Antifouling implantable materials and methods of making

Abstract

Antifouling implantable materials and methods for manufacturing them are disclosed. The antifouling implantable material includes a polymer reinforcing layer, an intermediate layer comprising a protective polymer membrane, and an outer layer comprising an ionomer. The antifouling implantable material may possess chemical and / or physical properties compatible with those of body tissue. The antifouling implantable material can be used in implantable medical devices, such as artificial heart valves and vascular grafts, etc.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Patent Application 63 / 055,293, filed July 22, 2020, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] This disclosure relates to antifouling implantable materials and methods for manufacturing antifouling implantable materials. Background Technology

[0003] A major aspect of constructing implantable prostheses (such as artificial heart valves and vascular grafts) using animal-derived pericardial tissue is the challenge associated with time-consuming tissue processing techniques. Furthermore, animal-derived tissue can have highly variable thickness, softness, and mechanical properties in one or more of these areas. This variability can lead to extremely low yields and / or additional, expensive, and lengthy quality checkpoints during manufacturing.

[0004] The pericardium is a mechanically strong double membrane that surrounds the heart. Pericardial tissue consists of a very compact layer of fibrous collagen and thin elastic fibers, all interconnected by chemical bonds. The fibrotic nature of the pericardium gives it incredible strength, while the soft, hydrophilic structure of the collagen creates an environment conducive to cell proliferation.

[0005] The limitations of pericardial tissue have spurred the search for materials that incorporate its positive properties while overcoming its negative effects, such as synthetic materials. A problem with synthetic lobular materials (SLMs) is that the host immune response leads to fibrosis of the SLMs, significantly limiting their performance and lifespan. The surface physicochemical properties of SLMs play a crucial role in modulating the fibrosis response. Summary of the Invention

[0006] This disclosure relates to antifouling implantable materials and implantable medical devices comprising antifouling implantable materials. A method for manufacturing antifouling implantable materials is also disclosed.

[0007] In some instances, the antifouling implantable material includes (i) a reinforcing layer comprising a plurality of polymeric filaments containing a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; (ii) an intermediate layer comprising a protective film attached to at least a portion of the first surface, the protective film comprising a protective polymer; and (iii) an outer layer comprising an ionic polymer grafted to an exposed surface of the intermediate layer.

[0008] In any of the foregoing or following examples, the polymeric filaments may be (i) randomly oriented, (ii) unidirectionally aligned, (iii) formed into an interwoven web, (iv) formed into a sheet-like inner web, (v) formed into a knitted material, or (vi) twisted into yarn and then arranged as described in any of (i)-(v). In any of the foregoing or following examples, the filamentous polymer may include a natural or synthetic polymer. In one example, the filamentous polymer is biostable. In another example, the filamentous polymer is biodegradable. In any of the foregoing or following examples, the polymeric filament may include a core and a shell surrounding the core, wherein the core contains the filamentous polymer and the shell contains a shell polymer. The shell polymer may be a biodegradable polymer or a biostable polymer. In any of the foregoing examples, the polymeric filament may have an average diameter in the range of 0.001 μm to 2000 μm. In some examples, the polymeric filament is a nanofilament or microfilament having an average diameter in the range of 0.001 μm to 50 μm. In the foregoing or any of the following examples, the reinforcing layer may have a thickness in the range of 25-500 μm, a burst strength in the range of 50-800 N, a tensile strength in the range of 50-800 N, or any combination thereof.

[0009] The intermediate layer includes a protective film attached to at least a portion of the first surface of the reinforcing layer, the protective film comprising a protective polymer. The protective polymer may be a biostable polymer or a biodegradable polymer. In any of the foregoing or following examples, the intermediate layer may further include a second protective film attached to at least a portion of the opposing surface of the reinforcing layer, the second protective film comprising a protective polymer. In any of the foregoing or following examples, the intermediate layer may have (i) an average thickness in the range of 0.1-100 μm, (ii) a Shore hardness in the range of 10A-80A, and (iii) a hardness of 1-50 N / mm². 2 Flexural modulus in the range of (iv) 10-60 N / mm 2 The dry ultimate tensile strength (v) is in the range of 5-40 N / mm. 2 The wet ultimate tensile strength within the range, or any combination of (vi) (i), (ii), (iii), (iv) and (v).

[0010] The outer layer comprises an ionic polymer grafted onto the exposed surface of the intermediate layer. The ionic polymer can be an anionic polymer, a cationic polymer, or an amphoteric polymer. In some examples, the ionic polymer is a polyampholyte or a polybetaine. In the foregoing or any of the following examples, the outer layer may have an average thickness in the range of 0.001–25 μm.

[0011] Examples of methods for manufacturing antifouling implantable materials include forming an intermediate layer comprising a protective film on at least a portion of a first surface of a reinforcing layer, the reinforcing layer comprising a plurality of polymeric filaments containing a filamentous polymer, and the protective film comprising a protective polymer; and forming an outer layer by grafting an ionic polymer onto an exposed surface of the intermediate layer. In some examples, the intermediate layer further includes a second protective film on at least a portion of an opposing surface of the reinforcing layer, the second protective film comprising a protective polymer.

[0012] In any of the foregoing or following examples, the method may further include forming a reinforcing layer. In any of the foregoing or following examples, the method may also include forming a plurality of polymeric filaments. In some examples, forming polymeric filaments includes forming a core comprising a filamentous polymer and a shell surrounding the core, the shell comprising a shell polymer.

[0013] In any of the foregoing or following examples, forming an intermediate layer including a protective film may include attaching the protective film to at least a portion of a first surface of the reinforcing layer. In some examples, forming an intermediate layer including a protective film further includes forming the protective film. The protective film may be formed and then attached to the reinforcing layer. Optionally, the protective film may be formed in situ on the surface of the reinforcing layer.

[0014] In any of the foregoing or following examples, grafting an ionomer onto an exposed surface of an intermediate layer may include coating the exposed surface with a solution containing the ionomer to form an ionomer-coated material; and drying the ionomer-coated material to provide a fouling-resistant implantable material. In some examples, the ionomer is an amphoteric ionomer.

[0015] The foregoing and other objects, features and advantages will become more apparent from the following detailed description, which is taken into account in the accompanying drawings. Attached Figure Description

[0016] The patent or application document shall contain at least one color drawing. A copy of the color drawing of this patent or patent application publication shall be provided by the Patent Office upon request, at the cost of which the necessary fees shall be paid.

[0017] Figure 1 This is a schematic diagram showing an example of an implantable material.

[0018] Figures 2A-2F Several reinforcement layer arrangements of polymer fibers are shown: Figure 2A This is a schematic diagram showing randomly oriented filaments; Figure 2B This is a schematic diagram showing unidirectionally aligned wires; Figure 2C This is a schematic diagram showing the inner mesh of the sheet containing filaments; Figure 2D This is a schematic diagram showing an interwoven web containing filaments. Figure 2E These are microscope images of knitted materials containing silk threads; Figure 2FThis is a scanning electron microscope image of a material knitted from yarn fibers containing multiple polymer filaments.

[0019] Figure 3 This is a schematic diagram showing an example of a polymer filament, which includes a core fiber and a shell surrounding the core fiber.

[0020] Figure 4A and 4B This is a microscope image of a reinforcing layer consisting of woven fibers with a poly(lactic acid) core and a polycarbonate-urethane (PCU) shell. Figure 4A Microscopic images of the synthetic leaflet material, including a reinforcing layer sandwiched between two thermoplastic PCU protective films. Figure 4B ).

[0021] Figure 5A and 5B Microscopic images of a reinforcing layer knitted from yarns comprising a poly(ethylene terephthalate) (PET) core fiber and a hydrolyzed PET shell. Figure 5A Microscopic images of synthetic leaflet material formed by dip-coating a reinforcing layer, including the reinforcing layer and a thermoplastic PCU protective film. Figure 5B ).

[0022] Figure 6 This is a microscope image of a reinforcing layer knitted from yarn containing PET filaments.

[0023] Figure 7A and 7B This compares the burst strength of PET fabric (SLM-1) and fixed pericardial tissue (average tissue). Figure 7A ) and tensile strength ( Figure 7B (Charts)

[0024] Figure 8A and 8B This is a microscope image of a knitted reinforcing layer, which comprises filaments (upper half) having a poly(ethylene terephthalate) (PET) core and a hydrolyzed PET shell, and a thermoplastic PCU protective film covering part of the reinforcing layer (lower half). Figure 8A (30x magnification); Figure 8B Showing Figure 8A The PCU-covered reinforcement layer (right half) and the reinforcement layer covered with two PCU protective films (left half) (100x magnification).

[0025] Figures 9A-9C Here are scanning electron microscope (SEM) images of a reinforcement layer in the following case: a knitted reinforcement layer completely covered with a 127 μm thermoplastic PCU film, the knitted reinforcement layer consisting of filaments with a PET core fiber and a hydrolyzed PET shell. Figure 9A(103x magnification); uncoated reinforcement layer (left), partially coated with a 127 μm thermoplastic PCU film (right) ( Figure 9B (100x magnification); and the reinforcement layer is partially covered with a 127 μm thermoplastic PCU film, but there are defects in the coverage ( Figure 9C (75x magnification).

[0026] Figure 10 This is an X-ray image of a PET-PCU synthetic leaflet material sample after in vivo calcification and cleaning of explants in rabbits.

[0027] Figure 11A-11C This is an energy dispersive X-ray spectroscopy (EDS) / SEM layered image of a synthetic leaflet material (SLM) comprising a PET core-shell filament and a thermoplastic PCU protective film. Figure 11A ), carbon images ( Figure 11B ) and oxygen images ( Figure 11C ).

[0028] Figure 12A-12D This is an EDS / SEM layered image of an SLM comprising a PET core-shell filament and a thermoplastic PCU protective film coated with 2-methacryloyloxyethylphosphonic choline. Figure 12A ), carbon images ( Figure 12B ), oxygen images ( Figure 12C ) and phosphorus images ( Figure 12D ).

[0029] Figure 13 The FTIR spectra of SLMs, including PET core-shell filaments and thermoplastic PCU protective films with and without coatings containing 2-methacryloyloxyethylphosphonic choline, are shown.

[0030] Figure 14 This is a perspective view of an exemplary transcatheter artificial heart valve based on one example.

[0031] Figure 15 This is a perspective view of an exemplary surgical artificial heart valve based on one example. Detailed Implementation

[0032] This disclosure relates to examples of antifouling implantable materials and methods for manufacturing antifouling implantable materials. In some examples, the antifouling implantable material includes a reinforcing layer, an intermediate layer including a protective membrane, and an outer layer including an ionomer grafted to the intermediate layer. Some examples of the disclosed antifouling implantable materials can be used in implantable medical devices, such as artificial heart valves and / or vascular grafts. Compared to similar implantable materials that do not include the outer layer, the antifouling implantable material may exhibit reduced fibrosis, homogenization, and / or immunogenicity.

[0033] I. Definitions and Abbreviations The following terms and abbreviations are provided for explanation in order to better describe this disclosure and to guide those skilled in the art in the practice of this disclosure. As used herein, “comprising” means “including” and the singular forms “a”, “an”, or “the” include plural references unless the context clearly specifies otherwise. The term “or” refers to a single element or a combination of two or more elements of the stated alternative elements unless the context clearly specifies otherwise.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While similar or equivalent methods and materials to those described herein may be used in practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. Further features of this disclosure will become apparent from the following detailed description and the claims.

[0035] Unless otherwise stated, the disclosure of numerical ranges should be understood to refer to each discrete point within the range, including the endpoints. Unless otherwise stated, all figures used in the specification or claims to represent the quantity, molecular weight, percentage, temperature, time, etc., of components should be understood to be modified by the term "about". Therefore, unless otherwise implied or expressly stated, or unless the context is correctly understood by one of ordinary skill in the art to have a more explicit structure, the numerical parameters presented are approximate values ​​that may depend on the desired properties sought and / or the detection limits under standard test conditions / methods known to one of ordinary skill in the art. When examples are directly and explicitly distinguished from the prior art discussed, the example figures are not approximate values ​​unless the word "about" is stated.

[0036] Although various alternatives to components, parameters, operating conditions, etc., are described herein, this does not imply that those alternatives must be equivalent and / or perform as well. Unless otherwise stated, the alternatives are not listed in a preferred order.

[0037] Definitions of commonly used chemical terms can be found in Richard J. Lewis, Sr. (ed.). Hawley's Condensed Chemical Dictionary Found in John Wiley & Sons, Inc., 2016 (ISBN 978-1-118-13515-0).

[0038] To facilitate the examination of various instances of this disclosure, the following explanations of specific terms are provided: Biodegradable: As used herein, the term biodegradable means that it can be broken down or destroyed in the body.

[0039] Biologically stable: As used in this article, the term biologically stable means chemically stable in vivo.

[0040] Copolymer: A polymer formed by the polymerization of two or more different monomers.

[0041] High elastomers: As defined by IUPAC, high elastomers are polymers that exhibit rubber-like elasticity. They are polymers that can be stretched by applied force and return to their original shape upon release.

[0042] Filament: A linear structure, a fiber. Unless otherwise specified, the term "microfilament" as used herein refers to a filament having an average diameter of 1 μm to 100 μm. The term "nanofilament" refers to a filament having an average diameter of less than 1 μm.

[0043] Hydrogels are cross-linked three-dimensional networks of polymeric chains capable of absorbing and retaining molecules (e.g., water, polar solvents, non-polar solvents, liquid drugs, etc.) within their three-dimensional network. The polymeric chains forming hydrogels include one or more hydrophilic functional groups in their polymeric structure, such as amino (NH2), hydroxyl (OH), amide (-CONH-, -CONH2), sulfate (-SO3H), or any combination thereof, and can be networks based on natural or synthetic polymerization.

[0044] Hydrolysis: The breakdown of molecules through reaction with water. The hydrolysis of macromolecules (such as polymers) can be partial or complete. For example, cellulose can be hydrolyzed to form smaller polysaccharides and / or glucose.

[0045] Membrane: A thin, flexible sheet of synthetic or natural material. As used herein, the term protective membrane refers to a membrane that inhibits the biodegradation of the underlying material, at least for a period of time.

[0046] Net: A loosely textured knitted, woven, or knotted material made of a network of silk or yarn.

[0047] Monomer: A molecule or compound that can react and combine to form a polymer, and usually contains carbon.

[0048] MPC: 2-Methylacryloyloxyethylphosphocholine PCU: Polycarbonate-urethane or Polycarbonate-polyurethane PET: Poly(ethylene terephthalate) PGS: Poly(glycerol sebacate) PGSU: Poly(glyceryl sebacate) / Thermoplastic Polyurethane Polyampholyte: A polymer in which different monomers have anionic and cationic groups.

[0049] Polybetaine: A polymer comprising betaine monomers. Betaine monomers include both anionic and cationic groups.

[0050] Polymer: A molecule of repeating structural units (e.g., monomers) formed through a chemical reaction (e.g., polymerization).

[0051] Protective polymer: As used herein, the term protective polymer refers to a polymer that inhibits the biodegradation of the underlying material for at least a period of time.

[0052] SLM: Synthetic Leaf Material Subjects: Animals (human or non-human) that have undergone treatment, observation, or experimentation.

[0053] Thermoplastic: refers to plastics that can be heated and softened repeatedly.

[0054] TPU: Thermoplastic Polyurethane UPy: Ureaprinone (Upy) Yarn: A continuous strand, usually folded, composed of multiple fibers or filaments.

[0055] Amphoteric ions: Molecules or ions that have separate positively charged and negatively charged groups.

[0056] II. Antifouling implantable materials The term "fouling" refers to the nonspecific absorption of proteins on at least a portion of the surface of an implant material. These proteins can trigger cellular responses, including cell attachment, wound healing, inflammation, encapsulation, or any combination of these responses. "Antifouling" materials reduce or eliminate at least some of the nonspecific protein absorption. Some examples of antifouling materials exhibit selective protein absorption, such as proteins that promote cell attachment without triggering at least one of inflammation, immune responses, encapsulation, or fibroblast proliferation. Some examples of antifouling materials exhibit at least one of reduced pannus formation and reduced calcification. In some instances, antifouling materials have not shown calcification for at least 90 days after intramuscular implantation, as demonstrated by X-ray or inductively coupled plasma mass spectrometry analysis.

[0057] Examples of antifouling implantable materials have been disclosed. In some examples, such as Figure 1 As shown, the antifouling implantable material 100 includes a reinforcing layer 110 comprising a plurality of polymer filaments 112, the reinforcing layer having a first surface 114 and an opposing surface 115. Figure 1In some examples, polymer filaments 112 are woven to form a fabric. An intermediate layer including a protective film 120 is disposed over or attached to at least a portion of the first surface 114. In some examples, the intermediate layer further includes a second protective film 122 disposed over or attached to at least a portion of an opposing surface 115. The antifouling implantable material 100 further includes an outer layer comprising an ionomer 130 grafted to an exposed surface of the protective film 120. The ionomer may also be grafted to an exposed surface of the second protective film 122. Figure 1 (Not shown in the view).

[0058] The reinforcing layer 110 includes a plurality of polymer filaments 112 comprising a filamentous polymer. The polymer filaments 112 can be arranged in several different ways to form the reinforcing layer 110. For example... Figure 1 and Figure 2A In one arrangement shown, the polymer filaments are randomly oriented to form a reinforcing layer containing entangled filaments. In another arrangement ( Figure 2B In another arrangement ( ), the polymer filaments are unidirectionally aligned. Figure 2C In this arrangement, polymer filaments form a multi-layered internal network, wherein the polymer filaments in each layer have a common extension direction, and the polymer filaments in adjacent layers are oriented in different extension directions. In yet another arrangement ( Figure 2D In this arrangement, polymer filaments form an interwoven web, which includes a first plurality of polymer filaments having a first common extension direction and a second plurality of polymer filaments having a second common extension direction, the second common extension direction being orthogonal to the first common extension direction. In another arrangement ( Figure 2E In this process, polymeric filaments are knitted to form a knitted material. In some instances, the polymeric filaments are twisted into yarn fibers 113 containing multiple polymeric filaments (see...). Figure 2F The yarn fibers can then be (i) randomly oriented to form a material comprising randomly oriented, entangled yarn fibers, (ii) unidirectionally aligned, (iii) woven to form an interlaced web, (iv) aligned to form a layered inner web comprising multiple layers, or (v) knitted to form a knitted material. Figure 2F ).

[0059] In any of the foregoing examples, the filamentous polymer may include a biostable polymer or a biodegradable polymer. The polymer may be a synthetic polymer or a natural polymer. In some examples, the filamentous polymer includes polyurethane, polyetherketone, polyethylene terephthalate, polycarbonate, polyester, polyacrylate, polysiloxane, aromatic polyolefin, aliphatic polyolefin, polyamide, glycerol-ester polymer, polycarboxylic acid, polysulfone, polysaccharide, polyamine, polyamino acid, polypeptide, or any combination thereof. Suitable polyurethanes include polyester polyurethane, polyether polyurethane, and polycarbonate polyurethane. The terms polyether polyurethane, polyether-urethane, and polyether-based polyurethane are used interchangeably. Similarly, the terms polycarbonate polyurethane, polycarbonate-urethane, and polycarbonate-based polyurethane are used interchangeably. Exemplary polyamides include nylon. Exemplary polycarboxylic acids include polylactic acid and poly(lactic-co-glycolic acid). Suitable polysaccharides include, but are not limited to, chitin, cellulose, hyaluronic acid, chondroitin, and chondroitin-4-sulfate. Suitable polypeptides include, but are not limited to, silk and gelatin. In some instances, filamentous polymers include poly(ethylene terephthalate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(glycerol sebacic acid), polyethylene, polypropylene, chitosan, cellulose, collagen, silk, fibroin, gelatin, and combinations thereof. In one instance, the filamentous polymer is a biodegradable polymer, such as poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharides (e.g., chitosan, cellulose), polyamino acids, polypeptides (e.g., silk, gelatin), poly(glycerol sebacic acid), or combinations thereof. In another instance, the filament is a biostable polymer, such as polyurethane, polyester, poly(ethylene terephthalate), polycarbonate, polysiloxane, aromatic polyolefin, aliphatic polyolefin, or combinations thereof. In independent embodiments, the filamentous polymer includes combinations of biostable and biodegradable polymers, such as a combination of silk and polyester.

[0060] In some instances, such as Figure 3 As shown, the polymer filament 112 includes a core 116 comprising a filamentous polymer and a shell 118 surrounding the core, wherein the shell comprises a shell polymer. The shell can be a nonwoven material. In one example, the shell polymer has a different chemical composition than the filamentous polymer. In another example, the shell polymer has the same chemical composition as the filamentous polymer. The shell can be mechanically or chemically attached to the core.

[0061] In any of the foregoing examples, the shell polymer may include polyurethane (e.g., polyester polyurethane, polyether polyurethane, or polycarbonate polyurethane), polyetherketone, poly(ethylene terephthalate), polycarbonate, polyacrylate, polysiloxane, aromatic polyolefin, aliphatic polyolefin, polyamide (e.g., nylon), glycerol-ester polymer, polycarboxylic acid (e.g., polylactic acid, poly(lactic-co-glycolic acid)), polysulfone, polysaccharide (e.g., hyaluronic acid, chondroitin, chondroitin-4-sulfate, chitosan, cellulose, glycosaminoglycans), polyamine, polyamino acid, polypeptide, or any combination thereof. In one example, the shell polymer is biostable, such as hydrolyzed poly(ethylene terephthalate) or polyurethane (e.g., polycarbonate polyurethane). In another example, the shell polymer is biodegradable, such as polylactic acid, poly(lactic-co-glycolic acid), polysaccharide, polypeptide, chitosan, cellulose, poly(glycerol sebate), poly(xylitol sebate), or combinations thereof. In one example, the core is thermoplastic polyurethane, and the shell is poly(glycerol sebacate). In another example, the core is poly(ethylene terephthalate), and the shell is hydrolyzed poly(ethylene terephthalate). In any of the foregoing examples, the shell may have an average thickness in the range of 200 to 800 μm, such as 200-250 μm.

[0062] In any of the foregoing examples, the polymer filament may have an average diameter ranging from 0.001 μm to 2000 μm. In some examples, the polymer filament is a microfilament or nanofilament. In some examples, the polymer filament has an average diameter ranging from 0.001 to 50 μm.

[0063] like Figure 1As shown, an intermediate layer including a protective film 120 is disposed over or attached to at least a portion of the first surface 114 of the reinforcing layer 110, the protective film comprising a protective polymer. In some embodiments, the intermediate layer further includes a second protective film 122 disposed over or attached to at least a portion of the opposing surface 115 of the reinforcing layer 110, the second protective film comprising a protective polymer. The protective polymers of the protective film and the second protective film may have the same chemical composition or different chemical compositions. "At least a portion" means at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the first surface, the opposite surface, or both the first surface and the opposite surface, such as from 10-100%, 20-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, or even 95-100%. In some instances, an intermediate layer including a protective film 120 is disposed over or attached to the entire first surface 114. In some instances, the intermediate layer further includes a second protective film 122, wherein the second protective film is disposed over or attached to the entire opposite surface 115. In any of the foregoing examples, the intermediate layer may have an average thickness in the range of 10-250 μm, such as 25-200 μm, 25-100 μm, 25-75 μm, or 25-50 μm. In some examples, the intermediate layer seals the pores in the reinforcing layer and / or the pores in the polymer filaments or yarns comprising polymer filaments. The intermediate layer may also provide a uniform outer surface for the antifouling implantable material, such as a surface that is clearly free of irregularities or roughness when viewed with the naked eye or at low magnification (e.g., 5-10x).

[0064] In any of the foregoing examples, the protective polymer may include a biodegradable polymer or a biostable polymer. The polymer may be a synthetic polymer or a natural polymer. In some examples, the polymer is a natural or synthetic polymer that forms a hydrogel. Suitable biostable synthetic polymers include, but are not limited to, polyethylene (PE) (including low-density PE (LDPE) - molecular weight less than 50,000 g / mol, high-density PE (HDPE) - molecular weight 2 x 10⁻⁶). 5 Up to 3 x 10 6 g / mol, and ultra-high molecular weight PE (UHMWPE) - molecular weight 3-7.5 x 10 6Polypropylene, polytetrafluoroethylene, polyether, polycarbonate polyurethane, polysiloxane polyurethane, polyether polyurethane elastomer, polyester polyurethane elastomer, silicone, polycarbonate, polysulfone, polyether ether ketone, poly(ethylene terephthalate), polyester, and combinations thereof. Suitable biodegradable synthetic polymers include, but are not limited to: polyester, polyacrylate, polyamide, hydrophilic polyester polyurethane, hydrophilic polyurea, poly(amide-enamine), polyanhydride, poly(esteramide), poly(ethylene glycol), poly(glycerol sebate), poly(xylitol sebate), polylactic acid, polyglycolic acid, polycaprolactone, poly(hydroxybutyrate), poly(ε-caprolactone), poly(ethylene glycol) diacrylate (PEGDA), poly(2-hydroxyethyl methacrylate) (poly(HEMA)), ureidopyrimidinone-based polymers, poly(vinyl alcohol)-hyaluronic acid, hyaluronic acid amine, and combinations thereof. Suitable hydrogel-forming polymers include, but are not limited to, proteins (e.g., collagen, gelatin), polysaccharides (e.g., chitosan, cellulose, starch, alginate, agarose), hydrophilic polyurethanes, poly(ethylene oxide) (PEO), polyacrylamide (PAAm), polyethylene glycol (PEG), polyacrylates, peptides, poly(glycerol sebate), poly(xylitol sebate), and combinations thereof. In some examples, the protective polymer includes thermoplastic polyurethanes, poly(glycerol sebate), or combinations thereof. In some examples, the thermoplastic polyurethane includes polycarbonate polyurethane or polyether polyurethane. In a separate example, the protective polymer includes poly(ethylene glycol) diacrylate. In another separate example, the protective polymer includes poly(2-hydroxyethyl methacrylate). In yet another separate example, the protective polymer includes a ureidopyrimidinone-based polymer.

[0065] In any of the foregoing examples, the antifouling implantable material 100 may further include an outer layer comprising an ionomer 130 grafted to an exposed surface of an intermediate layer including a protective membrane 120. Figure 1 The outer layer containing the ionomer can also be grafted onto the second protective film 122 (in...). Figure 1 The exposed surface (not shown in the view). The ionomer grafted to the exposed surface of the second protective film 122 may be the same as or different from the ionomer 130 grafted to the exposed surface of the protective film 120. In any of the foregoing examples, the outer layer may have an average thickness in the range of 0.001 μm to 25 μm. In some examples, the outer layer may have 0.1-2.5 chains / nm. 2 The polymer grafting density.

[0066] In any of the foregoing examples, the ionic polymer can be an anionic polymer, a cationic polymer, or a zwitterionic polymer. In any of the foregoing examples, the ionic polymer can have a chain length of 5 to 500 ionic units. In some examples, the ionic polymer is a zwitterionic polymer. The zwitterionic polymer can be a polyamphoteric electrolyte or a polybetaine. In some examples, the zwitterionic polymer includes poly(phosphocholine), poly(sulfobetaine), poly(carboxybetaine), zwitterionic polysaccharides, diethylethanolamine quaternized with 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid, or any combination thereof. In some examples, the zwitterionic polymer includes, but is not limited to, polymers comprising a 2-methacryloyloxyethylphosphocholine (MPC) moiety, a sulfobetaine methacrylate (SBMA) moiety, a carboxybetaine methacrylate (CBMA) moiety, or any combination thereof. In the exemplary zwitterionic monomer formulas below, m and n It is an integer. In some instances, m It is 1 and n It is 1.

[0067] MPC SMBA CBMA In some instances, the ionic polymer is a copolymer, such as a copolymer of MPC, SMBA, or CBMA and at least one other monomer. Exemplary ionic polymers include, but are not limited to, poly(MPC-co-2-ethylhexyl methacrylate-co- N, N 2-Diethylaminoethyl methacrylate, poly(MPC-co-p-nitrophenoxycarbonyl poly(ethylene glycol) methacrylate), poly(2-hydroxyethyl methacrylate)-MPC copolymer, polyvinylpyrrolidone-MPC copolymer and combinations thereof.

[0068] In some instances, grafted ionomers form polymer brushes on the exposed surfaces of the protective membrane. In these polymer brushes, one end of the polymer is attached to the surface, while the other end remains free. When the antifouling implantable material is implanted into a subject, the polymer brush conformation or construction can provide resistance to protein adsorption and / or cell adhesion.

[0069] In some instances, ionomers have reduced fibrosis, hemolysis, and / or immunogenic reactions when antifouling implantable materials are implanted in subjects. Ionomer coatings modify the surface of antifouling implantable materials and can reduce tissue reactions by minimizing fibrosis. Certain zwitterionic groups, such as phosphorylcholine, can prevent biological reactions due to their affinity for the phospholipid structure of cell membranes. Phospholipid-assembled surfaces inhibit many biological reactions and exhibit excellent antithrombotic responses when the polymer is in contact with platelet-rich plasma. In the absence of ionomers, proteins can adsorb onto the surface within seconds of the material contacting bodily fluids such as blood or plasma. However, for example, protein adsorption on MPC-containing polymers from human plasma, as determined by radioimmunoassay and immunocolloid labeling techniques, shows that the amount of adsorbed protein is relatively small and decreases with increasing MPC moiety.

[0070] In one example, the antifouling implantable material comprises a woven mesh reinforcement layer made of polymer filaments comprising a biodegradable poly(lactic acid) (PLA) core fiber and a thermoplastic polycarbonate-urethane (PCU) shell. The reinforcement layer is sandwiched between two protective PCU membranes. The outer layer comprises a zwitterionic polymer, such as an MPC-containing polymer, grafted onto the surface of the PCU protective membrane.

[0071] In another example, the stain-resistant implantable material includes a knitted fabric reinforcement layer made of poly(ethylene terephthalate) PET yarn, which comprises PET fibers twisted together. The surface of the PET yarn is hydrolyzed to provide a core-shell structure. The intermediate layer includes a PCU protective film attached to the exposed surface of the knitted PET fabric. In a separate example, the intermediate layer includes two PCU protective films. The outer layer includes a zwitterionic polymer, such as an MPC-containing polymer, grafted to the exposed surface of the intermediate layer.

[0072] In another example, the antifouling implantable material comprises a knitted fabric reinforcement layer made of PET yarn, which consists of PET fibers twisted together. An intermediate layer comprising an aromatic PCU protective film having a Shore hardness of 30A-75A and a thickness of 40-50 μm is applied to the entire outer surface of the reinforcement layer. The intermediate layer comprises two PCU protective films, each having a thickness of 20-25 μm. The outer layer comprises a zwitterionic polymer containing 2-MPC grafted to the intermediate layer.

[0073] In yet another example, the antifouling implantable material comprises a knitted fabric reinforcement layer made of PET yarn, which consists of PET fibers twisted together. The surface of the PET yarn is hydrolyzed to provide a core-shell structure. The intermediate layer comprises a polyether-based hydrogel thermoplastic polyurethane protective film attached to the exposed surface of the reinforcement layer. The outer layer comprises a zwitterionic polymer, such as an MPC-containing polymer, grafted to the exposed surface of the intermediate layer.

[0074] In another example, the antifouling implantable material includes a reinforcing layer comprising electrospun aromatic polycarbonate polyurethane filaments to provide a porous structure with both small and large pore sizes. In some examples, the pore size has an average diameter of 0.1-50 μm. In some examples, the small pores may have an average diameter of 0.1-10 μm and / or the large pores may have an average diameter of 10-50 μm. The intermediate layer comprises a poly(glycerol sebacate) protective membrane having a weight-average molecular weight of 5,000-1,000,000 g / mol (e.g., 31,000 g / mol). The outer layer comprises a zwitterionic polymer comprising 2-MPC grafted to the intermediate layer.

[0075] In yet another example, the antifouling implantable material includes a reinforcing layer comprising electrospun filaments comprising two co-spun polymers: an aliphatic, hydrophilic polyether-based polyurethane hydrogel and a bio-stable aromatic polycarbonate polyurethane. The intermediate layer comprises a PEG-based hydrogel protective film. The outer layer comprises a zwitterionic polymer comprising 2-MPC grafted onto the intermediate layer.

[0076] Advantageously, some examples of the disclosed antifouling implantable materials have chemical and / or physical properties compatible with body tissue characteristics. For example, in some examples, the antifouling implantable materials have properties compatible with pericardial tissue and / or vascular tissue. In any of the foregoing examples, the reinforcing layer may have a burst strength (measured according to ASTM D3787-01) in the range of 50-1000 N, such as a burst strength in the range of 500-800 N. In any of the foregoing examples, the reinforcing layer may have a tensile strength (wet or dry, measured according to ASTM D412) in the range of 20-800 N, such as a tensile strength in the range of 50-300 N. In any of the foregoing examples, the intermediate layer may have (i) a Shore hardness (ASTM D785) in the range of 10A-80A, (ii) a Shore hardness of 1-50 N / mm². 2 (iii) Flexural modulus within the range of 10-60 N / mm² (ASTM D790). 2 The dry ultimate tensile strength (ASTM D412) is within the range of 5-40 N / mm². 2(v) Wet ultimate tensile strength (ASTM D412) within the range of 25-500%, (vi) Dry ultimate elongation (ASTM D412) within the range of 25-500%, or (vii) Any combination thereof. In any of the foregoing examples, the antifouling implantable material may have a burst strength in the range of 50-1000 N, such as in the range of 500-800 N.

[0077] Unbound by any theory, it is believed that materials with Shore hardness within the stated range allow for natural bonding of leaflets made from them. Although bonding in some instances of leaflets can be improved by methods including shape setting or thermal setting.

[0078] In any of the foregoing examples, the filamentous polymer (including the core fibrous polymer and / or shell polymer), the protective polymer, or both may be biodegradable. In some examples, the biodegradable material may allow tissue regeneration when the antifouling implantable material is implanted in the body. In some examples, the filamentous polymer (including the core fibrous polymer and / or shell polymer), the protective polymer, or both may be biostable. In any of the foregoing examples, the antifouling implantable material may include a combination of biostable and biodegradable polymers. By way of non-limiting example only, the filamentous polymer may be biostable while the protective polymer is biodegradable.

[0079] In any of the foregoing examples, antifouling implantable materials can be used to form implantable medical devices or components thereof. In some examples, implantable medical devices include artificial heart valves, wherein antifouling implantable materials can be used to form the prosthetic leaflet of the artificial valve or other soft components of the artificial valve, such as a sealing skirt or cover for the metal components of the artificial valve. In some examples, implantable medical devices are surgically implantable artificial heart valves for replacing any natural heart valve (aortic, mitral, tricuspid, and pulmonary valves). In other examples, implantable medical devices are transcatheter artificial heart valves for replacing any natural heart valve. Examples of disclosable, implantable materials disclosed herein that may be useful in relation to artificial heart valves include exemplary patents and publications such as US 7,993,394; US 8,252,051; US ​​8,454,685; US 8,568,475; US 9,393,110; US 9,636,223; US 9,662,204; US 9,974,650; US 9,974,652; US 10,195,025; US 10,226,334; US 10,363,130; US 10,413,407; US 10,426,611; US ​​10,433,958; US 10,433,959; US 2018 / 0028310; US 2019 / 0167422A1 and WO 2018 / 222799, each of which is incorporated herein in its entirety by reference for all purposes.

[0080] In other instances, implantable medical devices may include docking devices for receiving an artificial heart valve at a location within the heart, such as those disclosed in U.S. Patent Publications 2019 / 0000615 and 2017 / 0231756 and U.S. Patent 10,463,479, all of which are incorporated herein by reference in their entirety for all purposes. Antifouling materials disclosed herein may be incorporated into such docking devices in which antifouling properties are desired. For example, antifouling materials may be used to form the inner and / or outer layers of the docking device.

[0081] In other instances, implantable medical devices may include valve repair devices for repairing any of the natural heart valves (aortic, mitral, tricuspid, or pulmonary valves). Repair devices may include, for example, complete or partial valvuloplasty rings; leaflet clamping devices, such as those disclosed in U.S. Patent Publication Nos. 2016 / 0331523 and 10,524,913; or leaflet enlarging devices, such as those disclosed in U.S. Patent Publication No. 2015 / 0230919, the entire disclosure of all these patents of which is incorporated herein by reference for all purposes. Antifouling materials disclosed herein may be incorporated into such valve repair devices in which antifouling properties are desired. For example, antifouling materials may be used to form the outer layer or covering of the repair device, such as the tubular covering of a valvuloplasty ring.

[0082] In other instances, implantable medical devices may be cardiovascular patches or vascular grafts.

[0083] Figure 14 A transcatheter artificial heart valve 10 according to one example is shown, configured for implantation via a catheter as known in the art. The illustrated artificial valve is suitable for implantation into a natural aortic valve annulus, although other examples are suitable for replacing other natural heart valves (e.g., pulmonary valve, mitral valve, and tricuspid valve). The artificial valve may also be suitable for implantation into other tubular organs or channels within the body. The artificial valve 10 may have four main components: a stent or frame 12, a valve structure 14, an inner skirt 16, and a perivalvular external sealing member or outer skirt 18. The prosthetic valve 10 may have an inflow end portion 15, a middle portion 17, and an outflow end portion 19. The inner skirt 16 may be disposed on and / or coupled to the inner surface of the frame 12, while the outer skirt 18 may be disposed on and / or coupled to the outer surface of the frame 12.

[0084] Valve structure 14 may include three leaflets 40 that together form a leaflet structure, which may be arranged to collapse in a tricuspid valve arrangement, although in other instances there may be more or fewer leaflets (e.g., one or more leaflets 40). Leaflets 40 may be secured to each other on their adjacent sides to form a commissure 22 of leaflet structure 14. The lower edge of valve structure 14 may have an undulating, curved fan shape and may be secured to inner skirt 16 by sutures (not shown). Leaflets 40 may be formed of a contamination-resistant implantable material disclosed herein. In some instances, it may be desirable to form inner skirt 16 and / or outer skirt 18 as of a contamination-resistant implantable material disclosed herein.

[0085] The frame 12 can be formed using multiple circumferentially spaced slots or using an engagement window 20 suitable for mounting the ferrule 22 of the valve structure 14 to the frame. As is known in the art, the frame 12 can be made of any of a variety of suitable plastic expandable materials (e.g., stainless steel, etc.) or self-expanding materials (e.g., nickel-titanium alloys, such as NiTi). In some instances, when constructed of a plastic expandable material, the frame 12 (and therefore the artificial valve 10) can be crimped into a radially collapsed configuration on the delivery catheter and then expanded inside the patient by an inflatable balloon or equivalent expansion mechanism. When constructed of a self-expanding material, the frame 12 (and therefore the artificial valve 10) can be crimped into a radially collapsed configuration and confined in the collapsed configuration by an equivalent mechanism inserted into the sheath or delivery catheter. Once inside the body, the artificial valve can be advanced from the delivery sheath, which allows the artificial valve to expand to its functional size.

[0086] Suitable plastic expandable materials that can be used to form the frame 12 include, but are not limited to, stainless steel; biocompatible high-strength alloys (e.g., cobalt-chromium or nickel-cobalt-chromium alloys); polymers; or combinations thereof. In a specific example, the frame 12 is made of a nickel-cobalt-chromium-molybdenum alloy, such as MP35N. ® The alloy (SPS Technologies, Jenkintown, Pennsylvania) is equivalent to UNS R30035 alloy (covered by ASTM F562-02). MP35N ® The alloy / UNS R30035 comprises 35% nickel, 35% cobalt, 20% chromium, and 10% molybdenum by weight. Additional details regarding the artificial valve 10 and its various components are described in WIPO patent application publication number WO 2018 / 222799, which is incorporated herein by reference for all purposes.

[0087] Figure 15A perspective view of an exemplary artificial heart valve 50 according to one example is shown. As is known in the art, the artificial heart valve 50 can be implanted in open-heart surgery. The heart valve 50 includes a plurality (typically three) of flexible leaflets 54, which are partially supported by undulating wireforms 56, support bands 58, and sewing loops 66. The wireforms 56 define a support frame for the leaflets 54. The wireforms 56 may be formed of a suitably resilient metal, such as a Co-Cr-Ni alloy (e.g., Elgiloy® alloy), while the support bands or stents may be metallic, plastic, or a combination of both. The wireforms 56 define an undulating periphery to which alternating compartments 62 and tips 64 are secured. Each compartment 62 is located between two arcuate tips 34 that bend toward the inflow direction. The wireforms 56, support bands 58, and sewing loops 66, as shown, are typically covered with polyester fabric 68 to facilitate assembly and reduce direct blood exposure after implantation. Leaflet 54 can be formed from the stain-resistant implantable material disclosed herein. In some instances, polyester fabric 68 can be replaced by the stain-resistant implantable material disclosed herein.

[0088] III. Methods for manufacturing antifouling implantable materials In some instances, the method of fabricating the antifouling implantable material disclosed herein involves forming an intermediate layer comprising a protective film on at least a portion of a first surface of a reinforcing layer, the reinforcing layer comprising a plurality of polymeric filaments containing filamentous polymers, and the protective film comprising a protective polymer. The method may further include forming an outer layer by grafting an ionic polymer onto an exposed surface of the intermediate layer. In any of the foregoing instances, the intermediate layer may further include grafting a second protective film comprising a protective polymer onto at least a portion of an opposing surface of the reinforcing layer.

[0089] In any of the foregoing examples, the method may further include forming a reinforcing layer. In one example, forming the reinforcing layer includes jet spinning, electrospinning, or melt spinning a plurality of polymeric filaments to form a material comprising randomly oriented, entangled filaments. In a separate example, forming the reinforcing layer includes unidirectionally aligning the plurality of polymeric filaments. In another separate example, forming the reinforcing layer includes weaving the plurality of polymeric filaments to form an interwoven web comprising a first plurality of filaments having a first common extension direction and a second plurality of filaments having a second common extension direction orthogonal to the first common extension direction. In yet another separate example, forming the reinforcing layer includes aligning the plurality of polymeric filaments to form a sheet-like inner web comprising a plurality of sheets, wherein the filaments in each sheet have a common extension direction and the filaments in adjacent sheets are oriented in different extension directions. In yet another separate example, forming the reinforcing layer includes knitting the plurality of polymeric filaments to form a knitted material. In yet another separate example, forming the reinforcing layer includes twisting a plurality of polymer filaments to form yarn fibers, followed by (i) randomly orienting the yarn fibers to form a material comprising randomly oriented, entangled yarn fibers, (ii) unidirectionally aligning the yarn fibers, (iii) weaving the yarn fibers to form an interwoven web, (iv) aligning the yarn fibers to form a sheet-like inner web comprising multiple layers, or (v) knitting the yarn fibers to form a knitted material. In yet another separate example, forming the reinforcing layer includes printing a pattern of the plurality of polymer filaments using 3D printing. The pattern can be any desired pattern, such as a single layer of aligned polymer filaments, a sheet-like inner web, etc.

[0090] In any of the foregoing examples, the method may further include forming a plurality of polymer filaments comprising filamentous polymers. Suitable methods for forming polymer filaments include, but are not limited to, jet spinning, electrospinning, melt spinning, 3D printing, extrusion, or meltblowing processes.

[0091] In some instances, the polymer filament comprises a core containing a filamentous polymer and a shell surrounding the core, the shell comprising a shell polymer. In one instance, the core and shell are formed in a single step by jet spinning (e.g., using a high-speed rotating nozzle), electrospinning, co-extrusion, or 3D printing. In some instances, the filamentous polymer and shell polymer are provided as a solution, melt, two-part composition (e.g., epoxy resin), or suspension. In some instances, the core is formed as described above, and then coated with a shell polymer to form the shell. For example, the shell can be formed by immersing the core fibers in molten shell polymer and allowing the shell polymer to cool around the core fibers. In another instance, the shell is formed in a solvent-based process by depositing the shell polymer onto the core fibers by immersing the core fibers in a solution containing the polymer and allowing the solvent to evaporate. In yet another separate instance, the core is formed as described above, and then the surface of the core is hydrolyzed to form the shell.

[0092] In any of the foregoing examples, forming the intermediate layer may further include forming a protective film. In one example, the protective film is formed by melting or extruding a protective polymer to form a thin film. In a separate example, the protective polymer may be compressed to form a thin film. In yet another separate example, the protective polymer is dissolved in a solvent to form a solution containing the protective polymer; a thin film is then formed from the solution. Depending on the protective polymer, suitable solvents may include methanol, ethanol, propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, acetone, acetonitrile, 2-butanone, chloroform, chloroform, dimethoxyethane, trifluoroethanol, diethylene glycol dimethyl ether, diethyl ether, methyl tert-butyl ether, dichloromethane, ethyl acetate, ethylene glycol, glycerol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetic acid, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dimethylacetamide (DMAc or DMA), dioxane, heptane, dihydroglucosamine (Cyrene™ solvent, Sigma-Aldrich), polyethylene glycol (MW400), and water-based buffers (e.g., 3-( N (morpholino)propanesulfonic acid (MOPS), tris(hydroxymethyl)aminomethane (Tris), and phosphate-buffered saline (PBS) buffer, and mixtures thereof. The mixed solvents may include water and organic solvents combined in a ratio of 1:2 v / v to 1:20 v / v. In one example, the protective polymer includes a thermoplastic polyurethane, and the polymer is dissolved in a solution containing dimethylacetamide, tetrahydrofuran, or a combination thereof.

[0093] In any of the foregoing examples, the intermediate layer, including the protective film, may be attached to or disposed over at least a portion of the first surface by any suitable method. Suitable methods include, but are not limited to, thermal attachment, mechanical attachment, ultrasonic attachment, laser attachment, chemical attachment, solvent-based attachment, and 3D printing. In some examples, the intermediate layer further includes a second protective film, which is similarly attached to or disposed over at least a portion of the opposing surface of the reinforcing layer.

[0094] In some instances, the protective film, including an intermediate layer, is thermally attached to the surface by hot-pressing the protective film onto the surface of the reinforcing layer (e.g., over at least a portion of the first surface and optionally over at least a portion of the opposing surface), forming the protective film on the surface, or by extruding a protective polymer onto the surface. Hot-pressing is performed at a temperature and time that effectively adheres the protective film to the surface of the reinforcing layer without causing the filamentous polymer or the protective polymer to crystallize. In one instance, a temperature in the range of 190-200°C and 0.7-0.8 N / mm² are used. 2 Under pressure, the thermoplastic aromatic polyurethane protective film is adhered to the PET reinforcement layer for 15 seconds.

[0095] In some instances, an intermediate layer, including a protective film, is mechanically attached to the surface of the reinforcing layer. Mechanical attachment can include pressing the protective film onto the surface without increasing heat. Alternatively, mechanical attachment can be enhanced by modifying the surface morphology of the protective film. Surface modification of the protective film can be performed using processes including, but not limited to, laser ablation, ion milling, and sputtering etching.

[0096] In one instance, the intermediate layer, including the protective film, is ultrasonically attached to the surface of the reinforcing layer. In another instance, a laser is used to attach the intermediate layer, including the protective film, to the surface of the reinforcing layer.

[0097] In some instances, an intermediate layer comprising a protective film is chemically attached to the surface of the reinforcing layer. In such instances, the protective polymer includes functional groups capable of reacting with functional groups on the surface of the reinforcing layer, such as those on filamentous polymers, or, in the case of a core-shell filament, with functional groups on the shell polymer. Chemical attachment can be achieved through hydrolysis or oxidation of the reinforcing layer surface and the protective polymer, whereby the chemical functional groups of the filamentous or shell polymer react with the functional groups of the protective polymer. In some instances, acetic acid and / or sodium hydroxide are used for hydrolysis. Oxidation can be carried out using hydrogen peroxide. In another instance, ultraviolet, plasma, or corona treatment techniques are used to alter the surface chemistry and chemically attach the intermediate layer to the surface of the reinforcing layer.

[0098] In some instances, an intermediate layer, including a protective film, is formed in situ on the surface of the reinforcing layer. For example, the reinforcing layer can be coated with a solution containing a protective polymer. Coating can be performed by any suitable method, including but not limited to dip coating, spray coating, or spin coating. The solution viscosity is adjusted so that the dissolved protective polymer moves slowly as the solvent evaporates. In some instances, the solvent is evaporated to form a protective film. In some instances, the protective polymer can be cured using ultraviolet radiation.

[0099] In some instances, the protective film is formed in situ via a reactive dip-coating process. As a non-limiting example, the reinforcing layer can be continuously immersed in a chemically reactive impregnation solution of poly(ethylene glycol)(PEG) methyl ether acrylate (e.g., average Mn 480), followed by immersion in poly(ethyleneimine)(PEI) (e.g., 10-50% (w / v) in H₂O). The two polymers react with each other via a Michael addition reaction. The reactive impregnation solution can be prepared in various solvents at concentrations ranging from 2-70% (w / v). Suitable solvents include, for example, toluene, ethanol, and 1-heptanol.

[0100] In some instances, forming an intermediate layer including a protective film in situ involves printing the protective film onto the surface of the reinforcing layer using a 3D printing process. In some instances, forming the intermediate layer involves forming two protective films comprising a protective polymer. The first layer seals the pores in the reinforcing layer filaments or yarns, and the second layer provides a uniformly coated surface on the antifouling implantable material.

[0101] In any of the foregoing examples, forming the outer layer by grafting an ionic polymer onto the exposed surface of the intermediate layer may include contacting the exposed surface with a solution comprising the ionic polymer to form a material coated with the ionic polymer, and drying the material coated with the ionic polymer. In some examples, grafting an ionic polymer onto the exposed surface of the intermediate layer includes spraying an ionic polymer solution onto the exposed surface. Spraying may include plasma spraying or thermal spraying processes. In a separate example, an implantable material may be immersed in an ionic polymer solution to coat the implantable material with the ionic polymer. In another separate example, the ionic polymer may be vapor-deposited onto the exposed surface of the intermediate layer by physical or chemical vapor deposition. If the intermediate layer includes a second protective film, the ionic polymer may also be grafted onto the exposed surface of the second protective film. The ionic polymer grafted onto the second protective film may be the same as or different from the ionic polymer on the protective film. In some examples, the ionic polymer is an amphoteric ionic polymer as discussed above.

[0102] Ionic polymers can be chemically or mechanically grafted onto a protective film. In some instances, the ionic polymer includes side chains containing functional groups that can react with functional groups on the protective polymer molecule, thereby chemically grafting or bonding the ionic polymer onto the protective film. Suitable functional groups include, but are not limited to, anionic groups, cationic groups, hydrogen-bonding groups, photoreactive groups, or alkoxysilyl groups. For example, the ionic polymer may include side chains terminated in a carboxylic acid (-COOH) group, which can react with functional groups (e.g., carboxylic acid, hydroxyl, or amine groups, etc.) on the protective polymer, thereby chemically bonding the ionic polymer to the protective film. In some instances, the protective film (such as a polyurethane-containing protective film) is treated with dilute acid or plasma to generate additional carboxylic acid groups on the surface of the protective film for reaction with the ionic polymer. Chemically grafting the ionic polymer onto the protective film involves contacting the protective film with the ionic polymer under conditions that effectively promote a chemical reaction between the functional groups of the ionic polymer and the functional groups of the protective polymer. Effective conditions may include a temperature and / or contact time that effectively promotes the chemical reaction. Contacting the protective film with the ionomer can include spraying the protective film with a solution containing the ionomer, vapor-depositing the solution containing the ionomer onto the protective film, immersing the protective film in a solution containing the ionomer, or any other suitable method. Following the reaction, the antifouling implantable material can be washed to remove any unbound ionomer and / or reaction byproducts.

[0103] In some instances, the ionic polymer comprises side chains that can intercalate between molecules of the protective film, thereby mechanically grafting the ionic polymer onto the protective film. For example, the ionic polymer may include side chains containing hydrophobic groups (e.g., aliphatic groups). The ionic polymer is mechanically grafted onto the protective film by swelling the protective film to provide space between the protective polymer molecules. The protective film can be swollen by contacting or immersing it in a suitable solvent. For example, some polyurethanes swell upon contact with ethanol. The swollen protective film is then contacted with the ionic polymer, thereby intercalating at least some of the ionic polymer side chains into the space between the protective polymer molecules. Contacting the swollen protective film with the ionic polymer may include spraying the protective film with a solution containing the ionic polymer, vapor-depositing a solution containing the ionic polymer onto the protective film, immersing the protective film in a solution containing the ionic polymer, or any other suitable method. The antifouling implantable material is then dried. When the antifouling implantable material dries, the space between the protective polymer molecules closes and traps the ionic polymer side chains, thereby mechanically grafting the ionic polymer onto the protective film.

[0104] In any of the foregoing or following examples, the method may further include forming a plurality of leaflets from an implantable material and coupling the leaflets to a framework of an artificial heart valve.

[0105] In one example, a method of fabricating an antifouling implantable material includes providing a reinforcing layer comprising a web of polymeric filaments containing poly(lactic acid). The reinforcing layer is dip-coated in a solution containing polycarbonate-urethane (PCU) to form a dip-coated reinforcing layer comprising a web of polymeric filaments containing a poly(lactic acid) core fiber and a PCU shell. The dip-coated reinforcing layer has a first surface and an opposing surface. A protective film containing PCU is thermally attached to at least a portion of the first surface. Optionally, a second protective film containing PCU is thermally attached to at least a portion of the opposing surface. A zwitterionic polymer is chemically or mechanically grafted onto an exposed surface of the protective film or onto the exposed surfaces of the protective film and the second protective film. In some examples, the zwitterionic polymer comprises 2-methacryloyloxyethylphosphorylcholine.

[0106] In another example, a method of fabricating a stain-resistant implantable material includes providing a reinforcing layer comprising a knitted material formed from yarn, the yarn comprising a plurality of polymeric filaments comprising poly(ethylene terephthalate) (PET). The surface of the yarn is hydrolyzed to form a hydrolyzed PET shell on the PET-containing polymeric filaments. A protective film comprising PCU or poly(glycerol sebate) (PGS) is attached to at least a portion of a first surface of the reinforcing layer. In some examples, the protective film is attached by: (i) thermally attaching the protective film to at least a portion of the first surface, (ii) dip-coating the reinforcing layer in a solution comprising PCU or PGS, or (iii) depositing the protective film onto at least a portion of the first surface by three-dimensional printing. In some examples, the protective film is thermally attached to a portion of the first surface, and the method further includes thermally attaching a second protective film to at least a portion of an opposing surface of the reinforcing layer. A zwitterionic polymer is chemically or mechanically grafted onto an exposed surface of the protective film or an exposed surface of the protective film and the second protective film. In some instances, zwitterionic polymers include 2-methacryloyloxyethylphosphorylcholine.

[0107] In yet another example, a method of fabricating a stain-resistant implantable material includes providing a knitted fabric reinforcement layer made of poly(ethylene terephthalate) PET yarn, which comprises PET fibers twisted together. The surface of the PET yarn is hydrolyzed to provide a core-shell structure. An intermediate layer comprising a PCU protective film is attached to the exposed surface of the knitted PET fabric, for example, by impregnating the reinforcement layer in a solution containing PCU. In a separate example, two layers of PCU protective film are applied to the reinforcement layer. A zwitterionic polymer, such as MPC, may be grafted onto the exposed surface of the PCU protective film.

[0108] In yet another example, a method for producing a stain-resistant implantable material involves providing a knitted fabric reinforcement layer made of PET yarn containing PET fibers twisted together. An intermediate layer comprising an aromatic PCU protective film having a Shore hardness of 30A-75A and a thickness of 40-50 μm is applied to the entire outer surface of the reinforcement layer. The intermediate layer comprises two PCU protective films, each 20-25 μm thick, which are thermally attached to the reinforcement layer. A temperature and time are selected to melt the PCU material and promote attachment. An outer layer comprising a zwitterionic polymer containing poly(2-methacryloyloxyethylphosphorylcholine) is grafted onto the intermediate layer by dissolving the zwitterionic polymer in ethanol and immersing the implantable material in the polymer solution.

[0109] In another example, a method for fabricating a stain-resistant implantable material includes providing a knitted fabric reinforcement layer made of PET yarn containing PET fibers twisted together. The surface of the PET yarn is hydrolyzed to provide a core-shell structure. A protective film comprising a polyether-based hydrogel thermoplastic polyurethane is attached to the exposed surface of the reinforcement layer. A zwitterionic polymer, such as MPC, may be grafted onto the exposed surface of the protective film.

[0110] In yet another example, a method for producing an antifouling implantable material includes forming a reinforcing layer by electrospinning a filament comprising an aromatic polycarbonate polyurethane. An intermediate layer comprising a poly(glycerol sebate) (weight-average molecular weight 31,000 g / mol) protective film is thermally attached to the exposed surface of the reinforcing layer to encapsulate the reinforcing layer and form the implantable material. The implantable material is then dipped into a solution comprising poly(2-methacryloyloxyethylphosphorylcholine) to form an outer layer comprising a polymer brush on the surface of the intermediate layer.

[0111] In yet another example, a method for manufacturing antifouling implantable materials involves forming a reinforcing layer by simultaneously electrospinning two types of polyurethane—an aliphatic, hydrophilic polyether-based polyurethane and a biostable aromatic polycarbonate polyurethane. The reinforcing layer is then dipped into a prepolymer solution containing PEGDA (poly(ethylene glycol) diacrylate, 10 kDa) and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone (photoinitiator) in a phosphate-buffered saline solution (pH 7.4) and polymerized under ultraviolet light to form an intermediate layer comprising a PEG-based hydrogel protective film.

[0112] IV. Additional embodiments of the disclosed technology In view of the above-described implementations of the disclosed subject matter, this application discloses additional embodiments listed below. It should be noted that a feature or combination of features of an isolated embodiment, or more than one feature combination of an embodiment, and optionally one or more feature combinations with one or more further embodiments, are also further embodiments falling within the scope of this disclosure.

[0113] Example 1. An antifouling implantable material comprising: a reinforcing layer including a plurality of polymeric filaments comprising a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; an intermediate layer including a protective film attached to at least a portion of the first surface, the protective film comprising a protective polymer; and an outer layer including an ionic polymer grafted to an exposed surface of the intermediate layer.

[0114] Example 2. Any embodiment herein, particularly the antifouling implantable material of Example 1, wherein the polymer filaments of the reinforcing layer are: randomly oriented to form a material comprising entangled polymer filaments; or unidirectionally aligned; or formed into an interwoven web comprising a first plurality of polymer filaments having a first common extension direction interwoven with a second plurality of polymer filaments having a second common extension direction orthogonal to the first common extension direction; or formed into a sheet inner web comprising a plurality of sheets, wherein the polymer filaments in each sheet have a common extension direction and the polymer filaments in adjacent sheets are oriented in different extension directions; or knitted to form a knitted material; or twisted into a yarn fiber comprising a plurality of polymer filaments, wherein the yarn fiber is subsequently (i) randomly oriented to form a material comprising randomly oriented, entangled yarn fibers, (ii) unidirectionally aligned, (iii) woven to form an interwoven web, (iv) aligned to form a sheet inner web comprising a plurality of sheets, or (v) knitted to form a knitted material.

[0115] Example 3. Any of the examples in this document, particularly the antifouling implantable material of Example 1 or Example 2, wherein the filamentous polymer includes polyurethane, polyetherketone, poly(ethylene terephthalate), polycarbonate, polyester, polyacrylate, polysiloxane, aromatic polyolefin, aliphatic polyolefin, polyamide, glycerol-ester polymer, polycarboxylic acid, polysulfone, polysaccharide, polyamine, polyamino acid, polypeptide, or any combination thereof.

[0116] Example 4. Any example in this document, particularly any of Examples 1-3, of an antifouling implantable material, wherein the filamentous polymer comprises a synthetic polymer.

[0117] Example 5. Any example in this document, particularly any of Examples 1-4, of an antifouling implantable material, wherein the filamentous polymer comprises a biostable polymer or a biodegradable polymer.

[0118] Example 6. Any of the examples herein, particularly the antifouling implantable material of Example 5, wherein: the biostable polymers include polyurethane, polyester, poly(ethylene terephthalate), polycarbonate, polysiloxane, aromatic polyolefin or aliphatic polyolefin; or the biodegradable polymers include poly(lactic acid), poly(lactic acid-co-glycolic acid), polysaccharide, polyamino acid, polypeptide or poly(glycerol sebacate).

[0119] Example 7. Any of the embodiments herein, particularly any one of Examples 1-6, of an antifouling implantable material, wherein the polymer filament comprises a core and a shell surrounding the core, wherein the core comprises a filamentous polymer and the shell comprises a shell polymer.

[0120] Example 8. Any of the examples in this document, particularly the antifouling implantable material of Example 7, wherein the shell polymer has a different chemical composition than the filamentous polymer.

[0121] Example 9. Any of the examples herein, particularly Example 7 or Example 8, of the antifouling implantable material, wherein the shell polymer comprises a biodegradable polymer or a biostable polymer.

[0122] Example 10. Any of the examples herein, particularly the antifouling implantable material of Example 9, wherein: the biodegradable polymer includes poly(lactic acid), poly(lactic acid-co-glycolic acid), polysaccharide, polyamino acid, polypeptide or poly(glycerol sebacate); or the biostable polymer includes hydrolyzed poly(ethylene terephthalate) or polyurethane.

[0123] Example 11. Any example in this document, particularly any one of Examples 1-10, of an antifouling implantable material, wherein the polymer filaments have an average diameter in the range of 0.001 μm to 2000 μm.

[0124] Example 12. Any example in this document, particularly the antifouling implantable material of Example 11, wherein: the polymer filaments are nanofilaments or microfilaments having an average diameter in the range of 0.001 μm to 50 μm; and at least some of the polymer filaments are chemically, thermally or mechanically fused together.

[0125] Example 13. Any embodiment in this document, particularly any one of Examples 1-12, of an antifouling implantable material, wherein the reinforcing layer has: (i) a thickness in the range of 25 μm to 500 μm; or (ii) a burst strength in the range of 50-800 N; or (iii) a tensile strength in the range of 50-800 N; or (iv) any combination of (i), (ii) and (iii).

[0126] Example 14. Any example in this document, particularly any of Examples 1-13, of an antifouling implantable material, wherein the protective polymer comprises a biostable or biodegradable polymer.

[0127] Example 15. In any of the examples herein, particularly the antifouling implantable material of Example 14, the protective polymer comprises: a biostable synthetic polymer selected from polyethylene, polypropylene, polytetrafluoroethylene, polyether, polycarbonate polyurethane, polysiloxane polyurethane, polyether polyurethane elastomer, polyester polyurethane elastomer, silicone, polycarbonate, polysulfone, polyetheretherketone, poly(ethylene terephthalate), polyester, or any combination thereof; or a biodegradable synthetic polymer selected from polyester, polyacrylate, polyamide, hydrophilic polyester polyurethane, hydrophilic polyurethane, etc. Urea, poly(amide-enamine), polyanhydride, poly(ester-amide), poly(glycolic acid), polylactic acid, polyglycolic acid, polycaprolactone, poly(hydroxybutyrate), poly(ε-caprolactone), poly(vinyl alcohol)-hyaluronic acid, hyaluronic acid amine, ureidopyrimidinone-based polymers, or any combination thereof; or polymers that form hydrogels selected from proteins, polysaccharides, hydrophilic polyurethanes, poly(ethylene oxide), polyacrylamide, polyethylene glycol, polyacrylates, polypeptides, poly(glycerol sebate), poly(xylitol sebate), or any combination thereof.

[0128] Example 16. Any embodiment herein, particularly any of Examples 1-15, of an antifouling implantable material, wherein the intermediate layer further includes a second protective film attached to at least a portion of the opposing surface of the reinforcing layer, the second protective film comprising a protective polymer, wherein the protective polymer of the second protective film may have the same or different chemical composition as the protective polymer of the protective film attached to the first surface of the reinforcing layer.

[0129] Example 17. Any example in this document, particularly any one of Examples 14-16, of an antifouling implantable material, wherein the intermediate layer has: (i) an average thickness in the range of 0.1 μm to 100 μm; or (ii) a Shore hardness in the range of 10A to 80A; or (iii) a Shore hardness of 1 N / mm². 2 Up to 50 N / mm 2 Flexural modulus within the range of; or (iv) within 10 N / mm 2 Up to 60 N / mm 2 The dry ultimate tensile strength within the range; or (v) at 5 N / mm 2 Up to 40 N / mm 2 The wet ultimate tensile strength within the range; or any combination of (vi)(i), (ii), (iii), (iv) and (v).

[0130] Example 18. Any example in this document, particularly any of Examples 1-17, of an antifouling implantable material, wherein the ionopolymer is an anionic polymer, a cationic polymer, or an amphoteric polymer.

[0131] Example 19. Any example in this document, particularly the antifouling implantable material of Example 18, wherein the ionomer is a polyampholyte or polybetaine.

[0132] Example 20. Any of the examples herein, particularly Example 18 or Example 19, describes an antifouling implantable material in which the ionic polymer comprises poly(phosphocholine), poly(sulfobetaine), poly(carboxybetaine), zwitterionic polysaccharides, diethylethanolamine quaternized with 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid, or any combination thereof.

[0133] Example 21. Any example in this document, particularly Example 20, of the antifouling implantable material, wherein the poly(phosphocholine) comprises the 2-methacryloyloxyethylphosphocholine (MPC) moiety.

[0134] Example 22. Any example in this document, particularly any of Examples 18-21, of an antifouling implantable material, wherein the ionomer comprises: poly(MPC); or poly(MPC-co-2-ethylhexyl methacrylate-co- N,N -Diethylaminoethyl methacrylate; or poly(MPC-co-p-nitrophenoxycarbonyl poly(ethylene glycol) methacrylate); or poly(2-hydroxyethyl methacrylate)-MPC copolymer; or polyvinylpyrrolidone-MPC copolymer; or any combination thereof.

[0135] Example 23. Any example in this document, particularly any of Examples 1-22, of an antifouling implantable material, wherein the outer layer has an average thickness in the range of 0.001 μm to 25 μm.

[0136] Example 24. Any example in this document, particularly any one of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises poly(lactic acid) and the intermediate layer comprises polycarbonate-urethane.

[0137] Example 25. Any of the embodiments herein, particularly Example 24, of the antifouling implantable material, wherein the polymer filament reinforcement layer forms an interwoven web.

[0138] Example 26. Any example in this document, particularly any one of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises poly(ethylene terephthalate) and the intermediate layer comprises polycarbonate-urethane.

[0139] Example 27. Any of the examples herein, particularly Example 26, describes a stain-resistant implantable material in which polymer fibers are knitted to form a knitted material.

[0140] Example 28. Any of the examples herein, particularly Example 26 or Example 27, describes a nonfouling implantable material in which the polymer filament comprises a core and a shell surrounding the core, wherein the core comprises a filamentous polymer and the shell comprises a shell polymer containing hydrolyzed poly(ethylene terephthalate).

[0141] Example 29. Any example in this document, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises poly(ethylene terephthalate) and the intermediate layer comprises a polyether-based hydrogel thermoplastic polyurethane.

[0142] Example 30. Any example in this document, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises polycarbonate-polyurethane and the intermediate layer comprises poly(glycerol sebacate).

[0143] Example 31. Any of the embodiments herein, particularly the antifouling implantable material of Example 30, wherein the intermediate layer further comprises thermoplastic polyurethane.

[0144] Example 32. Any of the examples herein, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises an aliphatic polyether-based polyurethane hydrogel and an aromatic polycarbonate polyurethane, and the intermediate layer comprises poly(ethylene glycol) diacrylate.

[0145] Example 33. Any example in this document, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises poly(ethylene terephthalate) and the intermediate layer comprises poly(2-hydroxyethyl methacrylate).

[0146] Example 34. Any of the examples herein, particularly Example 33, describes a stain-resistant implantable material in which polymer fibers are knitted to form a knitted material.

[0147] Example 35. Any example in this document, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises silk.

[0148] Example 36. Any of the embodiments herein, particularly Example 36, of the antifouling implantable material, wherein the polymer filament comprises a core and a shell surrounding the core, wherein the core comprises silk and the shell comprises a shell polymer comprising an aromatic polycarbonate polyurethane or an aliphatic polyether polyurethane.

[0149] Example 37. Any of the embodiments herein, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises silk and polyester, and the intermediate layer comprises a ureidopyrimidinone-based polymer.

[0150] Example 38. Any example in this document, particularly the antifouling implantable material of Example 37, wherein the ureidopyrimidinone-based polymer comprises , Where a, b, and c are independent integers greater than or equal to 1.

[0151] Example 39. Any of the embodiments herein, particularly Example 37 or Example 38, of the antifouling implantable material wherein polymer fibers are woven to form a knitted material.

[0152] Example 40. Any of the embodiments herein, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises gelatin and the intermediate layer comprises polycarbonate polyurethane and polyether polyurethane.

[0153] Example 41. Any of the examples herein, particularly Example 40, describes a nonfouling implantable material in which the gelatin is cross-linked.

[0154] Example 42. Any of the embodiments herein, particularly Example 40 or Example 41, of the antifouling implantable material, wherein the reinforcing layer and the intermediate layer have an average combined thickness of 0.2 mm to 0.6 mm.

[0155] Example 43. Any example in this document, particularly any of Examples 1-23, of an antifouling implantable material, wherein the filamentous polymer comprises polycarbonate polyurethane and polyether polyurethane, and the intermediate layer comprises poly(glycerol sebacate) and thermoplastic polyurethane.

[0156] Example 44. Any of the examples herein, particularly Example 43, describes an antifouling implantable material in which the reinforcing layer has an average pore size of 0.1 μm to 45 μm.

[0157] Example 45. Any of the embodiments herein, particularly Example 43 or Example 44, of the antifouling implantable material, wherein the reinforcing layer and the intermediate layer have an average combined thickness of 0.2 mm to 0.6 mm.

[0158] Example 46. Any example in this document, particularly any of Examples 24-46, of an antifouling implantable material, wherein the ionomer comprises 2-methacryloyloxyethylphosphocholine.

[0159] Example 47. An implantable medical device comprising any of the embodiments herein, particularly any of Examples 1-46, of a foul-resistant implantable material.

[0160] Example 48. Any of the embodiments herein, particularly Example 47, of an implantable medical device, wherein the implantable medical device includes an artificial heart valve, a vascular graft, a valvuloplasty ring, a cardiovascular patch, or a splice clip.

[0161] Example 49. Any embodiment herein, particularly Example 47, of an implantable medical device, wherein the implantable medical device includes an artificial heart valve comprising a plurality of leaflets formed of a nonfouling implantable material, a sealing skirt, a cover of metal components, or any combination thereof.

[0162] Example 50. An artificial heart valve comprising a fouling-resistant implantable material, the fouling-resistant material comprising: a reinforcing layer comprising a plurality of polymeric filaments including a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; an intermediate layer comprising a protective membrane attached to at least a portion of the first surface, the protective membrane comprising a protective polymer; and an outer layer comprising an ionomer grafted to an exposed surface of the intermediate layer.

[0163] Example 51. Any embodiment herein, particularly Example 50, of an artificial heart valve, wherein the artificial heart valve comprises a plurality of leaflets formed of a contamination-resistant implantable material, a sealing skirt, a cover of metal components, or any combination thereof.

[0164] Example 52. A valve repair device comprising a fouling-resistant implantable material, the fouling-resistant material comprising: a reinforcing layer comprising a plurality of polymeric filaments comprising a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; an intermediate layer comprising a protective film attached to at least a portion of the first surface, the protective film comprising a protective polymer; and an outer layer comprising an ionic polymer grafted to an exposed surface of the intermediate layer.

[0165] Example 53. Any of the embodiments herein, particularly Example 52, of the valve repair device, wherein the valve repair device includes a valve repair ring, a leaflet clamping device, or a leaflet enlargement device.

[0166] Example 54. Any of the embodiments herein, particularly Example 52 or Example 53, of the valve repair device, wherein the valve repair device includes an outer layer or cover comprising a contamination-resistant implantable material.

[0167] Example 55. A cardiovascular patch or vascular graft comprising an antifouling implantable material, the antifouling material comprising: a reinforcing layer including a plurality of polymeric filaments comprising a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; an intermediate layer including a protective film attached to at least a portion of the first surface, the protective film comprising a protective polymer; and an outer layer including an ionomer grafted to an exposed surface of the intermediate layer.

[0168] Example 56. A docking device for receiving an artificial heart valve at a location within the heart, the docking device comprising a fouling-resistant implantable material, the fouling-resistant material comprising: a reinforcing layer comprising a plurality of polymeric filaments containing a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; an intermediate layer comprising a protective film attached to at least a portion of the first surface, the protective film containing a protective polymer; and an outer layer comprising an ionomer grafted to an exposed surface of the intermediate layer.

[0169] Example 57. A method of manufacturing an antifouling implantable material, comprising: forming an intermediate layer including a protective film on at least a portion of a first surface of a reinforcing layer, the reinforcing layer including a plurality of polymeric filaments comprising a filamentous polymer, and the protective film comprising a protective polymer; and forming an outer layer by grafting an ionic polymer onto an exposed surface of the intermediate layer.

[0170] Example 58. Any of the embodiments herein, particularly the method of Example 57, wherein the intermediate layer further includes a second protective film on at least a portion of the opposing surfaces of the reinforcing layer, the second protective film comprising a protective polymer.

[0171] Example 59. Any embodiment herein, particularly the method of Example 57 or Example 58, further includes forming the reinforcing layer by: jet spinning, electrospinning, or melt spinning a plurality of polymeric filaments to form a material comprising randomly oriented, entangled filaments; or unidirectionally aligning the plurality of polymeric filaments; or weaving the plurality of polymeric filaments to form an interwoven web comprising a first plurality of filaments having a first common extension direction interwoven with a second plurality of filaments having a second common extension direction orthogonal to the first common extension direction; or aligning the plurality of polymeric filaments to form a sheet-like inner web comprising a plurality of sheets, wherein each sheet The filaments in the layers have a common extension direction, and the filaments in adjacent layers are oriented in different extension directions; or multiple polymer filaments are knitted to form a knitted material; or multiple polymer filaments are twisted to form yarn fibers, and then (i) the yarn fibers are randomly oriented to form a material comprising randomly oriented, entangled yarn fibers, (ii) the yarn fibers are unidirectionally aligned, (iii) the yarn fibers are woven to form an interwoven web, (iv) the yarn fibers are aligned to form an inner web comprising multiple layers, or (v) the yarn fibers are knitted to form a knitted material; or multiple polymer filaments are printed into a pattern by 3D printing.

[0172] Example 60. Any of the embodiments herein, particularly any of Examples 57-59, further includes forming a plurality of polymer filaments comprising a filamentous polymer by jet spinning, electrospinning, melt spinning, 3D printing, extrusion, or meltblowing processes.

[0173] Example 61. Any of the embodiments herein, particularly any one of Examples 57-60, wherein the polymer filament comprises a core containing a filamentous polymer and a shell surrounding the core, the shell comprising a shell polymer, the method further comprising: forming the core and shell in a single step by jet spinning, electrospinning, co-extrusion, or three-dimensional printing; or forming the core and then coating the core with a shell polymer to form the shell; or forming the core and hydrolyzing the surface of the core to form the shell.

[0174] Example 62. Any of the embodiments herein, particularly the method of any one of Examples 57-61, further includes forming a protective film by: melting or extruding a protective polymer to form a film; or dissolving the protective polymer in a solvent to form a solution containing the protective polymer and forming a film from the solution; or compressing the protective polymer to form a film.

[0175] Example 63. Any of the embodiments herein, particularly any one of Examples 57-62, wherein forming an intermediate layer including a protective film on at least a portion of the first surface of the reinforcing layer further comprises: thermally attaching the protective film to at least a portion of the first surface; or mechanically attaching the protective film to at least a portion of the first surface; or ultrasonically attaching the protective film to at least a portion of the first surface; or attaching the protective film to at least a portion of the first surface using a laser; or chemically attaching the protective film to at least a portion of the first surface by hydrolysis or oxidation of the reinforcing layer and the protective polymer, whereby the chemical functional groups of the filamentous polymer or shell polymer react with the functional groups of the protective polymer; or coating the reinforcing layer with a solution containing the protective polymer and a solvent, and removing the solvent to form the protective film; or forming the protective film from a solution containing the protective polymer by a reactive dip-coating process; or coating the reinforcing layer with a solution containing the protective polymer and curing the protective polymer by ultraviolet irradiation; or printing the protective film onto at least a portion of the first surface by a three-dimensional printing process.

[0176] Example 64. Any of the embodiments herein, particularly any one of Examples 57-63, wherein grafting an ionomer onto an exposed surface of an intermediate layer comprises: coating the exposed surface with a solution containing the ionomer to form a material coated with the ionomer; and drying the material coated with the ionomer.

[0177] Example 65. Any example in this document, particularly the method of any one of Examples 57-64, wherein the ionic polymer is an amphoteric ionic polymer.

[0178] Example 66. Any example in this document, particularly the method of any one of Examples 57-65, wherein the ionic polymer comprises poly(phosphocholine), poly(sulfobetaine), poly(carboxybetaine), zwitterionic polysaccharide, diethylethanolamine quaternized with 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid, or any combination thereof.

[0179] Example 67. Any of the examples herein, particularly the method of Example 66, wherein the poly(phosphocholine) comprises the 2-methacryloyloxyethylphosphocholine (MPC) moiety.

[0180] Example 68. The method of any of the examples herein, particularly Example 66 or Example 67, wherein the ionomer comprises: poly(MPC-co-2-ethylhexyl methacrylate-co- N,N -Diethylaminoethyl methacrylate); or poly(MPC-co-p-nitrophenoxycarbonyl poly(ethylene glycol) methacrylate); or poly(2-hydroxyethyl methacrylate)-MPC copolymer; or polyvinylpyrrolidone-MPC copolymer; or any combination thereof.

[0181] Example 69. Any of the embodiments herein, particularly any one of Examples 57-60 or 62-68, wherein forming the reinforcing layer comprises melt-spinning poly(lactic acid) to form a plurality of polymeric fibers and weaving a plurality of polymeric filaments to form an interwoven web.

[0182] Example 70. Any of the embodiments herein, particularly the method of Example 69, wherein forming an intermediate layer comprising a protective film on at least a portion of a first surface of the reinforcing layer further comprises coating the reinforcing layer with a solution comprising polycarbonate-urethane and a solvent, and removing the solvent to form the protective film.

[0183] Example 71. Any of the embodiments herein, particularly any one of Examples 57-68, wherein forming the reinforcing layer comprises melt-spinning poly(ethylene terephthalate) (PET) to form a plurality of polymeric fibers, twisting the plurality of polymeric fibers together to form yarn fibers, knitting the yarn fibers to form a knitted material, and hydrolyzing the surface of the polymeric fibers to form a shell comprising hydrolyzed PET on a PET-containing core.

[0184] Example 72. Any embodiment herein, particularly the method of Example 71, wherein forming an intermediate layer including a protective film on at least a portion of a first surface of the reinforcing layer further comprises thermally attaching the protective film to at least a portion of the first surface, wherein the protective film comprises aromatic polycarbonate-urethane, aliphatic polycarbonate-urethane, or a combination thereof.

[0185] Example 73. Any example herein, particularly the method of Example 72, wherein thermal attachment comprises a temperature of 180°C to 200°C and 0.7-0.8 N / mm. 2 The protective film is pressed onto the first surface of the reinforcement layer under pressure for 10 to 20 seconds.

[0186] Example 74. Any of the embodiments herein, particularly the methods of Example 72 or Example 73, wherein the protective film has a thickness of 25 μm to 130 μm.

[0187] Example 75. Any of the embodiments herein, particularly the method of Example 71, wherein forming an intermediate layer including a protective film on at least a portion of a first surface of the reinforcing layer further includes thermally attaching the protective film to at least a portion of the first surface, wherein the protective film comprises a polyether-based hydrogel thermoplastic polyurethane.

[0188] Example 76. Any example herein, particularly the method of Example 75, wherein thermal attachment comprises a temperature of 190°C to 200°C and a temperature of 0.5-0.7 N / mm. 2 The protective film is pressed onto the first surface of the reinforcement layer under pressure for 10 to 20 seconds.

[0189] Example 77. Any of the embodiments herein, particularly the method of Example 71, wherein forming an intermediate layer comprising a protective film on at least a portion of a first surface of the reinforcing layer further comprises coating the reinforcing layer with a solution comprising a protective polymer and a solvent, and removing the solvent to form a protective film, wherein the protective polymer comprises poly(2-hydroxyethyl methacrylate), and the coating comprises spraying.

[0190] Example 78. Any of the embodiments herein, particularly the method of any one of Examples 57-60 or 62-68, wherein forming the reinforcing layer comprises electrospinning an aromatic polycarbonate polyurethane to form a plurality of polymeric fibers.

[0191] Example 79. Any of the embodiments herein, particularly the method of Example 78, wherein forming an intermediate layer comprising a protective film on at least a portion of the first surface of the reinforcing layer further comprises chemically attaching the protective film by dissolving poly(glycerol sebacate) and thermoplastic polyurethane in a solvent to form a solution, applying the solution to the first surface of the reinforcing layer, and removing the solvent.

[0192] Example 80. Any of the embodiments herein, particularly the methods of any one of Examples 57-60 or 62-68, wherein the formation of the reinforcing layer comprises simultaneously electrospun aliphatic, hydrophilic polyether-based polyurethane and aromatic polycarbonate polyurethane.

[0193] Example 81. Any of the embodiments herein, particularly the method of Example 80, wherein forming an intermediate layer comprising a protective film on at least a portion of a first surface of the reinforcing layer further comprises coating the reinforcing layer with a solution comprising a protective polymer and curing the protective polymer by ultraviolet irradiation, wherein the protective polymer comprises poly(ethylene glycol) diacrylate.

[0194] Example 82. Any of the embodiments herein, particularly any one of Examples 57-60 or 62-68, wherein forming the reinforcing layer comprises knitting a yarn containing silk fibers to form a knitted material.

[0195] Example 83. Any of the embodiments herein, particularly the method of Example 82, further includes forming a protective film by compression molding a protective polymer to form a film, wherein the protective polymer comprises an aromatic polycarbonate polyurethane or an aliphatic polyether polyurethane.

[0196] Example 84. Any of the embodiments herein, particularly any one of Examples 57-60 or 62-68, wherein forming the reinforcing layer comprises knitting yarn fibers comprising silk and polyester to form a knitted material.

[0197] Example 85. Any of the embodiments herein, particularly the method of Example 84, wherein forming an intermediate layer comprising a protective film on at least a portion of a first surface of the reinforcing layer further comprises coating the reinforcing layer with a solution comprising a protective polymer and a solvent, and removing the solvent, wherein the protective polymer comprises a ureidopyrimidinone polymer.

[0198] Example 86. Any example herein, particularly the method of Example 85, wherein the ureidopyrimidinone polymer comprises , Where a, b, and c are independent integers greater than or equal to 1.

[0199] Example 87. Any of the embodiments herein, particularly the method of any one of Examples 84-86, wherein the reinforcing layer and the intermediate layer have a combined average thickness of 0.2 mm to 0.6 mm.

[0200] Example 88. Any of the embodiments herein, particularly the method of any one of Examples 57-60 or 62-68, wherein forming the reinforcing layer comprises electrospinning gelatin to form a plurality of polymeric fibers.

[0201] Example 89. Any of the embodiments herein, particularly the method of Example 88, further includes crosslinking the gelatin.

[0202] Example 90. Any of the embodiments herein, particularly the methods of Example 88 or Example 89, wherein forming an intermediate layer comprising a protective film on at least a portion of a first surface of the reinforcing layer further comprises coating the reinforcing layer with a solution comprising a protective polymer and a solvent, and removing the solvent, wherein the protective polymer comprises polycarbonate polyurethane and polyether polyurethane.

[0203] Example 91. Any of the embodiments herein, particularly any one of Examples 57-60 or 62-68, wherein forming the reinforcing layer comprises electrospun polycarbonate polyurethane and polyether polyurethane to form a plurality of polymeric fibers.

[0204] Example 92. Any of the embodiments herein, particularly the method of Example 91, wherein forming an intermediate layer comprising a protective film on at least a portion of a first surface of the reinforcing layer further comprises coating the reinforcing layer with a solution comprising a protective polymer and a solvent, and removing the solvent, wherein the protective polymer comprises poly(glycerol sebacate) and thermoplastic polyurethane.

[0205] Example 93. Any of the embodiments herein, particularly the methods of Example 91 or Example 92, wherein the reinforcing layer and the intermediate layer have a combined average thickness of 0.2 mm to 0.6 mm.

[0206] Example 94. Any of the embodiments herein, particularly any one of Examples 57-93, wherein grafting an ionomer onto an exposed surface of an intermediate layer comprises: coating the exposed surface with a solution containing poly(2-methacryloyloxyethylphosphocholine) to form a material coated with the ionomer; and drying the material coated with the ionomer.

[0207] Example 95. Any of the embodiments herein, particularly any of Examples 57-94, further includes forming a plurality of leaflets from a contamination-resistant implantable material and coupling the leaflets to the framework of the artificial heart valve.

[0208] V. Experimental Examples Example 1 Biodegradable PLA-PCU Synthetic Leaf Material Biodegradable poly(lactic acid) (PLA) fibers are created via a melt spinning process. The resulting PLA fibers are woven into a mesh. This mesh is dip-coated in a solution of polycarbonate-urethane (PCU) to provide a reinforcing layer with a core-shell structure. The dried reinforcing layer is sandwiched between two thin layers of PCU by hot pressing to form a synthetic leaflet material (SLM). Figure 4A and 4B These are images of the hardening layer and the SLM, respectively.

[0209] Example 2 Bio-stable PET-PCU Synthetic Leaf Material Bio-stabilized poly(ethylene terephthalate) fibers are created through melt spinning and twisted together to form yarn. The yarn is then knitted into PET fabric. Figure 5A PET fabric was hydrolyzed to chemically modify the PET fiber surface and provide a reinforcing layer with core-shell technology. Hydrolysis was achieved by immersing the PET fabric in a 2.5M NaOH solution at 50°C for 360 minutes. The hydrolyzed fabric was then immersed in 1N acetic acid to replace sodium ions with protons. Hydrolysis was confirmed by Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR). Surface hydrolysis improved the adhesion of the protective film to the PET fabric, avoiding the need to be bound by specific operational theories. The reinforcing layer was dried overnight at 50°C before applying the protective film. The reinforcing layer was then dipped into a solution of PCU to form SLM (Structured Laminate). Figure 5B ).

[0210] Knitted PET fabric was prepared using high-quality warp-knitted yarn (33 dtex / 18 filament) of 18-filament PET. Figure 6 The fabric was warp-knitted and scourted with a structure of 40 ± 5 wales / inch (16 ± 2 wales / cm) and 90 ± 10 course / inch (35 ± 4 course / cm). The burst strength (based on ASTM D3887-96 Tolerance Standard Specification for Knitted Fabrics and ASTM D3787-01 Standard Test Method for Bursting Strength of Textiles – Constant Transverse Rate (CRT) Ball Bursting Test) was determined to be 356 N (80 lbf). In contrast, the burst strength of the pericardial tissue in 30 samples varied between 450–700 N (100–160 lbf). Figure 7A The tensile strength of PET fabric and pericardial tissue is similar. Figure 7B As described above, the PET fabric surface is hydrolyzed, and the resulting reinforcing layer is dried overnight in an oven at 45°C.

[0211] SLM is made by attaching one or two layers of PCU protective film to a dried reinforcing layer to form an intermediate layer. PCU film is an aromatic and aliphatic thermoplastic polyurethane (TPU) film with a thickness ranging from 25 to 127 μm (0.001”–0.005”) and a Shore hardness of 75A. It withstands 100–120 psi (0.7–0.8 N / mm²) at 380°F (190°C). 2The intermediate layer is attached to the reinforcing layer by hot pressing for 15 seconds. Alternatively, a co-extrusion process is used to encapsulate the PET textile skeleton at 175-215°C (350-420°F) using a die extruder, followed by a molding press to control the final thickness of the film.

[0212] Figure 8A and 8B These are microscopic images of the dried reinforcement layer and the SLM containing the PET / hydrolyzed PET reinforcement layer and the TPU protective film. Figures 9A-9C These are scanning electron microscope (SEM) images of the reinforcement layer completely covered by TPU film (9A, 103X), the uncoated reinforcement layer (left half of 9B), and the reinforcement layer partially covered by defective TPU film (right half of 9C). The burst strength of the SLM was evaluated (ASTM D3887-96, ASTM D3787-01). The results are shown in Table 1.

[0213] Table 1 Long-term mechanical properties of valves The synthetic leaflet material was manufactured as described above and subjected to accelerated wear tests of more than 200 million or 300 million cycles, with the results conforming to ISO 5840-1.

[0214] SLM material calcifies in vivo in a rabbit intramuscular model. SLM samples were intramuscularly implanted into rabbits according to previously published methods (Wright). et al. , Comp Med. 2009, 59(3):266). The intramuscular rabbit model has been shown to be a rapid and aggressive differentiator for anti-calcification therapy. Each rabbit received a disk from each sample group, and the disks were placed randomly.

[0215] All rabbits were required to survive during implantation and monitoring. The discs were removed 60 days post-implantation. Discs from two rabbits were explanted along with surrounding muscle for histological evaluation. Figure 10 As shown, calcium was analyzed in the remaining part of the disk by X-ray imaging and quantified by elemental analysis using ICP-OES.

[0216] Valve in vivo calcification resistance assessment Adolescent / juvenile sheep models are sensitive in the study of the calcification process of heart valve prostheses, such as... The Journal of Thoracic and Cardiovascular SurgeryThis study was reported in 2006, (132)1:89-98. Valves at the mitral and aortic locations were implanted into sheep less than 12 months old and weighing between 29 and 63 kg for 3–6 months (moths) to assess valve calcification. Following explantation, the presence of calcium on the leaflets was determined by X-ray imaging. Cross-sections of the leaflets were then sent for histological evaluation. Calcium quantification of the remaining leaflets was performed using elemental analysis via ICP-OES.

[0217] Example 3 PET / Polyether-based hydrogel polyurethane synthetic leaf material SLM comprising a polyether-based hydrogel thermoplastic polyurethane (HTPRU) protective film was prepared and characterized. The film was tested at 385°F (196°C) and 90 psi (0.6 N / m). 2 The film was then applied to the reinforcement layer of Example 2. The film properties are shown in Table 2, where the TPU thickness, SLM strength, and melt temperature were measured on the dry material.

[0218] Table 2 Example 4 Synthetic leaf material with zwitterionic polymer coating SLMs can be coated with zwitterionic polymers to enhance surface chemistry. The PCU-coated SLM described in Example 2 is coated with a polymer containing 2-methacryloyloxyethylphosphorylcholine (MPC). The zwitterionic phosphorylcholine side chain exhibits excellent resistance to nonspecific protein adsorption, cell adhesion, and / or blood coagulation. Two MPC polymers, Lipidure® CM5206 and Lipidure® AC 01 (NOF America, White Plains, NY), were evaluated. In Lipidure® CM5206, R' is a hydrophobic group, anionic group, cationic group, hydrogen-bonded group, photoreactive group, or alkoxysilyl group; and m and n It is an integer. In Lipidure® AC 01, m and n It is an integer. Lipidure® CM5206 Lipidure® AC 01 A solution of MPC containing 2–3 wt% Lipidure® CM5206 in ethanol was prepared (e.g., 0.257 g in 10 mL). MPC was mechanically attached to the SLM by immersing it in the MPC solution for one minute. Ethanol swells the exposed surface of the TPU protective film, allowing MPC molecules to insert between the TPU polymer chains, providing mechanical attachment as the ethanol evaporates and the TPU swelling disappears. The MPC-coated SLM was dried at room temperature or 50°C for one hour. FTIR-ATR testing was performed to confirm the presence of the MPC coating on the SLM. Energy-dispersive X-ray spectroscopy (EDS) / SEM analysis was performed to confirm the MPC coverage of the SLM. Figure 11A-11C These are layered images of SLM before MPC coating (11A), carbon (11B), and oxygen (11C). Figure 12A-12D These are layered images (12A), carbon image (12B), oxygen image (12C), and phosphorus image (12D) of an SLM coated with MPC.

[0219] Surface analysis using FTIR-ATR was used to confirm the MPC coating and surface chemistry. Only TPU with an MPC coating was observed at 1240, 1080, and 970 cm⁻¹. -1 The transmission absorption peak is at 1725 cm⁻¹. -1 The absorption observed in the vicinity of TPU-MPC corresponds to the carbonyl group in the MPC unit. Figure 13 The spectra of an uncoated SLM and an SLM coated with MPC are shown. At 1704 cm⁻¹ -1 and 1728 cm -1 Bound and unbound urethane bands appear at 1639 cm⁻¹. -1 The relatively weak band at 963 cm⁻¹ is due to amide I. -1 A strong band at this point is due to the trans-1,4-addition of HC=CH. Absorption bands for phosphocholine (PO4, NH, C=O bond) and quaternary ammonium were also observed. Further absorption bands were observed at an additional 1156 cm⁻¹. -1 The presence of peaks confirms the MPC coating.

[0220] Another MPC solution containing 5 wt% Lipidure® AC 01 in water was prepared and mixed with 10 mL of ethanol for treating the SLM, as described in detail above for Lipidure® CM5206. In short, the SLM was treated with dilute acetic acid or plasma to generate additional carboxylic acid groups on the TPU protective film. MPC was chemically attached to the SLM by immersing it in the MPC solution for one minute. The MPC-coated SLM was then dried at room temperature or at 50°C for one hour.

[0221] The MPC-coated SLM was characterized by tensile testing (ASTM 412) and stress relaxation (ASTM D6048). Stress relaxation was measured by subjecting the samples to a load of 1 MPa. Oxidative biostability and water absorption over time were important measures of SLM performance. The SLM material was exposed to 30% H2O2 at 50°C and then aged in a salt solution at 60°C for one month. SLM leaflets were removed from the aging solution and their dimensions were analyzed using a high-precision digital microscope. Ball burst testing (ASTM 3787) was performed. Creep / fatigue testing was conducted via dynamic mechanical analysis. The Tt of the PET reinforcement layer was evaluated using differential scanning calorimetry at a rate of 5°C / min from 30°C to 200°C using a DSC 4000 system from Perkin Elmer (Waltham, MA). g .

[0222] Long-term mechanical performance evaluation: The synthetic leaflet material was manufactured as described above and subjected to accelerated wear testing (AWT) of over 300 million cycles, with results conforming to ISO 5840-1.

[0223] In rabbit calcification assessment 90 days after intramuscular implantation, X-ray or inductively coupled plasma mass spectrometry (ICP-MS) analysis showed no presence of Ca+.

[0224] Calcification assessment in young sheep (3-6 months) with valve sizes of 21-25 mm showed no calcification as assessed by X-ray or inductively coupled plasma mass spectrometry (ICP-MS) analysis.

[0225] Example 5 PCU-PGS Synthetic Leaf Material An aromatic polycarbonate polyurethane (PCU) filament (Carbothane™ AC-4075A, Lubrizol Advanced Materials, Inc., Cleveland, Ohio) is used to form a reinforcing layer using an electrospinning process. An intermediate layer comprising poly(glycerol sebacic acid) (PGS, weight average molecular weight 300,000 g / mol) and a thermoplastic polyurethane (TPU) protective film is chemically attached to the surface of the reinforcing layer. To manufacture a TPU-PGS film (TPU, such as Pellethane 80A or Carbothane 75A), the particles are dissolved in one or a mixture of organic solvents (chloroform (CF) / N,N-dimethylformamide (DMF) (v / v = 6:4), tetrahydrofuran (THF), DMAc, acetone, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), or a binary solvent of 2,2,2-trifluoroethanol (TFE) and acetic acid) to obtain a 3-10% (w / v) solution. PGS particles are also dissolved in CF, DMF, DMAC, and / or acetone. The two solutions are then combined to provide TPU / PGS at different polymer ratios (6:6, 6:4, and 6:2). The PCU concentration is maintained at 3–10% (w / v).

[0226] Morphological characterization using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR-ATR) was employed to determine surface chemistry and morphology to ensure film uniformity. Fiber diameter and diameter distribution were analyzed from SEM images. At least 50 fibers were measured from three SEM images to calculate average geometric information. The average pore size and pore size distribution of the electrospun PCU scaffold were determined.

[0227] In rabbit calcification assessment 90 days after intramuscular implantation, X-ray or inductively coupled plasma mass spectrometry (ICP-MS) analysis showed no presence of Ca+.

[0228] Example 6 Polyurethane-PEG-MPC Synthetic Leaf Material The reinforcing layer was formed by simultaneous electrospinning of two polyurethanes: an aliphatic, hydrophilic polyether-based polyurethane (Tecophilic™ HP-60D-20, Lubrizol Advanced Materials, Inc., Cleveland, Ohio) hydrogel and a bio-stable aromatic polycarbonate polyurethane (PCU) (Carbothane™ 4075A, Lubrizol Advanced Materials, Inc.). The reinforcing layer was dip-coated in a prepolymer solution containing PEGDA (poly(ethylene glycol) diacrylate, 10 kDa, 10 wt%) and 0.5 wt% 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone (photoinitiator) in phosphate-buffered saline (PBS, pH 7.4), followed by UV exposure (centered at 367 nm, 6 mW / cm²). 2 Polymerize for 9 minutes to form an intermediate layer including a PEG-based hydrogel protective film. Dip the implantable material into a solution containing the zwitterionic polymer poly(2-methacryloyloxyethylphosphorylcholine) (Lipidure® PC, NOF America, White Plains, NY) dissolved in ethanol at 2% v / v to form an outer layer containing the zwitterionic polymer on the surface.

[0229] Example 7 PET-HEMA-MPC Synthetic Leaf Material As in Example 2, a reinforcing layer is formed using warp-knitted PET fabric. An intermediate layer comprising poly(2-hydroxyethyl methacrylate) (poly(HEMA)) (MW 300,000-1,000,000) is dissolved in DMF and applied to the PET fabric by spraying onto the reinforcing layer. An implantable material is dipped into a solution comprising the zwitterionic polymer poly(2-methacryloyloxyethylphosphocholine) (Lipidure® PC, NOF America, White Plains, NY) dissolved in ethanol at 2% v / v, thereby forming an outer layer comprising the zwitterionic polymer on the surface.

[0230] Example 8 Silk-polyether polyurethane synthetic leaf material The reinforcing layer is made of warp-knitted or weft-knitted pure silk, then encapsulated in aromatic polycarbonate polyurethane or aliphatic polyether polyurethane using a compression molding process. The fabric is warp-knitted and scrubbed, with a structure of 40±5 wales / inch (16±2 wales / cm) and 90±10 course / inch (35±4 course / cm). The burst strength (based on the standard specification of ASTM D3887-96 tolerances for knitted fabrics and the standard test method for burst strength of textiles—constant transverse rate (CRT) ball burst test) was determined to be 356 N (80 lbf). In contrast, the burst strength of the pericardial tissue in 30 samples varied between 450–700 N (100–160 lbf). Figure 7A The tensile strength of the silk-based SLM is higher than that of pericardial tissue. Biostability assessment of the final film under oxidative aging showed that the silk maintained its strength for at least 2–3 years after implantation.

[0231] Example 9 UPy polymer-silk-polyester synthetic leaf material Using a Class 3 solvent, 2-amino-5-(2-hydroxyethyl)-6-methyl-4-(3-hydroxyethyl)-6-methyl-4-(2 ... H Uriidine pyrimidinone (UPy) technology polymers (antifouling coatings) were synthesized from pyrimidinone, hexane diisocyanate, hexanediol, and hydrogenated polybutylene glycol (Mn=2000). Residual solvent was below 5000 ppm after polymer fabrication. The resulting polymer exhibited a low modulus between 0.6 and 10 MPa. GPC in THF was compared to Pst-standards: Mn=44 kDa, Mw=72 kDa. Polymer identity was confirmed by FT-IR. Mechanical testing (50 mm / min for dog-bone shaped samples) was performed as previously described. The films were cast from an 8-10 w% solution in THF and dried under atmospheric conditions for at least 14 days (2 days after removal from the mold) without vacuum.

[0232] UPy polymers are encapsulated in silk and polyester (PET) warp and weft knitted fabrics by solvent casting with a THF solution followed by atmospheric drying. The resulting material thickness varies between 0.2 and 0.6 mm. UPy technology polymer In rabbit calcification assessment 90 days after intramuscular implantation, X-ray imaging or inductively coupled plasma mass spectrometry (ICP-MS) analysis showed no presence of Ca+.

[0233] Example 10 Gelatin-polycarbonate polyether polyurethane synthetic leaf material A reinforcing layer, made of electrospun gelatin and further crosslinked with gelatin crosslinked with EDC / NHS and / or genipin, was then dipped into a THF solution containing polycarbonate and polyether polyurethane to achieve a final thickness of 0.2 to 0.6 mm. Standard test method for burst strength, ASTM D3787-01, was performed, revealing acceptable stiffness and UTS values.

[0234] Example 11 Polycarbonate polyether polyurethane-PGS-PGSU synthetic leaf material The reinforcing layers at both high and low densities are made of electrospun polycarbonate and polyether polyurethane (Carbothane AC and PC 75A) with pore sizes ranging from 0.1 to 45 micrometers. PGS and PGSU (TPU and PGS) polymers are used as antifouling coatings and are applied by spraying from toluene until a thickness range of 0.2–0.6 mm is achieved. Poly(glycerol sebacate) The electrospinning parameters were as follows: applied voltage of 18 kV, flow rate maintained at 0.5 mL / h, and distance from the needle to the collector of 20 cm. The ambient temperature and humidity were approximately 25°C and 30%, respectively. A flat aluminum foil was used as the collector to gather all the electrospun fibers.

[0235] In rabbit calcification assessment 90 days after intramuscular implantation, X-ray or inductively coupled plasma mass spectrometry (ICP-MS) analysis showed no presence of Ca+.

[0236] Given that the principles of this disclosure can be applied to many possible instances, it should be recognized that the illustrated examples are merely preferred examples and should not be considered as limiting its scope. Rather, the scope is defined by the appended claims. Therefore, we claim protection for all contents within the scope and spirit of these claims.

Claims

1. An antifouling implantable material, comprising: A reinforcing layer comprising a plurality of polymeric filaments containing a filamentous polymer, the reinforcing layer having a first surface and an opposing surface; An intermediate layer includes a protective film attached to at least a portion of the first surface, the protective film comprising a protective polymer, optionally wherein the intermediate layer further includes a second protective film attached to at least a portion of the opposing surface of the reinforcing layer, the second protective film comprising a second protective polymer, wherein the second protective polymer of the second protective film has the same or different chemical composition as the protective polymer. as well as The outer layer comprises an ionic polymer grafted onto the exposed surface of the intermediate layer; The polymeric filament comprises a core and a shell surrounding the core, wherein the core contains the filamentous polymer and the shell contains a shell polymer, the shell polymer being a biostable polymer comprising hydrolyzed poly(ethylene terephthalate).

2. The antifouling implantable material according to claim 1, wherein the polymer filaments of the reinforcing layer are: Materials randomly oriented to form polymer filaments containing entanglements; or unidirectional alignment; or A web is formed, comprising a first plurality of polymeric filaments having a first common extension direction and a second plurality of polymeric filaments having a second common extension direction, wherein the second common extension direction is orthogonal to the first common extension direction. or A layered internal network is formed, comprising multiple layers, wherein the polymer fibers in each layer have a common extension direction, and the polymer fibers in adjacent layers are oriented in different extension directions; or Knitting to form knitted materials; or The yarn fibers are twisted into a yarn containing multiple polymer filaments, wherein the yarn fibers are then (i) randomly oriented to form a material containing randomly oriented, entangled yarn fibers, (ii) unidirectionally aligned, (iii) woven to form an interlaced web, (iv) aligned to form a layered inner web containing multiple layers, or (v) knitted to form a knitted material.

3. The antifouling implantable material according to claim 1 or claim 2, wherein the filamentous polymer comprises polyurethane, polyetherketone, poly(ethylene terephthalate), polycarbonate, polyester, polyacrylate, polysiloxane, aromatic polyolefin, aliphatic polyolefin, polyamide, glycerol ester polymer, polycarboxylic acid, polysulfone, polysaccharide, polyamine, polyamino acid, polypeptide, or any combination thereof.

4. The antifouling implantable material according to claim 1 or claim 2, wherein: The filamentous polymer is a biostable polymer, including polyurethane, polyester, poly(ethylene terephthalate), polycarbonate, polysiloxane, aromatic polyolefin, or aliphatic polyolefin; or The filamentous polymer is a biodegradable polymer, including poly(lactic acid), poly(lactic acid-co-glycolic acid), polysaccharides, polyamino acids, polypeptides, or poly(glycerol sebacate).

5. The antifouling implantable material according to claim 1, wherein: The shell polymer is a biodegradable polymer, including poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharides, polyamino acids, polypeptides, or poly(glycerol sebacate); or The shell polymer is a bio-stable polymer including polyurethane.

6. The antifouling implantable material according to claim 1 or claim 2, wherein the polymer filament has an average diameter in the range of 0.001 μm to 2000 μm.

7. The antifouling implantable material according to claim 1 or claim 2, wherein the reinforcing layer comprises: (i) a thickness in the range of 25 μm to 500 μm; or (ii) Bursting strength in the range of 50-800 N; or (iii) Tensile strength in the range of 50-800 N; or (iv) Any combination of (i), (ii), and (iii).

8. The antifouling implantable material according to claim 1 or claim 2, wherein the protective polymer comprises: Biostable synthetic polymers selected from polyethylene, polypropylene, polytetrafluoroethylene, polyether, polycarbonate polyurethane, polysiloxane polyurethane, polyether polyurethane elastomer, polyester polyurethane elastomer, silicone, polycarbonate, polysulfone, polyetheretherketone, poly(ethylene terephthalate), polyester, or any combination thereof; or Biodegradable synthetic polymers selected from polyesters, polyacrylates, polyamides, hydrophilic polyester polyurethanes, hydrophilic polyureas, poly(amide-enamine), polyanhydride, poly(esteramide), poly(glycolic acid), polylactic acid, polyglycolic acid, polycaprolactone, poly(hydroxybutyrate), poly(ε-caprolactone), poly(vinyl alcohol)-hyaluronic acid, hyaluronic acid amine, ureidopyrimidinone-based polymers, or any combination thereof; or The polymer that forms the hydrogel is selected from proteins, polysaccharides, hydrophilic polyurethanes, poly(ethylene oxide), polyacrylamide, polyethylene glycol, polyacrylate, polypeptides, poly(glycerol sebacate), poly(xylitol sebacate), or any combination thereof.

9. The antifouling implantable material according to claim 1 or claim 2, wherein the intermediate layer comprises: (i) The average thickness in the range of 0.1 μm to 100 μm; or (ii) Shore hardness of a hardness tester in the range of 10A to 80A; or (iii) a flexural modulus in the range of 1 N / mm 2 to 50 N / mm 2 ; or (iv) a dry ultimate tensile strength in the range of 10 N / mm 2 to 60 N / mm 2 ; or (v) a wet ultimate tensile strength in the range of 5 N / mm 2 to 40 N / mm 2 or (vi) Any combination of (i), (ii), (iii), (iv), and (v).

10. The antifouling implantable material according to claim 1 or claim 2, wherein the ionic polymer is an anionic polymer, a cationic polymer, or an amphoteric polymer.

11. The antifouling implantable material according to claim 10, wherein the ionic polymer comprises poly(phosphocholine), poly(sulfobetaine), poly(carboxybetaine), zwitterionic polysaccharide, diethylethanolamine quaternized with 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid, or any combination thereof.

12. The antifouling implantable material of claim 10, wherein the ionomer comprises: Poly(2-methacryloyloxyethylphosphorylcholine) (MPC); or Poly(MPC-co-2-ethylhexyl methacrylate-co-) N,N -Diethylaminoethyl methacrylate); or Poly(MPC-co-p-nitrophenoxycarbonyl poly(ethylene glycol) methacrylate); or Poly(2-hydroxyethyl methacrylate)-MPC copolymer; or Polyvinylpyrrolidone-MPC copolymer; or Any combination thereof.

13. The antifouling implantable material according to claim 1 or claim 2, wherein the outer layer has an average thickness in the range of 0.001 μm to 25 μm.

14. An implantable medical device comprising a contamination-resistant implantable material according to any one of claims 1-13.

15. The implantable medical device of claim 14, wherein the implantable medical device comprises an artificial heart valve, a vascular graft, a valvuloplasty ring, a cardiovascular patch, or a splice clip.

16. The implantable medical device of claim 14, wherein the implantable medical device comprises an artificial heart valve, the artificial heart valve comprising a plurality of leaflets, a sealing skirt, a cover of metal components, or any combination thereof formed of the antifouling implantable material.

17. A method for manufacturing the antifouling implantable material according to claim 1, comprising: An intermediate layer comprising a protective film is formed on at least a portion of a first surface of the reinforcing layer, the reinforcing layer comprising a plurality of polymeric filaments containing filamentous polymers, and the protective film comprising a protective polymer; and The outer layer is formed by grafting an ionomer onto the exposed surface of the intermediate layer; The polymer filament comprises a core containing the filamentous polymer and a shell surrounding the core, the shell containing a shell polymer, and the method further comprises forming the core and hydrolyzing the surface of the core to form the shell.

18. The method of claim 17, further comprising forming the reinforcing layer by: Spray spinning, electrospinning, or melt spinning of the plurality of polymerized filaments to form a material comprising randomly oriented, entangled filaments; or unidirectionally aligning the plurality of polymeric filaments; or The plurality of polymer filaments are woven to form an interwoven web, the interwoven web comprising a first plurality of filaments having a first common extension direction and a second plurality of filaments having a second common extension direction, the second common extension direction being orthogonal to the first common extension direction; or The plurality of polymer filaments are aligned to form a sheet-like inner network comprising multiple sheets, wherein the filaments in each sheet have a common extension direction and the filaments in adjacent sheets are oriented in different extension directions; or Knit the plurality of polymer filaments to form a knitted material; or The plurality of polymer filaments are twisted to form yarn fibers, and then (i) the yarn fibers are randomly oriented to form a material comprising randomly oriented, entangled yarn fibers, (ii) the yarn fibers are unidirectionally aligned, (iii) the yarn fibers are woven to form an interwoven web, (iv) the yarn fibers are aligned to form a layered inner web comprising a plurality of layers, or (v) the yarn fibers are knitted to form a knitted material; or The multiple polymer filaments are printed into patterns using 3D printing.

19. The method of claim 17 or claim 18, further comprising forming the plurality of polymer filaments comprising the filamentous polymer by jet spinning, electrospinning, melt spinning, three-dimensional printing, extrusion or meltblowing processes.

20. The method according to claim 17 or claim 18, wherein the method further comprises: The core and shell are formed in a single step by jet spinning, electrospinning, co-extrusion, or 3D printing. or The core is formed, and the core is coated with the shell polymer to form the shell.

21. The method of claim 17 or claim 18, wherein forming the intermediate layer including the protective film on at least a portion of the first surface of the reinforcing layer further comprises: The protective film is thermally attached to at least a portion of the first surface; or The protective film is mechanically attached to at least a portion of the first surface; or The protective film is ultrasonically attached to at least a portion of the first surface; or The protective film is attached to at least a portion of the first surface using a laser; or The protective film is chemically attached to at least a portion of the first surface by hydrolysis or oxidation of the reinforcing layer and the protective polymer, whereby the chemical functional groups of the filamentous polymer or shell polymer react with the functional groups of the protective polymer; or The reinforcing layer is coated with a solution containing the protective polymer and a solvent, and the solvent is removed to form the protective film; or The protective film is formed from a solution containing the protective polymer using a reactive dip-coating process; or The reinforcing layer is coated with a solution containing the protective polymer, and the protective polymer is cured by ultraviolet irradiation; or The protective film is printed onto at least a portion of the first surface using a 3D printing process.

22. The method of claim 17 or claim 18, wherein grafting the ionomer onto the exposed surface of the intermediate layer comprises: The exposed surface is coated with a solution containing the ionomer to form a material coated with the ionomer; and The material coated with the ionomer is dried.

23. The method according to claim 17 or claim 18, wherein the ionic polymer comprises poly(phosphocholine), poly(sulfobetaine), poly(carboxybetaine), zwitterionic polysaccharide, diethylethanolamine quaternized with 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid, or any combination thereof.

24. The method of claim 17 or claim 18, further comprising forming a plurality of leaflets from the antifouling implantable material and coupling the leaflets to the framework of the artificial heart valve.

Images