set forth herein. In another preferred embodiment, the tissue can be treated as described in U.S. Pat. No. 6,534,004, issued Mar. 18, 2003, issued to The Cleveland Clinic Foundation, the entire contents of which are incorporated herein by reference in its entirety as if fully set forth herein.
• In a preferred embodiment, the adaptive seal is made of a material that expands after exposure to one or more initiating conditions. The adaptive seal is preferably a hydrophilic polymer or a hydrogel-coated wire that is made up of a hydrogel material that expands or swells when exposed to an aqueous liquid, such as saline or blood. Preferably, the hydrogel material does not fully expand or swell until after a period of contact with the initiating condition (e.g., fluid), which provides physicians the ability to deliver and control the implantation of the device at the desired location. This can be accomplished by utilizing hydrogels or hydrogel-coated wires in which the hydrogel material has been cross-linked with a degradable cross-linker. Thus, the substantial expansion of the adaptive seal takes place after initial contact with the initiating condition. Alternatively, the seal can be made of a hydrogel that initially expands slowly and then expands more rapidly after a period of time has elapsed from exposure to the initiating condition. In a preferred embodiment, the rapid expansion of the adaptive seal occurs about 30 seconds, about 60 seconds, about 2 minutes, or about 5 minutes after exposure to the initiating condition. In embodiments where the initiating condition is exposure to fluid, preferably an aqueous fluid such as blood, the adaptive seal is provided in a substantially dehydrated state.
• The adaptive seal described herein can be provided in the form of a cloth, a film, a coating, a foam, or a hydrogel-coated wire and comprise an expandable material that impregnates a suitable substrate, is chemically coupled to a suitable substrate, or is contained within a permeable or semi-permeable barrier that permits the entry of fluid but contains the expandable material. The expandable material is preferably a hydrogel or an organic polymer that is cross-linked via covalent, ionic or hydrogen bonds to create a three-dimensional open lattice structure which entraps water molecules to form a gel. Alternatively, the adaptive seal is a hydrogel-coated wire, such as HYDROCOIL® (MicroVention Terumo, Inc., Aliso Viejo, Calif.), which is a platinum coil with an expandable poly(acrylamide-co-acrylic acid) hydrogel and overcoiled with a stretched platinum coil. When positioned in situ, the adaptive seal expands from its reduced radial profile to an increased radial profile. U.S. Patent Application Publication No. 2013/0190857, published Jul. 25, 2013, to Endoluminal Sciences Pty. Ltd. is incorporated herein by reference in its entirety.
• The bioprosthetic heart valve and adaptive seal can preferably be packaged in double sterile barrier packaging consisting of a rigid tray (PETG) with a TYVEK® non-woven polyolefin lid. The package is sealed in a cleanroom and sterilized in 100% ethylene oxide. Suitable packaging systems for the bioprosthetic heart valves disclosed herein are described in U.S. Patent Application Publication No. 2011/0214398, published Sep. 8, 2011, to Edwards Lifesciences Corp., and is incorporated herein by reference in its entirety. In embodiments where the bioprosthetic heart valve is provided along with a delivery device, suitable packaging systems are described in U.S. Patent Application Publication No. 2013/0152659, published Jun. 20, 2013; U.S. Patent Application Publication No. 2012/0158128, Jun. 21, 2012, and U.S. Patent Application Publication No. 2012/0239142, published Sep. 20, 2012, all to Edwards Lifesciences Corp, and all incorporated by reference herein in their entireties.
• The invention described and claimed herein is not to be limited in scope by the specific preferred embodiments disclosed herein, as these embodiments are intended as illustrations of several aspects of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims (20)

What is claimed is:

1. A method for manufacturing a bioprosthetic heart valve comprising:

providing a bioprosthetic heart valve comprising a biological tissue that has been treated with a treatment solution comprising a polyhydric alcohol, the bioprosthetic heart valve having a periphery, an inflow portion and an outflow portion;

coupling an adaptive seal to the bioprosthetic heart valve, the adaptive seal comprising an expandable material that expands after exposure to an initiating condition; and

packaging the bioprosthetic heart valve and the coupled adaptive seal in a package that does not contain a liquid storage solution in contact with the bioprosthetic heart valve and the coupled adaptive seal.

2. The method ofclaim 1, wherein the polyhydric alcohol is glycerol.

3. The method ofclaim 1, wherein the biological tissue is at least partially dehydrated following treatment with the treatment solution.

4. The method ofclaim 1, wherein the adaptive seal is a hydrophilic polymer or a hydrogel-coated wire.

5. The method ofclaim 4, wherein the hydrophilic polymer or the hydrogel-coated wire comprises a biodegradable cross-linker and wherein expansion of the adaptive seal is delayed for a period of time after exposure to the initiating condition.

6. The method ofclaim 1, wherein the initiating condition is one or more selected from the group consisting of: a change in temperature, a change in the electrical field, a change in the magnetic field, a change in the chemical environment, a change in pH, and contact with a liquid.

7. The method ofclaim 1, wherein the expandable material expands longitudinally, radially, or both longitudinally and radially relative to the bioprosthetic heart valve after exposure to the initiating condition.

8. The method ofclaim 1, wherein the bioprosthetic heart valve comprises a stent and wherein the coupling comprises coating the stent with the adaptive seal or coupling patches within open cells defined by the stent.

9. A packaged bioprosthetic heart valve comprising:

a bioprosthetic heart valve comprising a dehydrated biological tissue leaflet structure coupled to a supporting frame, the bioprosthetic heart valve having a periphery, an inflow portion, and an outflow portion;

an adaptive seal coupled to the bioprosthetic heart valve, the adaptive seal comprising an expandable material that expands after exposure to an initiating condition;

a sealed package containing the bioprosthetic heart valve and the adaptive seal, wherein the package does not contain a liquid storage solution in contact with the bioprosthetic heart valve and the adaptive seal.

10. The packaged bioprosthetic heart valve ofclaim 10, wherein the adaptive seal is a hydrophilic polymer or a hydrogel-coated wire.

11. The packaged bioprosthetic heart valve ofclaim 10, wherein the adaptive seal is a hydrogel comprising a biodegradable cross-linker and wherein expansion of the adaptive seal is delayed for a period of time after exposure to the initiating condition.

12. The packaged bioprosthetic heart valve ofclaim 11, wherein the adaptive seal is a hydrogel-coated wire comprising a shape memory metal, the hydrogel-coated wire changing from a first configuration to a second configuration upon reaching or exceeding a transformation temperature.

13. The packaged bioprosthetic heart valve ofclaim 12, wherein in the first configuration, the hydrogel-coated wire has one of a straight or a coiled configuration and wherein in the second configuration, the hydrogel-coated wire has the other of the straight or coiled configuration.

14. The packaged bioprosthetic heart valve ofclaim 9, wherein the adaptive seal is coupled to the bioprosthetic heart valve at a spaced distance from both of the inflow and outflow portions.

15. The packaged bioprosthetic heart valve ofclaim 9, wherein the adaptive seal is provided circumferentially about the bioprosthetic heart valve.

16. The packaged bioprosthetic heart valve ofclaim 15, wherein the bioprosthetic heart valve further comprises a sewing ring and wherein the adaptive seal is coupled to and exposed from the sewing ring or contained within the sewing ring.

17. The packaged bioprosthetic heart valve ofclaim 9, wherein the supporting frame is a stent comprising a plurality of struts and open cells.

18. The packaged bioprosthetic heart valve ofclaim 17, wherein the adaptive seal is coupled to one or more struts of the supporting frame.

19. The packaged bioprosthetic heart valve ofclaim 17, wherein the adaptive seal forms one of a coating on at least a portion of the stent.

20. The packaged bioprosthetic heart valve ofclaim 17, wherein the adaptive seal is provided as patches disposed within the open cells defined by the stent.

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