Patent Description:
This disclosure relates generally to apparatuses for heart valve repair and, more particularly, to annuloplasty rings comprising bioprosthetic tissue.

The human heart generally includes four valves. Of these valves, the mitral valve is located in the left atrioventricular opening and the tricuspid valve is located in the right atrioventricular opening. Both of these valves are intended to prevent regurgitation of blood from the ventricle into the atrium when the ventricle contracts. In preventing blood regurgitation, both valves must be able to withstand considerable back pressure as the ventricle contracts. The valve cusps are anchored to the muscular wall of the heart by delicate but strong fibrous cords in order to support the cusps during ventricular contraction. Furthermore, the geometry of the heart valves ensure that the cusps overlay each other to assist in controlling the regurgitation of the blood during ventricular contraction.

Diseases and certain natural defects to heart valves can impair the functioning of the cusps in preventing regurgitation. For example, certain diseases cause the dilation of the heart valve annulus. Dilation may also cause deformation of the valve geometry or shape displacing one or more of the valve cusps from the center of the valve. Other diseases or natural heart valve defects result in deformation of the valve annulus with little or no dilation.

Dilation and/or deformation result in the displacement of the cusps away from the center of the valve. This results in an ineffective closure of the valve during ventricular contraction, which results in the regurgitation or leakage of blood during ventricle contraction. For example, diseases such as rheumatic fever or bacterial inflammations of the heart tissue can cause distortion or dilation of the valvular annulus. Other diseases or malformations result in the distortion of the cusps, which will also lead to ineffective closure of the valve.

Various surgical procedures have been developed to correct the deformation of the valve annulus and retain the intact natural heart. These surgical techniques involve repairing the shape of the dilated or elongated valve. Such techniques, generally known as annuloplasty, require surgically restricting the valve annulus to minimize dilation. Typically, a prosthesis is sutured about the base of the valve leaflets to reshape the valve annulus and restrict the movement of the valve annulus during the opening and closing of the valve.

A suitable prosthesis should allow the surgeon to properly reconstruct the heart valve annulus and minimize dilation, while allowing natural movement of the valve annulus during the opening and closing of the valve. The ability of the prosthesis to allow for a natural opening and closing of the valve is particularly important since such prostheses are not normally removed from the heart valve, even if the valve annulus heals to a normal geometry.

Many different types of prostheses have been developed for use in
annuloplasty surgery. In general prostheses are annular or partially annular shaped members which fit about the base of the valve annulus. Initially the prostheses were designed as rigid frame members, to correct the dilation and reshape the valve annulus to the natural state. These annular prostheses were formed from a metallic or other rigid material, which flexes little, if at all, during the normal opening and closing of the valve.

Current annuloplasty rings are typically comprised of a silicone and metal base that is wrapped with a sewing ring made of cloth. Repair of the valve annulus using current annuloplasty rings can, however, fail due to ring dehiscence at the implanting suture line and/or as a result of fibrous tissue overgrowth or pannus that can be triggered by the host response to the annuloplasty ring.

What is therefore desired are devices and methods for repairing a valve annulus which reduce the likelihood of dehiscence and which promote sufficient host tissue ingrowth to stabilize device once implanted in the host.

<CIT> describes a treatment for bioprosthetic tissue used in implants or for assembled bioprosthetic heart valves to reduce in vivo calcification. The method includes applying a calcification mitigant such as a capping agent or an antioxidant to the tissue to specifically inhibit oxidation in tissue. The tissue may comprise glutaraldehyde-fixed bovine pericardial tissue. <CIT> discloses a heart valve prosthesis comprising a harvested tissue heart valve with integral leaflets, the heart valve having an annulus at one end of the valve, and a belt secured around at least a substantial portion of an outer circumference of the annulus of the harvested tissue heart valve.

Any "embodiment", "example", or "aspect" which is disclosed in the description but is not covered by the claims should be considered as presented for illustrative purposes only.

The present disclosure includes an annuloplasty ring prosthesis comprising a frame and a cover surrounding an outer surface of the frame. The cover comprises a bioprosthetic tissue.

In the presently claimed invention, the cover comprises a sheet of bioprosthetic tissue, the sheet having a first edge and a second edge. The sheet covers the outer surface of the frame, and the first edge and the second edge are joined together to form a seam. In an example, the cover can comprise a plurality of sheets that abut each other at abutment seams. In the presently claimed invention, the sheet is dimensioned to permit the first edge and the second edge of the sheet to fold or roll upon each other to form a lip. The lip protrudes away from the outer surface of the frame.

In the presently claimed invention, the bioprosthetic tissue is fixed and non-regenerative. In an example, the fixed, non-regenerative bioprosthetic tissue can be selected from the group consisting of pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. In a further example, the fixed, non-regenerative bioprosthetic tissue can be a pericardium. In an additional example, the fixed, non-regenerative bioprosthetic tissue can be fixed with an aldehyde. In yet another example, the aldehyde can be a glutaraldehyde.

In one example, the free aldehyde groups in the fixed, non-regenerative bioprosthetic tissue can be subjected to a capping treatment comprising a capping agent. In one example, the capping agent can comprise an amine. In another example, the capping treatment can further comprise a reducing agent. In an additional example, the reducing agent can be a borohydride. In yet another example, the fixed, non-regenerative bioprosthetic tissue can be plasticized. In one example, the fixed, non-regenerative bioprosthetic tissue can be plasticized with a polyol. In another example, the polyol can be a glycerol.

In one example, not covered by the claims, the bioprosthetic tissue can be regenerative. In another example, not covered by the claims, the regenerative bioprosthetic tissue can be a decellularized biological tissue. In a further example, not covered by the claims, the decellularized tissue can be selected from the group consisting of: pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. In an additional example, not covered by the claims, the regenerative bioprosthetic tissue can be an artificial scaffold. In yet another example, not covered by the claims, the artificial scaffold can be a biodegradable polymer scaffold. In one example, not covered by the claims, the biodegradable polymer scaffold can comprise a polyglycolic acid. In another example, not covered by the claims, the artificial scaffold can further comprise an extracellular matrix protein. In another example, not covered by the claims, the extracellular matrix protein can be one or more proteins selected from the group consisting of: hydroxyproline, vitronectin, fibronectin, collagen I, collagen III, collagen IV, collagen VI, collagen XI, collagen XII, fibrillin I, tenascin, decorin, byglycan, versican, asporin, agrin, and combinations thereof.

In one example, the frame can comprise one or both of a non-degradable polymer and a non-degradable metal or metal alloy. In another example, the frame can comprise a non-degradable metal or metal alloy selected from the group consisting of: stainless steel, a nickel-based alloy, a cobalt-chromium alloy, a nickel-cobalt-chromium alloy, nitinol, and combinations thereof.

In one example, the frame can be bioabsorbable. In another example, the bioabsorbable frame can comprise a metal or a metal alloy. In another example, the metal or the metal alloy can comprise one or a combination selected from the group consisting of magnesium, aluminum, iron, and zinc. In a further example, the metal or the metal alloy can have an ultimate tensile strength of about <NUM> MPa to about <NUM> MPa. In an additional example, the metal or the metal alloy can have an elongation of about <NUM> percent to about <NUM> percent. In yet another example, the bioabsorbable frame can be a bioabsorbable material. In one example, the bioabsorbable material can be one or a combination of polymers selected from the group consisting of: poly(L-lactide), poly(D-lactide), polyglycolide, poly(L-lactide-co-glycolide), polyhydroxyalkonate, polysaccharides, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polylactide-co-polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, terminal dials, poly(L-lactide-co-trimethylene carbonate), polyhydroxybutyrate, polyhydroxyvalerate, poly-orthoesters, poly-anhydrides, polyiminocarbonate, and copolymers. In another example, the bioabsorbable frame can be reinforced with a reinforcing composition. In a further example, the reinforcing composition can comprise magnesium or a magnesium alloy.

The present disclosure further includes a sewing ring for a prosthetic heart valve, not falling within the scope of the claimed subject-matter. The sewing ring comprises a suture-permeable annular member and a cover surrounding an outer surface of the suture-permeable annular member. The cover comprises a bioprosthetic tissue.

In one example, not falling within the scope of the claimed subject-matter, the cover can comprise a sheet of bioprosthetic tissue, the sheet having a first edge and a second edge. The sheet can cover the outer surface of the suture-permeable annular member, and the first edge and the second edge can be joined together to form a seam. In another example, the cover can comprise a plurality of sheets that abut each other at abutment seams. In a further example, the sheet can be dimensioned to permit the first edge and the second edge of the sheet to fold or roll upon each other to form a lip. In an additional example, the lip can protrude away from the outer surface of the suture-permeable annular member.

In one example, not falling within the scope of the claimed subject-matter, the suture-permeable annular member can be molded from a suture-permeable, biocompatible polymer. In another example, the biocompatible polymer can be silicone. In a further example, the annular member can comprise a molded polymer. In an additional example, the molded polymer can be selected from the group consisting of: silicone, polyurethane, and combinations thereof.

In one example, not falling within the scope of the claimed subject-matter, the bioprosthetic tissue can be fixed and non-regenerative. In another example, the fixed, non-regenerative bioprosthetic tissue can be selected from the group consisting of pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. In a further example, the fixed, non-regenerative bioprosthetic tissue can be a pericardium. In an additional example, the fixed, non-regenerative bioprosthetic tissue can be fixed with an aldehyde. In yet another example, the aldehyde can be a glutaraldehyde.

In one example, not falling within the scope of the claimed subject-matter, the free aldehyde groups in the fixed, non-regenerative bioprosthetic tissue can be subjected to a capping treatment comprising a capping agent. In one example, the capping agent can comprise an amine. In another example, the capping treatment can further comprise a reducing agent. In an additional example, the reducing agent can be a borohydride. In yet another example, the fixed, non-regenerative bioprosthetic tissue can be plasticized. In one example, the fixed, non-regenerative bioprosthetic tissue can be plasticized with a polyol. In another example, the polyol can be a glycerol.

In one example, not falling within the scope of the claimed subject-matter, the bioprosthetic tissue can be regenerative. In another example, not falling within the scope of the claimed subject-matter, the regenerative bioprosthetic tissue can be a decellularized biological tissue. In a further example, the decellularized tissue can be selected from the group consisting of: pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. In an additional example, not falling within the scope of the claimed subject-matter, the regenerative bioprosthetic tissue can be an artificial scaffold. In yet another example, not falling within the scope of the claimed subject-matter, the artificial scaffold can be a biodegradable polymer scaffold. In one example, not falling within the scope of the claimed subject-matter, the biodegradable polymer scaffold can comprise a polyglycolic acid. In another example, the artificial scaffold can further comprise an extracellular matrix protein. In another example, not falling within the scope of the claimed subject-matter, the extracellular matrix protein can be one or more proteins selected from the group consisting of: hydroxyproline, vitronectin, fibronectin, collagen I, collagen III, collagen IV, collagen VI, collagen XI, collagen XII, fibrillin I, tenascin, decorin, byglycan, versican, asporin, agrin, and combinations thereof.

The present disclosure further includes a ring prosthesis, not falling within the scope of the claimed subject-matter. The ring prosthesis can comprise an elongated rod member that can be formed into a substantially ring shape. The elongated rod member can have a rod body, first and second ends and a free edge between the first and second ends. The free edge of the rod member can be secured to the rod body. The elongated rod member can be formed from a substantially flat bioprosthetic tissue having a length, a width, a first surface and a second surface opposing the first surface.

In one example, the second surface of the bioprosthetic tissue can have a texture that is smoother than the first surface of the bioprosthetic tissue. In another example, the first surface of the bioprosthetic tissue can have a texture that is rougher than the second surface of the bioprosthetic tissue. In one example, the first surface of the bioprosthetic tissue can form an external surface of the rod body. In a further example, the second surface of the bioprosthetic tissue can form an external surface of the rod body.

In an additional example, the free edge can be secured to the rod body with sutures. In accordance with this example, the ring prosthesis can consist of the substantially flat bioprosthetic tissue and sutures. In a further example, the free edge can be secured to the rod body with an adhesive. In accordance with this further example, the ring prosthesis can consist of the substantially flat bioprosthetic tissue and the adhesive.

In a further example, the ring prosthesis may not have a frame or a support. In another example, the ring prosthesis can consist essentially of the bioprosthetic tissue. In a further example, the rod member consists essentially of the bioprosthetic tissue.

In yet another example, the first and second ends of the elongated rod member can be spaced apart such that the ring prosthesis is an open ring. In a further embodiment, the first and second ends of the elongated rod members can be joined together such that the ring prosthesis is a closed ring.

In yet a further example, the elongated rod member can have a substantially cylindrical shape and the substantially flat bioprosthetic tissue can be rolled upon itself to form the substantially cylindrical shape. In yet a further embodiment, the elongated rod member can have a substantially triangular shape and the substantially flat bioprosthetic tissue can be folded upon itself to form the substantially triangular shape. In yet a further embodiment, the elongated rod member can have a substantially rectilinear shape and the substantially flat bioprosthetic tissue can be folded upon itself to form the substantially rectilinear shape. In yet a further embodiment, the tissue can be folded upon itself in an alternating sequence to form the substantially rectilinear shape.

In yet another example, the bioprosthetic tissue can be selected from the group consisting of: pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. In another example, the bioprosthetic tissue can be a pericardium.

In yet another example, the bioprosthetic tissue can be fixed with an aldehyde. In another example, the aldehyde can be a glutaraldehyde. In yet another example, free aldehyde groups in the fixed bioprosthetic tissue can be subjected to a capping treatment with a capping agent. In yet another example, the capping agent can comprise an amine. In yet a further example, the capping treatment can further comprise a reducing agent. In yet a further example, the reducing agent can be a borohydride.

In yet a further example, the bioprosthetic tissue can be plasticized. In a further example, the bioprosthetic tissue can be plasticized with a polyol. In a further example, the polyol can be a glycerol.

The present disclosure also further includes a method for manufacturing a ring prosthesis, which is not covered by the claims. The method can comprise shaping a substantially flat bioprosthetic tissue to form an elongated rod. The bioprosthetic tissue can have a length, a width, a first surface and a second surface opposing the first surface. The rod can comprise a body having first and second ends and a free edge between the first and second ends. The method can further comprise securing the free edge of the rod onto the rod body. The method can further comprise arranging the first and second ends of the rod body in proximity to one another such that the rod is substantially shaped as a ring.

In one example, the shaping can further comprise folding the substantially flat bioprosthetic tissue. In another example, the shaping can comprise rolling the substantially flat bioprosthetic tissue.

In another example, the first surface can be rough or fibrous and the second surface can be smoother than the first surface. In another example, the second surface can be rough or fibrous and the first surface can be smoother than the second surface. In a further embodiment, the first surface forms an exposed surface of the elongated rod and the second surface form an internal surface of the elongated rod. In another embodiment, the second surface can form an exposed surface of the elongated rod and the first surface can form an internal surface of the elongated rod.

In a further example, the step of securing can comprise suturing the free edge of the rod onto the rod body. In yet another example, the step of securing can comprise gluing the free edge of the rod onto the rod body.

In yet another example, the rod can be substantially shaped as an open ring. In yet a further example, the first and second ends of the rod body can be joined together to form a closed ring. In one example, the first and second ends can be joined with sutures. In another example, the first and second ends can be joined with an adhesive.

In yet a further example, a cross-section of the rod body can be substantially circular. In yet another example, a cross-section of the rod body can be substantially triangular. In yet a further example, a cross-section of the rod body can be substantially rectangular.

In yet a further example, the method can further comprise decellularizing the bioprosthetic tissue.

In yet a further example, the bioprosthetic tissue can be selected from the group consisting of: pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. In a further example, the bioprosthetic tissue can be a pericardium.

In yet another example, the bioprosthetic tissue can be fixed with an aldehyde. In another example, the aldehyde is a glutaraldehyde. In another example, free aldehyde groups in the fixed bioprosthetic tissue can be subjected to a capping treatment with a capping agent. In another example, the capping agent can comprise an amine. In another example, the capping treatment can further comprise a reducing agent. In another example, the reducing agent can be a borohydride.

All methods disclosed herein which encompass simulations of the methods, for example, for training; testing; demonstration; or device or procedure development, are also not covered by the claims. Methods for treating a patient can include simulating treatment on a simulated human or non-human patient, for example, an anthropomorphic ghost. Examples of suitable simulated patients can include both an entire body, any portion of a body, or at least a portion of an organ, for example, a heart. The simulations can be physical, virtual, or any combination thereof. Examples of physical simulations can include any combination of natural or manufactured whole human or animal cadavers, portions thereof, or cadaver organs. Virtual simulations can include any combination of virtual reality, projections onto a screen or on at least a portion of a physical simulation, or other in silico elements. Some simulations can include non-visual elements, for example, auditory, tactile, or olfactory stimuli.

With reference to <FIG> and <FIG> of the illustrative drawings, there are shown examples of annuloplasty rings <NUM>. The annuloplasty ring <NUM> can be suitable for annulus of a valve, such as the mitral annulus (<FIG>) or the tricuspid annulus (<FIG>).

<FIG> illustrate examples of a mitral annuloplasty ring <NUM> having a continuous or D-shaped periphery. The mitral annuloplasty ring <NUM> can be shaped to closely mimic the geometry of a healthy mitral annulus, and can be configured to minimize the likelihood of dehiscence while maintaining the shape of a healthy valve annulus.

<FIG> illustrate examples of a tricuspid annuloplasty ring <NUM>, with a discontinuous or C-shaped periphery, including two free ends <NUM> that define a gap therebetween. The tricuspid annuloplasty ring <NUM> can be shaped to closely mimic the geometry of a healthy tricuspid annulus, and can be configured to minimize the likelihood of dehiscence while maintaining the shape of a healthy valve annulus. The tricuspid annuloplasty ring <NUM> is not complete in about ten percent of the circumference around the anteroseptal commissure of the tricuspid annulus. This is to prevent suture injury to the conduction system. With particular reference to <FIG>, the tricuspid annuloplasty ring <NUM> can have a somewhat spiral shape that mimics the shape of a healthy tricuspid annulus.

In one example, the two free ends <NUM> are separated at a distance to define a gap therebetween. The distance between the two free ends <NUM> can be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% of a length of the tricuspid annuloplasty ring <NUM>, or in a range that includes and is between any two of the foregoing values.

In one example, the two free ends <NUM> can be coplanar with the frame <NUM>. In another example, one of the two free ends <NUM> can be offset from the other one of the free ends <NUM>. The two free ends <NUM> can be vertically offset from one another at a distance that is about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% of a length of the tricuspid annuloplasty ring <NUM>, or in a range that includes and is between any two of the foregoing values.

The annuloplasty ring <NUM> can comprise a frame <NUM> having an outer surface <NUM>, and a cover <NUM> surrounding the frame <NUM>. The cover <NUM> comprises a bioprosthetic tissue. The bioprosthetic tissue is fixed and non-regenerative. In other examples, not covered by the claims, the bioprosthetic tissue can be regenerative.

The term "regenerative" as it relates to bioprosthetic tissue is understood to mean tissue that permits or even stimulates ingrowth of host cells and tissue into the bioprosthetic tissue after implantation. Thus, "regenerative tissue" can include three-dimensional scaffolds that support the ingrowth of host cells and tissue. In one example, the regenerative tissue can remain after in-growth of host cells and tissue. In another example, the regenerative tissue can partially or completely biodegrade after in-growth of host cells and tissue.

For the fixed and non-regenerative examples, the bioprosthetic tissue can be selected from the group consisting of: pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. For example, the fixed, non-regenerative bioprosthetic tissue can be a pericardium. In one example, the fixed, non-regenerative bioprosthetic tissue can be fixed with an aldehyde such as a glutaraldehyde. In another example, the free aldehyde groups in the fixed, non-regenerative bioprosthetic tissue can be subjected to a capping treatment comprising a capping agent. In a one example, the capping treatment can comprise an amine. In an additional example, the capping treatment can further comprise a reducing agent such as a borohydride. In one example, the fixed, non-regenerative bioprosthetic tissue can be plasticized. In another example, the fixed, non-regenerative bioprosthetic tissue can be plasticized with a polyol such as a glycerol.

In one example, the bioprosthetic tissue can be subjected to a fixation or cross-linking treatment, as a result of which the bioprosthetic tissue is rendered less antigenic and is at least partially or completely cross-linked. The fixation process can also render the tissue non-regenerative. The fixation process is understood to include any chemical, heat or other processes, as a result of which the bioprosthetic tissue is preserved and rendered mechanically and dimensionally stable.

The fixation process can include contacting the tissue with one or more fixatives. Known fixatives include aldehydes, polyaldehydes, diisocyanates, carbodiimides, photo-oxidation agents, and polyepoxide compounds. In a preferred example, the fixative used is glutaraldehyde. Glutaraldehyde-fixed tissue, however, is particularly vulnerable to calcification since glutaraldehyde fixation results in the generation of residual aldehyde groups and labile Schiff bases. The residual aldehydes and Schiff bases can be potential binding sites for calcium. The aldehyde groups can oxidize to carboxylic acid groups, which are known to attract and bind calcium.

Various techniques have therefore been developed to reduce the aldehyde and acid levels of glutaraldehyde-fixed tissues, and thus reduce its propensity to calcify after implantation in the patient.

The fixation process can include adjusting the pH of the glutaraldehyde fixative in solution to reduce the generation of calcium binding sites, as disclosed in <CIT>. In a preferred example, the pH of the glutaraldehyde fixative in solution is about or provided in a range including and between any two of the following pH values: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>.

The fixation process can also further include the addition of a heat-treating step after contacting with the one or more fixatives. Glutaraldehyde-fixed tissue have demonstrated a reduced aldehyde and carboxylic acid content after heat treatment, and thus a marked reduction in calcification after implantation, as compared to glutaraldehyde-fixed tissue without heat treatment. The glutaraldehyde fixative in solution can be heat treated before, during, or after the bioprosthetic tissue is immersed in the solution. The heat treatment can include heating the glutaraldehyde fixative in solution to a temperature provided in a range including and between any two of the following temperatures: <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, <NUM>° C, and <NUM>° C. Exemplary processes for heat treating glutaraldehyde-fixed tissue are described in <CIT> to Edwards Lifesciences. The heat treatment of glutaraldehyde-fixed tissue is also commercially known as the Carpentier-Edwards ThermaFix® (TFX) tissue treatment process from Edwards Lifesciences.

Following or concurrently with the fixation process, the bioprosthetic tissue can be subjected to a capping treatment that comprises a capping agent, a reducing agent, or both. The bioprosthetic tissue can include functional groups that exist either inherently in the bioprosthetic tissue, as a result of being cross-linked or fixed, or as a result of being subjected to any number of chemical or physical processes, including the pre-conditioning, pre-stressing, or pre-damaging processes disclosed in this description. Exemplary processes for treatment with capping and reducing agents are described in <CIT>.

In one example, the bioprosthetic tissue can be subjected to a capping treatment without the step of fixing or crosslinking the bioprosthetic tissue. In another example, the bioprosthetic tissue can be subjected to the capping treatment before, during, or after the step of fixing or crosslinking the bioprosthetic tissue.

In one example, the capping agent can include any one or a combination of the following: an amine, such as an alkyl amine, amino alcohols and ethanolamine; an amino acid, such lysine and hydroxylysine; an amino sulfonate, such as taurine, amino sulfates, dextran sulfate, and chondroitin sulfate; hydrophilic multifunctional polymers, such as polyvinyl alcohols and polyethyleneimines; a hydrophobic multifunctional polymer; α-dicarbonyls, including methylglyoxal, <NUM>-deoxyglucosone, and glyoxal; hydrazines, such as adipic hydrazide; disuccinimidyl N,N-carbonate; carbodiimides, such as <NUM>-ethyl-<NUM>-[<NUM>-dimethylaminopropyl]carbodiimide hydrochloride (EDC), N-cyclohexyl-N'-(<NUM>-morpholinoethyl)carbodiimide (CMC), and <NUM>,<NUM>-dicyclohexyl carbodiimide (DCC); and <NUM>-chloro-<NUM>-methylpyridinium iodide (CMPI).

In another example, the capping agent can be any agent that is reactive with a functional group, wherein the functional group is a free aldehyde or a free carboxylic acid. The capping agent can be an amine, such as an alkyl amine or an amino alcohol. The capping agent can be an ethanolamine.

In a further example, the capping agent can be any agent that is reactive with a functional group, wherein the functional group is an amine, a hydroxyl, or a sulfhydryl group. In accordance with this example, the capping agent can comprise a carbonyl functional group. The carbonyl functional group can be an aldehyde or a carboxylic acid and can be selected from a monoaldehyde, a polyaldehyde, a monocarboxylic acid, a polycarboxylic acid, and the like.

Regardless, certain reactions of the capping agent and functional groups can produce labile Schiff bases and it can be desirable to reduce the Schiff bases and replace them with a more stable amine.

Accordingly, the capping treatment of the bioprosthetic tissue can further include treatment with a reducing agent. The reducing agent can be selected to reduce Schiff bases formed from the reaction of the crosslinking agent and the bioprosthetic tissue, the capping agent and the bioprosthetic tissue, and the capping agent and the crosslinking agent. In one example, the bioprosthetic tissue can be treated with the reducing agent, with or without the fixing or crosslinking the bioprosthetic tissue. In another example, the bioprosthetic tissue can be treated with the reducing agent, with or without the capping agent. In a further example, the bioprosthetic tissue can be treated with the reducing agent, with or without both the fixing or crosslinking and capping the bioprosthetic tissue.

The reducing agent can be any one or a combination of agents that comprise a borohydride. In one example, the reducing agent can be one or a combination selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium bisulfate in acetylacetone, formic acid in formaldehyde, alkyl borohydride, amino borohydride, lithium aminoborohydrides, and an organoborate hydride salt having the formula XBR<NUM>H, where R is an alkyl group and X is lithium, sodium, or potassium. The lithium aminoborohydride can be a lithium dimethylaminoborohydride, a lithium morpholinoborohydride, and a lithium pyrrolidinoborohydride, to name a few. The organoborate hydride salt reducing agent can be a lithium tri-sec-butyl(hydrido)borate, a sodium tri-sec-butyl(hydrido)borate, a potassium tri-sec-butyl(hydrido)borate, or a lithium aluminum hydride.

The bioprosthetic tissue can be subjected to a capping treatment in which it is treated with a capping agent and a reducing agent in a solution. In one example, the capping agent is selected to react with one or more functional groups associated with the bioprosthetic tissue and the reducing agent is selected to reduce Schiff bases. The Schiff bases can be formed from any one or more of the reaction of the crosslinking agent and the bioprosthetic tissue, the reaction of the capping agent and the bioprosthetic tissue, and the reaction of the capping agent and the crosslinking agent. The capping agent can be an amine or an amino alcohol, such as an ethanolamine; the functional groups can be an aldehyde or a carboxylic acid; the reducing agent can be a borohydride, such as a sodium borohydride; and the crosslinking agent can be an aldehyde-containing agent, such as a glutaraldehyde. The capping treating can be performed sequentially with first the capping agent and then the reducing agent in solution or simultaneously with both the capping and reducing agents present in the solution. In one example, the capping treating can be performed with the capping agent and reducing agent in a solution on an orbital shaker operating at about <NUM> to about <NUM> rpm for about <NUM> hours.

Exemplary methods for treating bioprosthetic tissue with capping and reducing agents are described in <CIT>.

The capping treatment can comprise a capping agent, a reducing agent, or both. The capping treatment can be performed after the fixed bioprosthetic tissue has been subjected to a process of pre-conditioning, pre-stressing, or pre-damaging to generate additional acid binding sites, which can subsequently be capped, as described in <CIT>. In one example, the bioprosthetic tissue can be subjected to a rapid pulsed fluid flow (in the range of about <NUM> to about <NUM>,<NUM>), repeated flexion of the bioprosthetic tissue valve, elevated temperature (in the range of about <NUM>° C to about <NUM>° C), an acidic solution (pH in the range of about <NUM> to about <NUM>), alkaline solution (pH in the range of about <NUM> to about <NUM>), or any combination of the foregoing for the purpose of generating additional acid binding sites, which can be capped, reduced, or both, in a separate treatment process.

The bioprosthetic tissue can further undergo treatment with anhydrous, non-aqueous, or aqueous solutions to substantially, if not completely, dehydrate the bioprosthetic tissue for dry storage. The bioprosthetic tissue following glycerol treatment can contain residual water or moisture within the tissue interstices but can be packaged for dry storage.

In one example, the bioprosthetic tissue can be treated with an anhydrous, non-aqueous, or aqueous solution that comprises glycerol. In one example, the anhydrous, non-aqueous, or aqueous solution can comprise about <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, <NUM>% by volume, or <NUM>% by volume glycerol. In another example, the anhydrous, non-aqueous, or aqueous solution comprises an amount of glycerol within and including any two of the foregoing values.

In another example, the anhydrous, non-aqueous, or aqueous glycerol solution can comprise alcohol. In one example, the anhydrous, non-aqueous, or aqueous solution can comprise about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, about <NUM>% by volume, or about <NUM>% by volume alcohol. In another example, the anhydrous, non-aqueous, or aqueous solution comprises an amount of alcohol within and including any two of the foregoing values. The alcohol can be any one or a combination of C<NUM>, C<NUM>, C<NUM>, C<NUM>, and C<NUM> alcohols, such as ethanol, propanol, and butanol.

In one example, the solution is a non-aqueous solution of about <NUM>% by volume glycerol and <NUM>% by volume ethanol. The bioprosthetic tissue is immersed in the solution for a period of time sufficient to permit the solution to permeate the bioprosthetic tissue. The bioprosthetic tissue is then removed from the solution to allow removal of excess solution. Suitable treatment for the bioprosthetic tissues is described in <CIT>.

In another preferred example, an aqueous glycerol solution can be used to at least partially dehydrate the tissue, as described in <CIT>.

The bioprosthetic tissue can also be treated by means other than the glycerol treatment process described above to dry or dehydrate the bioprosthetic tissue. The terms "dry" or "dehydrate," as used in this disclosure with reference to the bioprosthetic tissue or the implantable bioprosthetic device, is understood to include residual water or moisture that can be present in the bioprosthetic tissue following glycerol or other treatment to reduce the water content of the bioprosthetic tissue. In one example, the water content of the dried or dehydrated bioprosthetic tissue following glycerol or other treatment is about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, about <NUM>% by weight or less, or about <NUM>% by weight or less. These percentages are understood to be based on the combined weight of the bioprosthetic tissue and water content.

For the regenerative examples, not falling within the scope of the claimed subject-matter, the bioprosthetic tissue can be an artificial or biological scaffold or a decellularized biological tissue. For example, the bioprosthetic tissue can be selected from the group consisting of: pericardium, blood vessels, skin, dura mater, small intestinal submucosa, ligaments, tendons, muscle, ureter, urinary bladder, liver, and heart. It is understood that the tissue selected is decellularized using any suitable method.

In one example, not falling within the scope of the claimed subject-matter, the regenerative bioprosthetic tissue can be an artificial scaffold. In another example, the artificial scaffold can be a biodegradable polymer scaffold. A biodegradable polymer can include a polymer in which the bonds of the polymer-chain cleave, primarily by aqueous hydrolysis as a result of contact with blood and other bodily fluids at physiological pH (e.g., around <NUM> to <NUM>). This process results in the fragmentation and eventual decomposition of the polymer in vivo. The fragmentation and decomposition process can be catalyzed by enzymes or other endogenous biological compounds. In a further example, the biodegradable polymer scaffold can comprise a polyglycolic acid. In an additional example, the artificial scaffold can further comprise one or more extracellular matrix proteins. For example, the extracellular matrix protein can be one or more proteins selected from the group consisting of: hydroxyproline, vitronectin, fibronectin, collagen I, collagen III, collagen IV, collagen VI, collagen XI, collagen XII, fibrillin I, tenascin, decorin, byglycan, versican, asporin, agrin, and combinations thereof.

In the presently claimed invention, the cover <NUM> is formed from a sheet <NUM> of bioprosthetic tissue (<FIG>). The sheet <NUM> has a first edge <NUM> and a second edge <NUM>. With reference to <FIG> and <FIG>, the sheet <NUM> covers the outer surface <NUM> of the frame <NUM>, and the first edge <NUM> and the second edge <NUM> are sewn, glued, or otherwise joined together to form a seam <NUM>. In some examples of a tricuspid annuloplasty ring <NUM> (<FIG>), the sheet <NUM> can extend beyond the frame <NUM> to form an enlarged region of covering <NUM> at the free ends (<FIG>).

The glue used to form and shape the cover <NUM>, such as joining the first and second edges <NUM>, <NUM>, is preferably one that is biocompatible and strongly bonds tissue in a wet environment (e.g., flowing blood). In one example, the glue is a hydrophobic light-activated adhesive (HLAA). The HLAA can be formed by combining a poly(glycerol sebacate acrylate) (PGSA) with a photo-initiator, such as <NUM>-hydroxy-<NUM>-[<NUM>-(<NUM>-hydroxyethoxy)phenyl]-<NUM>-methyl-l-propanone) (IRGACURE <NUM>, Sigma-Aldrich) to create the HLAA. The HLAA can be a thick gel that can be applied onto the cover and then cross-linked by ultraviolet light. The resulting bond is preferably water-tight yet flexible and stays intact in the face of high pressure and flowing blood.

With reference to <FIG>, <FIG>, the cover <NUM> can comprise a plurality of sheets <NUM> that abut each other at part-interface seams <NUM>. In some examples, the part-interface seams <NUM> can define markings to aid a surgeon with correct positioning of the ring <NUM> on the valve anulus. With reference to <FIG>, in the presently claimed invention, the sheet <NUM> is dimensioned to permit the first edge <NUM> and the second edge <NUM> of the sheet to fold or roll upon each other to form a lip <NUM>. The lip <NUM> protrudes away from the outer surface <NUM> of the frame <NUM>.

The outer cover <NUM> comprising a bioprosthetic tissue can encourage native tissue growth on the annuloplasty ring <NUM>, which can help to maintain the ring <NUM> in place on the valve annulus. In addition, bioprosthetic-tissue cover <NUM> can be used in patients with endocarditis or in patients who are otherwise intolerant of cloth-covered implants.

As discussed above, the cover <NUM> is wrapped around a frame <NUM>. In some examples, the frame <NUM> can be bioabsorbable. In other examples, the frame <NUM> can be non- de gradable.

For the non-degradable examples, the frame <NUM> can comprise one or both of a non-degradable polymer and a non-degradable metal or metal alloy. For example, in one example, the frame <NUM> can comprise a non-degradable metal or metal alloy selected from the group consisting of: stainless steel, a nickel-based alloy, a cobalt-chromium alloy, a nickel-cobalt-chromium alloy, nitinol, and combinations thereof.

For the bioabsorbable examples, the bioabsorbable frame <NUM> can comprise a degradable metal or a metal alloy. For example, the degradable metal or metal alloy can comprise one or a combination selected from the group consisting of: magnesium, aluminum, iron, and zinc. The metal or metal alloy can have an ultimate tensile strength of about <NUM> MPa to about <NUM> MPa and an elongation of about <NUM> percent to about <NUM> percent.

In one example, the bioabsorbable frame <NUM> can be a bioabsorbable material. For example, the bioabsorbable material can be one or a combination of polymers selected from the group consisting of: poly(L-lactide), poly(D-lactide), polyglycolide, poly(L-lactide-co-glycolide), polyhydroxyalkonate, polysaccharides, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polylactide-co-polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, terminal dials, poly(L-lactide-co-trimethylene carbonate), polyhydroxybutyrate, polyhydroxyvalerate, poly-orthoesters, poly-anhydrides, polyiminocarbonate, and copolymers.

In another example, the bioabsorbable frame <NUM> can be reinforced with a reinforcing composition. For example, in one example, the reinforcing composition can comprise magnesium or a magnesium alloy.

While the frame <NUM> is shown to have a circular cross-section in <FIG>, <FIG>, and <FIG>, it should be understood that the frame <NUM> can have other cross-sectional shapes and thicknesses. For example, in some examples, the frame <NUM> can have a rounded semi-circular or even polygonal cross-section. In other examples, the shape or thickness of the frame <NUM> can be uniform across the periphery of the ring <NUM> or it can vary across the periphery of the ring <NUM>.

In some examples, the ring <NUM> can further include a suture-permeable interface <NUM> having one or more layers between the frame <NUM> and the cover <NUM>. For instance, the suture-permeable interface can comprise an elastomeric sleeve (<FIG> and <FIG>) such as a silicone rubber molded around the frame <NUM>. The elastomeric sleeve can provide bulk to the ring for ease of handling and implant, and permit passage of sutures though not significantly adding to the anchoring function of the outer cover <NUM>. In one example, the suture-permeable interface <NUM> can be provided around at least a portion of the periphery of the ring <NUM> (<FIG>). In another example, the suture-permeable interface <NUM> can be provided around the entire periphery of the ring <NUM>.

With reference now to <FIG> of the illustrative drawings, there is shown a sewing ring <NUM> for a prosthetic heart valve <NUM>. The prosthetic heart valve <NUM> can comprise a support frame <NUM> defining an orifice <NUM> about an axis A along an inflow-outflow direction. A plurality of leaflets <NUM> can be mounted for movement on the support frame <NUM> to provide a one-way valve <NUM> in the orifice <NUM>. Each of the plurality of leaflets <NUM> can comprise the bioprosthetic tissue described above.

The sewing ring <NUM> can be connected to and positioned around the support frame <NUM> for attaching the heart valve <NUM> to a valve annulus (not shown). The sewing ring <NUM> can include a suture-permeable annular member <NUM> comprising an outer surface <NUM>, and a cover <NUM> surrounding the annular member <NUM>.

The cover <NUM> comprises the bioprosthetic tissue described above. For example, as previously outlined, the cover <NUM> can comprise bioprosthetic tissue that is fixed and non-regenerative, or bioprosthetic tissue that is regenerative. In either case, the cover <NUM> is wrapped around the annular member <NUM>, which can be molded from a suture-permeable, biocompatible polymer such as silicone. In one example, the annular member <NUM> can comprise a molded polymer selected from the group consisting of: silicone, polyurethane, and combinations thereof. As with the cover <NUM> for the annuloplasty ring <NUM>, the cover <NUM> for the sewing ring <NUM> can be formed from a sheet <NUM> of bioprosthetic tissue (<FIG>), as discussed above.

In one example, the cover <NUM> and the plurality of leaflets <NUM> are made from the same bioprosthetic tissue.

With reference to <FIG> of the illustrative drawings, there is shown a method of manufacturing various embodiments of ring protheses which includes annuloplasty rings and sewing rings, including those depicted in <FIG>. As with the annuloplasty rings described herein, ring protheses fabricated in accordance with the depicted method can be suitable for the annulus of a valve, such as the tricuspid annulus (<FIG>) or the mitral annulus (<FIG>). Additionally, ring protheses fabricated in accordance with the depicted manner can be used in fabricating a prosthetic heart valve, as shown in <FIG>.

<FIG> depicts an example of a bioprosthetic tissue <NUM> having a length L and a width W. The bioprosthetic tissue <NUM> can comprise two opposing surfaces: a first surface <NUM> and a second surface <NUM>. In one embodiment, the first surface <NUM> can have a rough texture or can be fibrous and the second surface <NUM> can be smoother than the first surface <NUM>. Certain biological tissues can be characterized as having such surfaces, such as pericardial tissue and dura mater. These tissues are covered by a cell surface layer only on one side and thus have a smooth and even surface on this side while the opposing side is rough and fibrous. For purposes of cellular integration and infiltration by the host, the rough side can provide a suitable surface.

While <FIG> depicts a perfectly rectilinear shape, it is understood that the biological tissue <NUM> can be of any shape of a defined length and width so long as it can provide the desired diameter of the resulting ring prosthesis. <FIG> depict one example of how the biological tissue <NUM> can be rolled upon itself to produce an elongated rod member <NUM> having a free edge <NUM> between the first and second secured ends 501A and 501B. While <FIG> depict the elongated rod member <NUM> as has having a substantially cylindrical cross-sectional shape (<FIG>), it is understood that the biological tissue <NUM> can be rolled or folded in a manner to produce other cross-sectional shapes, such as a triangular cross-sectional shape (<FIG>). Alternatively, the elongated rod member <NUM> can be formed into a rectilinear cross-sectional shape by alternating folds in an accordion-style (<FIG>).

The elongated rod body <NUM> can be secured at its first and second secured ends 501A, 501B by wrapping with a string or suture <NUM> so that it may retain its substantially cylindrical shape. Once the first and second ends 501A, 501B are secured, the free edge <NUM> can be secured to the rod body <NUM>. While <FIG> depicts the free edge <NUM> being secured to the rod body <NUM> with sutures <NUM>, it is understood that the free edge <NUM> can be secured with any biocompatible substance, such as the adhesives described herein.

As shown in <FIG> and <FIG>, the free edge <NUM> may be sutured in such a manner to impart a curvature to the shape of the rod body <NUM>. The two free ends 500A and 500B can be separated at a distance d to define a gap therebetween to produce an open ring <NUM> as depicted in <FIG>. The distance D between the two free ends 500A and 500B can be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% of a length of the rod body <NUM>, or in a range that includes and is between any two of the foregoing values. Once the free edge <NUM> is sutured, the first and second secured ends 501A, 501B can be cut off to produce first and second free ends 500A and 500B. The resulting rod body <NUM> can consist only of the biological tissue <NUM> and the sutures <NUM> which can be made of a dissolvable or bioabsorbable material.

In one example, the two free ends 500A and 500B can be coplanar with the rod body <NUM>. In another example, one of the two free ends 500A, 500B can be offset from the other one of the free ends. The two free ends 500A, 500B can be vertically offset from one another at a distance that is about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% of a length of the ring prosthesis, or in a range that includes and is between any two of the foregoing values.

In another example, the two free ends 500A, 500B can be joined together to produce an enclosed ring <NUM> as depicted in <FIG>. In one example, the two free ends 500A, 500B can be sutured together to produce a seam <NUM> therebetween.

It is understood that the bioprosthetic tissue can be treated in any manner as described above either before or after it is formed into a ring prosthesis.

It should be appreciated from the foregoing description that the present disclosure provides improved ring prostheses, including annuloplasty rings that can encourage native tissue growth around the implant, to help maintain the implants in place, and that can be used in patients with endocarditis or in patients who or otherwise intolerant of cloth-covered implants.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this example belongs. The terms "a," "an," and "at least one" encompass one or more of the specified element. That is, if two of a particular element are present, one of these elements is also present and thus "an" element is present. The terms "a plurality of" and "plural" mean two or more of the specified element. The term "or" used between the last two of a list of elements means any one or more of the listed elements. For example, the phrase "A, B, or C" means "A, B, and/or C," which means "A," "B," "C," "A and B," "A and C," "B and C," or "A, B, and C. " The term "coupled" generally means physically coupled or linked and does not exclude the presence of intermediate elements between the coupled items absent specific contrary language.

Claim 1:
An annuloplasty ring prosthesis comprising:
a frame comprising an outer surface; and
a cover surrounding the frame, the cover comprising a fixed, non-regenerative bioprosthetic tissue wherein:
the cover comprises a sheet having a first edge and a second edge;
the sheet covers the outer surface of the frame;
the first edge and the second edge are joined together to form a seam;
the sheet is dimensioned to permit the first edge and the second edge of the sheet to fold or roll upon each other to form a lip; and
the lip protrudes away from the outer surface of the frame.