Medical Tubular Devices

Abstract

To provide a new medical tubular device, which is very suitable for use in contact with body fluids, such as blood, urine, saliva or fragments thereof.SOLUTION: The medical tubular device has a high biocompatibility e.g. for use as implant. The medical tubular device may have a body structure extending from a first end to a second end of the medical tubular device and having a luminal surface and an external surface, wherein the body structure comprises an interpenetrating polymer network (IPN) comprising a host polymer matrix and at least one hydrogel guest polymer domain of a guest polymer, which is interpenetrating the host polymer matrix.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] The present invention relates generally to medical devices, particularly medical tubular devices, and methods for manufacturing such medical tubular devices. More specifically, the medical devices disclosed herein are suitable for use in contact with bodily fluids such as blood. Examples of medical tubular devices include dialysis tubing, surgical drainage tubing, and / or implants, including vascular grafts, dialysis grafts, central venous catheters, peripherally inserted central catheters, shunts, stents, or stent grafts. Antifouling polymers containing zwitterionic moieties are also included herein. [Background technology]

[0002] Medical tubular devices are essential devices for the treatment of humans and animals. Medical tubular devices are generally made of polymers, such as elastomeric polymers. Over the years, many medical tubular devices have been developed from biocompatible materials. Among other things, properties such as strength, flexibility, antibacterial properties, non-fouling properties, and / or non-thrombogenic properties are important.

[0003] US Patent No. 5,949,999 discloses a vascular graft of expanded PTFE having a node and fibril microstructure. Patent Document 2 discloses a layered artificial implantable device that provides reduced fluid loss when the device is punctured by a dialysis needle, suture needle, or the like. The device includes inner and outer layers of porous material having a microstructure of nodes interconnected by curved fibrils with voids between adjacent curved fibrils. The inner and outer layers are bonded together by an elastomeric adhesive that can entangle with the inner and outer surfaces of the outer layer to form an adhesive polymer blend layer.

[0004] Patent Document 3 discloses a method for reducing or preventing the occurrence of neointimal hyperplasia and / or thrombosis after implantation of a vascular implant, the method comprising contacting the vascular implant with all-trans retinoic acid (ATRA) and implanting the vascular implant in a patient in need thereof, wherein the vascular implant comprises a biocompatible polymer matrix, and the vascular implant releases a therapeutically effective amount of ATRA sufficient to inhibit or prevent neointimal hyperplasia and / or thrombosis when implanted in a patient.

[0005] Patent Document 4 discloses a vascular graft including a blood contact layer formed of a first microporous biomaterial, a non-porous intermediate layer, and a tissue interface layer having a textured microporous surface that contacts host tissue when implanted.

[0006] Patent Document 5 discloses an antithrombogenic vascular graft, which is a decellularized tissue covered with an antithrombogenic coating. Patent Document 6 discloses antimicrobial polymer compositions for medical devices containing antimicrobial oligomeric or polymeric additives. The additives include bloom-promoting, adhesion-promoting, and biocidal monomers and / or moieties. The additives may further include non-fouling and / or non-thrombogenic monomers and / or moieties. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] US Patent Application Publication No. 2006147665 [Patent Document 2] US Patent Application Publication No. 2006118236 [Patent Document 3] US Patent Application Publication No. 2010 / 036476 [Patent Document 4] US Patent Application Publication No. 2015 / 238306 [Patent Document 5] US Patent Application Publication No. 2016058913 [Patent Document 6] International Publication No. 17066242 Summary of the Invention [Problem to be solved by the invention]

[0008] The object of the present invention is to provide a new medical tubular device that is highly suitable for use in contact with bodily fluids such as blood, urine, saliva or fractions thereof. In one embodiment, it is an object to provide a medical tubular device that can maintain high patency for a relatively long period of time during use and has a low risk of occlusion.

[0009] In one embodiment, it is an object to provide a medical tubular device that has a desirably high suture retention strength. In one embodiment, it is an object to provide an implantable medical tubular device that has a low risk of inducing neointimal hyperplasia and / or stenosis when implanted.

[0010] In one embodiment, it is an object to provide a medical tubular device that can be designed in a relatively simple manner. In one embodiment, it is an object to provide a medical tubular device that is well suited as a vascular graft and that, once implanted, has a relatively long-term high patency and a low risk of occlusion.

[0011] In one embodiment, it is an object to provide a method for manufacturing a medical tubular device. These and other objects have been solved by the present invention as defined in the claims and described hereinafter.

[0012] The present invention and its embodiments have been found to have several additional advantages that will become apparent to those skilled in the art from the following description. [Means for solving the problem]

[0013] The medical tubular device includes a body structure extending from a first end to a second end of the medical tubular device. The body structure has an inner surface, a luminal surface, and an outer surface opposite the luminal surface. The body structure includes at least one interpenetrating polymer network (IPN). The IPN includes a host polymer matrix and at least one hydrogel guest polymer domain of a guest polymer interpenetrating the host polymer matrix.

[0014] The medical tubular device of the present invention has been shown to be highly suitable for many different medical applications, as further described below. The hydrogel domain ensures high compatibility in contact with tissue and further ensures that the medical tubular device can be designed for various purposes in a relatively simple manner. The host polymer ensures that the medical tubular device has the desired mechanical properties. For example, the host polymer matrix can be selected to be highly flexible. Preferably, the host polymer matrix is ​​an elastomer, such as a silicone elastomer, so that the medical tubular device substantially mimics the mechanical properties of a native blood vessel. At the same time, the host polymer provides the medical tubular device with high strength, for example, high suture retention strength suitable for suturing to a native blood vessel. The elastic properties of the host polymer can further ensure that the wall of the medical tubular device can be pierced with a needle, and then, when the needle is removed, the elastic properties ensure that the piercing hole instantly closes (self-heals). This may make the medical tubular device highly suitable for use as a dialysis graft.

[0015] The term "biological fluid" is used herein to mean a biological fluid such as urine, sweat, saliva, breast milk, blood, cerebrospinal fluid, vesicular fluid or cyst fluid. The terms "moiety" and "moieties" are used interchangeably.

[0016] The term "suture retention force" should be determined in accordance with ISO 7198:2016. The term "substantially," as used herein, should be construed to mean that normal manufacturing variations and tolerances are included.

[0017] The term "about" is often used to include things within the uncertainty of measurement. When used in relation to a range, the term "about" should be interpreted herein to mean that things within the uncertainty of measurement are included in the range.

[0018] The term "monomer" is used herein to refer to single unit monomers and small number of unit monomers, also called oligomers, such as oligomers containing up to 10 monomer units. In one embodiment, a monomer is or comprises at least one single unit monomer.

[0019] In one embodiment, the monomer is or comprises at least one oligomer. The term "drug" can be a single chemical component, or a composition or mixture of two or more components.

[0020] As used herein, the term "comprises" should be interpreted as an open term, i.e., to specify the presence of specifically stated features, such as elements, units, integers, steps, components, and combinations thereof, but without excluding the presence or addition of one or more other stated features.

[0021] Throughout the specification or claims, the singular encompasses the plural unless the context otherwise indicates or requires. "Embodiments" should be construed to include examples of the invention that include features of the referenced embodiment.

[0022] All features of the invention and embodiments of the invention described herein, including ranges and preferred ranges, can be combined in various ways within the scope of the invention, unless there is a specific reason not to combine such features.

[0023] In one embodiment, the medical tubular device may be comprised of a body structure, hi another embodiment, the medical tubular device may include support elements, reinforcing elements, and / or additional elements such as those further described herein.

[0024] The body structure advantageously has an elongated hollow structure, preferably generally circular, preferably having a circular cross-sectional perimeter. The body structure has a wall between a luminal surface and an outer surface. The body structure may be straight, curved, or branched, and may optionally have a varying inner diameter, outer diameter, and / or thickness along its length. In one embodiment, the body structure is twisted or otherwise serpentine.

[0025] The body structure may be bifurcated, which may be tapered or non-tapered (even). Advantageously, the body structure comprises a continuous matrix of host polymer, and at least one hydrogel polymer domain comprises a plurality of interconnected pathways of guest polymer, and the at least one hydrogel polymer domain preferably comprises a luminal surface guest polymer domain comprising at least a portion of the luminal surface, an outer surface guest polymer domain comprising at least a portion of the outer surface, and / or an intermediate guest polymer domain comprising neither the luminal nor outer surface.

[0026] The hydrogel guest polymer is also referred to as a “guest polymer.” The hydrogel guest polymer serves, among other things, to ensure high flexibility and high biocompatibility of the body structure and, therefore, of the medical tubular device.

[0027] At least a portion of the body structure wall is an IPN. In one embodiment, substantially the entire body structure wall is an IPN. In one embodiment, the body structure wall has a layered structure comprising two or more layers, and at least one of the layers is or comprises an IPN.

[0028] The host polymer matrix can be selected to ensure that the body structure has desired mechanical properties, such as flexibility and / or strength, including tear strength, etc. Advantageously, the host polymer comprises a crosslinked elastomer, such as a thermoplastic elastomer (TPE), a polyolefin elastomer (POE), a polyurethane (PU), a rubber, a thermoplastic polyurethane (TPU), a silicone elastomer, or any combination comprising one of the foregoing elastomers.

[0029] Medical tubular devices in which the host polymer is a crosslinked elastomer have been found to have particularly desirable high suture retention strength. Furthermore, medical tubular devices with crosslinked elastomeric host polymers have been shown to have desirable low leakage or a low risk of leakage after repeated punctures, making them well suited for use as dialysis grafts.

[0030] In one embodiment, the host polymer is a crosslinked polymer, such as a crosslinked elastomer, such as a thermoplastic elastomer (TPE), a polyolefin elastomer (POE), a polyurethane (PU), a polyether block amide (PEBAX), a rubber, e.g., a latex rubber, a silicone, or any combination thereof.

[0031] In one embodiment, the host polymer is physically crosslinked, preferably a physically crosslinked TPE. The physically crosslinked TPE comprises physically crosslinked stabilization domains that are reversible and can be reformed, for example, by heat or ion exchange. The stabilization domains can be amorphous or crystalline.

[0032] In one embodiment, the host polymer is crosslinked by ionic bonds. In one embodiment, the host polymer is chemically crosslinked, and preferably the host polymer is covalently crosslinked. Covalently crosslinked host polymers are particularly desirable when high strength is desired.

[0033] In one embodiment, the rubber is a natural or synthetic rubber such as a vulcanized polymer of isoprene, and the rubber is preferably a silicone rubber or a crosslinked polyurethane. Suitable TPUs include, for example, those sold by Lubrizol under the trade names Carbothane®, Isoplast®, Pellethane®, Tecoflex™, Tecophillic™, and Tecothane™.

[0034] TPUs are linear segmented block copolymers composed of hard and soft segments. The hard segments can be either aromatic or aliphatic. Aromatic TPUs may be based on isocyanates such as MDI, while aliphatic TPUs may be based on isocyanates such as H12 MDI. These isocyanates, when combined with short-chain diols, result in the hard block. This is usually aromatic, although aliphatic hard segments are often used when color and clarity retention in sunlight are a priority.

[0035] TPUs are relatively easy to process and can contain large amounts of guest polymers. Furthermore, they are highly stretchable and have high elasticity. They advantageously contain soft segments that can be of the polyether or polyester type. TPUs are preferably polyether-based.

[0036] In a preferred embodiment, the host polymer comprises a silicone. In one embodiment, the host polymer comprises at least 10% by weight, such as at least 20%, such as at least 40%, such as at least 60% of a host polymer consisting of Si and O atoms or having a backbone consisting of Si atoms, and the host polymer preferably comprises poly(dimethylsiloxane), poly(methylphenylsiloxane), fluorosilicone rubber, silicone ester, polysiloxane, polysilane, polychlorosilane, polyalkoxysilane, polyaminosilane, polysilane, polydialkylsiloxane, polysiloxane comprising at least one phenyl substituent, vinyl-functionalized silicone, partially or fully fluorinated silicone, or a mixture of two or more of the foregoing silicones.

[0037] The guest polymer may include one or more functional moieties. The mechanical properties of the host polymer can be important, especially when the body structure is composed of an IPN or primarily an IPN. This is because hydrogel guest polymers can have low mechanical strength and do not substantially increase the strength of the medical tubular device. High elastic compliance, i.e., a low modulus, has been found to ensure high patency of the medical tubular device. However, in some applications, a modulus that is too low can cause the body structure to expand to an undesirable diameter when the pressure inside the medical tubular device increases beyond a certain threshold. A modulus that is too low can result in relatively low tear strength, which may be undesirable in some applications. Furthermore, in applications where the medical tubular device is adapted for suturing, the suture can form needle penetration channels that close immediately with a high modulus but can reopen if the medical tubular device is deformed in a way that retracts, potentially causing undesirable bleeding.

[0038] To meet one or more of these preferred properties, it has been found advantageous for the host polymer to have a stress at 200% elongation of at least about 0.3 MPA, such as at least about 0.4 MPA, for example at least about 0.5 MPa, such as at least about 0.6 MPa, for example up to about 3 MPa, such as up to about 2 MPa, for example up to about 1 MPa.

[0039] Advantageously, the host polymer has a Shore A hardness of from about 15 to about 70, such as from about 20 to about 55, such as from about 25 to about 50. In most cases, softer elastomeric materials have a lower modulus than less soft elastomeric materials.

[0040] Advantageously, the host polymer has a tensile strength of at least about 8 MPa, such as at least about 10 MPa, such as at least about 11 MPa or more, such as 15 MPa or more.

[0041] Additionally, it is desirable for the host polymer to have a tear strength of at least about 25 kN / m, such as at least about 30 kN / m, such as at least about 35 kN / m, such as at least about 40 kN / m.

[0042] Examples of suitable host polymers include Nusil® Avantor® high concentration silicone materials. In one embodiment, the host polymer is prepared with excess residue that can be extracted with organic solvents and / or CO2 (dense or supercritical) that swell but do not dissolve the host polymer.

[0043] Examples of methods for providing IPN are described, for example, in the following publications: Antimicrob.Agents Chemother 2017,61(7),e00604-17 DOI:10.1128 / AAC.00604-17.Plasmid 2016,87-88,72,DOI:10.1016 / j.plasmid.2016.10.001.J.Control.Release 2016,241,125-134 DOI:10.1016 / j.jconrel.2016.09.018.J. Mat.Chem.Phys.2016,181,495-500 DOI:10.1016 / j.matchemphys.2016.06.086.J.Indus.Eng.Chem.2016,33,142-149 DOI:10.1016 / j.jiec.2015.09.026.Biomacromolecules.2016,17(4),1321-1329 DOI:10.1021 / acs.biomac.5b01722.J.Biomed.Mater.Res.Part B Appl.Biomater.2016,104(2),402-410 DOI:10.1002 / jbm.b.33371.Eur.J.Pharm.Biopharm.2015,94,305-311 DOI:10.1016 / j.ejpb.2015.05.014.Martin Alm,Peter Thomsen.A delivery device.Patent,PA 2015 / 70520.Martin Alm,Soren Langer Steffensen.A method of producing a Patent, WO 2013 / 075724. Martin Alm, Maike Benter, Anne Marie Jensen. A method of producing an article comprising an interpenetrating polymer network (IPN) and an article comprising an IPN. Patent, WO 2008 / 052568. Martin Alm, Maike Benter, Anne Marie Jensen. A method of producing an article comprising an interpenetrating polymer network (IPN) and an article comprising an IPN. Patent, WO 2008 / 052563. Maike Benter, Martin Alm. A method of coating a polymer surface with a polymer containing coating and an item comprising a polymer coated polymer. Patent, WO 2006 / 074666. Joachim Karthauser, Maike Benter, and Martin Alm. A method of producing a silicone elastomer rubber item and the product is obtainable by the method. Patent, International Publication No. 2006 / 045320.

[0044] The hydrogel guest polymer may be in swollen or dry form, for example, as a partially or fully swollen hydrogel, aerogel, or xerogel. It may be desirable to at least partially swell the hydrogel prior to use, for example, in an aqueous medium such as water or saline. The amount of hydrogel polymer is generally listed as the dry form unless otherwise specified.

[0045] The body structure may comprise a continuous matrix of host polymer and multiple interconnected pathways of guest polymer. Advantageously, the domains of the guest polymer form continuous interpenetrating pathways of the hydrogel guest polymer. The interpenetrating pathways of the hydrogel may thereby provide a pathway for desired components and / or molecules and / or for delivery of desired drugs, e.g., loaded into the hydrogel or otherwise deposited in contact with the hydrogel guest polymer. In one embodiment, the drug is molded into the host polymer, e.g., during extrusion of the host polymer. The embedded drug may then be released via the interconnected pathways of the guest polymer.

[0046] Advantageously, the luminal surface at least partially comprises the surface of the guest polymer, i.e., at least one guest polymer domain comprises at least a portion of the luminal surface. The guest polymer at the luminal surface may be a guest polymer at the exit point of an interpenetrating pathway and / or it may comprise a coating comprising the guest polymer.

[0047] A surface coating of a guest polymer is considered to form part of at least one guest polymer domain when it contacts or connects with a hydrogel guest polymer within the pathway of the host polymer. Because the guest polymer may have relatively low mechanical strength and the layer may result from propagating polymer chains polymerizing from within or across the surface, the surface coating is typically very thin. Suitable surface coatings can be, for example, less than 10 μm, e.g., about 1 μm or less, e.g., about 100 nm or less, e.g., about 50 nm or less, e.g., about 10 nm or less, e.g., 1-2 nm.

[0048] The luminal surface comprising the guest polymer has been found to be highly compatible for use within or in contact with the mammalian body, for example, when the medical tubular device is applied / utilized as a vascular graft, dialysis graft, or other graft within the mammalian body. The medical tubular device has been found to have a significantly lower risk of infection compared to prior art tubing for similar applications. Furthermore, the risk of occlusion and poor patency of the new medical tubular device is significantly lower compared to the prior art. In one embodiment, multiple channels of the guest polymer together form at least a portion of the luminal surface.

[0049] In one embodiment, the guest polymer extends from multiple channels to provide at least a portion of the luminal surface. In one embodiment, the luminal surface comprises a layer of hydrogel polymer, such as a layer comprising or consisting of the same hydrogel polymer as the guest polymer, i.e., the interpenetrating guest polymer.

[0050] In one embodiment, the luminal surface comprises a layer of a polymer different from the guest polymer, such as another hydrogel polymer or a non-hydrogel, hi one embodiment, the guest polymer may form ciliary-shaped structures (e.g., brushes and / or microscopic hair-like structures) on the luminal surface and / or exterior surface, such as partially or fully entangled ciliary-shaped and / or bridge-shaped fibers of the guest polymer.

[0051] Such cilium-shaped structures and / or bridge-shaped structures can be formed, for example, by exposing an IPN having guest polymer domains on its surface (luminal and / or outer surface) to multiple, e.g., five or more, cycles of temperature and / or wetness (dry / wet / moist, cold / hot).

[0052] In one embodiment, the exterior surface at least partially comprises a surface of a guest polymer provided, for example, by a coating, the guest polymer pathways joining together to form at least a portion of the exterior surface, and / or the guest polymer extending from multiple pathways to provide at least a portion of the exterior surface.

[0053] In one embodiment, the luminal surface comprises a layer of a polymer different from the guest polymer, such as another hydrogel polymer or a non-hydrogel. It should be understood that when it is disclosed that a guest polymer is located on the surface or anywhere else outside a host polymer, the guest polymer outside the host polymer is referred to as "guest" to indicate that it is embedded in the host polymer and in contact with and / or bonded to the guest polymer within.

[0054] Alternatively, or in addition, the medical tubular device may include a hydrogel polymer coating that is embedded in a host polymer and may not be in contact with or bonded to the hydrogel guest polymer therein. Such a hydrogel polymer coating may be similar to the hydrogel guest polymers described herein, except for the difference that it is embedded in a host polymer and not in contact with or bonded to the hydrogel guest polymer therein.

[0055] The term "hydrogel polymer" by itself, in one embodiment, can be taken to mean a hydrogel guest polymer (i.e., in contact with an interpenetrating guest polymer). The term "hydrogel polymer" by itself, in another embodiment, can be taken to mean a hydrogel polymer that is not in contact with an interpenetrating guest polymer.

[0056] The outer surface may advantageously be as described for the luminal surface above. In one embodiment, the outer surface includes a layer of a polymer similar to or different from the guest polymer, such as a layer comprising or consisting of the guest polymer. When the outer surface includes a layer of a hydrogel polymer, the medical tubular device can be more compatible with mammalian tissue and therefore more suitable for use in contact with mammalian tissue. As further described below, the hydrogel polymer can include functional moieties that can further enhance biocompatibility.

[0057] The hydrophilic properties of the hydrogel guest polymer domains on the luminal and / or outer surfaces are believed to provide a slippery surface that reduces protein and bacterial adhesion while maintaining a normal immune response. The luminal and / or outer surfaces have been found to mimic / resemble those of natural blood vessels and thus preferably possess stealth properties that do not trigger the complement system, thereby reducing the risk of inflammation and / or infection. Furthermore, this new medical tubular device has been found to have a significantly lower risk of inducing neointimal hyperplasia and / or stenosis and / or ensure longer-term patency.

[0058] It has been found that hydrogel polymers, for example, provided in the form of hydrogel guest polymer domains on the luminal and / or exterior surfaces, provide highly desirable non-fouling surfaces.

[0059] To further enhance biocompatibility, it has been found desirable for the luminal and / or exterior surfaces to contain functional moieties in the form of zwitterionic moieties, which are advantageously covalently attached to the hydrogel (guest) polymer.

[0060] The term "hydrogel (guest) polymer" refers to a guest polymer and / or another hydrogel polymer at the luminal and / or outer surface of the body structure. The "another" hydrogel polymer can be as described for the guest polymer, but in certain embodiments, it can be different from the guest polymer of the guest polymer domain.

[0061] It has been found that the zwitterionic moiety further enhances the stealth properties of the surface, thus reducing the risk of infection and / or inflammation. When the medical tubular device is a vascular graft and the zwitterionic moiety is present on the luminal surface, it has been found that the zwitterionic moiety can reliably reduce or even completely prevent the risk of thrombosis. The zwitterionic moiety can further reduce or inhibit activation of the complement system and the coagulation cascade.

[0062] Thus, in a preferred embodiment, the luminal surface comprises zwitterionic moieties covalently attached to the guest polymer. In one embodiment, the exterior surface comprises zwitterionic moieties covalently bound to the hydrogel (guest) polymer.

[0063] Advantageously, the zwitterionic moieties are provided by incorporating them into a guest polymer. In one embodiment, the guest polymer comprises a zwitterionic hydrogel, which comprises a crosslinked network of polymerized monomers, the polymerized monomers comprising one or more monomers, preferably including zwitterionic monomer(s) and / or a combination of cationic and anionic monomers.

[0064] Zwitterionic monomers are monomers that contain at least one zwitterionic moiety. Cationic monomers are monomers that contain at least one cationic moiety. Anionic monomers are monomers that contain at least one anionic moiety. It should be noted that a monomer may simultaneously satisfy two or all three of the above monomer types, e.g., be both anionic and cationic.

[0065] Examples of zwitterionic monomers include sulfobetaines, carbobetaines, phosphobetaines, phosphocholines, or any combination thereof. In a preferred embodiment, the zwitterionic monomer has the formula 1-ethenyl-3-(4-sulfonatobutyl)-1H-imidazol-3-ium:

[0066] [ka]

[0067] is or comprises a zwitterionic monomer having This is a zwitterionic monomer designated CK1573 in Figure 6. In a preferred embodiment, the zwitterionic monomer is the following zwitterionic monomer: 1-Ethenyl-3-(3-sulfonatopropyl)-1H-imidazol-3-ium (SK1572):

[0068] [ka]

[0069] 1-Methyl-4-(2-methylprop-2-enoyl)-1-(4-sulfonatobutyl)piperazin-1-ium (CK1578):

[0070] [ka]

[0071] 3-[dimethyl(2-{2-[(2-methylprop-2-enoyl)oxy]ethoxy}ethyl)azaniumyl]propane-1-sulfonate (CK1582):

[0072] [ka]

[0073] 4-[dimethyl({2-[(2-methylprop-2-enoyl)oxy]ethyl})azaniumyl]butane-1-sulfonate (SK1583):

[0074] [ka]

[0075] is or includes one or more of: In a preferred embodiment, the zwitterionic monomer is the following zwitterionic monomer: 4-(2-methylprop-2-enoyloxymethoxymethylammonio)butane-1-sulfonate (CK1591):

[0076] [ka]

[0077] 4-{dimethyl[3-(2-methylprop-2-enamido)propyl]azaniumyl}butane-1-sulfonate (CK1584):

[0078] [ka]

[0079] 1-Methyl-4-(2-methylprop-2-enoyl)-1-(4-sulfonatobutyl)piperazin-1-ium (CK1586):

[0080] [ka]

[0081] 1-Carboxy-N,N-dimethyl-N-(2'-methacryloyloxyethyl)methanaminium (CK1581):

[0082] [ka]

[0083] 2-[dimethyl(2-{2-[(2-methylprop-2-enoyl)oxy]ethoxy}-ethyl)azaniumyl]acetate (cCK1589):

[0084] [ka]

[0085] 2-{dimethyl[3-(2-methylprop-2-enamido)propyl]-azamniumyl}acetate (CK1588):

[0086] [ka]

[0087] 1-(carboxylatomethyl)-1-methyl-4-(2-methylprop-2-enoyl)piperazin-1-ium (CK1585):

[0088] [ka]

[0089] 3-(carboxylatomethyl)-1-ethenyl-1H-imidazol-3-ium (CK1587):

[0090] [ka]

[0091] is or includes one or more of: The IPN may further comprise one or more bound drugs, such as drugs at the luminal and / or external surface. The drugs may advantageously be covalently bound to the hydrogel guest polymer. Advantageously, the drugs are specifically bound to the guest polymer at the luminal and / or external surface. In one embodiment, the body structure may comprise a first drug bound to the hydrogel guest polymer at the external surface and a second, different drug bound to the hydrogel (guest) polymer at the luminal surface.

[0092] Examples of drugs that can be conjugated include enzymes, immunosuppressants, extracellular matrix proteins, antimicrobials, inactivating drugs, and / or any combination comprising one of the above drugs. In one embodiment, the drug that can be conjugated is an antithrombogenic agent.

[0093] The drug is advantageously a catalytically functional drug such that when its biological effect is utilized, it is not consumed but rather remains active for a desired period of time, and thus when it is bound to the luminal and / or external surface, the surface will have and substantially maintain the biological effect of the drug.

[0094] The drug can be selected according to the intended use of the medical tubular device. In one embodiment, the body structure comprises at least one drug bound (preferably covalently attached) to the guest polymer and / or the host polymer at the luminal surface.

[0095] In one embodiment, the body structure comprises at least one drug bound (preferably covalently attached) to the guest polymer and / or the host polymer at its outer surface. Advantageously, the attached (e.g., covalently attached) drug is a thrombosis inactivating agent, preferably comprising heparin, EDTA, antibiotic citrate, and / or any combination comprising one of the above thrombosis inactivating agents.

[0096] Heparin is a well-known thrombosis inactivating agent. Preferably, heparin molecules are directly bound to the luminal surface body structure. Heparin is a polysaccharide anticoagulant with a strong antiproliferative effect on vascular smooth muscle cells. It has been found that heparin on the luminal surface effectively inactivates thrombin, thereby allowing fibrin to remain soluble rather than being converted into insoluble fibers, thereby reducing or eliminating the risk of thrombosis.

[0097] It is expected that the thrombosis-inactivating effect of the thrombosis-inactivating drug may last for a very long period of time, such as one year, two years, three years or more, or even longer. Covalently bound drugs can be advantageously covalently bound to the hydrogel (guest) polymer and / or the host polymer via a linker molecule to ensure optimal drug efficacy. Suitable linkers include those described in U.S. Patent Application Publication No. 20080227092. Prior to binding to a drug, the linker advantageously includes a functional moiety (e.g., a capture moiety) for binding to the drug. The linker can, for example, be cleavable to expose the functional moiety. The body structure can further include one or more releasable drugs, for example, to further improve the biocompatibility and beneficial effects of the drug.

[0098] In one embodiment, the releasable drug comprises an anti-proliferative drug such as paclitaxel (taxol) and / or rapamycin and / or other suitable anti-proliferative drugs. Where there is a risk of cell proliferation within the lumen of a medical tubular device, it is desirable to have the anti-proliferative agent disposed on at least a portion of the luminal surface.

[0099] If it is desired that the medical tubular device not grow with the surrounding tissues that it comes into contact with during use, the antiproliferative agent may advantageously be disposed on at least a portion of the outer surface of the body structure. Such a medical tubular device with low ingrowth characteristics may be, for example, a tube for temporary use that is inserted into contact with a patient's tissue, such as a tube for delivering a chemotherapy drug to the patient. Furthermore, if the medical tubular device is suitable for implantation and it is anticipated that the implant will need to be retrieved or replaced, it may be desirable for it to have low ingrowth potential and therefore be able to be retrieved or explanted in a relatively simple manner.

[0100] In one embodiment, the releasable drug comprises an anti-infective drug, which is preferably selected from rifampicin and / or minocycline. Anti-infectives are drugs that can act against infections, preferably by inhibiting the attachment and spread of infectious pathogens or by killing infectious microorganisms altogether.

[0101] Anti-infective agents include, for example, antibiotics and / or antiseptics. Anti-infective agents may be particularly desirable when there is a high risk of infection, such as in situations where the medical tubular device is adapted for use in contact with patients who are at high risk of infection and / or have low immune defenses.

[0102] The anti-infective agent can be placed anywhere on the medical tubular device. Advantageously, the anti-infective agent is placed on the outer surface of the body structure to reduce the risk of infection between the body structure and the tissue it is adapted to contact. This may limit and / or reduce the risk of surgical site infection. Dialysis grafts generally have a higher risk of infection than "normal" grafts. This is because each time a patient receives treatment (dialysis), there is a significantly higher risk of needles penetrating the skin, tissue, or graft and causing / inflicting infection (which may occur multiple times each week).

[0103] Blood access devices (e.g., CVCs and dialysis grafts) pose a high risk of infection, especially central venous catheters (CVC grafts), which provide a pathway for bacteria to enter the body.

[0104] In one embodiment, the antiinfective is located within a guest polymer domain located away from both the luminal and external surfaces, i.e., within an intermediate guest polymer domain that does not include the luminal or external surfaces. In such a case, the antiinfective can be released when the body structure is pierced, for example, by a needle during suturing, or by a needle if the medical tubular device is a dialysis graft. Thus, release of the antiinfective can be located in a high-risk location, and the release period can be very long until the releasable amount of antiinfective is used.

[0105] In one embodiment, the anti-infective is an amebicide; an aminoglycoside; an anthelmintic; an antifungal agent, such as an azole antifungal, an echinocandin, other antifungal or polyene; an antimalarial agent, such as an antimalarial combination, an antimalarial quinoline or other antimalarial; an antitubercular agent, such as an aminosalicylates, an antitubercular combination, a diarylquinoline, a hydrazide derivative, other antitubercular, a nicotinic acid derivative, a rifamycin derivative or a Streptomyces derivative; an antiviral agent, such as an adamantane antiviral, an antiviral booster, an antiviral combination, an antiviral interferon, a chemokine receptor antagonist, an integrase strand transfer inhibitor, other antiviral, a neuraminidase inhibitor, an NNRTI, an NS5A inhibitor, a nucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor or a purine nucleoside; and / or any combination thereof. The antibiotics may include one or more of: rubapenems; carbapenems / beta-lactamase inhibitors; cephalosporins, such as cephalosporin / beta-lactamase inhibitors, first generation cephalosporins, fourth generation cephalosporins, next generation cephalosporins, second generation cephalosporins, or third generation cephalosporins; glycopeptide antibiotics; glycylcyclines; leprostatics; lincomycin derivatives; macrolide derivatives, such as ketolides or macrolides; other antibiotics; oxazolidinone antibiotics; penicillins, such as aminopenicillins, antipseudomonal penicillins, beta-lactamase inhibitors, natural penicillins, or penicillinase-resistant penicillins; quinolones; sulfonamides; tetracyclines; urinary tract anti-infectives; skin anti-infectives; quaternary ammonium compounds (quats), or any combination thereof.

[0106] Advantageously, the releasable drug is loaded primarily into the guest polymer. Drugs can be loaded into the guest polymer, for example, by applying an IPN to a drug-containing fluid under conditions in which at least a portion of the hydrogel guest polymer is swollen. Examples of loading methods are described in WO 2013075724, Santos et al., "Poly(hydroxyethyl methacrylate-co-methacrylated-β-cyclodextrin) hydrogels: Synthesis, cytocompatibility, mechanical properties, and drug loading / release properties," Science Direct, Acta Biomaterialia 4 (2008) 745-755, and WO 2005 / 055972.

[0107] Advantageously, the releasable drug is releasable via at least one of the luminal surface and the outer surface. If the drug is an antiproliferative drug, it may advantageously be releasable via at least the luminal surface. Antiproliferative drugs have been shown to prevent or reduce the migration of vascular smooth muscle cells from the native blood vessel to the luminal surface (intima, the inner layer adjacent to the blood vessel / lumen), as well as their proliferation and extracellular matrix deposition. Antiproliferative drugs thereby function to reduce the risk of or prevent intimal hyperplasia.

[0108] In one embodiment, the drug is an anti-infective drug and the drug is releasable through at least the outer surface, which may further reduce or completely prevent the risk of infection. The guest polymer (and / or hydrogel) may comprise a homopolymer or a copolymer. Preferably, the guest polymer is crosslinked.

[0109] The guest polymers can be physically crosslinked and / or chemically crosslinked. Copolymer means a polymer obtained by copolymerization of two or more monomer species.

[0110] In one embodiment, the copolymer guest polymer is a biopolymer having two monomer species. The composition of the guest polymer can be uniform and / or constant throughout the guest polymer domain, or it can vary, e.g., by varying the amount of one or more monomers, e.g., in a gradient fashion. This can be achieved, for example, by varying the relative amounts of the monomers during loading of the monomers into the host polymer and / or during its polymerization. For example, the guest polymer can consist primarily of PHEMA in a first portion of the domain, PHEMA and PEGMEA in a second, intermediate portion of the domain, and PHEMA, PEGMEA, and sulfobetaine in a third, e.g., luminal, portion. Those skilled in the art will appreciate that any combination of monomers is possible and can be selected according to the desired properties of the medical tubular device.

[0111] In one embodiment, the copolymer guest polymer is a terpolymer derived from three monomer species. In one embodiment, the copolymer guest polymer is a quaternary polymer derived from four monomer species. The guest polymer may be completely hydrophilic or may contain hydrophobic domains. In one embodiment, the hydrogel (guest) polymer is a hydrophobic-hydrophilic hybrid hydrogel. Hydrogel (guest) polymers with hydrophobic domains can be prepared from a mixture of monomers including hydrophilic and hydrophobic monomers. Preferably, the hydrophobic monomers are present at about 20% by weight or less of the monomers, e.g., 10% or less. In one embodiment, the hydrogel (guest) polymer includes moieties that can be phase-switched upon irradiation, pH, and / or mechanical influence to provide localized domains with hydrophilic and hydrophobic properties, respectively. Such moieties can be, for example, photoactive moieties as described herein. In one embodiment, the hydrogel (guest) polymer includes a copolymer or multipolymer including a spiropyran and a hydrophobic monomer. This is advantageous, for example, when the guest polymer includes a drug, such as a hydrophilic drug for controlled and / or triggered release.

[0112] The guest polymer may preferably be polymerized from one or more monomers including: acrylates; vinyl monomers such as n-vinylpyrrolidone (nVP); styrene; oxygen-containing, phenyl, amino- and nitrogen-containing acrylic and methacrylic derivatives, such as acrylic acid esters, acrylic acid, methacrylic acid and esters, alkyl and hydroxyalkyl acrylates and methacrylates; functionalized (meth)acrylates, such as 2-hydroxyethyl methacrylate (HEMA), glycerol monomethacrylate (GMMA), heptafluorobutyl acrylate (HFBA), 2-methacryloyloxyethyl phosphorylcholine (MPC) and [2-(methacryloyloxy)ethyl]-dimethyl-(3-sulfopropyl)-ammonium hydroxide (betaine); alkyl-substituted acrylates and methacrylates, such as Methyl methacrylate (MMA), ethyl methacrylate (EMA), butyl methacrylate (BMA), dodecyl methacrylate (DMA); PEGylated (meth)actylates such as poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) and poly(ethylene glycol) methyl ether acrylate (PEGMEA); substituted β- and γ-lactones, lactic acid monomers; carbohydrates and fluorinated monomers; urethanes; mono- and difunctional alcohols; carboxylic acids; amines; isocyanates; epoxides; aromatics with alkyl groups; sulfonated aromatics, aromatic resins; imidazoles; imidazole derivatives; zwitterionic monomers; pyrazoles; quaternary ammonium monomers; spiropyran monomers, chitin or its derivatives (chitosan), and any and / or any combination comprising one or more of the above.

[0113] A hydrogel (guest) polymer comprising a monomer "X" is meant herein to refer to a guest polymer derived from one or more monomers that comprise the monomer "X". In one embodiment, the guest polymer comprises poly(2-hydroxyethyl methacrylate) (PHEMA), and preferably the guest polymer is a cross-linked copolymer of PHEMA and PEGMEA.

[0114] In one embodiment, the hydrogel guest polymer comprises a copolymer polymerized from a monomer comprising at least one zwitterion and at least one of PHEMA, PEGMEA, or vinylimidazole butanesulfonate; preferably, the hydrogel guest polymer comprises a copolymer polymerized from a monomer comprising PHEMA, PEGMEA vinylimidazole butanesulfonate, and / or sulfobetaine.

[0115] In one embodiment, the guest polymer comprises a homopolymer or copolymer polymerized from monomers comprising at least one monomer comprising a protecting group that protects a functional moiety, the protecting group preferably being fluorenylmethyloxycarbonyl (FMOC), and / or the protected functional moiety preferably comprising an —NH group.

[0116] Examples of suitable protective moieties can be found in US Patent Application Publication No. 2008 / 0227092. Examples of suitable functional moieties can be found in US Patent Application Publication No. 2008 / 0227092.

[0117] After polymerization and optional cross-linking, the protecting groups on the luminal and / or outer surfaces can be removed to deprotect the functional moieties, and drugs such as those described above can be attached to the guest polymer via the functional moieties (e.g., -NH2) and, optionally, a linker (e.g., PEG, PEO).

[0118] In one embodiment, the guest polymer comprises a copolymer, preferably a copolymer polymerized from monomers comprising at least one zwitterionic moiety, such as a sulfobetaine, carbobetaine, phosphobetaine, or phosphocholine, as described above.

[0119] In one embodiment, the guest polymer comprises a copolymer polymerized from monomers including a photoactive monomer that includes a photoactive moiety such as a spiropyran group. The photoactive monomer is advantageously photochromic.

[0120] "Photoactive monomer" as used herein means a monomer that includes at least one photoactive moiety. The guest polymer advantageously comprises a spiropyran acrylate.

[0121] By including a photoactive moiety in the guest polymer, the guest polymer itself becomes photoactive, thereby allowing the position and / or one or more properties of the medical tubular device to be determined, altered, and / or adjusted by light, for example, by irradiating the body structure with ultraviolet light, thereby allowing a surgeon (including a physician or other trained human or trained robot) to switch on and off certain biological properties (such as hydrophilicity and / or drug release properties).

[0122] Further information regarding photochromic moieties suitable for application to the guest polymer-forming monomers can be found in Nordin et al., "PREPARATION AND ACTIVATION OF SPIROPYRAN-MEROCYANINE SYSTEM," Malaysian Journal of Analytical Sciences, Vol. 17, No. 3 (2013): 422-429.

[0123] In one embodiment, the guest polymer comprises embedded chitosan, such as a subguest interpenetrating chitosan network. The chitosan network can be modified with a photoresponsive derivative, such as a spiropyran derivative.

[0124] The synthesis of interpenetrating chitosan networks modified with spiropyran (SP) derivatives and suitable for providing subguest interpenetrating networks has been reported by Cheol Woo Lee et al. in "Fabrication of photochromic hydrogels using interpenetrating chitosan networks." The chitosan may be loaded into the guest and / or host polymer after the guest polymer is crosslinked.

[0125] The guest polymer of the IPN can include two or more types of guest polymer domains with equal or different compositions. In one embodiment, the two or more types of guest polymer domains include a surface guest polymer domain comprising a guest polymer at least on the luminal or outer surface, and an intermediate guest polymer domain having a different type of guest polymer.

[0126] In one embodiment, the two or more types of guest polymer domains include a first type of guest polymer that includes a guest polymer on the luminal surface and a second type of guest polymer that includes a guest polymer on the external surface.

[0127] In one embodiment, the two or more types of guest polymer domains include a third, intermediate guest polymer that may be the same or different on either the luminal or exterior surface. The guest polymer of the body structure may advantageously constitute at least about 1% of the IPN by dry weight, such as at least about 10% of the IPN by dry weight, such as from about 15% to about 85% of the IPN by dry weight, such as from about 25% to about 60%.

[0128] Advantageously, at least one guest polymer domain of the body structure comprises at least one surface of the body structure, such as at least one of the luminal surface and the exterior surface of the body structure. In one embodiment, the guest polymer in the at least one guest polymer domain is substantially uniformly distributed in the host polymer matrix.

[0129] In one embodiment, at least one guest polymer domain has a gradient of guest polymer content in a direction perpendicular (normal) to the luminal and / or outer surface of the body structure, preferably such that the amount of guest polymer closer to the surface of the body structure is greater than the amount of guest polymer further from the surface of the body structure.

[0130] By structuring the amount and / or distribution of monomers in the host polymer, the body structure can be designed and optimized for many different applications, such as controlling the release profile of a releasable drug.

[0131] In one embodiment, the body structure comprises a single guest polymer domain, e.g., including an optional coating of guest polymer. Preferably, the guest polymer extends to and / or comprises a coating of the luminal surface at least in part.

[0132] In one embodiment, the guest polymer domains extend through the entire thickness of the host polymer matrix, and preferably the IPN extends through the entire thickness of the body structure. In certain applications, it is desirable for the body structure to have a high tissue ingrowth capacity to ensure that the medical tubular device will grow (mature) relatively quickly with the tissue it contacts when deployed, which can significantly reduce the potential risk of infection between the tissue and the medical tubular device, and can significantly reduce the potential risk of blood accumulation due to potential bleeding, which can cause a hematoma, between the outer surface of the medical tubular device and the surrounding tissue.

[0133] It has been found that this may reduce the risk of forming an excessive amount of scar tissue. It has been found that if there is a high amount of scar tissue formation, the tissue tends to contract around the body structure, thereby reducing the internal diameter of the body structure. By ensuring that the body structure has a high ingrowth capacity, both the risk of infection and the risk of contraction can be reduced.

[0134] The present inventors have found that at least one guest polymer domain comprises a blood clot-promoting domain and / or a cell proliferation-promoting domain, and the blood clot-promoting domain and / or the cell proliferation-promoting domain is located away from the luminal surface, preferably not comprising the luminal surface, thereby ensuring that the main body structure has high ingrowth capability, thereby reducing the risk of cell proliferation within the lumen of the medical tubular device and simultaneously ensuring that the main body structure has high ingrowth capability.

[0135] The body structure may have, for example, an outer surface guest polymer domain comprising a clot promoting and / or cell proliferation domain and a luminal surface guest polymer domain comprising an anti-proliferative drug. It has been found that medical tubular devices comprising guest polymer domains having clot-promoting and / or cell proliferation domains can also significantly reduce the risk of excessive bleeding, for example, during implantation of the medical tubular device. This effect has been confirmed even when the medical tubular device comprises an antiproliferative and / or thrombosis-inactivating agent on the luminal surface and / or in the luminal surface guest polymer domain. Advantageously, the clot-promoting guest polymer comprises an outer surface guest polymer domain comprising at least a portion of the outer surface.

[0136] In one embodiment, the clot-promoting and / or cell proliferation domains are located in intermediate guest polymer domains that do not include either the luminal or outer surface. While the medical tubular device of this embodiment may or may not have high ingrowth capacity, intermediate guest polymer domains with cell proliferation-promoting and / or clot-promoting agents can significantly reduce the risk of excessive bleeding, for example, during implantation of the medical tubular device and / or after access implantation (dialysis). Thus, the medical tubular device of this embodiment may advantageously have outer surface guest polymer domains that include antiproliferative agents to reduce ingrowth capacity.

[0137] In one embodiment, a clot-promoting domain containing a releasable clot-promoting drug is desirably disposed at each end of a medical tubular device adapted to be sutured to another graft or a native blood vessel, which can significantly reduce the risk of excessive bleeding, for example, during implantation of the medical tubular device.

[0138] In one embodiment, the cell proliferation domain containing the releasable cell proliferation drug is desirably an outer domain along substantially the entire length of the body structure, thereby ensuring rapid ingrowth of the outer surface into surrounding tissue with low risk of scar tissue.

[0139] The clot-promoting and / or cell proliferation domain may, for example, comprise a cell proliferation-promoting and / or clot-promoting agent, such as a fibrinolytic agent, a heparin antagonist, a platelet-stimulating agent, or any combination thereof including one or more of the above clot-promoting agents.

[0140] In many applications, it is desirable for a medical tubular device to have a high ingrowth capacity to ensure rapid ingrowth into surrounding tissue after implantation, thereby reducing the tendency and / or risk of lateral bleeding around the implanted device, which is particularly preferred when the medical tubular device is a dialysis graft.

[0141] In one embodiment, the host polymer comprises two or more guest polymer domains. In one embodiment, the two or more guest polymer domains comprise a luminal guest polymer domain and an external guest polymer domain. The two or more guest polymer domains may advantageously be separated by a polymer portion of the body structure that is essentially free of guest polymer, which polymer portion is preferably identical to the host polymer matrix but essentially free of guest polymer.

[0142] The body structure may be a single layer or may comprise several layers, such as several tubular layers. Advantageously, at least the host polymer forms a tubular layer over the entire length of the body structure. The additional layers may be completely tubular over the entire length of the body structure, or they may be only local layers, for example over part of the length of the body structure.

[0143] In one embodiment, the body structure is a layered body structure comprising two or more layers, at least one of the layers comprising at least one IPN portion comprising or consisting of an IPN. In one embodiment, the body structure comprises a luminal layer comprising a luminal surface, the luminal layer comprising or consisting of at least one IPN. Preferably, the luminal surface comprises a guest polymer, e.g., as described above. Advantageously, the guest polymer domain comprises a luminal surface guest polymer domain comprising at least a portion of the luminal surface, such as the entire luminal surface.

[0144] In one embodiment, the body structure comprises an outer layer comprising an outer surface, the outer layer comprising at least one IPN. Preferably, the outer surface comprises a guest polymer, e.g., as described above. Advantageously, the guest polymer domain comprises an outer surface guest polymer domain comprising at least a portion of the outer surface, such as the entire outer surface.

[0145] The body structure may comprise one or more intermediate layers and / or domains that do not comprise a surface of the body structure. Advantageously, the guest polymer domain comprises an intermediate guest polymer domain that does not comprise a luminal or external surface.

[0146] In one embodiment, at least one layer of the body structure is a polymer layer that does not contain an IPN, such as a polymer layer of polytetrafluoroethylene (PTFE), expanded PTFE (e.g., Goretex®), polyurethane (PU), polyethylene terephthalate (PET, e.g., Dacron®), and / or a silicone elastomer.

[0147] Such materials and / or layers of materials are described, for example, in U.S. Patent Application Publication No. 20160354217, U.S. Patent Application Publication No. 20140142682, U.S. Patent Application Publication No. 20090258958, U.S. Patent No. 6,517,571, U.S. Patent Application Publication No. 0060118236, and / or U.S. Patent No. 5,931,865.

[0148] In one embodiment, at least one polymer layer of the body structure that does not include an IPN is an elastomeric layer. Advantageously, two or more layers are concentrically arranged to form a layered body structure, and the concentrically arranged layers are preferably in full surface-to-surface (interfacial) contact with adjacent layers. The two or more layers may have the same length or different lengths.

[0149] The two or more layers can be unbonded layers, locally fixed layers, or interfacially bonded layers. In one embodiment, at least two of the two or more layers are not chemically secured to one another, and the at least two unsecured layers may be mechanically held together, for example, via a mechanical interlock.

[0150] In one embodiment, at least two of the two or more layers are interfacially bonded to one another, for example, by an adhesive therebetween. In one embodiment, at least two of the two or more layers are secured to one another, preferably by topical adhesive bonds, sutures, staples and / or clips, pinholes.

[0151] The medical tubular device may further include a tubular support structure disposed concentrically with the body structure, for example, inside or around the body structure. The support structure may include, for example, a support structure disposed in contact with the luminal surface or in contact with the exterior surface of the body structure.

[0152] The support structure advantageously has a higher stiffness than the body structure, thereby enabling the support structure to support the medical tubular device in a desired position. Advantageously, the tubular support structure, or simply "support structure," does not entirely cover either the outer surface or the luminal surface of the body structure. Preferably, the support structure covers up to 50% of the outer surface or luminal surface of the body structure, for example up to 40%, such as up to 30%, for example up to 20%, for example up to 10% of the outer surface or luminal surface of the body structure.

[0153] The support structure may include, for example, a helical wire. The helical wire may be positioned, for example, to contact the luminal surface to prevent collapse of the body structure. The helical wire may be positioned, for example, to surround and contact the outer surface. This may provide enhanced growth and faster ingrowth of the body structure. The helical wire may be embedded, for example, within the body structure. This may provide mechanical support without interfering with biological properties.

[0154] In one embodiment, the tubular support structure includes a cuff shaped to fit over the outer surface of the body structure. The cuff can have an open cross-hatch configuration and preferably covers up to about 25% of the outer surface of the body structure, for example, from about 1% to about 20% of the outer surface of the body structure.

[0155] The cuff may be, for example, of a polymeric material, preferably including collagen, Dacron®, nylon, polytetrafluoroethylene (PTFE), expanded PTFE (e.g., Goretex®), polyethylene terephthalate (PET, e.g., Dacron®), polyurethane (PU), and / or silicone elastomer. In one embodiment, the cuff includes fibers, e.g., for faster ingrowth. In one embodiment, the cuff includes fluorinated ethylene propylene (FEP). FEP is a copolymer of hexafluoropropylene and tetrafluoroethylene and is sold, for example, under the brand names Teflon® (DuPont), FEP, Neoflon® FEP (Daikin), or Dyneon® FEP (Dyneon / 3M). The cuff may advantageously include an IPN material loaded with one or more drugs, such as growth hormones, antifibrinolytic agents, clotting promoters, and / or cell proliferation agents.

[0156] Advantageously, the cuff forms a scaffold for cell infiltration, proliferation and growth. In one embodiment, at least a portion of the outer surface of the body structure and / or at least a portion of the outer surface of the support structure comprises an ingrowth-enhancing drug such as a growth hormone, an antifibrinolytic drug, a blood clot promoting drug and / or a cell proliferation promoting drug.

[0157] The ingrowth-enhancing drug may advantageously form a scaffold for cell infiltration, proliferation, and / or growth. The medical tubular device comprising the ingrowth-enhancing drug is preferably an implantable medical tubular device such as a dialysis graft, a vascular graft or carrier, and / or an insulator for an artificial nerve graft.

[0158] In-growth enhancing agents on the outer surface of the body structure and / or the outer surface of the support structure ensure faster ingrowth and outer surface maturation of the medical tubular device, thereby ensuring a reduced tendency and / or risk of lateral bleeding.

[0159] The extremely high ingrowth capacity of the medical tubular device, which includes an ingrowth-enhancing agent on the outer surface of the main structure and / or the outer surface of the support structure, ensures that the medical tubular device will grow relatively quickly with the tissue it contacts when deployed. This significantly reduces the potential risk of infection between the tissue and the medical tubular device, and also reduces the risk of excessive scar tissue formation, thereby reducing the risk of tissue shrinkage surrounding the main structure, which also extends the patency period. Furthermore, if the medical tubular device is a dialysis graft, the faster maturation allows dialysis treatment to begin earlier than with prior art dialysis grafts. If the graft is not fully matured and self-healing is insufficient, blood leakage from the needle penetration channels may cause some blood to accumulate in the gap between the outer surface and the tissue.

[0160] The clot-promoting agent can be, for example, as described above, a fibrinolytic agent, a heparin antagonist, a platelet stimulating agent, or any combination thereof comprising one or more of the clot-promoting agents described above. Advantageously, the ingrowth-enhancing agent comprises an extracellular matrix (ECM) molecule, preferably comprising a fibrous protein and / or a proteoglycan, hi one embodiment, the ingrowth-enhancing agent comprises collagen.

[0161] The main fibrous proteins that make up the extracellular matrix are collagen, elastin, and laminin, all of which are relatively sturdy protein macromolecules. Their toughness may provide cushioning and load-bearing properties to the extracellular matrix.

[0162] In one embodiment, the ingrowth-enhancing agent comprises a natural extracellular matrix or a synthetic extracellular matrix, or any combination or fraction thereof. The ECM can be, for example, OASIS® Wound Matrix, an intact matrix naturally derived from porcine small intestinal submucosa (SIS) adapted for wound treatment. OASIS® Wound Matrix is ​​sold by Smith & Nephew.

[0163] Another example is ECM available from the Swedish company VERIGRAFT, which creates personalized tissue-engineered implants for use in regenerative medicine.

[0164] A further example of an ECM material is Corning Matrigel matrix, a solubilized basement membrane preparation extracted from Engelbreth-Holm-Swarm (EHS) mouse sarcoma, a tumor rich in ECM proteins such as laminin (the main component), collagen IV, heparan sulfate proteoglycans, entactin / nidogen, and several growth factors.

[0165] Further information and examples of ECM can be found, for example, in the article by Eduardo A. Silva and David J. Mooney, "Synthetic Extracellular Matrices for Tissue Engineering and Regeneration," ELSEVIER, Vol. 64, 2004, pp. 181-205, https: / / doi.org / 10.1016 / S0070-2153(04)64008-7.

[0166] To further enhance the ingrowth characteristics of the medical tubular device, at least a portion of the outer surface of the body structure and / or at least a portion of the outer surface of the support structure may include pre-grown cells. Such pre-grown cells may be provided, for example, by seeding stem cells onto at least a portion of the outer surface of the body structure and / or at least a portion of the outer surface of a support structure, followed by embedding the body structure together with the optional support structure in a differentiation and growth medium. To prevent cells from migrating into the lumens (channels) of the medical tubular device, the lumens of the medical tubular device may advantageously be closed and / or sealed at both ends of the medical tubular device.

[0167] In one embodiment, at least a portion of the exterior surface of the body structure and / or at least a portion of the exterior surface of the support structure comprises a bioadhesive, such as a hydrogel or hydrogelable bioadhesive, preferably the bioadhesive comprises chitosan.

[0168] The bioadhesive on the outer surface of the body structure and / or the outer surface of the support structure ensures a reduced tendency and / or risk of lateral bleeding around the implanted device immediately after implantation and even before ingrowth begins. The bioadhesive thereby ensures more rapid ingrowth and maturation, which is particularly desirable when the medical tubular device is a dialysis graft. Furthermore, it has been found that the bioadhesive can also reduce the formation of scar tissue. This is believed to occur because the bioadhesive reduces friction and relative movement between the body structure and the tissue surrounding it. Furthermore, the bioadhesive also further reduces the risk of infection and inflammation.

[0169] In one embodiment, the body structure comprises an exterior surface guest polymer domain, the exterior surface guest polymer domain comprises at least a portion of the exterior surface, and at least a portion of the bioadhesive comprises at least a portion of the exterior surface guest polymer. For example, the exterior surface guest polymer may comprise chitosan bound to and / or embedded in (interpenetrating) the guest polymer.

[0170] The bioadhesive may be adhered to the tubular support structure and / or body structure using, for example, a silicone elastomer such as Sylgard® 184 (Dow Corning, Diatom), Silastic® (Dow Corning), and / or adhesive silicone type A MED-1137 (Nusil). The bioadhesive may be, for example, chitosan, such as that sold by KitoZyme. Advantageously, the chitosan is in the form of a powder or dry foam, obtained, for example, by lyophilization. Advantageously, the chitosan may be secured to the body structure and optional support structure using a silicone elastomer or other suitable adhesive elastomer / adhesive.

[0171] In one embodiment, at least a portion of the bioadhesive is bonded to the tubular support structure and / or body structure by grafting. It has been discovered that the chemical composition of a medical tubular device can provide a medical tubular device with a very narrow lumen while ensuring long-term patency and reducing the risk of restenosis / luminal occlusion (e.g., due to neointimal hyperplasia, blood clotting, and biofilm formation from bacterial infection). Desired mechanical properties can also be achieved. The medical tubular device can have a narrow inner diameter, for example, up to 1 mm, or even narrower, depending on the intended use of the tubular device. In one embodiment, the medical tubular device has an inner diameter of about 2 mm to about 6 cm, e.g., about 3 mm to about 5 cm, e.g., about 4 mm to about 3 cm, which may be equal or different along the length of the body structure.

[0172] Additionally, the wall thickness of the body structure can be made very thin while maintaining desirable mechanical properties such as strength, elastic compliance, etc. In one embodiment, the body structure has a wall thickness of about 0.01 mm to about 5 mm, e.g., about 0.1 mm to about 3 mm, e.g., about 0.5 mm to about 1 mm.

[0173] It has been found that the elastic compliance should not be too low, but also not too high, as too high compliance can lead to increased deformation and suture tearing, and therefore unwanted bleeding at or near the sutures. Advantageous body structures have an elastic compliance between 1 and 10 (mmHg x 10 in the range of 80-200 mmHg (measured according to ISO 7198:2016, section A5.9)). 2 Generally, natural blood vessels have an elastic compliance greater than 2, for example, between about 2.5 and 6.

[0174] Therefore, it is desirable for the body structure to have an elastic compliance of from about 2 to about 8, such as from about 2.5 to about 6, such as from about 2.5 to about 6, such as from about 3 to about 5, such as from about 3.3 to about 4.5.

[0175] Additionally, it is desirable for the body structure to have a relatively low long-term dilatation, which may be determined, for example, as described in “Long-term dilatation of polyester and expanded polytetrafluoroethylene tube grafts after open repair of infrarenal abdominal aortic aneurysms” J Vasc Surg 2011;53:1506-13.

[0176] In one embodiment, the body structure has a long-term expansion of less than about 25%, such as less than about 20%, such as less than about 10%, such as less than about 5% after 12 months. In one embodiment, the body structure has a long-term expansion of less than about 50% after 6 years, such as less than about 30%, such as less than about 25%, such as less than about 15%.

[0177] The tubular device may advantageously be a vascular graft, a dialysis graft, a dialysis tubing, a catheter, a shunt, a stent, a stent graft, and / or an intestinal graft. Preferably, the medical tubular device is an implantable tubular device such as a vascular graft, a dialysis graft, or a stent.

[0178] In one embodiment, the medical tubular device is a dialysis tubing. In one embodiment, the medical tubular device is a feeding tube, such as a gastrostomy tube. In one embodiment, the medical tubular device is a venous catheter, such as a central venous catheter (CVC line) or a peripherally inserted central catheter (PICC line).

[0179] In one embodiment, the medical tubular device is a drug delivery tube, such as a tube for delivering an anti-cancer drug. The present invention also includes a method of manufacturing the above-described medical tubular device, which method comprises manufacturing a body structure by a process comprising: forming a tubular host polymer substrate having a luminal substrate surface and an outer substrate surface; filling at least a portion of a tubular host polymer substrate with the guest polymer monomer by at least partially swelling the host polymer substrate with a solvent containing the guest polymer monomer; and Polymerizing and optionally crosslinking the monomers to form an IPN comprising at least one guest polymer domain.

[0180] The host polymer matrix may be formed directly from the host polymer substrate, or optionally, residues may be extracted from the host polymer substrate prior to depositing the (guest) monomer within the host polymer matrix.

[0181] Extraction of the residues of the host polymer substrate, loading of the monomers for the guest polymer, polymerization and optional crosslinking, and other optional and / or desired process steps can be found in the following publications: Antimicrob.Agents Chemother 2017,61(7),e00604-17 DOI:10.1128 / AAC.00604-17.Plasmid 2016,87-88,72,DOI:10.1016 / j.plasmid.2016.10.001.J.Control.Release 2016,241,125-134 DOI:10.1016 / j.jconrel.2016.09.018.J. Mat.Chem.Phys.2016,181,495-500 DOI:10.1016 / j.matchemphys.2016.06.086.J.Indus.Eng.Chem.2016,33,142-149 DOI:10.1016 / j.jiec.2015.09.026.Biomacromolecules.2016,17(4),1321-1329 DOI:10.1021 / acs.biomac.5b01722.J.Biomed.Mater.Res.Part B Appl.Biomater.2016,104(2),402-410 DOI:10.1002 / jbm.b.33371.Eur.J.Pharm.Biopharm.2015,94,305-311 DOI:10.1016 / j.ejpb.2015.05.014.Martin Alm,Peter Thomsen.A delivery device.Patent,PA 2015 / 70520.Martin Alm,Soren Langer Steffensen. A method of making a delivery product (A method of WO 2013 / 075724, Martin Alm, Maike Benter, Anne Marie Jensen. An article comprising an interpenetrating polymer network (IPN) and a method for producing an article comprising an IPN. WO 2008 / 052568, Martin Alm, Maike Benter, Anne Marie Jensen. An article comprising an interpenetrating polymer network (IPN) and a method for producing an article comprising an IPN. WO 2008 / 052563, Maike Benter, Martin Alm. A method of coating a polymer surface with a polymer-containing coating and an item comprising a polymer-coated polymer. WO 2006 / 074666, Joachim Karthauser, Maike Benter, and Martin Alm. A method of producing a silicone elastomer rubber item and an article obtained by the method. and the product obtainable by the method), WO 2006 / 045320.

[0182] Advantageously, the tubular host polymer substrate is formed by extrusion or injection molding, and preferably the formed tubular host polymer is seamless. The tubular host polymer substrate can be extruded with any desired wall thickness, inner / outer diameter, and any desired length. In one embodiment, the tubular host polymer substrate is formed by a method including braiding.

[0183] In one embodiment, the tubular host polymer substrate is manufactured by using a mandrel, preferably by providing that the tubular host polymer to be formed is seamless. The tubular host polymer substrate can be manufactured using a mandrel having any desired design, shape, wall thickness, inner / outer diameter, and any desired length.

[0184] In one embodiment, a surface portion of the tubular host polymer substrate may be masked during at least a portion of the monomer loading step. The masked surface portion is preferably the luminal surface portion and / or the outer surface portion.

[0185] Optionally, the method further includes unmasking previously masked surface portions, masking previously unmasked portions, and repeating the monomer loading and polymerization steps. Preferably, the repeated loading steps include loading monomers containing at least one monomer different from the monomer loaded in the first loading step. The IPN can thereby have luminal surface guest polymer domains and external surface guest polymer domains, preferably with different guest polymer compositions. For example, the luminal surface can include the masked functional group portion to be unmasked and a drug, such as a thrombosis inactivating drug, bound thereto, and the external surface can include a zwitterionic portion. Other combinations and variations will be apparent to those skilled in the art from the specification.

[0186] In one embodiment, the step of loading the monomer comprises loading the tubular host polymer substrate with different concentrations and / or different types of monomers and / or loading for different loading times, thereby providing at least one guest polymer domain with an amount and / or monomer gradient perpendicular (normal) to the surface of the body structure of the guest polymer.

[0187] In one embodiment, the method comprises applying a guest polymer coating to at least a portion of the luminal surface and / or the exterior surface, the coating application step preferably comprising carrying out a polymerization step in a reactor while said portion of the luminal surface and / or the exterior surface is exposed to a monomer.

[0188] The guest polymer coating can be, for example, the same or a different guest polymer as the guest polymer that is filled, polymerized, and optionally crosslinked as described above.

[0189] The monomers of the guest polymer loaded onto the host polymer and / or the guest polymer coating may be those described above and advantageously comprise zwitterionic monomers, combinations of cationic and anionic monomers, spiropyran monomers and / or protected functional moieties (e.g., reactive moieties / anchors), preferably the monomers comprise at least one of sulfobetaine, carbobetaine, phosphobetaine, phosphocholine or any combination thereof.

[0190] In one embodiment, where the monomers of the guest polymer loaded into the host polymer and / or the monomers of the guest polymer coating comprise at least one monomer comprising a protecting group that protects a functional moiety, the method preferably further comprises the step of polymerizing and optionally crosslinking the monomer, and then attaching a drug to the guest polymer exposed on the luminal surface and / or the exterior surface of the body structure.

[0191] The step of attaching a drug to the guest polymer exposed on the luminal and / or external surfaces comprises deprotecting the functional moiety and reacting the deprotected functional moiety, optionally via a linker, with the drug to provide a covalent bond to the drug. The protecting group is preferably fluorenylmethyloxycarbonyl (FMOC) and / or the protected functional moiety preferably comprises an -NH group.

[0192] The method may further include loading at least one guest polymer domain with a releasable drug, such as those described above. For example, a drug can be loaded into the outer surface guest polymer domain, including at least a portion of the outer surface, by closing the lumen of the body structure and immersing the body structure in a drug-containing fluid, for example, at high pressure during loading.

[0193] The luminal surface guest polymer domain, comprising at least a portion of the luminal surface, can be loaded with a drug, for example, by flushing the lumen with a fluid containing the drug, for example, at high pressure. Intermediate guest polymer domains that do not include either the luminal or the exterior surface may be filled by forming the body structure of the layered article filled with guest polymer domains prior to stacking two or more layers.

[0194] In one embodiment, the method comprises providing two or more guest polymer domains separated by a polymer portion of the tubular host polymer that is essentially free of guest polymer, hi one embodiment, the method comprises providing at least one further layer concentrically, preferably in complete surface-to-surface contact, on or within the tubular host polymer substrate.

[0195] The at least one further layer may comprise a fluid impermeable (barrier) layer portion, a porous layer portion, and / or a portion having micropores, which may be part of the layer or the entire layer. Preferably, at least one of the further layers is a polymer layer that does not comprise an IPN, such as an elastomeric layer, for example a polymer layer of polytetrafluoroethylene (PTFE), expanded PTFE (e.g., Goretex®), polyethylene terephthalate (PET, e.g., Dacron®), polyurethane (PU) and / or a silicone elastomer. Further examples of polymer layers are provided elsewhere herein.

[0196] The method may further include providing a tubular support structure in contact with the luminal surface or in contact with the exterior surface of the body structure, hi one embodiment, the tubular support structure may be embedded in the body structure.

[0197] The tubular support structure includes a cuff shaped to fit over the outer surface of the body structure, the cuff being advantageously secured to the body structure to prevent passageways from forming between the body structure and the cuff. The support structure may be as described above.

[0198] In one embodiment, the method includes applying an ingrowth-enhancing agent, such as those disclosed above, to at least a portion of the outer surface of the body structure and / or at least a portion of the outer surface of the support structure.

[0199] In one embodiment, the method includes pre-growing cells on at least a portion of the outer surface of the body structure and / or at least a portion of the outer surface of the support structure, where the pre-growing cells may be provided as disclosed above.

[0200] In one embodiment, the method includes providing a bioadhesive, such as those described above, to at least a portion of the exterior surface of the body structure and / or at least a portion of the exterior surface of the support structure. The present invention also includes medical devices comprising a surface moiety comprising a surface coating polymer comprising zwitterionic moieties, a combination of cationic and anionic moieties, chitin or a derivative thereof (chitosan), spiropyran moieties, and / or protected functional group moieties, preferably the polymer comprises at least one of monomers of sulfobetaine, carbobetaine, phosphobetaine, phosphocholine, or any combination thereof.

[0201] In one embodiment, the polymeric surface coating comprises or is a hydrogel surface coating, which may be as described elsewhere herein, e.g., with respect to guest polymers, and may be derived from monomers as described above for guest polymers.

[0202] The surface-coating polymers comprising zwitterionic monomers, combinations of cationic and anionic monomers, collagen, chitin or its derivatives (chitosan), spiropyran monomers and / or monomers with protected functional moieties can be like the corresponding surface-coating polymers described above.

[0203] It should be noted that the medical device of this aspect of the invention may be tubular or may have another shape other than tubular. The medical device may advantageously be an implant such as a heart valve, eardrum, cornea, vascular patch, intestine, meniscus, cartilage, intervertebral disc or any part thereof.

[0204] In one embodiment, the medical device is the same as the medical tubular device disclosed above.In one embodiment, the medical device is the same as the medical tubular device disclosed above, except that it is not tubular.

[0205] In one embodiment, the polymer coating comprises at least one monomer comprising a protecting group that protects a functional moiety, the protecting group preferably being fluorenylmethyloxycarbonyl (FMOC), and / or the protected functional moiety preferably comprising an —NH group, e.g., as disclosed above.

[0206] In one embodiment, the polymer coating comprises at least one covalently attached drug, such as an enzyme, an immunosuppressant, an inactivating drug, a cell growth promoting drug and / or a blood clot promoting drug, and / or any combination comprising at least one of the foregoing drugs. The drug may be, for example, those disclosed above.

[0207] In one embodiment, the covalently attached drug is a thrombosis inactivating drug, preferably comprising heparin, EDTA, citrate, and / or any combination comprising one of the above thrombosis inactivating drugs. The drug may be, for example, those disclosed above.

[0208] In one embodiment, the covalently attached drug is covalently attached to the polymer coating via a linker molecule, for example, as disclosed above. In one embodiment, the polymer coating comprises a copolymer polymerized from monomers containing photoactive moieties, such as spiropyran monomers, for example as disclosed above.

[0209] In one embodiment, the polymer coating comprises a (sub)guest polymer interpenetrating chitosan polymer, for example as disclosed above. In one embodiment, the medical device has a total surface area that includes a surface portion, said surface portion including a polymer coated surface, that is 5 to about 100% of the total surface area.

[0210] In one embodiment, the medical device is partially or completely polymeric, with a polymer coating disposed on a surface portion of the medical device, and the polymer portion is preferably flexible. The term "flexible" is used as the opposite of "rigid." Thus, the polymer portion can be bent or deformed without sustaining permanent damage.

[0211] The present invention also includes medical devices that include an exterior surface portion that includes a bioadhesive, such as a bioadhesive that includes chitosan. The medical device may be as disclosed above.

[0212] In one embodiment, the medical device comprises a non-tubular device (ie, having an outer surface with a bioadhesive). In one embodiment, the medical device is a tubular device.

[0213] All features of the invention and embodiments of the invention (including ranges and preferred ranges) described herein can be combined in various ways within the scope of the invention, unless there is a specific reason not to combine such features.

[0214] The present invention also includes a method for producing zwitterionic polymers. The inventors have discovered that zwitterionic polymers containing zwitterionic moieties derived from sulfobetaine, carbobetaine, phosphobetaine, or phosphocholine have excellent antifouling properties. Specifically, zwitterionic polymers have been found to have protein-repelling properties. Zwitterionic polymers can be advantageously used as antifouling and / or protein-repelling coatings. In one embodiment, the zwitterionic polymer is used as a guest polymer, as described above.

[0215] A method for making a zwitterionic polymer comprises providing at least one zwitterionic monomer selected from sulfobetaine, carbobetaine, phosphobetaine, or phosphocholine, and polymerizing the at least one monomer; preferably, the method comprises crosslinking the polymerized monomer to form a hydrogel.

[0216] Advantageously, the method comprises providing two or more monomers and polymerizing the monomers, the monomers comprising at least said at least one monomer. Preferably, the method comprises crosslinking the polymerized monomers.

[0217] The use of one or more of the novel zwitterionic monomers of formulas I-XIII has been found to be highly beneficial.

[0218] [ka]

[0219] [ka]

[0220] [ka]

[0221] In a preferred embodiment, the zwitterionic monomer is of the formula 1-ethenyl-3-(4-sulfonatobutyl)-1H-imidazol-3-ium. This is a zwitterionic monomer designated CK1573 in Figure 6.

[0222] In a preferred embodiment, the zwitterionic monomer is the following zwitterionic monomer: 1-Ethenyl-3-(3-sulfonatopropyl)-1H-imidazol-3-ium (SK1572):

[0223] [ka]

[0224] 1-Methyl-4-(2-methylprop-2-enoyl)-1-(4-sulfonatobutyl)piperazin-1-ium (CK1578):

[0225] [ka]

[0226] 3-[dimethyl(2-{2-[(2-methylprop-2-enoyl)oxy]ethoxy}ethyl)azaniumyl]propane-1-sulfonate (CK1582):

[0227] [ka]

[0228] or 4-[dimethyl({2-[(2-methylprop-2-enoyl)oxy]ethyl})azaniumyl]butane-1-sulfonate (SK1583):

[0229] [ka]

[0230] is or includes one or more of: In a preferred embodiment, the zwitterionic monomer is the following zwitterionic monomer: 4-(2-methylprop-2-enoyloxymethoxymethylammonio)butane-1-sulfonate (CK1591):

[0231] [ka]

[0232] 4-{dimethyl[3-(2-methylprop-2-enamido)propyl]azaniumyl}butane-1-sulfonate (CK1584):

[0233] [ka]

[0234] 1-Methyl-4-(2-methylprop-2-enoyl)-1-(4-sulfonatobutyl)piperazin-1-ium (CK1586):

[0235] [ka]

[0236] 1-Carboxy-N,N-dimethyl-N-(2'-methacryloyloxyethyl)methanaminium (CK1581):

[0237] [ka]

[0238] 2-[dimethyl(2-{2-[(2-methylprop-2-enoyl)oxy]ethoxy}-ethyl)azaniumyl]acetate (cCK1589):

[0239] [ka]

[0240] 2-{dimethyl[3-(2-methylprop-2-enamido)propyl]-azamniumyl}acetate (CK1588):

[0241] [ka]

[0242] 1-(carboxylatomethyl)-1-methyl-4-(2-methylprop-2-enoyl)piperazin-1-ium (CK1585):

[0243] [ka]

[0244] or 3-(carboxylatomethyl)-1-ethenyl-1H-imidazol-3-ium (CK1587):

[0245] [ka]

[0246] is or includes one or more of: In one embodiment, the zwitterionic polymer is a homopolymer of a zwitterionic monomer.

[0247] In one embodiment, the zwitterionic polymer is a copolymer of two or more zwitterionic monomers. In one embodiment, the zwitterionic polymer is a copolymer of at least one zwitterionic monomer and at least one non-zwitterionic monomer, such as PHEMA, HEMA, and / or PEGMA.

[0248] Advantageously, the monomers comprise at least about 0.1% by mole of at least one zwitterionic monomer, such as at least about 0.5%, for example at least about 1%, for example at least about 2%, for example at least about 3%, such as at least about %, for example at least about 4%, for example at least about 5%, such as from 2 to 20% by mole of at least one zwitterionic monomer.

[0249] It has been found that zwitterionic polymers have particularly high antifouling properties when they are copolymers of monomers containing 1.5-10 mol % of zwitterionic monomers, thereby ensuring a specific distance between the zwitterionic moieties, resulting in a highly antifouling zwitterionic polymer.

[0250] Zwitterionic polymers may include one or more acrylates; vinyl monomers such as n-vinylpyrrolidone (nVP); styrene; oxygen-, phenyl-, amino-, and nitrogen-containing acrylic and methacrylic derivatives, such as acrylic acid esters, acrylic acid, methacrylic acid and esters, alkyl and hydroxyalkyl acrylates and methacrylates; functionalized methacrylates, such as 2-hydroxyethyl methacrylate (HEMA), glycerol monomethacrylate (GMMA), heptafluorobutyl acrylate (HFBA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and [2-(methacryloyloxy)ethyl]-dimethyl-(3-sulfopropyl)-ammonium hydroxide (betaine); alkyl-substituted acrylates and methacrylates, such as methyl methacrylate (MMA ), ethyl methacrylate (EMA), butyl methacrylate (BMA), dodecyl methacrylate (DMA); PEGylated (meth)actylates such as poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) and poly(ethylene glycol) methyl ether acrylate (PEGMEA); substituted β- and γ-lactones, lactic acid monomers; carbohydrate and fluorinated monomers; urethanes; mono- and difunctional alcohols; carboxylic acids; amines; isocyanates; epoxides; aromatics with alkyl groups; sulfonated aromatics, aromatic resins; imidazoles; imidazole derivatives; zwitterionic monomers; pyrazoles; quaternary ammonium monomers; spiropyran monomers; collagen, fibrin, chitin or its derivatives (chitosan), and any and / or any combination comprising one or more of the above.

[0251] Advantageously, the monomers include poly(2-hydroxyethyl methacrylate) (PHEMA), HEMA and / or PEGMEA. In one embodiment, the monomers include at least one zwitterionic monomer and at least one of PHEMA, PEGMEA, or vinylimidazole butylsulfonate.

[0252] The present invention also includes zwitterionic polymers obtained according to the above method. In one embodiment, the zwitterionic polymer comprises a copolymer polymerized from at least one zwitterionic monomer and at least one of HEMA, PEGMEA, or vinylimidazole butylsulfonate.

[0253] The zwitterionic polymer is advantageously a zwitterionic hydrogel. Zwitterionic hydrogels have been found to be very useful, particularly as moisturizing agents for products such as cosmetics that are intended to come into contact with the skin, hair and / or mucous membranes.

[0254] Thus, the present invention also includes moisturizers comprising zwitterionic hydrogels as described above, as well as cosmetic products comprising such moisturizers. "Cosmetic product" shall mean any substance or preparation intended to come into contact with the various external parts of the human body (epidermis, hair, nails, lips, external genitalia), or with the teeth or mucous membranes of the oral cavity.

[0255] The moisturizer is particularly advantageous for use in cosmetic products selected from creams and shampoos. In one embodiment, the cosmetic product is a cream containing from about 0.1 to about 10% by weight of a moisturizer. The present invention also includes a protein-repellent device having a protein-repellent surface region, wherein the surface region is a surface comprising a zwitterionic polymer as described above.

[0256] Advantageously, the protein repellent device comprises a coating of a zwitterionic polymer. The protein repellent device may advantageously be a contact lens comprising or consisting of a zwitterionic polymer.

[0257] In one embodiment, the protein repellent device is a reactor, vessel, or tube, and the protein repellent surface region is preferably a surface region adapted to contact a protein-containing fluid in use. It should be understood that the protein repellent device can be any device that includes a surface region formed of a zwitterionic polymer.

[0258] The present invention also includes an antifouling device having an antifouling surface region, wherein the surface region is a zwitterionic surface as described above. In one embodiment, the antifouling device comprises a coating of a zwitterionic polymer.

[0259] The zwitterionic polymer can be applied as a coating using, for example, spray coating, dip coating, spin coating, painting, hot molding, or other conventional methods. In one embodiment, the monomers of the zwitterionic polymer are polymerized directly onto a surface, for example, a silanized surface.

[0260] The present invention also includes each of the zwitterionic monomers having formulas I-XIII and their use to provide antifouling coatings and / or protein-repellent surfaces. Zwitterionic monomers of formulas I-XIII are as follows:

[0261] [ka]

[0262] [ka]

[0263] [ka]

[0264] BRIEF DESCRIPTION OF THE DRAWINGS The above and / or additional objects, features and advantages of the present invention will be further elucidated by the following illustrative and non-limiting description of embodiments and examples of the present invention, with reference to the accompanying drawings.

[0265] The figures are schematic, not drawn to scale and may be simplified for clarity, and the same reference numerals are used throughout to refer to identical or corresponding parts. [Brief explanation of the drawings]

[0266] [Figure 1a] 1 is a side view of an example of a medical tubular device of the present invention. [Figure 1b] 1 is a side view of an example of a medical tubular device of the present invention. [Figure 2a] FIG. 10 is a side view of a further example of a medical tubular device of the present invention. [Figure 2b] FIG. 10 is a side view of a further example of a medical tubular device of the present invention. [Figure 2c] FIG. 10 is a side view of a further example of a medical tubular device of the present invention. [Figure 2d] FIG. 10 is a side view of a further example of a medical tubular device of the present invention. [Figure 3a] 1 is a side cross-sectional view of a portion of the body structure of an example medical tubular device of the present invention, the cross-section being shown as a cut along the length of the body structure. [Figure 3b] 1 is a side cross-sectional view of a portion of the body structure of an example medical tubular device of the present invention, the cross-section being shown as a cut along the length of the body structure. [Figure 3c] 1 is a side cross-sectional view of a portion of the body structure of an example medical tubular device of the present invention, the cross-section being shown as a cut along the length of the body structure. [Figure 4]1 illustrates a simultaneous treatment setup, eg, loading and / or response of luminal surface guest polymer domains and external surface guest polymer domains of a medical tubular device according to an embodiment of the present invention. [Figure 5] 1A-1C provide examples of anions and cations that may form part of the zwitterionic portion of the zwitterionic hydrogels of the medical tubular devices of the present embodiments. [Figure 6] 1A-1C provide examples of monomers that can be used in the guest polymer domain of the medical tubular device of the present embodiments. [Figure 7] The essentially colorless "spiro-type" spiropyran and the purple "merocyanine-type" spiropyran are shown. [Figure 7a] The three steps for the synthesis of SP-OH are shown. [Figure 8a] 1 shows a sample of a medical tubular device comprising spiropyran in a first state (after exposure to visible light). [Figure 8b] 1 shows a sample of a medical tubular device containing spiropyran in a second state (after exposure to UV light). [Figure 9a] 1 is a curve showing the force required to remove a sample containing chitosan from a surface covered with an epithelial layer. [Figure 9b] 1 is a curve showing the force required to remove a sample containing no chitosan from a surface covered with an epithelial layer. [Figure 10] This shows the back of a pig used to assess the infection risk of tubular medical devices. Six pieces of a medical tubular device filled with a combination of minocycline and rifampicin were implanted on one side of the back. Six pieces of a commercially available, state-of-the-art vascular graft (heparin-coated Propaten® CBAS, Gore) were implanted on the other side. All pieces were challenged with a bacterial load. After two weeks, the implants were retrieved and the level of infection was determined / evaluated. [Figure 11a] 1 shows the implantation site of the novel medical tubular device after resumption after 14 days. [Figure 11b]1 shows the implantation site of a Gore® Propatene® CBAS heparin coated graft after reopening after 14 days. [Figure 12] Quantification of biofilm bacteria (S. aureus ATCC 29213) on IPN and GORE® Propatene® CBAS heparin-coated graft material (left) and within the surrounding subcutaneous tissue near the implanted material (right). [Figure 13] Quantification of bacterial challenge of biofilm bacteria (Staphylococcus aureus ATCC 29213) in IPN and GORE® Propatene® CBAS heparin-coated graft materials. [Figure 14]

[0033] Figure 1 shows an analysis of functional taxol release from a novel taxol-loaded tubular medical device. The graph shows cell proliferation (EA.hy926 endothelial cell culture) after exposure to release medium from 10 mm sections of taxol-loaded IPN grafts (●) or unloaded IPN controls (■). After 21 weeks, the grafts still exhibit taxol release at levels that completely inhibit endothelial cell proliferation. [Figure 15a] 1 shows an explant of a Gore® Propatene® CBAS heparin vascular graft after six months of implantation as a vascular bypass graft in the carotid artery of a sheep. [Figure 15b] 1 shows an explant of a novel medical tubular device after six months of implantation as a vascular bypass graft in the carotid artery of a sheep. [Figure 16] It shows a methacrylic monomer having a protecting group that protects the functional moiety, the protecting group being preferably fluorenylmethyloxycarbonyl (FMOC), and / or the protected functional moiety preferably comprising an -NH2 group. [Figure 17] Thrombin-antithrombin complex (TAT) levels are shown as % of silicone control. [Figure 18A] 1 shows the results of zwitterionic IPNs with different amounts of zwitterionic monomer compared to a silicone control (defibrillated plasma). [Figure 18B] 1 shows the results (citrated plasma) of zwitterionic IPNs with different amounts of zwitterionic monomer compared to a silicone control. DETAILED DESCRIPTION OF THE INVENTION

[0267] Figure 1a shows an embodiment of a linear medical tubular device 1 suitable for use as a vascular graft. In this embodiment, the medical tubular device consists of a body structure 1 and has a single lumen.

[0268] Figure 1b shows another embodiment of a bifurcated (bifurcated) medical tubular device suitable for use as a vascular graft, comprising a first portion 2a having a first lumen and bifurcated portions 2b and 2c that bifurcate the first lumen into two lumens.

[0269] In fact, the medical tubular device may have any desired number of branches. Preferably, the medical tubular device is a non-branched medical tubular device. FIG. 2a shows a medical tubular device with a body structure having small anchoring points 3 provided, for example, by small deformations on the outer surface and / or by ciliary-shaped brushes of hydrogel (guest) polymer.

[0270] 2b shows a medical tubular device with a body structure 4b having cuffs 4a disposed on the outer surface of each end of the body structure 4b. The cuffs may be, for example, as described above, and may function to strengthen the body structure, for example, for suturing or the like.

[0271] FIG. 2c shows a medical tubular device with a body structure having a supporting net and / or chitosan coating 5 on its outer surface. FIG. 2d shows a medical tubular device with a helical support structure 6a applied to the outer surface 6b of the body structure.

[0272] FIG. 3a shows a body structure with luminal surface guest polymer domains 7a and external surface guest polymer domains 7b separated by an (intermediate) layer 7c of host polymer that does not contain guest polymer.

[0273] FIG. 3b shows a body structure having a luminal surface guest polymer domain 8a, an intermediate guest polymer domain 8b, and an outer surface guest polymer domain 8c, with the guest polymer domains 8a, 8b, 8c separated by layers 8d, 8e of host polymer that do not contain guest polymer.

[0274] 3c shows a body structure having a layered structure including an IPN layer 10 and a further non-IPN layer 9, such as a PTFE layer. As explained above, the body structure of embodiments of the present invention may have several further layers, such as two, three, four or five.

[0275] The setup shown in FIG. 4 includes a first vessel 11 with a first processing fluid (for treating the luminal guest polymer), a second vessel 12 with a second processing fluid (for treating the external guest polymer), and a peristaltic pump 17.

[0276] Medical tubular devices 15 of the present embodiments are provided having luminal surface guest polymer domains and exterior surface guest polymer domains, as described elsewhere herein.

[0277] The medical tubular device is attached to a first hose section 13a and a second hose section 13b via a connecting stud 16 and a hose clamp 14. A free end 13a' of the first hose section 13a is submerged in a first treatment fluid in a first container 11, and a free end 13b' of the second hose section is positioned to have an outlet within the first container 11.

[0278] The first hose section 13a is connected to a peristaltic pump 17 so that a first process fluid is pumped, either continuously or stepwise, from the first container 11 via the first hose section 13a through the lumen of the medical tubular device 15 and further the process fluid is returned to the first container 11 via the second hose section 13b. The peristaltic pump 17 may of course alternatively be connected to the second hose section 13b'.

[0279] Alternatively, the first treatment fluid may be held stable within the tube for the treatment time. At the same time, the medical tubular device 15 is submerged in a second treatment fluid in a second container 12 . The first and second processing fluids (11 and 12) are advantageously different from each other and may be independently selected from a loading fluid comprising at least one loading drug for loading into the respective guest polymer domains, and a reaction fluid comprising at least one reagent adapted to process the guest polymer, e.g., chemically bond a drug to the guest polymer.

[0280] In one embodiment, the first processing fluid (11) is a loaded drug and the second processing fluid (12) is a reactive fluid. In one embodiment, the first processing fluid (11) is a reactive fluid and the second processing fluid (12) is a loaded drug. The drug may be as described elsewhere herein.

[0281] In one embodiment, the first processing fluid (11) is a loading fluid containing taxol for loading the luminal surface guest polymer domains, e.g., to provide a taxol concentration gradient in the luminal surface guest polymer domains. In this or another embodiment, the second processing fluid (12) is a loading fluid for loading an anti-infective drug, such as rifampicin and / or minocycline.

[0282] The anion and cation examples in Figure 5 are representative moieties that can be modified and / or combined to form desired zwitterionic moieties and / or monomers. The monomers shown in Figure 6 include sulfobetaines, carbobetaines, and phosphobetaines, which are zwitterionic monomers that can be advantageously applied to provide one or more guest polymer domains and / or guest polymer surfaces in medical tubular devices.

[0283] The zwitterionic monomers are synthesized from vinylimidazole, methacrylamide, and methacrylate esters, respectively. Example Example 1a - Synthesis of Spiropyran-OH The synthesis of SP-OH was carried out in three steps (Figure 7a), and for each step, H NMR studies were performed to confirm the structure. H NMR analysis was performed using Bruker software. For each of the three steps, the H NMR of the sample showed all the expected signals.

[0284] Step 1: Synthesis of 1-(2-hydroxyethyl)-2,3,3-trimethyl-3H-indolium bromide (1 in Figure 7a) A solution of 2,3,3-trimethyl-3H-indole (2.61 g, 16 mmol) and 2-bromoethanol (2.46 g, 20 mmol) in MeCN (20 mL) was heated under reflux and N2 for 24 h. After cooling to ambient temperature, the solvent was evaporated under reduced pressure. The residue was suspended in hexane (25 mL), and the mixture was sonicated and filtered. The resulting solid was crystallized from CHCl3 (35 mL) to give 1 (2.95 g, 69%) as a pink solid. The crystals were characterized by HNMR.

[0285] Step 2: Synthesis of 9,9,9a-trimethyl-2,3,9,9a-tetrahydro-oxazolo[3,2-a]indole (2 in Figure 7a) A solution of the compound from Step 1 (2.93 g, 10 mmol) and KOH (0.92 g, 16 mmol) in HO (50 mL) was stirred at ambient temperature for 10 min, and then it was extracted with EtO (3 × 20 mL). The organic phase was concentrated under reduced pressure to give 2 (1.84 g, 88%) as a yellow oil, which was characterized by HNMR.

[0286] Step 3: Synthesis of 2-(3,3'-dimethyl-6-nitro-3'H-spiro[chromene-2,2'-indol]-1'-yl)-ethanol (SP-OH) (3 in Figure 7a) A solution of 2-hydroxy-5-nitrobenzaldehyde (1.05 g, 6 mmol) and the compound from Step 2 (0.87 g, 4 mmol) in EtOH (10 mL) was heated under reflux and N for 3 h. After cooling to ambient temperature, the mixture was filtered. The resulting solid was washed with EtOH (2 mL) and dried to give SP-OH (1.22 g, 81%) as a purple solid, which was characterized by HNMR.

[0287] Example 1b - Synthesis of Spiropyran Monomer (SPMA): Photoactive Compound. SP is a photoactive compound that isomerizes from a hydrophobic (neutral) spiropyran state (the so-called closed form) to a hydrophilic (zwitterionic) merocyanine state (the so-called open form) under blue light irradiation (Figure 7). As shown, the hydrophobic state (SP) is transparent, while the hydrophilic state (MC) is purple. The photoisomerization of SP is completely reversible, and the hydrophilicity of the two isomers differs significantly.

[0288] Figure 7 shows the "spiro" form of spiropyran, which is essentially colorless under visible light, and the "merocyanine" form, which is dark purple. The "merocyanine" form is hydrophilic due to the formation of a zwitterion. The conversion between the "spiro" and "merocyanine" forms is reversible and occurs upon exposure of the material to UV and visible light, respectively. This creates a hydrophilic switch, which can change the hydrophilicity of the material depending on the wavelength of light striking the material. The hydrophilic switch can be used to trigger drug delivery and / or attach / detach to cells.

[0289] This figure shows that spiropyrans can be switched from the spiro form to the merocyanine form by exposure to UV radiation, e.g., at about 365 nm. After UV irradiation, the spiropyrans can slowly revert from the merocyanine form to the spiro form, or they can revert more quickly to the spiro form when irradiated with visible light.

[0290] The conversion between the spiropyran and merocyanine forms can also be induced by other influences such as pH or mechanical influences. Example 2 - Medical Tubular Device with Spiropyran A sample of a miniature medical tubular device was fabricated. A host polymer substrate was provided in the form of a tube of MED-4720 silicone elastomer from Nusil. The host polymer was filled with a monomer to provide a complete IPN, and the monomer was crosslinked as described elsewhere herein.

[0291] The hydrogel content of the medical tubular device was >30% by dry weight. As shown in Figures 8a and 8b, the comonomers were 2-hydroxyethyl methacrylate (HEMA) and a small amount of spiropyran. The percentage of spiropyran shown is the percentage of the monomer in the feed during the monomer charge.

[0292] Figure 8a shows 3 × 3 samples of tubular medical devices with varying spiropyran content after immersion in water until fully saturated. The samples were light brown in color, indicating that the spiropyran was in the spiro form.

[0293] Figure 8b shows three samples with varying spiropyran content (approximately 10, 20, and 30 wt. % of the hydrogel) after immersion in water until fully saturated and UV irradiation. The samples are deep purple, i.e., merocyanine type.

[0294] This property can be very advantageous, for example, for triggering drug delivery and / or attaching / detaching to cells. The change between the SP and MC forms changes the hydrophilicity of the polymer due to the formation of zwitterionic moieties.

[0295] Furthermore, this property can be used to verify correct implantation of the medical tubular device during surgery: before suturing, the surgeon can illuminate the medical tubular device and control the fixation and tension of the medical tubular device.

[0296] Example 3 - Chitosan loading Disk-shaped samples of silicone (PDMS) polymer (10 mm diameter, 2.0 mm thick) were punched from extruded PDMS pieces provided by Lebo Production (Lebo Production, Skågaas, Sweden) under the trade name "PE4062." Six samples were placed in a 16 ml reactor and impregnated with the guest polymer PHEMA (poly(2-hydroxyethyl methacrylate)) using CO2 at 22 °C for 24 hours at a pressure of 300 bar. The pressure was slowly released, and three samples (blinds) were collected in sealed bags.

[0297] The remaining three samples were loaded with chitosan in a 16 ml reactor. The reactor was filled with 10 ml of a 10 mg / ml chitosan solution (100 g chitosan in 7.5 ml EtOH, 2 ml H2O and 1 ml acetic acid).

[0298] The reactor was pressurized with CO2 to a pressure of 30.0 MPa (300 bar) at 22°C for 24 hours. The pressure was slowly released and three samples were collected in sealed bags.

[0299] Experimental setup for testing bioadhesion: Bioadhesion was measured with a Texture Analyzer Texture (TA:XT.plus, TA Instruments). Bioadhesion was simulated with absorbent paper moistened with a 2% solution of porcine gastric mucosa (Sigma) in phosphate buffer at pH 6.8. Discs were pressed against the mucus-moistened paper for 180 seconds before removal. Adhesion was measured as the peak force required to remove the disc and the total work required to remove the disc (area under the curve).

[0300] The results are shown in Figures 9a and 9b. Example 4 - Chitosan detection The samples obtained from Example 3 are each stained with 0.5 ml of 0.1% (w / v) optical brightener 28 (FB28 Sigma F3543) dissolved in 0.5 M Tris·HCl, pH 9.

[0301] Excess dye is removed by three washes, each consisting of 0.5 ml of water. Devices not treated with chitosan (blinds) are used as a reference to assess the fluorescence specifically related to the presence of chitosan in the treated devices.

[0302] Fluorescence is monitored by placing the device under a UV transilluminator (302 nm) and recording the emission with a CCD imager (G:BOX, Syngene). These images can be quantitatively accessed to estimate relative content or by referencing devices containing known amounts.

[0303] Example 5 - Attachment of chitosan to silicone Several chitosan foams are produced by freeze-drying chitosan gels with chitosan concentrations of about 0.5%, 1%, and 2%.

[0304] The thickness of the chitosan foam is 0.5 to 1 mm. 2 Cut into pieces. Cut the standard silicone sample into 1cm cubes to match the size of the KitoZyme chitosan foam preparation. 2 Cut into pieces.

[0305] The foam is attached to several standard silicone slabs using Sylgard® 184 (Dow Corning, Diatom). Uncured Sylgard® 184 is applied to the surface of the cast standard silicone using a brush.

[0306] Chitosan powder with a particle size of less than 80 μm is provided. Powder is attached to the surface of some cast standard silicone samples by immersing the samples in uncured Sylgard® 184 silicone and then contacting the surface with the powder.

[0307] Powdered chitosan can be easily applied to the surface of cast standard silicone and is found to be accessible. The chitosan remains attached even after overnight incubation. This allows all edges to be covered.

[0308] Furthermore, it can be seen that the large pores of chitosan foam allow for efficient attachment to the silicone surface. Chitosan foam remains attached even after overnight incubation in water. The foam appears to be embedded in the Sylgard® elastomer and is expected to be less available for cellular interaction than powdered chitosan.

[0309] Furthermore, it can be seen that chitosan with smaller pores also allows for efficient attachment to the cast silicone surface. Chitosan foam remains attached even after overnight incubation in water. The foam appears to be completely embedded in the Sylgard® elastomer, and much less chitosan is expected to be available for cell interaction than powdered chitosan.

[0310] Example 6 - Pig studies An induced surgical site infection (SSI) animal (pig) model was established to compare the resistance to infection of an interpenetrating polymer network (IPN) vascular graft material with the currently used heparin-coated ePTFE material (Gore-Tex®) by direct contamination with Staphylococcus aureus in the pig model.

[0311] IPN patches (host polymer: MED-4720 silicone elastomer / guest polymer: PHEMA-co-PEGMEA-23% hydrogel) were loaded. Loading occurred two weeks before the experiment. Loading was performed in two stages. In step 1, the patches were loaded with 10 mg / ml rifampicin in 96% ethanol for one week. In step 2, the patches were loaded with 10 mg / ml minocycline solution in MilliQ® water (approximately 2.5 mg / ml) saturated with rifampicin for one week. On the day of the experiment, the patches were washed by incubating in PBS at room temperature for 15 minutes before insertion.

[0312] A direct comparison experiment was conducted on six female Danish Landrace pigs weighing approximately 80 kg. Six Gore-Tex® Propatene® CBAS heparin-coated vascular graft patches (20.0 × 10.0 × 0.6 mm) were implanted on the right side of the pigs, and six IPNs of the same dimensions were implanted on the left side. These patches were then placed over a 10-cm area. 6 The implants were inoculated with Staphylococcus aureus and removed after 14 days.

[0313] In the first trial, a dose of Staphylococcus aureus was 3 From 10 7 The optimal attack is 10 bacteria. 6 Therefore, the second test was carried out using 10 6 The second study was conducted on two female Danish Landrace pigs weighing approximately 80 kg.

[0314] The patches were analyzed for the concentration of Staphylococcus aureus and the results are shown in Figure 13. It can be seen that there were far fewer infections with the IPN patch than with the Gore® patch. Figure 10 shows the right side of one of the pigs with the patch implant locations marked.

[0315] Figure 11a shows the IPN patch after 14 days, and the patch initially contained 10 6 Staphylococcus aureus was inoculated. Figure 11b shows the Gore® patch after 14 days, with the patch initially containing 10 6 Staphylococcus aureus was inoculated.

[0316] It can be seen that the IPN patch inhibits infection. The P value was determined based on the hypothesis that the risk of infection is independent of the patch used. The very low P value clearly demonstrates that this hypothesis is incorrect and that, in fact, the risk of infection is much lower when using the IPN patch compared to the Gore® patch. The rifampicin and minocycline-loaded IPN was tested in one further round of the porcine subcutaneous infection model and compared with the state-of-the-art Gore® graft material. The second test involved two female Danish Landrace pigs weighing approximately 80 kg, with 1000 bacteria inoculated into each surgical wound. 6 A bacterial challenge / filling was performed.

[0317] The results (see Figure 12) again showed the superior performance of the IPN material, with approximately 10% more biofilm bacteria adhering to the IPN material compared to Gore's Propatene®. 3 It was reduced to one-fifth.

[0318] Example 7 - Loading with Taxol Several medical tubular devices have been manufactured: IPN host polymer: Nusil® MED-4720 silicone elastomer extruded into a thin tube by Vesta (USA). The tube of host polymer had the following dimensions: ID 5.0 ​​mm, wall thickness 0.75 mm.

[0319] IPN guest polymer: PHEMA, a copolymer of PEGMEA-480 (poly(ethylene glycol) methyl ether acrylate, average Mn 480) and CK1573 (vinylimidazole butylsulfonate).

[0320] The hydrogel content (dry) was 41%. A sample of the medical tubular device (unfilled medical tubular device) was packaged in a sealed pouch. The IPN grafts were filled for 5 days in a taxol stock solution. "Paclitaxel 'Fresenius Kabi': 6 mg / ml PTX in a 50:50 solution of ethanol and castor oil." http: / / pro.medicin.dk / Medicin / Praeparater / 5984 After filling, the medical tubular device was packaged in a sealed bag.

[0321] Example 8 - Release An unfilled medical tubular device of Example 7 (control) and one taxol-filled medical tubular device of Example 7 were used.

[0322] The control sample and the taxol-loaded sample were each immersed in aqueous cell growth medium. Every week, a small sample of each aqueous cell growth medium was removed and added to each well, and approximately 25,000 endothelial cells (EA.hy926 endothelial cell culture) were added to each well. After two days, the cells were counted.

[0323] The results are shown in Figure 14. It can be seen that even after 21 weeks, the IPN grafts still exhibited taxol release at levels that completely inhibited endothelial cell proliferation. Example 9 - Testing in sheep They identified a particular breed of sheep, raised on the southwest coast of Jutland (Denmark), that is relatively docile and easy to handle after surgery.

[0324] Five sheep were selected for the study. Each sheep underwent end-to-side anastomotic bypass surgery of both common carotid arteries, using a Gore® Propatene® CBAS heparinized graft on one side and the Taxol-filled medical tubular (IPN) device of Example 7 as the graft on the other side. The sheep were examined monthly by duplex scanning.

[0325] After 6 months, the grafts were removed. Figure 15a shows one of the Gore® Propatene® CBAS heparinized grafts, and Figure 15b shows one of the taxol-filled medical tubular IPN devices of one embodiment of the present invention.

[0326] The Gore® Propatene® heparinized graft appears completely closed, while the IPN device appears fully open with no signs of hyperplasia.

[0327] Example 10 - FMOC Procedure Four samples, each 1cm x 4cm x 1mm, were used:

[0328] [Table 1]

[0329] The CK1594 monomer that forms part of the hydrogel guest polymer of Sample D is an FMOC-protected amine-containing monomer, as shown in FIG. The sample was placed in a wire mesh basket divided into four sections and immersed in a 25 ml beaker containing the following reagents:

[0330] Deprotection: 20% piperidine in DMF 2 x 2 min. Coupling: 0.38 mmol HBTU, 0.37 mmol linker, 0.5 mmol DIPEA in 20 ml DMF.

[0331] Capping: 20% acetic anhydride in MeOH for 2 hours. FITC (fluorescein isothiocyanate) tagging: 0.1 mg / ml FITC in DMF for 2 hours.

[0332] Washing: Objects were rinsed with MeOH and washed in DMF for at least 3 x 10 min before and after the reaction. Storage: After the reaction, the material was stored in DMF until the next reaction.

[0333] The excitation and emission spectrum of FITC has peak wavelengths of approximately 495 nm / 519 nm, resulting in a green color. When the samples were examined, the following was observed:

[0334] [Table 2]

[0335] The weak signal in sample C can be explained by the absorption of FITC into the hydrogel. However, the signal was much weaker compared to that of sample D, indicating that the signal observed in sample D was due to FITC attached / reacting with the IPN.

[0336] Example 11 - Heparin Graft A medical tubular IPN graft (OD 5 mm, ID 3 mm) containing a host polymer of PMDS and a guest polymer forming at least the luminal surface guest polymer domain of a PHEMA-co-PEGMEA-co-CK1594 hydrogel was fabricated (same method as Sample D in Example 10).

[0337] The IPN graft is placed in fluid contact at its luminal surface, as shown in the setup in Figure 4, but without the use of a second container. The luminal surface is reacted with a deprotection fluid, a coupling fluid, and a capping fluid according to the scheme of Example 10. The luminal surface is then reacted with heparin.

[0338] Heparin entities containing free terminal aldehydes (Examples 1-6) of US Patent Application Publication No. 2011064781 are dissolved in DI water at pH 3.9 with NaCl (approximately 0.5 g heparin and 2.95 g NaOH per 100 ml).

[0339] The luminal surface is contacted with the heparin solution at a temperature of 50-60°C for 1-2 hours. The IPN graft is then washed in water. Further scope of applicability of the present invention will become apparent from the description provided below. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given by way of example only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the detailed description.

[0340] Example 12 - Zwitterionic IPN As shown in Figure 6, several zwitterionic IPN samples were prepared using zwitterionic monomers.

[0341] A silicone sample (outer diameter (OD): 5.10 mm, inner diameter (ID): 4.10 mm, thickness: 0.50 mm, approximately 35 g of tubing) was structured in a stainless steel grid and placed in a 1-liter reactor (1 L, BC-2, HiP, Pennsylvania, USA) with a 4 cm magnetic bar (for stirring). Approximately 100 mL of HEMA, 100 mL of PEGMEA, 5 g of zwitterionic monomer, 6 mL of EGDMA, 50 mL of 0.2 M DEPDC in hexane, 70 mL of EtOH, and 70 mL of THF (tetrahydrofuran) were mixed in a separate beaker for 20 minutes. The solution was then added to the reactor, and the reactor was closed with the corresponding bolts at a torque of 169 Nm (125 ft-lb). The reactor was attached to a magnetic stirrer (Ret The reactor was placed on a 1000-kJ / min reactor (Basic, IKA, Germany). The reactor was wrapped in a custom-made heating jacket. The inlet and outlet were located at the top of the reactor, but the inlet tube was located at the bottom of the reactor for proper mixing, and the outlet tube was located in a waste container. All tubing was 1.588 mm (1 / 16 in.) with an inner diameter of 0.762 mm (0.03 in.) (15-9A1-030, HiP, Pennsylvania, USA). A pressure transmitter was connected to the inlet. Pressure and temperature were monitored and recorded via a custom-made LabView program. To ensure the operating pressure, a TharP-50 electrically driven high-pressure pump (Thar Designs Inc., USA) was used. The pump was equipped with a heat exchanger and supplied with cooling water at 5 °C. CO2 was added to the reactor, and the pressure was increased to approximately 300 bar at 40 °C for approximately 16 hours. During this time, the monomer diffused into the swollen silicone, polymerized, and crosslinked. The pressure was then released via an outlet tube to a waste container. Depressurizing the reactor took 30–60 minutes. The reactor was then washed first with ethanol and then with demineralized water. The resulting IPN samples were collected and rinsed with tap water to remove excess polymer. The IPN samples were placed in 96% EtOH for one week to extract excess monomer and non-crosslinked polymer. The IPN samples were then dried to a constant weight, and the hydrogel content was determined by weighing.

[0342] The samples produced are shown in Table 1.

[0343] [Table 3]

[0344] The G7 / G8 / G9 part of the name indicates the silicone used. G7: Nusil® Med 4020, Durometer: 25 Type A (Extruded tubing (Vesta, USA) L = 2 m, Wall = 0.5 mm, φ (inner diameter) = 4.1 mm).

[0345] G9: Nusil® Med 4720, Durometer: 25 Type A (extruded tube (Vesta, USA) L=2m, wall=0.75mm, φ(inner diameter)=5mm). G10: Nusil® Med 4027, Durometer: 30 Type A (extruded tube (Vesta, USA) L=0.5 m, wall=0.75 mm, φ (inner diameter)=5 mm).

[0346] Example 13 - Thrombin-antithrombin complex (TAT) levels. Several IPN samples from Example 12 were tested for hemocompatibility. The zwitterion-based IPNs were evaluated using an enzyme-linked immunosorbent assay (ELISA) that specifically measures thrombin-antithrombin (TAT) and the complement split product C3c as sensitive markers of coagulation and complement activation, respectively. Both markers are included in the ISO standard 10993-4 for the evaluation of biomaterials.

[0347] Plasma samples and silicone samples (reference samples) incubated on zwitterionic IPNs were analyzed for thrombin-antithrombin (TAT) levels using ELISA. Maxisorp® plates were coated with 2.0 μg / ml of anti-TAT monoclonal antibody (HYB14-22) overnight at 4°C. The following day, plates were washed three times in PBS containing 0.05% Tween®-20 and blocked for 15 minutes. Human plasma samples were diluted 1:320, and serum pools diluted 1:100–1:1024 in PBS + 0.1% BSA + aggregated IgG + 10 mM EDTA were used as standardization samples. Samples were incubated for 1 hour at room temperature and washed as described above. Biotinylated secondary antibody 230-01 was added at a 1:500 dilution and incubated for 1 hour. Each plate was washed, and streptavidin-conjugated HRP was added at 1:4000, incubated for 30 minutes, and then washed three times. Color was developed using OPD / H2O2 solution for 15 minutes and stopped with 100 μl of 1 M H2SO4. Plates were read at 490 nm with a reference at 650 nm, and TAT concentrations were quantified using SoftMax® Pro software.

[0348] The results are shown in Figure 17. Example 14 - Zwitterionic IPN with different amounts of zwitterionic monomer Several zwitterionic IPN samples were prepared using three different amounts of zwitterionic monomer CK1573: The zwitterionic IPN samples were fabricated as described in Example 12, but using 2 g, 5 g, and 10 g of zwitterionic monomer, respectively.

[0349] Six samples of each type (2 g, 5 g, and 10 g of zwitterionic monomer) were tested using defibrinated and citrated plasma, respectively, as described in Example 13. Each group was compared to the silicone control for significant differences using Dunnett's test. A P value of <0.05 was defined as significant, and is indicated by *P<0.05, **P<0.01, and ***P<0.001.

[0350] The results are shown in Figure 18A (defibrillated plasma) and Figure 18B (citrated plasma). Example 15 - Zwitterionic polymer coating inhibits protein adsorption Two test vessels, A and B, each with a capacity of 5 L, were provided. The inner surface of the vessel was made of aluminum.

[0351] The interior surface of container A is coated with a zwitterion-containing hydrogel coating provided by HEMA, PEGMA, and zwitterionic monomer 1573 in relative molar amounts of 35:10:1.

[0352] Container A was first subjected to a surface treatment with a silane coupling agent. The interior surface of the container was cleaned and then coated with a solution of 3-methacryloxypropyltrimethoxysilane (2 wt% v / v in a 0.01:1:4 mixture of acetic acid / water / ethanol). After 2 hours, the interior surface was rinsed with ethanol and dried.

[0353] Hydrogel coatings were prepared by direct monomer polymerization on silanized solid substrates. The surfaces were exposed to aqueous solutions of the monomer precursors and then UV photopolymerized (wavelength 365 nm, 30 mW cm). -2 ) for 30 minutes. The container was then filled with pure water for 3 days until swelling equilibrium was reached.

[0354] The precursor solution contains HEMA, PEGMA and zwitterionic monomer 1573 in relative molar amounts of 35:10:1, as well as 0.5 mol % crosslinker and 0.5 mol % initiator.

[0355] Three liters of freshly expressed milk was added to each container and kept at 5°C for 3 hours. Afterwards, the containers were emptied and the surfaces were washed by spraying tap water (20°C) onto them for 1 minute. The surfaces were then examined for adsorbed protein.

[0356] The amount of protein remaining on the inner surface of container A is significantly reduced compared to the amount of protein remaining on the inner surface of container B. Example 16 - Gradient loading of taxol in the lumen and luminal surface of a medical tubular device (graft) Where there is believed to be a risk of cell proliferation within the lumen of a medical tubular device, it may be desirable to have an anti-proliferative drug disposed on at least a portion of the luminal surface.

[0357] The grafts were sterilized by two 5-minute sonications in 70 vol% ETOH, then allowed to dry over the weekend in a sterile Petri dish in a sterile bench. The graft was mounted vertically on a stand with a clamp at the bottom and a pipette tip attached to the strip at the top.

[0358] Pure taxol solution (6 mg / ml taxol in a 50:50 mixture of ethanol and castor oil, Fresenius-Kabi) was filled into the lumen of the graft, squeezing out any air bubbles during filling.

[0359] The filling time was 2.5 hours on a sterile bench. The graft was emptied and the inside was rinsed vigorously with 100 ml of 70 vol% ETOH applied with a rod pipette. The outside and inside were rinsed from above with approximately 300 ml of 70 vol% ETOH.

[0360] The graft was allowed to dry briefly on a tripod, then cut into 10-14 cm pieces, placed in sterile autoclave bags, and the bags were sealed. The graft pieces were then ready for use in surgery.

[0361] Example 17 - Synthesis of 1-ethenyl-3-(4-sulfonatobutyl)-1H-imidazol-3-ium (CK1573) A 1 L, three-necked round-bottom flask was equipped with a mechanical stirrer, contact thermometer, and N2 bubbler. The flask was charged with 1,4-butanesultone (0.48 mol, 63.4 g), 1-vinylimidazole (0.40 mol, 37.6 g), and MeCN (250 mL). The reaction was stirred at 60 °C for 72 hours in the dark. The reaction was diluted with MeCN (125 mL) and cooled to room temperature with stirring, keeping the precipitate suspended. The reaction mixture was filtered, the reaction flask rinsed with MeCN, and the remaining precipitate transferred to the filter. The solid was washed with MeCN (250 ml) and MTBE (2 × 100 mL) and dried under reduced pressure for 24 hours to give 87.5 g (95%) of the title product as a white solid. 1H NMR(300MHz,D2O)δ7.80(d,J=2.2Hz,1H),7.63(d,J=2.1Hz,1H),7.16(dd,J=15.6,8.7Hz,1H),5.82(dd,J=15.6,2.8 Hz,1H), 5.45(dd,J=8.7,2.8Hz,1H),4.32(t,J=7.1Hz,2H),3.02~2.94(m,2H),2.14~2.02(m,2H),1.85~1.72(m,2H). 13C NMR(75MHz,d2o)δ134.2(t,1JC-D=34Hz),128.1,122.7,119.5,109.3,49.9,49.2,27.9,20.8.

[0362] One imidazole proton is missing due to deuterium exchange, which also gives rise to a 13C triplet at 134.2 ppm. Example 18: Synthesis of 1-ethenyl-3-(3-sulfonatopropyl)-1H-imidazol-3-ium (CK1572) A 1 L, three-necked round-bottom flask was equipped with a mechanical stirrer, contact thermometer, and N2 bubbler. The flask was charged with 1,3-propane sultone (0.48 mol, 58.6 g), 1-vinylimidazole (0.40 mol, 37.6 g), and MeCN (200 mL). The reaction was stirred at room temperature for 72 hours in the dark. The reaction was diluted with MeCN (125 mL) to keep the precipitate suspended. The reaction mixture was filtered, the reaction flask was rinsed with MeCN, and the remaining precipitate was transferred to the filter. The solid was washed with MeCN (250 mL) and MTBE (2 x 100 mL) and dried under reduced pressure for 24 hours to give 86.3 g (>99%) of the title product as a white solid. 1H NMR (300MHz, D2O) δ7.82(d,J=2.2Hz,1H),7.66(d,J=2.2Hz,1H),7.17(dd,J=15.6,8.7Hz,1H),5.83(dd,J= 15.6,2.8Hz,1H),5.46(dd,J=8.7,2.8Hz,1H),4.44(t,J=7.2Hz,2H),3.02~2.90(m,2H),2.45~2.28(m,2H). 13C NMR (75MHz, D2O) δ134.4(t,1JC-D=34Hz),128.1,122.7,119.6,109.4,48.0,47.1,24.9.

Claims

1. 1. A medical tubular device comprising: a body structure extending from a first end to a second end of the medical tubular device, the body structure having a luminal surface and an exterior surface, the body structure comprising an interpenetrating polymer network (IPN) comprising a matrix of a host polymer and at least one hydrogel guest polymer domain, wherein the hydrogel guest polymer domain comprises a plurality of interconnected pathways of hydrogel guest polymer interpenetrating a matrix of the host polymer, the host polymer comprising a covalently crosslinked crosslinked elastomer, and At least one hydrogel guest polymer domain comprises a luminal surface hydrogel guest polymer domain comprising at least a portion of the luminal surface, wherein a plurality of the pathways of the hydrogel guest polymer together form at least a portion of the luminal surface, the luminal surface comprising zwitterionic moieties, the zwitterionic moieties being covalently bonded to the hydrogel guest polymer, the hydrogel guest polymer comprising a crosslinked network of polymerized monomers comprising zwitterionic monomers forming the zwitterionic moieties and one or more methacrylate monomers, the zwitterionic monomers being CK1572: 1-ethenyl-3-(3-sulfonatopropyl)-1H-imidazol-3-ium, CK1573: 1-ethenyl-3-(4-sulfonatobutyl)-1H-imidazol-3-ium, CK1578: 1-methyl-4-(2-methylprop-2-enoyl)-1-(4-sulfonatopropyl)piperazin-1-ium, CK1582: 3-[dimethyl(2-{2-[(2-methylprop-2-enoyl)oxy]ethoxy}ethyl)azaniumyl]propane-1-sulfonate, CK1583: 4-[dimethyl({2-[(2-methylprop-2-enoyl)oxy]ethyl})azaniumyl]butane-1-sulfonate, CK1585: 1-(carboxylatomethyl)-1-methyl-4-(2-methylprop-2-enoyl)piperazin-1-ium, CK1586: 1-methyl-4-(2-methylprop-2-enoyl)-1-(4-sulfonatobutyl)piperazin-1-ium, CK1587: 3-(carboxylatomethyl)-1-ethenyl-1H-imidazol-3-ium, CK1599: N-(3-sulfopropyl)-N-methacryloylamidopropyl-N,N-dimethylammonium betaine, and CK3637: [2-(methacryloyloxy)ethyl]-dimethyl-(3-sulfopropyl)-ammonium hydroxide The tubular device is selected from the group consisting of:

2. 2. The tubular device of claim 1, wherein the outer surface at least partially comprises a surface of the hydrogel guest polymer, wherein a plurality of the channels of the hydrogel guest polymer together form at least a portion of the outer surface, and wherein the outer surface comprises zwitterionic moieties, the zwitterionic moieties preferably being covalently bonded to the hydrogel guest polymer.

3. 3. The tubular device of claim 1 or 2, wherein the luminal surface comprises at least one covalently bound drug comprising a thrombosis inactivating agent, preferably comprising heparin, EDTA, an antibiotic, citrate, and / or any combination comprising one of the above thrombosis inactivating agents.

4. 4. The tubular device of claim 1, wherein the body structure comprises a releasable drug selected from an anti-proliferative drug, such as paclitaxel (taxol) and / or rapamycin, releasable through at least the luminal surface, and an anti-infective drug, such as rifampicin and / or minocycline, releasable through at least the outer surface.

5. 5. The tubular device of any one of claims 1 to 4, wherein the host polymer is selected from a thermoplastic elastomer (TPE), a polyolefin elastomer (POE), a polyurethane (PU), a rubber, a thermoplastic polyurethane (TPU), a silicone elastomer, or any combination comprising one of the foregoing elastomers, preferably wherein the host polymer comprises a silicone elastomer (polysiloxane).

6. 6. The tubular device of any one of claims 1 to 5, wherein the host polymer has a Shore A hardness of from about 15 to about 70, a tear strength of at least about 25 kN / m, and a stress at 200% elongation of at least about 0.3 MPa, such as at least about 0.4 MPa, for example at least about 0.5 MPa, such as at least about 0.6 MPa, for example up to about 3 MPa, such as up to about 2 MPa, for example up to about 1 MPa.

7. The tubular device of any one of claims 1 to 6, wherein the hydrogel guest polymer is polymerized from at least one sulfobetaine zwitterion-containing monomer and at least PHEMA.

8. The tubular device of any one of claims 1 to 7, wherein the hydrogel guest polymer comprises a copolymer polymerized from monomers including photoactive monomers such as spiropyran monomers.

9. The tubular device of any one of claims 1 to 8, wherein the at least one hydrogel guest polymer domain comprises a blood clot-promoting domain and / or a cell proliferation-promoting domain located on the outer surface of the body structure and / or located in an intermediate hydrogel guest polymer domain that does not include either the luminal surface or the outer surface.

10. 10. The tubular device of claim 1, wherein the host polymer comprises two or more hydrogel guest polymer domains, the two or more hydrogel guest polymer domains comprising a luminal surface hydrogel guest polymer domain comprising at least a portion of the luminal surface and an outer surface hydrogel guest polymer domain comprising at least a portion of the outer surface, the two or more hydrogel guest polymer domains being separated by polymer portions that are essentially free of guest polymer, the polymer portions preferably being part of a matrix of the host polymer that is essentially free of interpenetrating guest polymer.

11. 11. The tubular device according to any one of claims 1 to 10, wherein the body structure is a layered body structure comprising two or more layers, at least one of the layers comprising or consisting of an IPN, and at least one layer of the body structure is a polymer layer not comprising an IPN, such as a polymer layer comprising or consisting of polytetrafluoroethylene (PTFE), expanded PTFE (e.g. Goretex®), polyethylene terephthalate (PET, e.g. Dacron®), polyurethane (PU) and / or a silicone elastomer, and preferably at least two of the two or more layers are interfacially bonded to each other by chemical bonding (grafting) and / or at least two of the two or more layers are fixed to each other, the fixing of the at least two layers preferably comprising local adhesive bonds, sutures, staples, clips and / or pinholes.

12. 12. The tubular device of any one of claims 1 to 11, wherein the tubular device comprises a tubular support structure concentrically arranged with the body structure, the support structure comprising a helical wire and / or a cuff shaped to fit over the outer surface of the body structure, the support structure being of a polymeric material, the polymeric material comprising collagen, nylon, polytetrafluoroethylene (PTFE), expanded PTFE (e.g., Goretex®), polyethylene terephthalate (PET, e.g., Dacron®), polyurethane (PU), and / or a silicone elastomer.

13. The tubular device of claim 12 , wherein the cuff comprises an IPN material loaded with one or more drugs, such as growth hormones, antifibrinolytic drugs, blood clot promoting drugs, and / or cell proliferation promoting drugs.

14. The body structure has an inner diameter of about 2 mm to about 6 cm, an elastic compliance of about 1 to about 10 (mmHg x 10 in the range of 80-200 mmHg), －２ 14. The tubular device of any one of claims 1 to 13, having a wall thickness of up to about 1 cm, such as from about 0.1 mm to about 3 mm, for example from about 0.5 mm to about 1 mm.

15. The tubular device of any one of claims 1 to 14, wherein the medical tubular device is an implantable tubular device such as a dialysis graft, a stent, a vascular graft, or a stent graft.

16. The tubular device according to any one of claims 1 to 14, wherein the medical tubular device is a dialysis tube, a feeding tube such as a gastrostomy tube, or a venous catheter such as a central venous catheter (CVC line) or a peripherally inserted central catheter (PICC line).

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