Polyurethane composite sheet, method for producing such a composite sheet and its use in the production of medical indwelling devices

Abstract

As used herein, a polyurethane composite sheet is provided, comprising: a biocompatible and biostable polyurethane elastomer containing polysiloxane segments, the polyurethane forming a continuous matrix of the sheet; A woven or braided fabric having a thickness of 15 to 150 μm and comprising biocompatible high-strength polymer fibers; Equipped with The composite sheet contains 10 to 90 mass % polyurethane, has a thickness of 25 to 250 μm, and has an areal density of 5 to 300 g / m 2 and; The composite sheet is disclosed as a polyurethane composite sheet exhibiting nonlinear uniaxial tensile behavior characterized by a 1% secant modulus of 20 to 200 MPa in at least one direction, a cure transition point between 10 and 45%, and a tensile strength of at least 25 MPa (measured in water at 37°C).

Description

Detailed Description of the Invention

[0001] [Field] The invention of the present disclosure relates to a polyurethane composite sheet suitable for manufacturing parts of medical indwelling devices such as artificial heart valve leaflets, a method for manufacturing such a composite sheet, the use of the polyurethane composite sheet in the manufacture of medical indwelling devices, and medical indwelling devices such as heart valve prostheses comprising such a composite sheet.

[0002] [background] The term sheet is generally used for thin-walled pieces of material such as pieces of paper or fabric, and composite is used for materials composed of two or more different structurally complementary components, usually a matrix material and a reinforcing material. Composite sheets are composites in sheet form that comprise a polymer matrix and reinforcing fibers, and can be used in the manufacture of medical devices for placement, particularly prosthetic heart valve leaflets.

[0003] Valvular heart disease is a leading cause of death. It can disrupt the control of blood flow into and out of the heart and its chambers approximately 30 million times per year, subjecting the heart to cyclical stress. Although diseased valves are preferably repaired surgically, approximately 300,000 patients worldwide require valve replacement surgery each year. This number is expected to increase rapidly as the average age of the population increases.

[0004] Heart valve prostheses have been in clinical use for over half a century. Initially, mechanical valves made of a metal-carbon combination were used and showed high durability. However, these valves are typically prone to infection, inflammation, and thrombosis, and patients must be on lifelong anticoagulant therapy. In addition, placement of these valves requires open-heart surgery, which may not be suitable for many patients.

[0005] Then came the so-called bioprosthetic valves. These valves usually use xenografts, such as chemically cross-linked bovine or porcine pericardium, for the leaflets, which are attached to a support structure. These bioprosthetic valves can undergo calcification, resulting in thickening and hardening, which ultimately leads to insufficient valve opening and closing. These valves have a limited life span of about 7-10 years. Nevertheless, bioprosthetic valves have become gold standard and offer clear advantages over mechanical valves, since they can be fabricated as collapsible / expandable prostheses that can be deployed using minimally invasive procedures such as transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve implantation (TAVI).

[0006] Typically, this type of bioprosthetic heart valve has a one-way valve structure, also called a valve assembly or leaflet assembly, mounted on a support structure also called a stent or frame, which can be made of metals or polymers such as Nitinol. In the case of collapsible / expandable prostheses, the stented valve can be self-expanding or balloon-expandable. The valve assembly can consist of two or (most often) three leaflets and a skirt or cuff to attach the leaflets. The skirt, and with it the leaflets, can be attached to the inner and / or outer surface of the stent, covering at least a portion of it and helping to prevent or reduce leakage around the outside of the valve (often called paravalvular leakage). The skirt can also be made of treated natural tissue, but is generally based on synthetic materials such as polyester fabrics or polytetrafluoroethylene films. The components can be attached to the stent in various ways, such as by suturing, gluing or heat bonding. Each leaflet has a free end, also called a free margin, which, in response to changes in blood pressure, move toward each other to close the valve, and toward the inner wall of the support structure to open the valve.

[0007] Research into alternative approaches using synthetic materials and tissue engineering to produce prosthetic valves that can function for longer than the 5-10 years of current biological valves has attracted considerable interest in recent decades. Tissue engineering aims to create tissue for transplantation by encapsulating or seeding cells in a biodegradable scaffold, culturing the cell construct under appropriate conditions in a bioreactor, and then implanting this pre-processed construct so that it gradually acquires the characteristics of the patient's own tissue in vivo. Such techniques have not yet reached clinical application.

[0008] The requirements for synthetic materials that can be used for the retainer are generally related to biocompatibility, biostability compared to biodegradability, mechanical properties such as strength, and purity (i.e., free of harmful substances and additives such as lubricants and sizing agents). Minimally invasive approaches are increasingly being adopted for prosthetic heart valves in view of clinical benefits such as reduced patient recovery time, and the need to use lower profile devices is also increasing. Therefore, materials are needed to obtain leaflets and skirts with a certain flexibility that allows for miniaturization and compression to fit within narrow delivery systems. While using thinner walled materials may seem a logical choice, this may adversely affect the long-term properties and performance of the material in use. Another constraint imposed in the selection of synthetic leaflet materials would be the design paradigm that prosthetic heart valves should closely mimic the design of natural valves, and the valve assembly should be cusped with cup-shaped or belly leaflets to obtain the necessary durability and hemodynamics that will not induce clotting. Methods commonly used to create such valve designs include creating shaped leaflets or leaflet assemblies, either by coating or thermoforming material onto a mold or mandrel, or by cutting shapes from a sheet-like material and assembling three pieces into a three-dimensional leaflet assembly, for example by sewing the leaflets to each other and to a skirt and / or stent.

[0009] Many synthetic polymers have been proposed and / or evaluated as materials for the manufacture of valve leaflets, but to date, no such synthetic heart valves have yet reached clinical use. In a review article, Bezuidenhout et al. describe this type of work, focusing on polyurethanes, a class of elastic segmented copolymers that have been widely investigated for such biomedical applications (see DOI: 10.1016 / j.biomaterials.2014.09.013). Traditional polyurethanes containing polyester or polyether soft segments have been found to be prone to hydrolytic and / or oxidative degradation, and calcification and thrombosis have been observed in animal studies with valve prostheses. Valves based on alternative polyurethanes containing polycarbonate and / or polysiloxane-based segments have shown promising results in terms of durability and hemodynamics.

[0010] The use of various composite materials has also been proposed to improve the mechanical properties and durability of synthetic valves. One of the advantages demonstrated is the creation of materials with a certain anisotropy, like the natural valve leaflets, which have a complex multi-layered structure with elastic sheet-like materials (elastin) and fibrous structures (collagen) oriented in various directions.

[0011] U.S. Patent Application Publication No. 2003 / 0114924A1 describes a trileaflet prosthetic heart valve that is molded in one piece from thermoplastic polyurethane, with leaflets having specific curvatures and non-uniform thickness that are separated from each other by gaps in the unloaded state, requiring the leaflet material to stretch into open and closed positions, just as in a natural valve.

[0012] US 2018 / 0016380A1 describes a method for manufacturing heart valves by reaction injection molding of polyurethane compositions. In this application, valve leaflets are made that include partially crosslinked polyurethanes based on aromatic diisocyanates, chain extenders, crosslinkers, and soft segments such as hydrogenated polybutadiene diol. Crosslinking the polyurethane reduces degradation and stress relaxation during use.

[0013] EP 0331345 A2 relates to a heart valve prosthesis with a frame and three leaflets, which are made from a triaxially woven fabric. Leaflets made with such fabrics can be made to have a higher radial stretchability than the circumferential stretchability of the valve. The use of different fibers in the strands of the fabric, for example high strength fibers and elastic fibers, can improve this bidirectional stretching behavior. It has further been shown that the fabric can be embedded in an elastic matrix, for example polyurethane. However, triaxial weaving is a complex technique that requires special equipment.

[0014] U.S. Patent Application Publication No. 2005 / 0177227A1 discloses a method of making a valve prosthesis from fabric by shaping a fabric material, such as a woven polyester fabric, over a shaped member, e.g., by cutting a piece from the fabric and heat setting it to replicate the shape of a trileaflet valve.

[0015] Cacciola et al. (Journal of Biomechanics, 33(6)(2000), p653-658 and NL1008349) describe a method for making synthetic fiber reinforced heart valves in which a shaped core is first given a layer of EPDM rubber by solution coating, then reinforcing UHMWPE fiber is applied by wrapping over it, and finally a second layer of rubber is applied.

[0016] WO 2002 / 24119 A1 relates to a valve prosthesis with leaflets made of a polymer, which have a reinforcing member at the free end to be joined, which makes the end up to three times more flexurally stiff than the unreinforced part of the leaflet. The polymer for the leaflet can be chosen from a long list, with preferred materials being polyurethane, polysiloxane and polytetrafluoroethylene. Suitable reinforcing members can be in strip or fiber form and can be based on metal, polymer composite, carbon material or other polymers that are stronger than the polymer of the leaflet. The leaflets can be made in a variety of ways, usually by a dip coating process using a shaped core metal.

[0017] US 2003 / 0078652 A1 discloses a stentless heart valve prosthesis that includes laminated composite leaflets in which the fibers are oriented along the stress lines of the material in use to increase strength at critical points that would otherwise be points of stress concentration during material failure. Such leaflets can be fabricated by aligning the fibers in a specific direction on a curved mold and laminating a polymer sheet thereto.

[0018] US 2010 / 0249922 A1 describes artificial heart valve leaflets made from a composite comprising a knitted or woven fabric covered or embedded in a flexible polymer. The composite stretches more easily along a first axis than along a second axis, mimicking the anisotropic stretch of natural valve leaflets. In addition, stretching along both axes can occur in two stages; the first stage stretching is primarily due to distortion of the fabric strands' alignment, and the second stage stretching is primarily due to the strands' elongation. Many polymers are listed as suitable fibers for the fabric, including polyester, nylon, and polyurethane, and the flexible polymer can be, for example, polyurethane, silicone, fluorinated elastomer, or styrene / isobutylene block copolymer. No actual sample compositions or properties are provided in this patent application.

[0019] In US 2012 / 0172978 A1, the valve leaflets are made by cutting pieces from isotropic filters with uniform pores made from polyester or polypropylene monofilament, melting or sealing the ends to prevent fraying, and assembling the pieces to form a valve that can be folded and sterilized.

[0020] US 2012 / 0290082 A1 describes a transcatheter heart valve prosthesis comprising a support structure and a valve with leaflets made of an anisotropic composite including a woven fabric embedded in an elastomeric matrix, the composite being locally reinforced, i.e., fiber-reinforced, to locally limit the elongation of areas that will be subject to high stress in the intended use. The composite can include high strength polyethylene fibers and polyurethane as a matrix material.

[0021] US 2013 / 0274874 A1 provides a leaflet for a prosthetic valve, which has fibers arranged in a V-shape or curved shape at an angle to the free end of the leaflet within the valve; resulting in less stiffness due to less fiber at the free end. Such leaflets can be made by casting the fibers into an elastomeric matrix or by sandwiching and bonding the fibers between two layers of an elastic matrix. Suitable matrix materials include polytetrafluoroethylene, polyurethane or polyester sheets; suitable fibers are carbon, aromatic polyester, aromatic polyamide or polyethylene based.

[0022] US 2014 / 0005772 A1 describes the manufacture of a prosthetic heart valve having three leaflets, where the leaflet assembly can be formed by first arranging fibers in one or two orientations on a shaped mold, and then applying at least one polyurethane by spraying or dip coating to embed at least a portion of the fibers in the polyurethane. The leaflets can have a substantially uniform or gradient thickness and can have isotropic or anisotropic mechanical properties.

[0023] US 2016 / 0296323 A1 discloses an artificial heart valve with leaflets made of a composite with electrospun fibers at least partially embedded in a matrix of polyisobutylene urethane copolymer. The fibers can be made of fluoropolymers, polyesters, poly(styrene-isobutylene-styrene) triblock copolymers (SIBS) or polyurethanes, in particular polyisobutylene urethane copolymers that are harder than the matrix. The electrospun fibers can be in woven form to obtain a composite with direction-dependent properties (anisotropic) or in non-woven form to obtain an isotropic material. Multilayer composites with three or more fiber layers are also described, where the fibers of different layers can be oriented differently, for example to provide anisotropic physical and / or mechanical properties. The fibers can then be selected from a large list. The composition of the composite and the associated properties can be widely varied, but are not exemplified, and various coatings can be applied, if desired.

[0024] US 2016 / 0296325 A1 also relates to a prosthetic valve with synthetic leaflets with anisotropic properties, which is obtained by using a composite material in which a number of wavy fibers are embedded in a polymer matrix. The fibers can extend in one or more directions within the composite, such as following the contour of the free end of the leaflet made with it. The wavy fibers give the composite multi-stage tensile properties. When the composite is pulled, the wavy fibers will be taut first, and after the fibers straighten, a higher tension will be required to further stretch the material. The elongation behavior of the initial composite may be similar to the matrix material, while after most of the fibers have straightened, the fibers mainly determine its stretchability. The document suggests a number of synthetic and natural polymeric materials from which the fibers and matrix can be made, and various methods of making this type of composite, but does not provide details or specific embodiments.

[0025] US 2017 / 0071729 A1 describes a prosthetic heart valve having leaflets made of a composite material made by embedding at least a portion of a plurality of pre-tensioned fibers in a polymer matrix. When tension is removed from the composite, the fibers can relax, so that the tensile behavior of the composite can be similar to the composite with pre-formed wavy fibers described herein above. The fibers can be made of metals such as nitinol or polymers such as PEEK, PES or UHMWPE; the polymer matrix can be a polyurethane based on polyisobutylene soft segments.

[0026] US 2017 / 0065411 A1 describes the use of flexible fabrics woven from UHMWPE fibers for the manufacture of leaflets for prosthetic heart valves. Taking into account the low extensibility of this type of material, an alternative design is described that provides extra length at the free ends of the leaflets.

[0027] US 2019 / 0351099A1 describes a low-profile composite sheet having a thickness of 15-250 μm, which comprises a fabric substrate layer and a liquid-impermeable polymer coating thermally laminated thereto, which can be used as a skirt or covering material for a heart valve prosthesis. The fabric substrate layer can be a cylindrical structure comprising high tenacity monofilaments or yarns made from absorbent or non-absorbent polymers, and the substrate layer can be made by knitting, weaving, braiding or non-woven techniques. The polymer coating can be selected from a large list of polymers and can also serve to adhere the composite sheet to a substrate, thereby reducing or eliminating the use of sutures.

[0028] US 2020 / 0188098 A1 relates to polymer-containing textile materials that can be used to manufacture medical devices such as venous valves, occluder plugs, artificial vascular conduits, grafts, skin patches, anti-adhesion barriers, and artificial heart valves. The textiles can be made from several polymers, such as polytetrafluoroethylene, polypropylene, polyethylene, polyurethane, polyester, and polyamide. The textiles can be uncoated or a polymer film can be applied as one or more layers on the textile and / or as a pattern with discontinuous layers on at least a portion of the textile surface. A polymer layer can be applied to change one or more properties of the textile, such as surface roughness, porosity, slip, anti-fraying, etc.; however, it has been shown that it is primarily the fibers of the textile that determine the properties. In one embodiment, a prosthetic heart valve is described with leaflets formed from a densely woven fabric having a thickness of 50-100 μm and warp and weft strands of UHMWPE fibers, the fibers typically extending in a direction that forms an angle of 30-60 degrees with respect to a line perpendicular to the free edge of the leaflet in its flat state (or with respect to a line parallel to the longitudinal axis of the heart valve). A UHMWPE film is laminated to at least a portion of the fabric and to at least one surface of the leaflet.

[0029] US 2017 / 035480A1 relates to a catheter assembly including an expandable medical balloon over which a braid is disposed, the braid being made of first and second fibers, the second fibers having a higher melting point than the first fibers, which may be UHMWPE, and a coating may be applied to an outer surface of the braid, which may be a thermoplastic polyurethane.

[0030] WO 2019 / 197353 A1 describes a porous hybrid elastomer / polyethylene film in which one or more spots, i.e., some of the pores, of a UHMWPE film are filled with an elastomer, such as polyurethane, such that the modified spots of the film improve resistance to initiation or occurrence of tears or other failures.

[0031] Despite the efforts proposed in the above mentioned literature, it seems that clinical success of heart valve prostheses based on polymeric leaflets has not yet been achieved; this is likely due in large part to the success of biological valves, limited durability in vivo, and the occurrence of thrombotic complications in some prototype valves with polymeric leaflets. Thus, there remains a need for synthetic polymeric materials that would ideally combine in vivo stability, biocompatibility and hemocompatibility with high flexibility and moldability, high toughness, sufficient elongation, high strength, and good fatigue resistance; allowing the creation of valve prostheses that combine the hemodynamics of biological valves with improved durability. Preferably, such polymeric materials and prosthetic valves can be manufactured economically and consistently.

[0032] [overview] An object of the present disclosure includes providing a synthetic material having a combination of properties that mitigates or avoids one or more of the shortcomings of the prior art materials identified above, the material being suitable for use in the manufacture of durable heart valve prostheses and optionally other biomedical applications.

[0033] Aspects and embodiments described herein below and characterized in the claims provide a composite sheet of polyurethane elastomer reinforced with a fabric made of biocompatible high strength polymeric fibers, which combines at least some of the desired properties described above, and which can be advantageously applied for manufacturing parts of intracardiac devices, such as skirts and / or leaflets for prosthetic heart valves.

[0034] More particularly, and in accordance with one aspect of the present disclosure, the present disclosure provides a polyurethane composite sheet comprising: a biocompatible and biostable polyurethane elastomer comprising polysiloxane segments, the polyurethane forming a continuous matrix of the sheet; A woven or braided fabric having a thickness of 15 to 150 μm and including biocompatible high-strength polymer fibers; Equipped with The composite sheet contains 10 to 90% by mass of polyurethane, has a thickness of 25 to 250 μm, and has an areal density of 5 to 300 g / m 2 and; The composite sheet provides a polyurethane composite sheet that exhibits nonlinear uniaxial tensile behavior characterized by a 1% secant modulus of 20 to 200 MPa in at least one direction, a hardening transition point at 10 to 40%, and a tensile strength of at least 25 MPa (measured in water at 37°C).

[0035] Such composite sheets have been found to be biocompatible and biostable, exhibiting very high hemocompatibility (as demonstrated in patent applications WO 2020 / 178227 A1 and WO 2020 / 178228 A1), and also exhibit good flexibility and moldability while having high strength. The composite sheets can be cut to the desired dimensions and shapes with a laser, resulting in cut edges with good fray resistance and suture retention. The composite sheets can have anisotropic properties, exhibiting a specific nonlinear stress-strain behavior in at least one direction, i.e., at least along an axis oriented at 45° to the warp and weft directions when based on woven fabrics with warp and weft oriented in a 0° / 90° direction. These types of tensile properties mimic the typical performance of native heart valve leaflets and engineered pericardium, stretching under an initial relatively low stress followed by strain hardening after reaching a hardening transition point at 10-40% strain, allowing the leaflets to rapidly elastically respond to pressure changes in the blood while preventing plastic deformation and overstretching.

[0036] Because the ultimate tensile strength of the composite sheets of the present invention is significantly higher than the stress levels experienced by the leaflets of an implanted prosthetic valve, it can be predicted, in theory, that the composite sheets will also have improved fatigue resistance over treated bovine pericardium materials, which would allow for the production of valve prostheses with improved durability.

[0037] Another advantage of the composite sheets of the present invention is that they can be based on known and / or commercially available materials, allowing for consistent production using existing manufacturing methods.

[0038] A further advantage of the polyurethane composite sheet would be that the polyurethane can also act as an adhesive when the composite sheet is used in another way. For example, the composite sheet can be formed into a flat or cylindrical multi-layer structure by solvent or heat activated bonding of one or more sheets together. Similarly, one or more composite sheets and / or pieces cut therefrom can be attached to other fibrous structures such as cables, tapes, fabrics or textiles by solvent or heat bonding, for example to optimize local properties; or to other articles, for example to stent frames to form (partially) covered stents, thereby reducing the need for attachment means such as fastenings or sutures. When fabrics composed of highly crystalline synthetic fibers such as PET or UHMWPE, which do not use polyurethane as in the composites of the present invention, are thermally bonded, for example using laser welding, the form and / or flexibility of the fabric is generally impaired.

[0039] In embodiments, the polyurethane composite sheet comprises: a biocompatible and biostable polyurethane elastomer containing polysiloxane segments; a woven fabric consisting essentially of biocompatible high strength polyethylene fibers; Equipped with.

[0040] According to another aspect, the present disclosure provides a method for making a polyurethane composite sheet, comprising: a) providing a braided or woven fabric comprising biocompatible high strength polymeric fibers; b) optionally activating the surface of the fabric by pre-treating it with a high energy source; c) embedding the fabric in a biocompatible and biostable polyurethane elastomer containing polysiloxane segments; Including, The resulting composite sheet contains 10-90% by weight of polyurethane, has a thickness of 25-250 μm, and an areal density of 5-300 g / m 2Next; The composite sheet exhibits nonlinear uniaxial tensile behavior characterized by a 1% secant modulus of 20-200 MPa in at least one direction, a set transition point between 10-45%, and a tensile strength of at least 25 MPa (measured in water at 37°C).

[0041] Further aspects of the present disclosure relate to the use of such polyurethane composite sheets in the manufacture of components for indwelling medical devices, and the use of such medical indwelling device components in the manufacture of indwelling medical devices; in particular the use relates to the manufacture of one or more valve leaflets and prosthetic heart valves comprising such leaflets.

[0042] The present disclosure further provides an indwelling medical device comprising a polyurethane composite sheet as defined herein.

[0043] In other aspects, the use of the polyurethane composite sheet of the present disclosure includes applications in which the composite sheet will come into contact with body tissue or fluids, such as orthopedic applications involving tissue reinforcement procedures or intracardiac devices. Examples of materials for soft tissue reinforcement include meshes for hernia repair, abdominal wall reconstruction, or degenerative tissue reinforcement. Intracardiac devices include devices such as vascular grafts, covers for stents, meshes, or venous valves. In many such applications, sutures are used to attach the device parts to other parts of the device or to surrounding soft or bony tissue.

[0044] Other aspects include such medical devices or medical indwelling devices as shown above that comprise said polyurethane composite sheet or part of a medical indwelling device.

[0045] Although the experiments have been directed primarily to fabrics based on UHMWPE or PET fibers and certain thermoplastic polyurethanes, those skilled in the art will appreciate that portions of the present disclosure are equally applicable to flexible fabrics made from other fibers and other polyurethanes, as further illustrated in the detailed description. [Brief description of the drawings]

[0046] [Figure 1] FIG. 1 shows a typical tensile stress-strain curve for soft biological tissue such as the leaflets of the human aortic and pulmonary valves. [Diagram 2] FIG. 2 depicts the stress-strain curves measured on specimens cut from sheets of treated pericardium. [Diagram 3] FIG. 3 shows the stress-strain curves of a polyurethane composite based on the woven fabric of Example 3, measured in the warp direction (0°), the weft direction (90°), and at an angle of 45° to the warp and weft directions.

[0047] [Detailed Description] In the context of this disclosure, the following definitions are used: Textile structures are understood to include structures such as ropes, cables, tapes or fabrics made by bonding one or more strands of fibers together, for example by entanglement, by means of adhesives or binders, or by partial melting. Ropes, cables and tapes are elongated structures based on strands or fibers. Textiles are flexible materials that include a mesh of fibers, typically having a thickness much smaller than its width and length, such as a flat sheet with two faces or surfaces, or in the form of a hollow cylinder with an inner and outer surface. Fabrics include nonwovens such as felts or unidirectional sheets with randomly oriented fibers, and fabrics such as structures made from strands of fibers by techniques such as knitting, crocheting, weaving or braiding. Fabrics may be isotropic, with similar physical or mechanical properties in different directions, or anisotropic, with varying fiber types, number and / or orientation, and may have a substantially constant thickness or may be non-uniform in thickness. Strand refers to a bundle or assembly of fibers, and is often used to describe a thread or component that forms a structure. Fiber is a general term that refers to one or more elongated (thin and long), thread-like structures; it encompasses continuous fibers (also called filaments) and / or short fibers (also called staple fibers), and may refer to a single fiber or filament and / or yarn. Filament is understood to be a (single) thin thread, generally with a diameter of less than 50 μm and generally with a round or oval cross section, typically produced by (melt or solution) spinning processes. Yarn is a continuous bundle of filaments and / or staple fibers, optionally twisted together to strengthen the yarn's cohesion. A multi-filament yarn is a bundle of filaments, such as at least five filaments, optionally twisted together to strengthen the cohesion of the yarn bundle. A spun yarn is a yarn made by twisting staple fibers together.High strength fibres are fibres with a strength of at least 0.6 N / tex, which is sometimes, but incorrectly, treated as the same as the (ultimate) tensile strength.

[0048] Composite sheets, like composite textiles, refer to structures that combine two or more structural elements, such as a combination of a polymeric composition as the matrix and a textile as the reinforcing fiber. A laminated textile is a textile that has a layer of polymer attached to one or two sides, which may be applied by heat or adhesive bonding of a polymer film or sheet, and a coated textile has a coating layer (e.g. of a polymer) on one or both sides, or a portion thereof, which coating may be applied as a solution, dispersion or melt, and which may partially penetrate between the fibers of the textile and / or cover some or all of the fibers of the textile.

[0049] Knitted or crocheted fabrics are made by connecting at least one strand to another by looping around itself; commercially available knitted fabrics are generally made using multiple strands on a knitting machine. Woven textiles are made from at least two strands, one running along the length of the structure (warp) and another substantially perpendicular to it (weft, fill), where the warp and fill strands interlace (cross over and under each other) in a specific weave. Knitted and woven fabrics can be flat, sheet-like or (hollow) cylindrical structures. Braided textile structures are typically relatively narrow, planar, cylindrical or cylindrical structures made from at least three strands interlaced with each other in diagonally overlapping braids. Non-woven textiles are such as felts or spunbonded or needlepunched fibrous webs that can be made from staple or continuous fibers bonded together by chemical, mechanical, solvent and / or thermal treatment. The fibers can be randomly oriented, for example in a felt, but can also be substantially oriented in one (or more) direction. In the last instance, such structures can also be referred to as unidirectional (UD) composites, especially when bonded with a polymer by lamination, coating or impregnation.

[0050] A biocompatible material is one that exhibits biological compatibility by not producing a toxic, injurious, or immunological response when in contact with living tissue. Biodegradable means that the material is susceptible to chemical degradation or breakdown by biological means, e.g., by enzymatic action, into simpler components. Biostable or bioinert means that the material does not exhibit substantial biodegradation under the intended conditions and times of use.

[0051] According to one aspect, the present invention provides a polyurethane composite sheet suitable for manufacturing a component of a medical indwelling device, the sheet comprising: a biocompatible and biostable polyurethane elastomer comprising polysiloxane blocks, the polyurethane forming a continuous matrix; A fabric having a thickness of 15 to 150 μm, the fabric being a woven or braided fabric comprising biocompatible high-strength polymer fibers; Equipped with The composite sheet contains 10 to 90% by mass of polyurethane, has a thickness of 25 to 250 μm, and has an areal density of 5 to 300 g / m 2 and; The composite sheet provides a nonlinear uniaxial tensile behavior characterized by a 1% secant modulus of 20-200 MPa in at least one direction, a set transition point between 10-45%, and a tensile strength of at least 25 MPa (measured in water at 37°C).

[0052] The polyurethane composite sheet can be part of a medical device component, i.e., the composite sheet can form a structural or strength-imparting portion of such a component, or the composite sheet is a component of the medical device. Examples of other items that can be part of a device component or can be part of a medical device include, in the case of a prosthetic heart valve, a metal or polymer stent frame, a skirt or cuff that can cover a portion of the stent, and sutures or other fastening structures that can connect the composite sheet to other members or components. Such device components can be temporarily covered with a protective compound or film for packaging, or can be compressed and crimped into a capsule, all of which can be removed before the device component is used.

[0053] In embodiments of the present invention, the polyurethane composite sheet is a component of a medical indwelling device, for example a piece of sheet formed into a particular shape, and does not include additional components, thus simplifying the fabrication of the indwelling device or device.

[0054] The polyurethane composite sheet of the present invention comprises a biocompatible and biostable polyurethane, which forms a continuous matrix with the fabric embedded therein, i.e., the polyurethane substantially covers or encapsulates the polymeric fibers of the fabric. This type of composite sheet can also be referred to as a fiber-reinforced or fabric-reinforced polyurethane sheet. When used as a part of an implanted medical device, the polyurethane and the unembedded fabric or fibers will come into contact with body tissues or fluids. The polyurethane used is biocompatible and biostable, which means that it does not degrade or degrades very slowly under physiological conditions, allowing the implanted medical device to function for a longer period of time.

[0055] Polyurethane elastomers are typically block copolymers (also called segmented copolymers) and can be thermoplastic or thermoset (crosslinkable or crosslinked oligomers or polymers). Elastomers are polymeric materials that exhibit a relatively low tensile (and flexural) modulus and better elastic recovery after elongation or deformation compared to other synthetic polymers, such as those used to make high-strength fibers. Thermoplastic elastomers can be repeatedly melted by heating and resolidified by cooling; they derive their elasticity from reversible physical crosslinks instead of chemical crosslinks as in the case of thermoset elastomers. The polyurethane elastomer component of the composite sheet may be a thermoplastic or may form a thermoset during or after forming the composite sheet.

[0056] Block copolymers are polymers that contain blocks (also called segments) of polymers (including oligomers) that are chemically distinct and exhibit different thermal and mechanical properties and different solubilities. Generally, the blocks in a block copolymer that contains two (or more) types of blocks are referred to as "hard" and "soft" polymer blocks, and the presence of such different blocks results in microphase separation of the hard and soft blocks. The hard blocks in a block copolymer typically have a melting temperature (T) above the use temperature, e.g., about 35° C. m ) or glass transition temperature (T g The soft block in the block copolymer often has a T of less than 25° C., preferably less than 0° C. g Most of the mechanical properties, T m and T g Thermal parameters such as are generally determined using known techniques such as DSC or DMA using dried samples. In phase-separated block copolymers, the hard segments act as physical crosslinks for the flexible soft segments, resulting in materials with properties ranging from very rigid to flexible and elastic, depending on the ratio of hard blocks to soft blocks. Depending on the type and amount of hard blocks, polyurethanes can exhibit good stability and elasticity over the desired temperature range without the need for chemical crosslinking, and can generally be processed as thermoplastics.

[0057] In some embodiments of the present disclosure, polyurethane is thermoplastic. The advantage is that the composite can be made not only by thermal bonding or lamination of polyurethane granules or sheets to fabric, but also by coating and impregnating the fabric with a solution of polyurethane. In addition, the composite sheet can be formed into a desired shape using a mold or mandrel and specific heating and cooling steps.

[0058] In other embodiments, the polyurethane is a thermosetting composition, which can be processed to form a composite with the fabric during and / or after crosslinking the polyurethane, thereby stabilizing the product and improving mechanical properties such as elasticity and fatigue resistance.

[0059] The term thermoplastic polyurethane elastomer (TPU) basically refers to a family of polymers with a substantially linear backbone, typically comprising a mixture of at least three main components: diisocyanate, diol chain extender and polymeric diol (also called macroglycol). Optionally, monofunctional compounds can be used as further components that act as chain terminators and form end groups. The end groups may only function to terminate the reaction, but they can also be functional groups, such as non-polar or hydrophobic end groups or hydrophilic end groups. Polyurethanes modified with this type of functional end group may have improved interaction with other materials, such as fibers in composites or biological materials as part of indwelling devices.

[0060] In embodiments, the backbone of the polyurethane elastomer or TPU applied in the present invention is linear and has, on average, one or two hydrophobic end groups.

[0061] In embodiments, the polyurethane elastomers include a hard block in the repeating units that includes urethane groups and optional urea groups obtained by reacting a diol and an optional diamine as a chain extender with a diisocyanate.

[0062] Suitable diisocyanates include aromatic, aliphatic and cycloaliphatic compounds having an average of 1.9 to 2.1 isocyanate groups per molecule. In one embodiment, the diisocyanate includes 4,4'-diphenylmethane diisocyanate (MDI), 2,4-toluene diisocyanate, 2,6-toluene diisocyanate (TDI), 1,4-phenylene diisocyanate, hexamethylene diisocyanate (HDI), tetramethylene-1,4-diisocyanate, cyclohexane-1,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate (HMDI), isophorone diisocyanate (IPDI) or mixtures thereof. In one embodiment, the diisocyanate includes hexamethylene diisocyanate, dicyclohexylmethane 4,4'-diisocyanate, isophorone diisocyanate or mixtures thereof. In one embodiment, the diisocyanate comprises hexamethylene diisocyanate, dicyclohexylmethane 4,4'-diisocyanate, isophorone diisocyanate, or mixtures thereof.

[0063] In some embodiments, the diisocyanate comprises 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, or 1,4-phenylene diisocyanate. In other embodiments, the diisocyanate comprises 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, 1,4-phenylene diisocyanate, or a mixture of two or more thereof. In one embodiment, the molar mass of the diisocyanate is 100 to 500 g / mol. In one embodiment, the molar mass of the diisocyanate is 150 to 260 g / mol.

[0064] Chain extenders are typically low molar mass aliphatic compounds with two or more hydroxyl or amine groups. Difunctional chain extenders are linear and generally produce thermoplastic polymers, while polyfunctional isocyanates and / or chain extenders will produce branched or crosslinked products. In some embodiments, the difunctional chain extender has a molar mass of at least 60 g / mol, at least 70 g / mol, at least 80 g / mol, at least 90 g / mol, or at least 100 g / mol. In other embodiments, the chain extender has a molar mass of at most 500 g / mol, at most 400 g / mol, to at most 300 g / mol, at most 200 g / mol, or at most 150 g / mol. In embodiments, the chain extender comprises at least one of ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, and 1,8-octanediol and / or the corresponding diamines of this type. The presence of urea groups resulting from the reaction of isocyanate with amine groups typically results in stronger molecular interactions; this can be advantageous in some applications. In embodiments, the polyurethane elastomer comprises only diol chain extenders and exhibits thermoplastic behavior, i.e., the polyurethane elastomer is a thermoplastic polyurethane elastomer or TPU.

[0065] In another embodiment, the polyurethane elastomer comprises a hard block having both urethane and urea linkages; this type of polymer may also be referred to as a polyurethane urea elastomer. The advantage is that the interaction between the hard blocks is strengthened, which allows for a higher content of soft blocks, resulting in a block copolymer with improved flexibility and elasticity and excellent flex life or fatigue resistance. Depending on the diol / diamine ratio, polyurethane elastomers may exhibit such strong interactions that they may be thermally degraded at melt processing temperatures, so solution processing may be preferred for optimal performance. Commercially available examples of such polyurethane elastomers containing both urethane and urea linkages include Biospan® products (e.g., available from DSM Biomedical BV, Sittard-Geleen NL).

[0066] In a further embodiment, the polyurethane elastomer comprises a soft block derived from a polysiloxane (also called silicone) diol or polyol and at least one aliphatic polymer diol or polyol selected from polyethers, polyesters, polyacrylates and polyolefins; the polymer is difunctional with hydroxyl (or amine) end groups. Such polymer diols for obtaining the soft block are understood herein to include oligomers, homopolymers and copolymers, and polyesters are considered to include polycarbonates. Commonly known polyurethane block copolymers and the preparation methods of these copolymers are described, for example, in US Pat. No. 4,739,013, US Pat. No. 4,810,749, US Pat. No. 5,133,742 and US Pat. No. 5,229,431.

[0067] In some embodiments of the present disclosure, the polyurethane elastomer comprises a soft block derived from a polysiloxane diol and at least one polymer diol selected from aliphatic polyester diol, aliphatic polyether diol, and poly(isobutylene) diol. As for the chain extender, an amine-functional soft block can be used, which results in the formation of additional urea bonds. The biocompatibility and biostability of such polyurethane block copolymers in the human body have been proven.

[0068] The mechanical and other properties of polyurethane elastomers can be adjusted by varying the chemical composition and / or molar mass of the blocks. The hard blocks of polyurethane elastomers used in the composite sheet can have a molar mass of about 160 to 10,000 Da, more preferably about 200 to 2,000 Da. The molar mass of the soft segments can typically be 200 to 100,000 Da, preferably at least about 400, 600, 800 or 1000 Da, and up to about 10,000, 7500, 5000, 4000, 3000 or 2500 Da. The molar mass of the polymers and oligomers discussed in connection with the present disclosure refers to the number average molar mass (M), derived, for example, from GPC measurements or by determining the amount of hydroxyl (or amine) end groups. n ) The ratio of soft block to hard block can be selected to provide a certain stiffness or hardness to the polymer. Typically, the hardness of polyurethanes, as measured by Shore hardness testing using the A or D scale, can be from 40ShA, or at least 50 or 60ShA, up to 80, 75, 70, 65 or 60ShD, or up to 100, 90 or 85ShA, which generally represents a flexural modulus in the range of about 10 to 2000 MPa. In some embodiments, the hardness of the polyurethane elastomer is from 40ShA to 60ShD, preferably 40 to 100ShA or 40 to 90ShA.

[0069] In a further embodiment of the present disclosure, the polyurethane elastomer further comprises an aliphatic polyether or an aliphatic polyester, more particularly an aliphatic polycarbonate, as a soft block. Suitable aliphatic polyethers include poly(propylene oxide) diol, poly(tetramethylene oxide) diol and copolymers thereof. Suitable aliphatic polyesters are generally those which are produced from at least one aliphatic dicarboxylic acid and at least one aliphatic diol, the components of which preferably have a T of less than 10, 0 or -10°C. g The polycarbonate diol is selected to form an essentially amorphous oligomer or polymer having the following structure: aliphatic polycarbonate diols can be synthesized via various routes known in the art based on aliphatic diols similar to those used for polyester diols. Suitable examples include poly(hexamethylene carbonate) diol and poly(polytetrahydrofuran carbonate) diol. In one embodiment, the soft block is based on poly(hexamethylene carbonate) diol, poly(polytetrahydrofuran carbonate) diol, or a mixture thereof.

[0070] In some embodiments, the polysiloxane soft block is derived from poly(dimethylsiloxane) diol. In further embodiments, the polyurethane soft block is derived from a polysiloxane diol, such as poly(dimethylsiloxane) diol, and an aliphatic polycarbonate diol or poly(tetramethylene oxide) diol. In one embodiment, the soft block is based on polysiloxane diol and polycarbonate diol, poly(tetramethylene oxide) diol, or mixtures thereof. In one embodiment, the soft block includes poly(dimethylsiloxane) diol and one or more of aliphatic polycarbonate diol and poly(tetramethylene oxide) diol. In one embodiment, the soft block is based on poly(dimethylsiloxane) diol and one or more of aliphatic polycarbonate diol and poly(tetramethylene oxide) diol.

[0071] In embodiments, the polyurethane elastomer soft block is 2 ~C 16 Fluoroalkyldiol or C 2 ~C 16 In one embodiment, the soft blocks in the polyurethane backbone are selected from the group consisting of 1H,1H,4H,4H-perfluoro-1,4-butanediol, 1H,1H,5H,5H-perfluoro-1,5-pentanediol, 1H,1H,6H,6H-perfluoro-1,6-hexanediol, 1H,1H,8H,8H-perfluoro-1,8-octanediol, 1H,1H,9H,9H-perfluoro-1,9-nonanediol, 1H,1H , 10H,10H-perfluoro-1,10-decanediol, 1H,1H,12H,12H-perfluoro-1,12-dodecanediol, 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol, 1H,1H,11H,11H-perfluoro-3,6,9-trioxaundecane-1,11-diol, fluorinated triethylene glycol or fluorinated tetraethylene glycol residues.

[0072] In some embodiments, C 2 ~C 16 Fluoroalkyldiol or C 2 ~C 16 The fluoroalkyl ether diol has an M of at least 150 g / mol, at least 250 g / mol, or at least 500 g / mol. n In one embodiment, the fluoroalkyl diol or fluoroalkyl ether diol has a molar mass of at most 1500 g / mol, at most 1000 g / mol, or at most 850 g / mol. 2 ~C 16 Fluoroalkyldiol or C 2 ~C 16The fluoroalkyl ether diol is present in an amount of at least 1 wt%, at least 2 wt%, or at least 5 wt%, based on the total weight of the polyurethane. 2 ~C 16 Fluoroalkyldiol or C 2 ~C 16 The fluoroalkyl ether diol is present in an amount of up to 15 weight percent, up to 10 weight percent, or up to 8 weight percent, based on the total weight of the polyurethane elastomer.

[0073] In embodiments, the polyurethane elastomer may include one or more hydrophobic end groups. An end group is generally a non-reactive portion at the end of a molecule. In one embodiment, the polyurethane elastomer is linear and includes a hydrophobic end group at one end or terminus, preferably at each end of the backbone, i.e., about two end groups on average. In one embodiment, the hydrophobic end group is a linear compound. In another embodiment, the hydrophobic end group is branched. The end group may be formed by reacting an isocyanate group with a co-reactive group on a monofunctional compound, also called a chain terminator, during or after the formation of the polymer backbone. For example, a formulation for forming a polyurethane may include a diisocyanate, a polymeric aliphatic diol, a chain extender, and a C 8 It may include monofunctional alcohols or amines such as 1-octanol or octylamine to form alkyl end groups.

[0074] In embodiments, the hydrophobic end group is C 2 ~C 20 Alkyl, C 2 ~C 16 Fluoroalkyl, C 2 ~C 16The hydrophobic end groups include fluoroalkyl ethers, hydrophobic poly(alkylene oxides) or polysiloxanes, including copolymers of each of these. In one embodiment, the hydrophobic poly(alkylene oxide) is poly(propylene oxide), poly(tetramethylene oxide) or copolymers thereof. In one embodiment, the hydrophobic end groups are polysiloxanes, such as poly(dimethylsiloxane) or copolymers thereof. In some embodiments, the end groups are C 2 ~C 20 Alkyl, C 2 ~C 16 Fluoroalkyl, C 2 ~C 16 The end groups include fluoroalkyl ethers or hydrophobic poly(alkylene oxides). Such end groups can be formed using monofunctional alcohols such as carbinols or the amines mentioned above. Such polyurethane elastomers with hydrophobic end groups have been found to favorably affect the properties of the polyurethane and its interaction with other materials, including other polymers such as polyolefins, and with body tissues and body fluids such as blood.

[0075] In one embodiment, the hydrophobic end group is C 2 ~C 16 Fluoroalkyl or C 2 ~C 16 Such end groups include C 2 ~C 16 Fluoroalkyl or C 2 ~C 16The terminal groups may be formed using monofunctional alcohols or amines, including fluoroalkyl ethers. In one embodiment, the terminal groups are 1H,1H-perfluoro-3,6-dioxaheptan-1-ol, 1H,1H-nonafluoro-1-pentanol, 1H,1H-perfluoro-1-hexyl alcohol, 1H,1H-perfluoro-3,6,9-trioxadecan-1-ol, 1H,1H-perfluoro-1-heptyl alcohol, 1H,1H-perfluoro-3,6-dioxadecan-1-ol, 1H,1H-perfluoro-1-oct ... The perfluoroalkyl alcohol may be formed from 1H,1H-perfluoro-1-nonyl alcohol, 1H,1H-perfluoro-3,6,9-trioxatridecan-1-ol, 1H,1H-perfluoro-1-decyl alcohol, 1H,1H-perfluoro-1-undecyl alcohol, 1H,1H-perfluoro-1-lauryl alcohol, 1H,1H-perfluoro-1-myristyl alcohol or 1H,1H-perfluoro-1-palmityl alcohol.

[0076] In one embodiment, the hydrophobic end group is monomeric and has a molar mass of 200 g / mol or more, 300 g / mol or more, or 500 g / mol or more, and 1,000 g / mol or less, or 800 g / mol or less. In other embodiments, the end group is polymeric and has a molar mass of 10,000 g / mol or less, 8,000 g / mol or less, 6,000 g / mol or less, or 4,000 g / mol or less. In one embodiment, the end group is polymeric and has a molar mass of 500 g / mol or more, 1,000 g / mol or more, or 2,000 g / mol or more.

[0077] In one embodiment, the hydrophobic end groups are present in an amount of at least 0.1%, at least 0.2%, at least 0.3%, or at least 0.5% by weight, based on the total weight of the polyurethane. In one embodiment, the hydrophobic end groups are present in an amount of at most 3%, at most 2%, or at most 1% by weight, based on the total weight of the polyurethane. In one embodiment, the hydrophobic end groups are present in an amount of at least 0.1%, at least 0.2%, at least 0.3%, or at least 0.5% by weight, and at most 3%, at most 2%, or at most 1% by weight, based on the total weight of the polyurethane.

[0078] The hard block in polyurethane elastomers or TPUs is typically based on aromatic diisocyanates such as toluene diisocyanate (TDI) or methylene diphenyl diisocyanate (MDI) and low molar mass aliphatic diols such as 1,4-butanediol. Polyether and polycarbonate polyurethanes can be suitably used in biomedical applications considering their flexibility, strength, in vivo stability, biocompatibility and abrasion resistance. TPUs containing a combination of polyether and polysiloxane or a combination of polycarbonate and polysiloxane in the soft block have a unique combination of properties and can be advantageously used as polyurethanes in composite sheets. Examples of commercially available polymers of this type include Carbosil® TSPCU products (available from DSM Biomedical BV, Sittard-Geleen NL).

[0079] In a further embodiment, the polyurethane or TPU may be a blend of two or more polymers differing in composition and / or molar mass, at least one of which contains polysiloxane segments.

[0080] In other embodiments, the polyurethane or TPU may contain one or more conventional additives that are acceptable for the targeted use of the composite sheet, for example in addition to catalyst residues. Examples of additives include stabilizers, antioxidants, processing aids, lubricants, surfactants, antistatic agents, colorants, and fillers. The additives may be present in typical effective amounts known in the art, such as 0.01 to 5% by weight, preferably 0.01 to 1% by weight, based on the amount of polyurethane. In other embodiments, the polyurethane or TPU consists essentially of polymer and is substantially free of additives. In some embodiments, the polyurethane or TPU does not contain catalyst residues.

[0081] In some embodiments, the composite sheet includes a biocompatible high strength polymer fiber and a biocompatible and biostable TPU, which can exhibit melt flow above its melting point at least 10 times higher than the melt flow of the polymer. The melting point of the TPU can be higher than the melting point of the polymer of the fiber, e.g., polyolefin, which can melt in the range of 130-190°C. The melting point of the polymer fiber will depend, among other things, on the degree of crystallinity and the amount of oriented crystals present; for example, high strength polyethylene fibers, such as UHMWPE fibers, exhibit multiple melting points in the range of 130-155°C. Essentially, this melt flow characteristic means that the melt viscosity of the polymer, e.g., polyethylene, is significantly higher than the melt viscosity of the TPU at a particular temperature above the melting point of the polymer and TPU, e.g., a temperature that can be reached during lamination of the TPU to a fabric or during laser cutting of the composite sheet. Due to this difference in melt viscosity, the molten TPU can flow into and / or around the fibers of the fabric, embedding the fibers, while the polymer of the molten fiber shows virtually no melt flow. Melt flow is typically measured as melt flow rate (MFR; also called melt flow index, MFI) according to the ASTM D1238 standard and reported as the amount of polymer extruded in a certain time (i.e. in g / 10 min) from a certain orifice under a certain load and at a certain temperature specified in the standard for various polymers. High molar mass polyolefins such as HMWPE typically have high melt viscosities, so in this test a high mass (21.6 kg compared to 2.16 kg for most polymers) is used to obtain measurable results (e.g. 0.2-1 g / 10 min at 190° C. and 21.6 kg). UHMWPE grades typically have such high viscosities that melt flow is not measurable under these conditions. In embodiments, the TPU exhibits a melt flow rate at temperatures above its melting point, such as 210-240° C., that is at least 10, 20, 40, 60, or even 100 times that of a polymer, such as a polyolefin, such as UHMWPE.If the fibers are made from a polymer that does not melt at temperatures above 250°C, the TPU can similarly flow around the fibers when laminating to form a composite sheet or when laser cutting the composite. Laser cutting itself is believed to induce very localized heating of the fibers and polyurethane matrix of the fabric by focusing the laser energy to such a temperature that the composite decomposes and vaporizes. Polyurethane composites may be suitable for cutting smaller pieces with the desired shape using a laser to produce parts for medical indwelling devices.

[0082] The polyurethane composite sheet according to the present disclosure comprises 10-90% by weight polyurethane as a matrix polymer. The amount of polyurethane, and therefore the relative amount of fabric, also plays a major role in determining the properties of the composite. For fabrics with an open structure and low areal density, a relatively small amount of polyurethane may only coat or cover the strands and / or fibers of the fabric, i.e., the coated fabric may still be porous, and a relatively large amount of polyurethane would be required to obtain a non-porous sheet. On the other hand, for example, for more densely woven fabrics, a relatively small amount of polyurethane may be used to readily obtain a non-porous composite sheet. In some embodiments, the polyurethane elastomer is present in at least an amount such that the fabric strands or fibers are completely covered and embedded, and the composite sheet is substantially non-porous.

[0083] In embodiments, a polyurethane composite sheet comprises a fabric having an open structure and low areal density and an amount of polyurethane elastomer that completely covers and embeds the strands of the fabric such that the composite sheet is substantially non-porous.

[0084] Depending on the type of fabric and the relative amount of polyurethane, the surface structure of the composite sheet may vary; for example, a non-porous composite sheet may have a particular surface texture that at least partially reflects the structure of the fabric, or the composite sheet may have a substantially smooth surface. In some embodiments, the polyurethane composite sheet may have two surfaces that are substantially identical, or may have surfaces with different textures; this is usually the result of using different methods to manufacture the composite. The properties of the composite sheet of the present disclosure may be tailored to a particular application by the relative amount of polyurethane and its surface texture, since the interaction with biological tissues and fluids is affected by both the type of polyurethane and the surface texture. In some embodiments, the composite sheet has a textured surface on one side of the sheet, while the other is substantially smooth. Such composite sheets may be utilized in medical devices, where the two sides of the composite sheet are in contact with different substrates, such as a stent graft or a valve skirt that contacts blood vessels and tissues. In other embodiments, the composite sheet has two textured surfaces, and in further embodiments, the composite sheet has two substantially smooth surfaces. A textured surface may also have a surface layer with pores, which do not extend to the opposite (smooth or textured) surface. Surface texture can be easily quantified in terms of surface roughness parameters, e.g., according to ISO25178 (e.g., Sa, Sz), using 3D laser scanning confocal microscopy.

[0085] In some embodiments, the composite sheet has at least one textured surface characterized by a surface roughness Sa of 3-12 μm and Sz of 20-100 μm, in other embodiments, the composite sheet has two textured surfaces characterized by a surface roughness Sa of 3-12 μm and Sz of 20-100 μm, one surface being less rough than the other.

[0086] In some embodiments, the amount of polyurethane in the composite sheet is at least 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85% by weight (based on the total weight of the composite sheet). In general, a higher amount will result in a more flexible and resilient composite sheet, depending on the fabric structure and type of fiber contained therein. The higher the relative amount of fabric in the composite sheet, the stronger the resulting composite will be, and the lower the strain it will exhibit strain hardening. In some embodiments, the amount of polyurethane is at most 85, 80, 80, 75, 70, 65, 60, 65, 60, 55, 50, 45, 40, 35, 30, 25, or 20% by weight. In other embodiments, the amount of polyurethane is about 25-90, 35-90, 45-90, 15-70, 20-65, 25-60, 15-55, or 20-50 weight percent.

[0087] The polyurethane composite sheet according to the present disclosure includes a woven or braided fabric as a cloth containing high-strength biocompatible polymeric fibers. The fabric can be substantially isotropic or can exhibit anisotropic properties. A person skilled in the art has knowledge of various weaving and braiding methods and the different characteristics of the resulting fabric; he or she will be able to select, optionally based on some experimentation, the type of fabric suitable for the specific application intended for the composite sheet and its requirements.

[0088] In some embodiments, the fabric is a braided fabric structure. A minimum of three strands are required for braiding (also called plaiting); the simplest structure is a flat three-stranded braid. Braiding machines can process multiple strands to create more complex braided structures such as cords, hoses, or some types of lace. For biomedical applications, examples of braided fabrics that can be used to manufacture composite sheets include braided cords, braided cylindrical structures, and two-dimensional or flat braided fabrics.

[0089] In another embodiment of the present disclosure, the fabric in the composite sheet is a woven fabric. Woven fabrics are generally made of two or more strands interwoven in an orthogonal weave; the strands of fibers running in the longitudinal (or machine) direction of the fabric are called warp strands, and the strands running in the perpendicular direction are called weft (fill) strands. Typically, woven fabrics with commonly used weaves such as plain, twill, gauze, satin, or basket weave weaves have been found to provide good performance. Woven fabrics can have similar numbers of strands in the warp and weft directions, and thus have substantially symmetrical, balanced properties. On the other hand, fabrics with anisotropic properties can be formed, for example, by using different numbers of strands or different types of strands in the warp versus weft, to reflect the typical properties of some natural tissue material, such as blood vessels or the leaflets of a heart valve. Woven fabrics can be flat fabrics with one or more layers, or can be cylindrical fabrics. Woven fabrics typically have selvedges at their longitudinal ends, where the weft strands running perpendicular to the ends of the structure do not extend from the structure as free ends, but are continuous by folding back at the ends and returning to the woven structure. However, whether such stable selvedges can function as ends in their entirety or whether they need to be cut into pieces of a particular shape from a larger composite sheet depends on the actual use in the retainer part and the design of the retainer part. The advantage of a composite sheet with a continuous polyurethane matrix is ​​that pieces can be cut out of the composite sheet using a laser, such as an ultrashort pulsed laser, to cut pieces with stable edges that exhibit good fray resistance and suture retention strength.

[0090] A further advantage of using woven or braided fabrics, rather than locally applied high strength fibers, as reinforcement for the polyurethane matrix to produce composite sheets suitable for the manufacture of, for example, prosthetic valve leaflets, is that the risk of "cheese-wiring" is greatly reduced. Such cheese-wiring can refer to high strength fibers or filaments damaging or even detaching the matrix due to repeated bending and pulling of the material. Fabrics with cross-woven fibers as reinforcement can similarly improve suture retention strength when sutures are used to connect pieces of the composite sheet together or to attach to other types of articles such as skirts or stents.

[0091] In some embodiments, the composite sheet comprises a fabric, such as a woven fabric, that includes or is substantially made from strands (warp and weft) having a fineness of 2 to 250 dtex. The unit dtex or decitex, as well as the related US unit denier, is commonly used in the textile industry to describe the linear density of a fiber, strand, yarn or filament, with 1 dtex being 1 gram per 10,000 meters of fiber. The lower the fineness, the thinner the strand. Although the type of strand and the type of polymer in the fiber and the type of fabric may also play a role, fabrics made from thin strands will generally be thinner and more flexible or pliable than fabrics made from thick strands. In embodiments of the invention, the fineness of the strands is at most 225, 200, 180, 160, 140, 120, 100, 80, 60 or 50 dtex, and at least 4, 5, 6, 8, 10, 15 or 20 dtex. In some embodiments, at least one strand has a fineness of 4-140, 6-100, or 8-60 dtex to provide a good balance between fabric handling, softness, low profile, and strength. Woven fabrics can include strands of equal or different linear densities. By using strands of different fineness, the thickness of the fabric can be varied in the length and / or width directions, creating local thickness or stiffness differences, or creating a particular texture with a particular organization, for example, depending on the type of weave. Those skilled in the art will be able to select the appropriate fineness of strands depending on the desired thickness and texture of the fabric.

[0092] In embodiments, the composite sheet comprises a woven fabric, typically expressed as warp picks per inch (EPI) and fill picks per inch (PPI), which may vary widely depending on the strand thickness and density of the fabric. Typically, the fabric contains 25 to 500 strands per inch (EPI, PPI). In embodiments, the fabric contains at least 30, 40, 50, 60, 70, 80, 90, or 100 strands per inch, and up to 450, 400, 350, 300, 250, 200, or 150 strands per inch. Given that thin, flexible fabrics are preferred for medical devices utilized in minimally invasive surgery, woven fabrics containing a small number of fine strands per unit length, for example, 30-350 strands per inch; preferably 50-250 strands per inch; more preferably 100-200 strands per inch, are preferred. Additionally, relatively open, porous structures, such as leno or mock leno weaves, are preferred.

[0093] The difference between EPI and DPI in the woven fabric is preferably small, which reduces the variation in bending stiffness when measured in different directions of the composite sheet, a desirable property for use in cardiac valve leaflets, among other applications. Typically, the difference between EPI and DPI is at most 200, preferably at most 150, more preferably at most 100 or at most 50. Expressed as a percentage, the difference between EPI and DPI is at most 100%, preferably at most 80%, more preferably at most 40%, 30% or 20%.

[0094] In some embodiments, the fineness of the warp and weft strands of the woven fabrics in the composite sheet are substantially equal. In such cases, especially when the number of warp and weft strands per unit length is also substantially equal, the woven fabrics and composite sheets containing such woven fabrics will be balanced; i.e., will exhibit similar properties in the warp (or longitudinal or 0°) and weft (orthogonal or 90°) directions. Typically, the tensile properties of the composite sheet (fabric therein) in the warp and weft directions will be determined largely by the polymer fibers in the fabric after the initial stages of stretching the sheet when the strands straighten out, but will differ from the tensile behavior measured in a direction or axis at an angle to the warp and weft directions; the tensile elongation in this direction will also be affected by the deformation of the woven fabric and the deformation of the polyurethane matrix, especially in the initial stages of stretching. In such directions at angles to the warp and weft yarns, particularly directions that are substantially between the warp and weft directions (i.e., angles of about 30-60°, particularly about 45°, relative to the warp and weft yarns), the composite sheet will exhibit nonlinear uniaxial tensile behavior.

[0095] In general, nonlinear tensile behavior is typical of some types of natural soft tissues, such as the leaflets of heart valves. Figure 1, taken from the paper by Hasan et al. (J.Biomechanics 47, p 1949-1963; or DOI: 10.1016 / j.jbiomech.2013.09.023), shows a schematic representation of such nonlinear behavior in the form of stress-strain curves. Hasan defines the "high modulus" (hereafter referred to as the hardening modulus) as E H and the "strain extrapolated to zero stress" (hereinafter referred to as the hardening transition point) is ε 0 and the "transition strain" is ε trIt has been stated that the stress-strain curve of soft tissue can be divided into several phases: (i) a low stress-low strain linear elastic region, (ii) a highly nonlinear transition region, (iii) a post-transition linear region involving elongation of oriented collagen fibers, and (iv) a nonlinear region where stress drops to failure. When the heart is functioning normally, the leaflets will typically elongate by about 10-15% during valve opening and closing; this is less than the stiffening transition. This is further illustrated in FIG. 2, which shows three stress-strain curves for specimens taken from a sheet of treated pericardium measured under physiological conditions (e.g., in water at 37° C.), which also illustrates the heterogeneity of such native tissues. The stiffening transition observed for this pericardium material is in the range of 25-45% strain.

[0096] The polyurethane composite sheet comprises a fabric comprising biocompatible, high strength polymeric fibers that form the strands of the fabric and can exist in different forms, such as as monofilaments, as multifilament (usually twisted) yarns, or as two or more twisted or braided yarns. In some embodiments, the fabric consists of a single strand of multifilament yarn, allowing for high flexibility and low thickness of the composite.

[0097] In some embodiments, the composite sheet comprises a woven or braided fabric comprising at least 50% by weight of high strength polymeric fibers and additional other fibers or strands that may have different characteristics so long as the fabric conforms to other characteristics described herein. In some embodiments, the fabric comprises at least 10, 20, 30, or 40% by weight of high strength polymeric fibers. In some embodiments, the fabric comprises at least 60, 70, 80, 90, or 95% by weight of said high strength polymeric fibers or is substantially made from said high strength polymeric fibers.

[0098] In some embodiments, the thickness of the fabric in the composite sheet is about 15-150 μm. The thickness of the fabric is related to the type of strands, the type of forming technique used in producing the fabric, and the density of the fabric; for example, the distance between the fibers or strands in the fabric. Preferably, the thickness of the fabric is at most 125, 100, 90, 80, or 75 μm to improve flexibility and softness, and at least 20, 25, 30, 35, 40, 45, or 50 μm to obtain a certain strength and durability. If the thickness of the fabric is not uniform, these values ​​represent the maximum and minimum thickness.

[0099] In some embodiments, the areal density of the fabric in the composite sheet is between 5 and 150 g / m 2 The areal density of the fabric is related to the type of strand, the type of forming technique used in producing the fabric, and the density of the fabric; for example, the distance between the fibers or strands in the fabric. Preferably, the areal density of the fabric is at least 6, 7, 8, 9, 10 g / m 2 and up to 125, 100, 90, 80, 70, 60, 50, 40, 30 or 25 g / m 2 It is.

[0100] The high strength fibers in the fabric can have a variety of different structures and can be made from a variety of synthetic polymers that are biocompatible and optionally biostable. In some embodiments, the fibers are present as monofilament yarns or as multifilament yarns. In the case of monofilaments, preferably the strands in the fabric are formed from one monofilament, typically having a fineness of 2 to 50 dtex. If the monofilament is thicker, the stiffness of the fabric may be too high for the intended application. Preferably, the fineness of the monofilament is up to 45, 40, 35 or 30 dtex to obtain a fabric with good flexibility.

[0101] In other embodiments, the fabric comprises or consists essentially of strands having at least one multifilament yarn. Taking into account the sizing considerations discussed above for strands in fabrics such as woven fabrics, the fineness of the multifilament yarns in the fabric can be about 2 to 250 dtex. The yarn fineness is preferably at most 225, 200, 180, 160, 140, 120, 100, 80, 60 or 50 dtex, and at least 4, 5, 6, 8, 10, 15 or 20 dtex. In some embodiments, at least one yarn has a fineness of 2 to 100, 4 to 80 or 6 to 60 dtex. When the strand comprises more than one yarn, the fineness is selected to fit within the ranges indicated for the strand. The multifilament yarns can be twisted or untwisted. Twisted yarns are generally easier to handle and convert into fabrics, while untwisted yarns can result in softer fabrics because the filaments can move more easily out of position with respect to each other and the cross section of the yarns can be more rectangular or flat in the fabric. In some embodiments, the fabric is made from strands that include untwisted multifilament yarns. Typically, the individual filaments in the multifilament yarns can vary widely in fineness per filament, such as 0.2-10 dtex, preferably 0.3-5 or 0.4-3 dtex per filament, and the filaments can be substantially circular, but can also have a rectangular or any other shaped cross section.

[0102] The polyurethane composite sheet comprises a fabric comprising biocompatible high strength polymeric fibers. The fibers can be biostable or biodegradable. In the context of the present disclosure, high strength fibers are fibers having a tenacity of at least 0.6 N / tex. In some embodiments, the fabric in the composite sheet comprises high strength fibers having a tenacity of at least 0.7, 0.8, 0.9 or 1.0 N / tex. Tenacity is typically measured on multifilament yarns, but can also be measured on single filaments; suitable methods are described in the experimental section. Suitable fibers are generally made from thermoplastic polymers that can vary widely in chemical composition. Biocompatible thermoplastic synthetic polymers used in the manufacture of the fibers include materials such as poly(meth)acrylates, polyolefins, vinyl polymers, fluorinated polymers, polyesters, polyamides, polysulfones, polyacrylics, polyacetals, polyimides, polycarbonates and polyurethanes, including copolymers, compounds and blends thereof. Such synthetic polymers may be based on natural compounds such as amino acids and / or synthetic monomers. In some embodiments, the biocompatible high strength fibers are based on polyolefins, polyketones, polyamides or polyesters. Suitable polyolefins include high molar mass polymers of this type, such as polyethylene and polypropylene, especially high molar mass polyethylene (HMWPE) and ultra-high molar mass polyethylene (UHMWPE). Suitable polyamides include aliphatic, semi-aromatic and aromatic polyamides, such as polyamide 66 and poly(p-phenylene terephthalamide). Suitable polyesters include aliphatic, semi-aromatic and aromatic polyesters, such as poly(l-lactic acid) (PLLA) and its copolymers, polyethylene terephthalate (PET) and liquid crystal aromatic copolyesters. In one embodiment, the fibers are made from PET or PLLA. The polymer fibers can be produced using a variety of fiber spinning methods known in the art, such as melt spinning and solution spinning, including specialized techniques such as gel spinning or electrospinning.

[0103] In a further embodiment, the high strength fibers in the fabric of the composite sheet are made from one or more polyolefins selected from homopolymers and copolymers, such as copolymers and terpolymers, containing one or more olefins, such as ethylene and propylene, as monomer units. Such polyolefins are preferably of high molar mass and can be formed by any method known to those skilled in the art. High molar mass is understood herein to mean a weight average molecular weight (or molar mass) of at least 350 kDa as determined by GPC or derived from solution viscosity measurements. Suitable examples of polyolefins include polypropylene, polyethylene and copolymers or blends thereof; polypropylene homopolymers, medium density polyethylene, linear or high density polyethylene, copolymers of ethylene with relatively small amounts of one or more alpha-olefins, such as butene-1, hexene-1 and octene-1, linear low density polyethylene, ethylene / propylene copolymers, propylene / ethylene copolymers, polyisoprene, etc. Polypropylene and polyethylene polymers are preferred. The advantage of such high molar mass polyolefin fibers is that, in addition to their good biocompatibility and biostability, fibers of this type have a relatively high tensile strength (both at the yarn and filament stage), i.e. a strength of at least 1.5 N / tex, which makes it possible to manufacture thin, yet strong and durable fabrics.

[0104] In a further embodiment, the fabric comprises fibers made from linear polyethylene, such as high molecular weight polyethylene (HMWPE) or ultra-high molecular weight polyethylene (UHMWPE). The old term molecular weight is still used interchangeably with molar mass in the art, as reflected in the commonly used abbreviations for (ultra) high molar mass polyethylene. UHMWPE is a synthetic polymer that combines high biostability or bioinertness with good biocompatibility and has been used in various biomedical devices and indwelling devices for quite some time now. UHMWPE is understood herein to be a polyethylene having an intrinsic viscosity (IV) of at least 4 dL / g, for example 4-40 dL / g. Intrinsic viscosity is a measure of molar mass and can be more easily determined than actual molar mass parameters such as Mn and Mw. IV is determined according to ASTM method D1601 (2004) by extrapolating the viscosity measured at various concentrations in decalin at 135°C, with a dissolution time of 16 hours and containing butylhydroxytoluene as an antioxidant at a level of 2 g / L solution, down to zero concentration. There are various empirical relationships between IV and Mw, which typically depend on factors such as molar mass distribution. The formula Mw=5.37×10 4 [IV] 1.37 Based on this, an IV of 8 dL / g corresponds to a Mw of about 930 kDa. See EP 0504954 A1. In embodiments, the IV of the UHMWPE in the fiber is at least 5, 6, 7 or 8 dL / g, and the IV is up to 30, 25, 20, 18, 16, or even up to 14 dL / g to balance high mechanical properties and ease of processability. In general, the measured IV of the UHMWPE polymer in the fiber or fabric may be somewhat lower than the IV of the polymer used to make the fiber. During fiber manufacturing processes, such as the gel extrusion process described below, polyolefins may undergo thermal, mechanical and / or chemical degradation, which may result in chain breaks, a reduction in molar mass, and / or a change in molar mass distribution.

[0105] In a further embodiment of the present disclosure, the UHMWPE in the fiber can be a linear or slightly branched polymer, with linear polyethylene being preferred. Linear polyethylene is understood herein to mean polyethylene with less than one side chain per 100 carbon atoms, preferably less than one side chain per 300 carbon atoms, the side chain or branch containing at least 10 carbon atoms. Furthermore, linear polyethylene can be copolymerized with one or more other alkenes copolymerizable with ethylene, such as C 6 alkene, e.g. propene, 1-butene, 1-pentene, 4-methylpentene, 1-hexene and / or 1-octene. 3 ~C 12 Alkenes can be included up to 5 mol %. Side chains and comonomers in UHMWPE can be suitably measured by FTIR, for example, on 2 mm thick compression molded films, by quantifying the absorbance at 1375 cm using a calibration curve based on NMR measurements (e.g., as described in EP 0269151).

[0106] The UHMWPE in the fibers may be a single polymer grade, but may also be a mixture of grades of polyethylene, differing, for example, in molar mass (distribution) and / or type and amount of side chains or comonomers. The UHMWPE in the fibers may also be a blend containing up to 25% by weight of other polyolefins as mentioned above. In general, the UHMWPE fibers are suitable for medical applications and contain only small amounts of conventional biocompatible additives and residual spin solvent. In some embodiments, the fibers contain up to 5, 4, 3, 2, or 1% by weight of additives. In other embodiments, the UHMWPE fibers, or at least a portion thereof, are doped with tantalum or Bi. 2 O 3In such cases, the fibers generally contain a relatively large amount, such as 15-50% by weight, of a submicron-sized particulate radiopaque agent to provide adequate contrast in imaging techniques. In further embodiments, the fibers contain up to 1000 ppm of spin solvent, preferably up to 500, 300, 200, 100 or 60 ppm.

[0107] In embodiments, the high strength polymer fibers contained in the fabric are UHMWPE fibers having a tensile strength or tenacity of at least 1.5, 2.0, 2.5, 2.8 or 3.0 N / tex, and typically at most about 4.5, 4.0, 3.7 or 3.5 N / tex; preferably, a tensile modulus of at least 30 and at most 150 N / tex. Tensile properties such as strength (or tenacity) and modulus (or Young's modulus) of UHMWPE fibers are defined and determined, for example, for multifilament yarns, at room temperature, i.e., about 20°C, using an Instron 2714 "Fibre Grip D5618C" type chuck, with a nominal fiber gauge length of 500 mm, a crosshead speed of 50% / min. The modulus is determined based on the measured stress-strain curve as the slope between 0.3 and 1% strain. Alternatively, the tensile properties can be measured on single filaments using the procedure shown in the experimental section. To calculate the modulus and strength, the measured tension is divided by the fineness, which is determined by weighing 10 meters of yarn; values ​​in MPa are calculated for UHMWPE fibers with a density of 0.97 g / cm 3 It can be calculated from N / tex assuming that

[0108] In embodiments, the high strength polyolefin fibers contained in the fabric may be produced by the so-called gel spinning process. In a typical gel spinning process, a solution of a polymer in a suitable spinning solvent, optionally containing further dissolved and / or dispersed components, is spun and cooled into a gel fiber, which is then stretched before, during and / or after partial or substantial removal of the spinning solvent. Gel spinning of solutions of UHMWPE is well known to those skilled in the art and has been described in numerous publications including EP 0205960A, EP 0213208A1, U.S. Pat. No. 4,413,110, GB 2042414A, EP 0200547B1, EP 0472114B1, WO 2001 / 73173A1, WO 2015 / 066401A1, Advanced Fiber Spinning Technology, Ed. T. Nakajima, Woodhead Publ. Ltd (1994), ISBN 1855731827, and references cited therein. Examples of UHMWPE multifilament yarns suitable for use in medical applications include those available as Dyneema Purity® grades (eg, from DSM Biomedical BV, Sittard-Geleen NL).

[0109] The polyurethane composite sheet comprises a fabric comprising biocompatible, high strength polymeric fibers. In some embodiments, the fabric comprises at least 80, 85, 90, or 95% by weight of high strength UHMWPE fibers or filaments. In other embodiments, the fabric, e.g., the warp and / or weft strands of a woven structure, consist essentially of or consist of UHMWPE fibers or multifilament yarns.

[0110] In further embodiments, the fabric may include more than one type of high strength fiber or may include high strength fibers and other fibers such as elastic fibers. In the case of a fabric, such different fibers may be present in some but not all strands, such as in the warp strands and not in the weft strands, or in the weft strands and not in the warp strands. In embodiments of the present disclosure, the fabric is a woven fabric including warp and weft strands of high strength fibers and warp and weft strands of other fibers, the composition in the warp and weft directions being substantially the same; the fabric exhibits similar properties in the warp and weft directions. In some embodiments, the warp strands are (substantially) made of UHMWPE and the weft strands are (substantially) made of other synthetic polymers such as polyesters, such as PET, or the weft strands are made of UHMWPE fibers and the warp strands are made of other polymers, such as PET. Such fabrics typically have anisotropic properties, such as different strengths and / or elongations in the warp versus weft directions.

[0111] In another embodiment, a polyurethane composite sheet comprises a fabric consisting essentially of or consisting of one type of high strength polymeric fibers.

[0112] In embodiments of the present disclosure, the polyurethane composite sheet comprises: a biocompatible and biostable polyurethane elastomer containing polysiloxane segments; a woven fabric consisting essentially of biocompatible high strength polyethylene fibers; Equipped with.

[0113] In one embodiment, the composite sheet of the present disclosure has a thickness of 25 to 250 μm and an areal density of 5 to 300 g / m 2In some embodiments, the composite sheet has a thickness of about 25 to 200 μm. Preferably, the composite sheet has a thickness of at most 150, 125, 100, 90, 80, or 75 μm to provide improved flexibility and softness, and a thickness of at least 30, 35, 40, 45, or 50 μm to provide a degree of strength and durability and a certain surface roughness. If the fabric is not of uniform thickness, these values ​​represent the maximum and minimum thicknesses measured.

[0114] In some embodiments, the areal density of the composite sheet is 10 to 200 g / m 2 Preferably, the areal density of the composite sheet is at least 12, 14, 16, 18 or 20 and at most 150, 125, 100, 90, 80, 70, 60, 50, 40 or 30 g / m 2 It is.

[0115] Having described that coated woven fabrics with anisotropic properties may be suitable for certain applications, the inventors have surprisingly found that polyurethane elastomer-based composite sheets with specific desired properties can be designed and obtained by selecting and optimizing a number of variables and parameters, including fabric properties such as fabric type, fiber orientation, weave structure, warp and weft density, strand thickness, type of polymer fiber in the warp and weft strands, and polyurethane elastomer type and amount, as discussed herein above, to obtain a composite sheet with a specific thickness, areal density, and flexibility; the composite sheet exhibits nonlinear uniaxial tensile behavior, characterized in at least one direction by a 1% secant modulus of 20-200 MPa, a cure transition point between 10-45%, and a tensile strength of at least 25 MPa (in water at 37°C).

[0116] Such polyurethane composite sheets with woven fabrics show nonlinear tensile properties in at least one direction when measured in a direction oblique to the warp and weft directions of the strands of the fabric, for example at about 45 degrees to the warp or weft. When measured under the same physiological conditions, the corresponding tensile properties, especially the secant modulus and strain hardening, were found to be comparable to those of the pericardium sheets, as illustrated by the results shown in Figure 2 (for the pericardium) and Figure 3 (for Example 3). In addition, the composite sheets have an ultimate tensile strength in any direction, especially in the warp and weft directions, that is substantially higher than the pericardium tested; this means that if the composite sheets are used, for example, in the leaflets of a prosthetic valve, the maximum level of stress experienced by the material in use will remain much lower than the stress that may lead to fracture. Several scientific papers have shown that in such cases the material will have improved fatigue behavior compared to materials exposed to levels of stress close to its ultimate strength. Accordingly, prosthetic valves having leaflets fabricated from polyurethane composite sheets according to the present disclosure can thus be expected to exhibit greatly improved durability over prior art biological and synthetic valves.

[0117] In exemplary embodiments, the polyurethane composite sheet comprises a woven fabric having high strength fibers in the warp and weft strands and a tensile strength of at least 30, 35, or 40 MPa in a direction at about 45° to the warp and weft strands, and in other embodiments, a woven fabric exhibiting at least such a tensile strength in any direction. There is no specific limit to the tensile strength, but in some embodiments, the tensile strength is up to about 400, 350, or 300 MPa.

[0118] In some embodiments, the polyurethane composite sheet comprises a woven fabric having high strength fibers in the warp and weft strands and a 1% secant modulus in a direction approximately 45° to the warp and weft strands of at least 25 MPa and at most 190, 170, 150, 130, 110, 90, 70, or 50 MPa.

[0119] In another embodiment, the polyurethane composite sheet comprises a woven fabric as the fabric having high strength fibers in the warp and weft strands and a set transition point in a direction approximately 45° to the warp and weft strands of at least 11, 12, 13, 14, or 15% and at most 42, 40, 38, or 36%.

[0120] In one embodiment, the polyurethane composite sheet of the present disclosure comprises 10-90% by weight of a biocompatible and biostable polyurethane elastomer containing polysiloxane segments; and the woven or braided fabric comprises biocompatible high-strength polymer fibers. The composite sheet may further comprise one or more adjuncts, such as one or more compounds selected from: antibiotics; pharmacological agents (e.g., paclitaxel) that inhibit (restenosis) of the graft; agents that inhibit thrombosis (e.g., heparin or similar natural or synthetic anticoagulants) that can be chemically or otherwise bound to the surface; other biologics and small molecules to induce a desired biological response; and radiopaque agents. Such optional adjunct compounds are preferably approved for their intended use by a regulatory agency such as the FDA; and may typically be present in relatively small and effective amounts such that their concentrations in the composite sheet are effective for their intended purpose and within the approved range, while not unacceptably degrading other performance properties of the composite sheet. Typically, the compounds are present at a maximum amount of about 5 or 2% by weight; except in the case of radiopaque compounds, where higher relative amounts are required to effectively enhance contrast in medical images.

[0121] For example, the bending properties of materials used as the leaflets of a heart valve prosthesis are important to open and close efficiently, which can affect, for example, blood flow. Typically, fiber-reinforced heart valve leaflets have an undesirably high stiffness. Thus, in one embodiment, a material is provided that has a relatively low bending stiffness. Additionally, in one embodiment, a material is provided that has a small change in bending stiffness measured in different directions, e.g., orthogonal directions. In this way, the orientation of the material in manufacturing the heart valve leaflets does not dictate the opening and closing of the valve.

[0122] The highest bending stiffness / unit width of the polyurethane composite sheet is typically at most 45 Nm. Preferably, it is at most 40 Nm, more preferably at most 35 Nm, even more preferably at most 30 Nm, 20 Nm, 15 Nm, 10 Nm, 5 Nm, or even at most 2 Nm. The lowest bending stiffness / unit width of the polyurethane composite sheet is typically at least 0.1 Nm. Preferably, it is at least 0.2 Nm, more preferably at least 0.5 Nm, 1 Nm, or even 1.5 Nm.

[0123] In one embodiment, the maximum difference between the bending stiffness / unit width measured in two orthogonal directions of the polyurethane composite sheet is at most 20 Nm. In other words, the difference between all measurements of the bending stiffness / unit width of the polyurethane composite sheet measured 90 degrees apart will be at most 20 Nm. Preferably, this is at most 15 Nm, more preferably at most 10 Nm, even more preferably at most 5 Nm, and most preferably at most 3 Nm. Typically, the minimum difference between the bending stiffness / unit width measured in two orthogonal directions of the polyurethane composite sheet is at least 1 Nm; preferably at least 2 Nm. In one embodiment, the maximum difference between the bending stiffness / unit width measured in any two orthogonal directions of the polyurethane composite sheet is less than 60% of the higher measurement. Preferably, this is no more than 50% of the higher measurement, more preferably no more than 40%, no more than 30%, no more than 20%, or even no more than 10% of the higher measurement. For example, if the measurement at 0° is 50Nm and the measurement at 90° is 15Nm, the difference is 70%.

[0124] In one embodiment, the maximum difference in bending stiffness / unit width measured in any two directions 45° apart of the polyurethane composite sheet is at most 20 Nm. Preferably, this is at most 15 Nm, more preferably at most 10 Nm, even more preferably at most 5 Nm, and most preferably at most 3 Nm. Typically, the minimum difference in bending stiffness / unit width measured in any two directions 45° apart of the polyurethane composite sheet is at least 1 Nm, preferably at least 2 Nm. In one embodiment, the maximum difference in bending stiffness / unit width measured in any two directions 45° apart of the polyurethane composite sheet is less than 60% of the higher measurement. Preferably, this is no more than 50% of the higher measurement, more preferably no more than 40%, no more than 30%, no more than 20%, or even no more than 10% of the higher measurement.

[0125] In one embodiment, the maximum difference in bending stiffness / unit width of the polyurethane composite sheet with respect to each of i) the warp direction (0°) at an angle of 45° to the warp and weft threads, and ii) the weft direction (90°) at an angle of 45° to the warp and weft threads, is at most 20 Nm. Preferably, it is at most 15 Nm, more preferably at most 10 Nm, even more preferably at most 5 Nm, and most preferably at most 3 Nm. Typically, the minimum difference in bending stiffness / unit width of the polyurethane composite sheet with respect to each of i) the warp direction (0°) at an angle of 45° to the warp and weft threads, and ii) the weft direction (90°) at an angle of 45° to the warp and weft threads, is at least 1 Nm, preferably at least 2 Nm. In one embodiment, the maximum difference in bending stiffness / unit width of the polyurethane composite sheet for each of i) the warp direction (0°) at an angle of 45° to the warp and weft yarns, and ii) the weft direction (90°) at an angle of 45° to the warp and weft yarns is less than 60% of the higher measurement, preferably no more than 50% of the higher measurement, more preferably no more than 40%, no more than 30%, no more than 20%, or even no more than 10% of the higher measurement.

[0126] In embodiments, the polyurethane composite sheet of the present disclosure comprises: 10 to 90 mass % of a polyurethane elastomer having biocompatibility and in vivo stability; 90 to 10 mass % of a fabric containing biocompatible high-strength polymer fibers; 0 to 25% by weight, preferably 0 to 5 or 0 to 2% by weight, of one or more auxiliary components; Equipped with.

[0127] The components in this case can be those described herein above for the polyurethane, for the fabric, and for the auxiliary components, including all variations and options disclosed for each component in the embodiments, and any possible combinations thereof, unless otherwise specified or physically not feasible.

[0128] The polyurethane composite sheet has in vivo stability and biocompatibility and exhibits very high blood compatibility. In a co-pending application currently published as WO 2020 / 178228A1, blood compatibility tests using a Chandler Blood Loop in vitro model and human blood demonstrated that polyurethane-coated UHMWPE fabrics based on materials similar to those disclosed herein exhibit superior blood compatibility to PET fabrics, which are often used in blood contact applications such as stent grafts.

[0129] A further advantage of the polyurethane composite sheet of the present disclosure is that the sheet can be cut into pieces using a variety of methods, such as a blade, scissors, or laser, resulting in pieces with stable cut edges. In embodiments, pieces of composite sheet cut using a pulsed laser, such as an ultrashort pulsed laser, are provided that have well-defined, stable cut edges and high fray resistance and suture retention strength, as also reported in WO2020178228A1 for composite sheets of similar composition.

[0130] According to another aspect, the present disclosure provides a method for making a polyurethane composite sheet, comprising: a) providing a braided or woven fabric comprising biocompatible high strength polymeric fibers; b) optionally activating the surface of the fabric by pre-treating it with a high energy source; c) embedding the fabric in a biocompatible and biostable polyurethane elastomer containing polysiloxane segments; Including, The resulting composite sheet contains 10-90% by weight of polyurethane, has a thickness of 25-250 μm, and an areal density of 5-300 g / m 2 Next; The composite sheet exhibits nonlinear uniaxial tensile behavior characterized in at least one direction by a 1% secant modulus of 20-200 MPa, a set transition point between 10-45%, and a tensile strength of at least 25 MPa.

[0131] In step a) of the method of the present disclosure, a fabric is provided as described above for the polyurethane composite sheet herein, including all variations and options disclosed as embodiments thereof and any possible combinations, unless otherwise specified or physically impossible. In embodiments of the present disclosure, the fabric is substantially flat, such as that obtained by a fabric manufacturing process, such as weaving. In other embodiments, the fabric is manufactured in a shaped form, such as a curved form. Examples of shaped fabrics include cylindrical structures, such as cylindrical braided or woven fabrics, 3-D woven fabrics, or woven or braided fabrics that are subsequently thermoformed using a mold or mandrel.

[0132] The disclosed method includes an optional step b) of pretreating the surface of the fabric with a high energy source in order to activate the surface. This type of treatment is aimed in particular at improving the adhesion of the fibers in the fabric to the polyurethane, but can also simultaneously clean the surface of the fabric, i.e. at least a portion of the fibers. Many synthetic polymer fibers, especially polyolefin fibers, have relatively non-polar and non-reactive surfaces to which polymers with higher polarity, such as some polyurethanes, may not adhere sufficiently to produce a composite with high durability under conditions of constantly changing loads without such pretreatment.

[0133] In some embodiments, the method includes a step b) of activating the surface. Such surface activation can be performed, for example, by plasma or corona treatment, as known in the art, and can introduce functional groups, such as oxygen-containing groups. Suitable examples of plasma surface treatments include low-temperature plasma treatments, which can be performed under atmospheric and reduced pressure, at temperatures that do not adversely affect the polymeric fibers of the fabric, such treatments being performed, for example, in the presence of oxygen.

[0134] In one embodiment, the pretreatment step includes activation with atmospheric plasma or corona treatment. In one embodiment, the pretreatment step is carried out to activate substantially the entire surface of the fabric to enhance adhesion of the fibers to the polyurethane. Depending on the polymer fiber used and its interaction with the polyurethane, a person skilled in the art will be able to evaluate the necessity and extent of pretreatment, possibly with the aid of some experimentation. The inventors have determined that for fabrics made from non-polar polymers such as polyolefins, for example, the combination of surface pretreatment and embedding the pretreated fabric in a polyurethane with hydrophobic segments or end groups as a matrix polymer contributes to favorable performance of the composite sheet produced.

[0135] In step c) of the method, the fabric is embedded in a biocompatible and biostable polyurethane elastomer. This step can be carried out in different ways, for example by laminating one or more thermoplastic polyurethane films to the fabric or by coating the fabric with a polyurethane composition, such as a solution of polyurethane. Generally, the fabric, i.e. the fibers therein, are not particularly tensioned during such steps, but the fabric can be optionally attached to a frame to prevent undesired deformations, for example creasing. Similarly, the fabric can be attached to a frame to carry out the pretreatment of the optional step b). The polyurethane elastomer used herein is as described herein above for the polyurethane composite sheet, including all variations and options disclosed in its embodiments and any possible combinations, unless otherwise specified or physically impossible.

[0136] In some embodiments, step c) can be carried out by lamination techniques; for example, by preparing a laminate of at least two thermoplastic polyurethane elastomer films and fabrics, preferably with the fabrics between the polyurethane films, and compressing the laminate, for example, using a platen press and a mold, while heating to a temperature above the melting point (or softening point) of the polyurethane and below the melting point of the polymeric fibers, so that the polyurethane substantially covers and encapsulates the fibers in the fabric. The mold may be flat, so that a substantially flat or shaped composite sheet is obtained, or may have a specific shape. Since polyurethanes typically absorb moisture from the environment, such as up to a few weight percent, the polyurethane elastomer is preferably dried, optionally at elevated temperature and / or in an inert gas flow or under reduced pressure, for example, to a moisture level of less than 0.05 weight percent, before lamination. Such drying processes are known to those skilled in the art.

[0137] In another embodiment, step c) is carried out by using a coating technique to apply a coating composition to the fabric; for example, by solution coating a coating composition comprising a biocompatible and biostable polyurethane elastomer, a polyurethane solvent, and optionally auxiliary compounds. The polyurethane elastomer component can be a thermoplastic polymer or a composition that forms a thermoset during or after the coating step; the polyurethane elastomer is soluble in a suitable solvent. The advantage of solution coating over melt lamination is that it allows the fabric to be impregnated and embedded using a relatively low viscosity polyurethane solution at a temperature well below the relaxation, softening or melting temperature of the polymer of the fibers. Coating at low temperatures prevents some of the fibers and fabric from melting and reducing their properties, and with this in mind, it allows the melting point of polymers such as polyolefins to be lower than that of thermoplastic polyurethane elastomers (TPUs). Another advantage of using a solution of polyurethane elastomers or TPUs to embed the fabric is that the amount of polyurethane and the extent to which the fibers are wetted and impregnated can be controlled by choosing the conditions and solution viscosity.

[0138] In some embodiments, step c) of the method comprises a step c1) of pre-wetting the fabric with the solvent used in the coating composition and then a step c2) of coating with the coating composition, which has been found to improve the wetting behavior of the polyurethane-containing coating solution and the impregnation of the fabric.

[0139] The coating composition can be applied to one or both sides of the fabric, depending on the viscosity of the coating composition, among other things, and the composition should optionally penetrate into the fabric to coat the fibers therein. If the polyurethane solution is applied to only one side of the fabric, the surface properties of the side to which the solution is applied may be different from the surface properties of the opposite side. For example, the relative amount of polyurethane may be different, such that one side is smoother than the other side, which is more textured. Composite sheets with such different textured surfaces may exhibit different interactions with biological materials; for example, a "smooth" side may exhibit good affinity with blood without causing clotting, while a "textured" side that is rougher and optionally has pores in the top layer may allow tissue to grow in when used as a graft material. Generally, the polyurethane coating composition is applied to the entire surfaces of both sides of the fabric, but it may also be applied locally to the entire surface of one side of the fabric and to selected portions of the opposite surface.

[0140] Prior to making the coating composition, the polyurethane elastomer is preferably dried to remove any moisture present, typically absorbed from the environment, such as up to a few percent by weight. Drying of polyurethanes is known to those skilled in the art and can be carried out at elevated temperature and / or under a stream of inert gas and / or reduced pressure, for example to a level of less than 0.05% by weight.

[0141] The coating composition applied in this method further comprises a solvent for polyurethane. A suitable solvent for polyurethane is one that can dissolve polyurethane substantially or preferably homogeneously, but does not dissolve the polymer of the fibers of the fabric, at least under the conditions in which the coating / impregnation method of the present invention is carried out. A person skilled in the art will be able to select a suitable solvent for a given polyurethane elastomer and polymer combination based on his general knowledge, optionally supported by some literature; for example, based on the solubility parameters of the solvent and polymer as given in the "Polymer Handbook", edited by Brandrup and Immergut. Those skilled in the art also recognize the effect of polymer molar mass on solubility.For the so-called good solvent of polyurethane such as TPU, the interaction between polymer chain and solvent molecule is energetically favorable, and the difference of solubility parameters of polymer and solvent is small.When searching for a solvent of polyurethane that is a non-solvent of polymer, those skilled in the art may carry out some dissolution experiments by including stirring or ultrasonication, and optionally applying some heating.

[0142] In an embodiment of the method, the solvent can be tetrahydrofuran (THF), methyltetrahydrofuran (m-THF), dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), dichloromethane, chloroform, hexafluoroisopropanol, dioxane, dioxolane, mixtures thereof, or mixtures with other less good solvents (or co-solvents), provided such mixtures are capable of dissolving the polyurethane. Considering the removal of the solvent from the fabric after application, a solvent with such volatility that the solvent can be substantially removed by evaporation, optionally by heating to a temperature at least 10° C. below the melting point of the polymer and polyurethane, is preferred. In one embodiment, THF or m-THF is used as the solvent, and preferably the solvent is THF.

[0143] The concentration of polyurethane elastomer in the coating composition applied in the solution application step is not critical, but generally the polyurethane will be in the range of 0.1-20% by weight in solution. However, experimentation has confirmed that it is preferable to use a relatively low viscosity solution to allow good penetration of the coating composition into the interstices or pores of the fabric strands or fibers, i.e., to impregnate the fabric. On the other hand, the higher the polyurethane concentration, the less solution needs to be applied to achieve efficient embedding. In embodiments, the Brookfield viscosity of the elastomer solution may be about 1-5000 mPa.s, or the viscosity may be at least 5, 10, 25, or 50 mPa.s and up to 3000, 2000, 1000, or 500 mPa.s.

[0144] The coating composition may further include one or more auxiliary compounds, such as antibiotics, pharmacologically active substances that inhibit (restenosis) of the graft (e.g., paclitaxel), substances that inhibit thrombosis (e.g., heparin or similar natural or synthetic anticoagulants), other biologics and small molecules to induce a desired biological response, or radiopaque agents. Such optional auxiliary compounds are preferably approved for their intended use by a regulatory agency, such as the FDA; typically, they may be present in relatively small and effective amounts such that their concentrations in the composite sheet are effective for their purpose and within the approved range, while not unacceptably degrading other performance properties of the composite sheet.

[0145] In some embodiments, the coating composition further comprises a radiopaque agent as an additive, typically in a relatively large amount, such as 15-80% by weight based on the polyurethane, to effectively visualize the composite sheet using medical imaging techniques that use X-rays or other radiation. In one embodiment, the radiopaque agent comprises tantalum, gold, platinum, tungsten, iridium, platinum-tungsten, platinum-iridium, palladium, rhodium, barium sulfate, bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, an ionic or non-ionic contrast agent, such as diatrizoate, iodipamide, iohexyl, iopamidol, iothalamate, ioversol, ioxaglat, and metrizamide, or a combination thereof. In one embodiment, the radiopaque agent comprises tantalum, gold, platinum, tungsten, or a mixture or alloy thereof. In one embodiment, the radiopaque agent is present as particles dispersed in the coating composition, for example, produced by dispersing the particles in a solution of polyurethane. In one embodiment, the radiopaque agent particles have an average particle size of at least 1 nm, preferably at least 5, 10, 25, 50, 100 or 200 nm. In one embodiment, the radiopaque agent particles have an average particle size of at most 3 μm, preferably at most 2, 1, 0.5 or 0.2 μm. The average particle size may also be measured using photon correlation spectroscopy (PCS) according to ISO 13321:1996. In one embodiment, the radiopaque agent is surface treated with an adhesion promoter, such as a glycidyl methacrylate (GMA) modified random ethylene / acrylate copolymer or a GMA and maleic anhydride (MA) modified random ethylene / acrylate copolymer, to enhance adhesion to polyurethane. In one embodiment, the radio-opacifying agent is present in the coating composition in an amount of at least 20, 25, 30, or 35% by weight, and up to 75, 70, 65, 60, 55, or 50% by weight, based on the polyurethane.

[0146] Solution application methods are well known per se to those skilled in the art. Coating for embedding fabric in polyurethane can be carried out using various application techniques, such as pipette or syringe, dip coating, spray coating, inkjet coating or screen printing; or using continuous methods such as roll coating process when the fabric substrate is rolled. Those skilled in the art can select the most suitable method for the actual situation and type of fabric based on general knowledge and some routine testing. The coating composition can be applied in one step, but also in multiple steps, for example by applying smaller amounts and leaving a certain time interval between steps for example to at least partially dry the solution.

[0147] Step c) of the method of embedding by coating also includes removing the solvent from the coated fabric, preferably substantially completely. A simple and preferred manner is to evaporate the solvent (or solvent mixture). This can be done at ambient conditions, but also by applying reduced pressure and / or elevated temperature to increase efficiency. When using elevated temperature, care must be taken to prevent degradation of the properties of the composite sheet, caused for example by partial dissolution and / or stress relaxation of the polymeric fibers in the fabric. Preferably, the temperature applied is kept well below, for example at least 10° C. below, the melting temperature of the polyurethane or TPU and the polymer. Optionally or alternatively, a washing step can be applied to substantially remove the solvent. The washing can be carried out with a liquid that includes or consists of a washing solvent that is a non-solvent for both the polyurethane and the polymer, but is miscible with the polyurethane solvent. Such a washing step can be carried out at ambient temperature, but also at elevated temperatures, under similar constraints as those indicated above. The removal of the solvent is typically carried out so that the residual solvent in the composite sheet is at a level that complies with specifications or regulations for use in medical indwelling devices. In one embodiment, the resulting composite sheet has a residual solvent content of less than 50 ppm, for example, by drying under nitrogen for 24 hours followed by drying in a convection oven at 50° C. for 1 hour.

[0148] In embodiments of the method, the fabric, particularly a relatively small piece of fabric, can be attached to a support or frame and then pretreated, solution coated, and solvent removed without significant tension on the strands of the fabric so as to maintain the fabric's configuration, e.g., uniform and flat. Advantages of doing so can include more even pretreatment and coating of the fabric, as well as preventing deformation, e.g., shrinkage or wrinkling, during the coating and solvent removal steps. One skilled in the art will be able to select an appropriate frame or other method to prevent the fabric from deforming, e.g., without preventing effective coating in desired locations.

[0149] Further aspects relate to the use of the polyurethane composite sheet of the present disclosure in the manufacture of a medical indwelling device part suitable for an indwelling medical device, and the use of such a medical indwelling device part in the manufacture of an indwelling medical device, including all variations and options of the composite sheet described in the embodiments herein above and any possible combinations thereof, unless otherwise specified or physically impossible, in which embodiments said use relates to the manufacture of one or more leaflets for a prosthetic heart valve and to the manufacture of a prosthetic heart valve comprising one or more such leaflets.

[0150] In embodiments, the method of manufacturing medical indwelling device components from a polyurethane composite sheet includes cutting pieces of a desired shape from the sheet. Such cutting can be accomplished by known methods such as using a blade, scissors, or laser cutting.

[0151] In some embodiments, the manufacture of medical detainer parts from polyurethane composite sheets involves cutting one or more pieces using a laser, which allows the creation of complex shaped pieces of material with stable cut edges that exhibit fray resistance and suture retention strength. A laser suitable for such purposes is selected and applied with settings that provide sufficient energy at the location of the composite sheet to cut, thereby optionally allowing the local cutting temperature to reach a temperature above the melting point of polyurethane, particularly TPU; thereby forming a local melt of TPU that can flow and bond the ends of the cut fibers to each other and / or to other fibers in the composite sheet. The laser cut itself appears to result in the polyurethane and fibers being heated very locally by the focused laser energy to a temperature where the material rapidly decomposes and vaporizes. Therefore, the laser settings are selected not to overheat the edge regions of the composite sheet near the cut, so that they do not become irregularly deformed or fall apart. Overheating of the edges can also cause undesirable stiffening in the edge regions and reduce the flexibility of the sheet. Those skilled in the art will appreciate that CO 2 One could select a suitable laser for the purpose, such as a CO, Nd or Nd-YAG laser, and select the appropriate settings, including controlling the energy of the beam, for example by pulsing. 2 Lasers can be suitably used to cut composite sheets, however, it has been observed that when using continuous wave lasers, excessive heat conduction can occur in the composite sheet, which can result in distorted cut edges or melting or shrinking of the polymer fibers and thus portions of the sheet, e.g., due to thermal relaxation effects.

[0152] In embodiments of the present disclosure, pulsed lasers, i.e. lasers that emit light in the form of light pulses rather than in a continuous mode, are utilized to cut the pieces from the composite sheet. Thus, in embodiments, short-pulsed or ultrashort-pulsed (USP) lasers, such as nano-, pico-, or femtosecond pulsed lasers, are utilized because they do not provide excessive heating that may distort the morphology of the composite sheet, while still allowing the polyurethane to melt so that the cut edge is stable. In exemplary embodiments, particularly those in which the composite sheet includes polyolefin fibers, such as UHMWPE fibers, the cutting is performed with a USP laser applied at an energy level setting of about 10-26 W, preferably 12-24 or 14-22 W. In further embodiments, the cutting is performed at a cutting speed of 1-12 mm / s, preferably 2-10 or 3-8 mm / s. More than one pass of the USP laser may be required to completely cut the composite sheet, depending, for example, on its thickness. To prevent damage to the composite sheet and the resulting medical device components, multiple cutting steps may be preferred over higher energy settings.

[0153] In other aspects, the use of the polyurethane composite sheet of the present disclosure or pieces cut therefrom include applications in which the composite sheet will come into contact with body tissues and / or body fluids, such as tissue reinforcement materials or orthopedic applications, including cardiovascular applications. Examples of materials for reinforcing soft tissue include meshes for hernia repair and meshes for abdominal wall reconstruction. Cardiovascular applications include vascular grafts, covers for stents, closure devices, artificial arteries, surgical meshes, valves, such as venous valves and heart valves, and devices and retainers, such as introducer sheaths used in transcatheter procedures. The composite sheet can be applied as a part of the device such that the direction or axis along which the sheet exhibits nonlinear tensile properties corresponds to the direction in which elastic extension and contraction is desired under the applied stress during use. In many such applications, the retainer parts need to be bonded or attached to other parts of the device or to the soft or bony tissue surrounding it. A further advantage of the polyurethane composite sheet is that a variety of techniques are available for making such bonds. For example, suturing to connect pieces of the composite sheet together and / or to attach the pieces to a stent, such as attaching the three pieces that form the leaflet cluster to a support frame, can be performed with reduced risk of the sutures detaching the material when the material is under tension. The polyurethane composite sheet can also be further adhesively bonded; in that case, the polyurethane matrix itself can act, at least in part, as a thermoplastic adhesive that can be activated by localized heating, such as with a laser.

[0154] Other aspects of the present disclosure include such medical devices or devices as indicated above, including the polyurethane composite sheet or medical device parts, such as aortic grafts for abdominal or thoracic aortic aneurysms, venous valves for venous insufficiency, total artificial heart devices, ventricular assist devices, peripheral stent grafts, arteriovenous (AV) grafts, surgical cardiac or vascular patches, hernia meshes, surgical protection, and other general cardiac and thoracic applications.

[0155] The words "a," "an," and "the," and similar demonstrative pronouns used in connection with the description of the present invention (particularly in connection with the exemplary embodiments and claims set forth below) should be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated. The recitation of ranges of values ​​herein is intended merely to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually set forth herein. The use of any examples or exemplary language herein, such as "such as" or "including," is intended merely to more fully illustrate the disclosure and does not limit the scope of the invention unless claimed. No language herein should be construed as indicating any non-claimed element essential to the practice of the invention.

[0156] Preferred embodiments for carrying out the invention are described herein, including the best mode known to the inventors. Variations of these preferred embodiments will become apparent to those skilled in the art upon reading the above description. The inventors expect that those skilled in the art will adopt such variations as necessary, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Although certain optional features are described as embodiments of the invention, this description means that any combination of these embodiments is also included and disclosed, unless otherwise specified or physically impossible.

[0157] The following experiments and samples further illustrate embodiments of the present invention but, of course, should not be construed as limiting the scope of the claims in any way.

[0158] [Examples and Comparative Experiments] [material] A woven polyolefin fabric (Dyneema Purity® TG 10 dtex; available from DSM Biomedical BV, Sittard-Geleen NL) made with the following medical grade low denier UHMWPE multifilament yarns as warp and weft strands was used as the reinforcement material in the experiments: Woven fabric with a 2 / 2 twill weave, 45 mm wide when laid flat, approximately 70 μm thick; Woven fabric with a plain weave, 45 mm wide when laid flat, approximately 62 μm thick; Woven fabric with mock leno weave, 45 mm wide when laid flat and approximately 79 μm thick.

[0159] A commercially available woven polyester fabric (Secant Group, PA, USA) containing 20-60 dtex polyethylene terephthalate (PET) multifilament yarns as warp and weft yarns was used as the reinforcement material in the experiments: Low profile PET medical woven fabric with plain weave, approximately 72μm thick; Low profile PET medical woven fabric with plain weave, approximately 93μm thick; A low profile PET medical woven fabric with a plain weave, approximately 122 μm thick.

[0160] The polyurethane used was CarboSil® TSPCU 20-80A (available from DSM Biomedical BV, Sittard-Geleen, NL), which is a thermoplastic silicone polycarbonate polyurethane elastomer with silicone end groups, hardness 80 ShA, MFR 52 g / 10 min (1.20 kg / 224° C.).

[0161] As an alternative reinforcement, a biaxially oriented microporous UHMWPE film, Solupor® 7P03A (obtained from Lydall Performance Materials, Heerlen, NL), was applied, which is shown to have a thickness of 50 μm, a porosity of 86%, and a mean flow pore size of 0.3 μm.

[0162] As a reference material, processed (cleaned, devitalized and cross-linked with glutaraldehyde) porcine pericardium material was used.

[0163] [method] [Solution preparation] A polyurethane solution was prepared by dissolving CarboSil® TSPCU 20-80A in THF (Lichrosolve). Prior to preparing the solution, polyurethane pellets were first dried at 70°C for up to 72 hours to remove moisture. The polyurethane was dissolved in THF by stirring overnight at room temperature to a concentration in the range of 8-12% by weight.

[0164] [Solution viscosity] A Brookfield DV-E viscometer fitted with a UL-adapter and a ULA-49EAY spindle was used to measure solution viscosities at 25°C, calibrated using silicone-based viscosity standards (Benelux Scientific). Viscosities in the range of 180-500 mPa.s were used in the experiments.

[0165] [Dip coating] Test specimens approximately 10-25 cm long were cut from a continuous UHMWPE woven fabric (or membrane) and mounted on a frame as a sample holder. The UHWMPE specimens were cleaned by spraying with heptane, wiping, and drying at ambient temperature. Fabric specimens were similarly prepared from woven PET and cleaned. The test specimens mounted on the frame were pretreated by plasma activation in a 15% oxygen atmosphere at 200 mTorr and 450 W for 60 seconds.

[0166] Dip coating was carried out under ambient conditions by immersing a framed specimen into the polymer solution and removing it at a withdrawal speed of 0.1 m / s, followed by drying at 40° C. for 20 min.

[0167] Sheet Thickness The thickness of the fabric or composite sheet was measured using a Helios Preisser Electronic Outside Micrometer with a measurement range of 0-25 mm (±0.001 mm).

[0168] [Tensile properties] Tests on porcine pericardium and polyurethane crosslinked with glutaraldehyde solution were performed according to ISO 527-2, using specimens in the 1BB geometry in accordance with this standard. For composite sheets with fibers embedded in the matrix material, specimens were cut to a gauge length of 20 mm and a gauge width of 5 mm. Specimens were cut at angles of 0, 45 and 90 degrees (relative to the warp direction for woven fabrics and to the machine direction for films) through the material. Displacement rates for ISO 527-2 and straight edged specimens were 25 mm / min and 41.5 mm / min, respectively, and specimens were preloaded with 0.05 N before testing began. All tensile tests were performed in a 37°C water bath, and all specimens except for porcine pericardium were conditioned in 37°C water for a minimum of 1 hour before testing. Porcine pericardium was conditioned in phosphate buffered saline (pH 7.4) for 1 hour before testing. Strain was determined by instrumental displacement, as underwater measurements do not allow optical tracking.

[0169] The 1% secant modulus was calculated from the stress measured at 1% strain. The hardening modulus was determined by fitting a line to strains between 50% and 55% of the maximum stress (see, for example, Figures 2 or 3). The hardening transition point was determined as the strain extrapolated to zero stress, i.e., by extending the hardening slope to intersect with zero stress. This has been taken as a reproducible indicator of the onset of strain hardening. If the initial secant modulus is much higher than the hardening modulus, the resulting value may be negative.

[0170] [Bending stiffness] Bending measurements were performed on an Ares 2 rheometer by bending the specimen material in a custom fixture as described by Sachs and Akkerman (DOI:10.1016 / j.compositesa.2017.05.032). The fixture applies a constant rotational speed to fully bend the material, especially for thin composite layers, and the applied moment is measured as a function of the rotation angle. The setup shown in Figure 1F of Sachs was used. A PTFE spacer was utilized between the specimen and fixture to reduce friction. The spacer thickness was optimized for each specimen to minimize the gap between the fixture and the specimen. The specimen dimensions were 25 mm wide and 35 mm long. Of the 35 mm, 10 mm from each end was placed in the fixture, resulting in an initial gauge length of 15 mm for bending. Tests were performed under ambient room temperature conditions. The applied moment M is directly correlated to the bending stiffness EI at a known curvature κ applied through a custom fixture. Bending stiffness is defined as the bending modulus E multiplied by the second moment of the cross section where the bending occurs, i.e.

number

[0171] All measurements were performed at room temperature and atmospheric pressure, with rotation angles between 0° and 70° and a rotation speed of 1 rpm. The specimens were unbent after bending and the test was repeated four times. To obtain the bending stiffness, the curvature versus applied moment was averaged over the linear region between 20° and 40° after run in effect. Measurements were performed on two different specimens for each material and all results were averaged to obtain the bending stiffness. Values ​​per unit width are reported for comparison between different materials.

[0172] [Surface roughness] The surface roughness was measured using a non-contact 3D surface profiler VR3200 from Keyence. In accordance with ISO25178, the surface roughness was approximately 2.7 mm 2The surface area of ​​the fabric was analyzed to obtain the arithmetic mean roughness (Sa) and the maximum surface height (Sz). The maximum height can represent, for example, the area where strands cross each other within the fabric.

[0173] [Suture retention strength] Suture retention or suture pull-out force was measured on a piece of sheet approximately 30×10 mm by inserting a high strength suture (FiberWire® 4.0) with a fine tapered needle into the center of the fabric, 2 mm from the edge of the short side. A Zwick Universal tester was used with pneumatic Instron grips (7 bar) and grip G13B, between which the looped suture and the other end of the fabric were attached with a grip distance of 50 mm, and a preload of 0.05 N was applied. The suture was then pulled at a rate of 50 mm / min until the specimen broke. Suture retention is reported as the yield point of the measured pull-out stress-strain curve (average of three measurements). This is the force required to pull the looped suture through the edge region of the fabric.

[0174] [result] Table 1 summarizes the composition of seven composite sheets based on the same polyurethane with polysiloxane soft segments as matrix material and several different woven fabrics made from UHMWPE fibers (Examples 1-3) or PET fibers (Examples 4-6). Comparative experiment 7 applies a porous nonwoven film for reinforcement. Table 2 shows the results of tests carried out on these materials and the Carbosil® 20-80 ATPU grade (Comparative experiment 8) as well as on a porcine pericardium material (Comparative experiment 9). The tensile properties of the films based on pure polyurethane were practically direction-independent. The results reported in Table 2 for the 45° direction for Comparative experiment 8 represent the average value of all measurements, since the material has no specific directionality. The pericardium sheets not only showed different average values ​​when measured on specimens cut at different sheet orientations, but also showed considerable variation between the different tensile specimens. This non-uniformity of natural products is further illustrated by three representative stress-strain curves shown in Figure 2.

[0175] The results of the composite sheets show that, except for the porous film-based sheet (Comparative Experiment 7), the composite sheets show nonlinear tensile behavior in the direction at a certain angle to the warp and weft of the woven fabric, especially in terms of the hardening transition point. This also shows that the corresponding tensile properties of the composite sheets of the present disclosure, measured under the same physiological-like conditions and at an angle of about 45° to the warp or weft direction of the woven fabric included in the composite, can be comparable to those of the pericardium sheets, with the actual values ​​being adjustable by changing the type of fabric. This is further shown by comparing Figure 2 (for pericardium) and Figure 3 (for Example 3), especially with respect to the secant modulus and strain hardening.

[0176] Moreover, the ultimate tensile strength of the composite sheets of Examples 1-6 was substantially higher than that of the tested pericardium in all directions, especially in the warp and weft directions. This means that if such composite sheets are used as materials to manufacture the leaflets of a prosthetic valve, the maximum stress applied to the material when used as a retainer will remain much lower than the stress level that would induce immediate failure. In such cases, it is recognized in the art that the material will be more resistant to fatigue failure and will exhibit a significantly longer fatigue life. Therefore, it can be expected that the durability of prosthetic valves having leaflets made from such polyurethane composite sheets according to the present disclosure will be significantly improved over biological and / or synthetic valves according to the prior art. Fatigue evaluation experiments to determine the expected life of leaflets made from the composite sheets of the present disclosure are still pending.

[0177] For example, the bending properties of materials used as the leaflets of a heart valve prosthesis are important for efficient opening and closing, which affects, for example, blood flow. The results for bending stiffness and other mechanical properties (see Table 2) indicate that the higher the number of strands in the fabric and the denser the fabric, the less flexible the composite is.

[0178] The results of the suture pull-out tests (warp and weft directions of the woven fabric in the composite sheet) are summarized in Table 2. The results indicate that a significantly higher force may be applied to pass a composite sheet of the present disclosure (near the cut edge) than to pass a sheet of treated pericardium (measured in one direction).

[0179] It should be noted that the composites based on microporous UHMWPE membranes (0° orientation in this case refers to the machine direction of the biaxially oriented film) exhibited good strength, extensibility and flexibility, but unlike the composite sheets based on woven fabrics, did not exhibit a stiffening transition point upon stretching and had relatively low forces to pull out the sutures.

[0180] Surface roughness measurements showed that the woven-based composites had average and maximum roughness comparable to the pericardium material. Composite sheets can also be made smoother on one side than the other, for example, by fabricating or post-treating the sheet on a support or mandrel having a smooth surface.

[0181] [Table 1]

[0182] [Table 2]

Claims

1. 1. A polyurethane composite sheet comprising: a biocompatible and biostable polyurethane elastomer comprising polysiloxane segments, said polyurethane forming a continuous matrix of said sheet; A woven or braided fabric having a thickness of 15 to 150 μm and comprising biocompatible high-strength polymeric fibers; Equipped with The composite sheet contains 10 to 90% by mass of polyurethane, has a thickness of 25 to 250 μm, and has an areal density of 5 to 300 g / m ２ and The composite sheet exhibits nonlinear uniaxial tensile behavior characterized in that the composite sheet has a 1% secant modulus of 20-200 MPa in at least one direction, a cure transition point between 10-45%, and a tensile strength of at least 25 MPa (measured in water at 37° C.).

2. 2. The polyurethane composite sheet of claim 1, wherein the polyurethane is a thermoplastic polyurethane elastomer (TPU) comprising soft blocks based on polysiloxane diol and one or more of aliphatic polycarbonate diol and poly(tetramethylene oxide) diol.

3. 3. The polyurethane composite sheet of claim 1 or 2, wherein the polyurethane elastomer comprises one or more hydrophobic end groups.

4. 4. The polyurethane composite sheet of claim 1, wherein the fabric has an open structure, the polyurethane elastomer completely covers or embeds the strands of the fabric, and the composite sheet is non-porous.

5. The polyurethane composite sheet according to any one of claims 1 to 4, wherein the composite sheet has a maximum flexural modulus of up to 45 Nm.

6. The polyurethane composite sheet according to any one of claims 1 to 5, wherein the maximum difference in bending stiffness / unit width of the polyurethane composite sheet measured in any two perpendicular directions of the polyurethane composite sheet is at most 20 Nm.

7. The polyurethane composite sheet according to any one of claims 1 to 6, wherein the maximum difference in bending stiffness / unit width of the polyurethane composite sheet in any two directions 45° apart is a maximum of 20 Nm.

8. The polyurethane composite sheet according to any one of claims 1 to 7, wherein the maximum difference in bending stiffness / unit width of the polyurethane composite sheet with respect to each of i) the warp direction (0°) with respect to an angle of 45° to the warp and weft yarns, and ii) the weft direction (90°) with respect to an angle of 45° to the warp and weft yarns, is a maximum of 20 Nm.

9. The polyurethane composite sheet according to any one of claims 1 to 8, wherein the maximum difference in bending stiffness / unit width of the composite sheet measured in any two perpendicular directions of the polyurethane composite sheet is less than 60% of the higher measured value.

10. The maximum difference in bending stiffness per unit width of said polyurethane composite sheet measured in any two directions 45° apart is less than 60% of the maximum measured value. The polyurethane composite sheet according to any one of claims 1 to 9.

11. 11. The polyurethane composite sheet according to claim 1, wherein the maximum difference in bending stiffness / unit width of the polyurethane composite sheet with respect to each of i) the warp direction (0°) with respect to an angle of 45° to the warp and weft yarns, and ii) the weft direction (90°) with respect to an angle of 45° to the warp and weft yarns is less than 60% of the maximum measured value.

12. 12. The polyurethane composite sheet of claim 1, wherein the fabric is woven and the woven fabric has a strand pick count in each of the warp and weft directions of up to 450 picks per inch.

13. 13. The polyurethane composite sheet of claim 1, wherein the fabric is woven and the warp strand picks per inch (EPI) and the weft strand picks per inch (PPI) are each between 30 and 350.

14. 14. The polyurethane composite sheet of claim 1, wherein the fabric is woven and the difference between the number of picks per inch (EPI) of the warp strands and the number of picks per inch (PPI) of the weft strands is at most 200.

15. 15. The polyurethane composite sheet of claim 1, wherein the fabric is woven and the difference between the number of picks per inch (EPI) of the warp strands and the number of picks per inch (PPI) of the weft strands is at most 40%.

16. 16. A polyurethane composite sheet according to any one of the preceding claims, wherein the composite sheet has at least one textured surface characterized by a surface roughness Sa of 3 to 12 μm and Sz of 20 to 100 μm (measured according to ISO 25178).

17. The polyurethane composite sheet according to any one of claims 1 to 16, wherein the fabric is a leno weave or a mock leno weave.

18. 18. The polyurethane composite sheet of claim 1, wherein the fabric of the composite sheet is a woven fabric made from warp and weft strands having a fineness of 2 to 100 dtex.

19. 19. The polyurethane composite sheet of any one of claims 1 to 18, wherein the fabric of the composite sheet is a balanced or unbalanced woven fabric with similar properties in the warp and weft directions, and the composite sheet exhibits non-linear uniaxial tensile behavior along an axis between the warp and weft strands at an angle of 45 degrees to the warp and weft.

20. The polyurethane composite sheet of any one of claims 1 to 19, wherein the fibers are present as multifilament yarns that form strands of the fabric.

21. 21. The polyurethane composite sheet of claim 1, wherein the fabric of the composite sheet comprises at least 10% by weight of high strength polymeric fibers.

22. The polyurethane composite sheet according to any one of claims 1 to 21, wherein the high strength polymer fibers are UHMWPE fibers or PET fibers, each having a strength of 0.6 to 4.0 N / tex.

23. The polyurethane composite sheet according to any one of claims 1 to 22, wherein the fabric has a thickness of 20 to 100 µm, and the composite sheet has a thickness of 25 to 125 µm.

24. 1. A method for making a polyurethane composite sheet, comprising: a. providing a braided or woven fabric comprising biocompatible high strength polymeric fibers; b. Optionally, activating the surface of the fabric by pre-treating it with a high energy source; c. embedding the fabric in a biocompatible and biostable polyurethane elastomer containing polysiloxane segments; Including, A process resulting in a composite sheet according to any one of claims 1 to 23.

25. 25. The method of claim 24, wherein step c) is carried out by laminating the fabric with one or more thermoplastic polyurethane films at a temperature above the melting point of the polyurethane and below the melting point of the polymer fibers in the fabric.

26. 25. The method of claim 24, wherein step c) is carried out by applying a coating composition to the fabric.

27. A method for manufacturing a medical indwelling device part, comprising the step of cutting one or more pieces having a desired shape from the polyurethane composite sheet according to any one of claims 1 to 23.

28. 25. An indwelling medical device obtainable using the method according to claim 24, for use in orthopedic and / or cardiovascular applications.

29. A medical device for placement comprising the polyurethane composite sheet according to any one of claims 1 to 23.

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