COATED DEVICES AND RELATED METHODS

Abstract

This description provides a method for grafting a polymer coating onto a first side of a device wall. The method comprises: applying an initiator substantially only to a second side of the wall; applying a coating composition to the first side of the wall; and grafting the coating composition.

Description

The present invention relates to polymer coatings. More specifically, the present invention relates, in some aspects, to coated devices and methods of coating devices with polymer coatings. BACKGROUND Modern medical devices are often composed of polymers that are generally well-tolerated by the human body. For this reason, along with their flexibility and chemical stability, polymer-based medical devices are widely used in current clinical practice. Coating methods for such devices are well-established and typically involve introducing or immersing the device in various solutions in a stepwise manner. For example, U.S. patents 6,808,738 and 8,840,927 describe a method for modifying the surfaces of polymeric materials with polymer coatings that can be subsequently treated to be lubricating and antimicrobial. The method comprises incubating a photoinitiator-coated polymeric material with an aqueous monomer capable of free-radical polymerization and exposing the incubated polymeric material to UV light, thereby creating a modified surface on the polymeric material. U.S. Patent No. 8,877,256 describes a photostable antimicrobial coating composition that affects photoinduced discoloration, does not stain tissue, and can be applied to the surface of a variety of medical materials. The composition comprises a silver-PCA complex and a dye. U.S. Patent No. 8,697,112 describes a method for treating a surface with a therapeutic agent. The method comprises precipitating a therapeutic agent from a hydrophilic polymeric base layer with which the therapeutic agent has been complexed, to form a layer comprising microparticles of the therapeutic agent on the hydrophilic polymeric base layer, the hydrophilic polymeric base layer being grafted onto the surface. U.S. Patents 8,746,168, 8,920,886, and 8,967,077 describe a system and method for photografting a coating polymer onto the surface of a medical device. The system comprises a plurality of stations, including a novel grafting station. The system and method of the invention save time and resources. The system includes several stations, each of which includes an immersion tank. The system permits the automatic, semi-automatic, or manual immersion of medical devices into the immersion tanks in a specific order, as desired, wherein at least one of the stations is a grafting station for photografting the coating polymer onto the surface of the medical device. U.S. Patent Application Publication No. 2018 / 0296737 describes a coating composition comprising an aqueous solution comprising at least one vinyl carboxylic acid monomer and at least one neutral monomer, wherein the at least one neutral monomer has a glass transition temperature of less than approximately 100 °C in homopolymeric form. There is a need for alternative methods to overcome or mitigate at least some of the shortcomings of the previous technique, or to provide a useful alternative. SUMMARY According to one aspect, a method is provided for grafting a polymeric coating onto a first side of a device wall, the method comprising: applying an initiator substantially only to a second side of the wall; Apply a coating composition to the first side of the wall; and graft polymerize the coating composition. In one aspect, the method also involves applying the coating composition to the second side of the wall before the polymerization stage. In one aspect, the device comprises a lumen defined by the wall, wherein the first side of the wall is oriented away from the lumen and the second side of the wall is oriented towards the lumen. In one aspect, the application of the initiator substantially only to a second side of the wall comprises drawing the initiator into the lumen and subsequently expelling the initiator from the lumen. In one aspect, the application of the initiator substantially only to a second side of the wall for a time of approximately 1 second to approximately 30 minutes, such as approximately 10 seconds to approximately 10 minutes, such as approximately 1 minute. In one respect, the initiator is a photoinitiator. In one respect, the photoinitiator is selected from the group consisting of a perester, a hydroxyketone, a benzyl ketal, a benzoin, their derivatives and mixtures thereof. In one respect, the photoinitiator is selected from tere-butyl peroxybenzoate and / or benzophenone. In one aspect, the initiator is in solution in an organic solvent such as alcohol, such as ethanol. In one respect, applying the coating composition to the first side of the wall involves applying the coating composition to both the first and second sides of the wall. In one aspect, applying the coating composition to the first and second sides of the wall involves inserting the device into the coating composition. In one aspect, the coating composition comprises one or more monomers. In one aspect, the one or more monomers comprise at least one vinyl carboxylic acid monomer and at least one neutral monomer. In one respect, the vinyl carboxylic acid monomer is selected from the group consisting of acrylic acid, 2-bromoacrylic acid, 2-(bromomethyl)acrylic acid, 2-carboxyethyl acrylate, 2-ethylacrylic acid, itaconic acid, methacrylic acid, 2-propylacrylic acid, sodium acrylate, sodium methacrylate, 2-(trifluoromethyl)acrylic acid, 4-vinylbenzoic acid and combinations thereof. In one respect, the neutral monomer is selected from the group consisting of acrylates, such as methyl acrylate, methacrylates, such as methyl methacrylate, acrylamides, methacrylamides, vinyl compounds and their combinations. In one aspect, vinyl carboxylic acid comprises acrylic acid and the neutral monomer comprises methyl acrylate. In one aspect, the composition comprises the vinyl carboxylic acid monomer in an amount of approximately 20% to approximately 95% by weight and / or in an amount of approximately 100 mM to approximately 500 mM, such as approximately 300 mM. In one aspect, the composition comprises the neutral monomer in an amount of approximately 5% to approximately 80% by weight and / or in an amount of approximately 10 mM to approximately 250 mM, such as approximately 50 mM. In one aspect, the graft polymerization stage involves applying UV light to the device. In one aspect, UV light is applied to the device for approximately 1 to approximately 10 minutes, such as approximately 3 minutes. In one aspect, the graft polymerization stage also involves bubbling an inert gas, such as nitrogen, through the composition, before and / or during the UV light application stage to the device. In one aspect, the bubbling of the inert gas is from approximately 1 to approximately 10 minutes, such as approximately 6 minutes. In one aspect, the method also includes the ionization of the coating after the polymerization stage. In one aspect, coating ionization involves applying a basic solution to the coating. In one respect, the basic solution has a pH greater than approximately 8.0. In one respect, the basic solution is selected from the group consisting of TR1ZMA base, disodium tetraborate, sodium carbonate, and hydroxides such as ammonium hydroxide, calcium hydroxide, sodium hydroxide, and mixtures thereof. In one aspect, the ionization of the coating involves immersing the device in the basic solution for a time of approximately 1 minute to approximately 30 minutes, such as approximately 6 minutes. In one aspect, the method also involves applying an antimicrobial agent to the coating after the coating ionization stage. In one aspect, the antimicrobial agent application stage comprises immersing the device in a solution comprising the antimicrobial agent for a time of approximately 1 to approximately 30 minutes, such as approximately 3 to approximately 5 minutes. In one respect, the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, ethonium, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, fluoroquinolones, beta-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof. In one aspect, the antimicrobial agent comprises silver ions. In one respect, silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver sulfate, silver palmitate, and mixtures thereof. In one aspect, the method also involves applying a photostabilizer such as brilliant green and / or pyrrolidone carboxylic acid to the device. In one aspect, the device is immersed in a solution comprising the photostabilizer, pyrrolidone carboxylic acid, and silver ions. In one aspect, the method also includes washing the device in a basic solution after the application stage of the antimicrobial agent. In one aspect, the method also includes protonation of the coating after the polymerization stage. In one aspect, coating protonation involves applying an acidic solution to the coating. In one aspect, the acid solution comprises an acid selected from the group consisting of HC1, HBr, Hl, HOCE, H2SO4, HNO3, sodium hydrogen sulfate, sulfonic acid, acetic acid, phosphoric acid, phosphorous acid, sulfurous acid, trichloroacetic acid, salicylic acid, italic acid, nitrous acid, lactic acid, hydroiodic acid, formic acid, citric acid, tartaric acid and combinations thereof. In one aspect, the stage of applying the acid solution to the coating for a time of approximately 1 to approximately 30 minutes, such as approximately 6 minutes. In one aspect, the method comprises a device washing step with ethanol immediately after the polymerization step for a time of approximately 1 minute to approximately 30 minutes, such as approximately 6 minutes. In one aspect, the method comprises a final stage of washing the device in deionized water and / or an alcohol such as ethanol for a time of approximately 1 minute to approximately 30 minutes, such as approximately 6 to approximately 10 minutes, such as approximately 6 minutes. In one aspect, the method also includes air drying of the device. In one aspect, the method also includes sterilization of the device. In one aspect, the coating: a) is inherently antimicrobial, optionally showing a reduction greater than approximately 2-log in microbes within approximately 24 hours, such as a reduction greater than approximately 2-log, 3-log, 4-log or 5-log in microbes within approximately 5 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours or 24 hours; b) is inherently antithrombogenic, optionally showing a reduction greater than approximately 80%, such as a reduction greater than approximately 85%, 90%, 95%, 96%, 97%, 98% or 99%, relative to an uncoated surface; c) releases few or no particles, and optionally releases fewer particles than an uncoated surface; d) it is a lubricant; e) has high resistance to cracking when it expands or inflates; and / or f) It has a high resistance to delamination, as demonstrated by the maintenance of hydrophilicity after exposure to a high shear force. In one respect, exposing the polymer coating to a modified pH environment restores its inherent biological activity, such as antimicrobial activity, antithrombogenicity, low or no particle release, lubricity, crack resistance and / or maintenance of hydrophilicity. In one aspect, the device is made from a material selected from the group consisting of polyurethanes, polyamides, polyesters, polycarbonates, polyureas, polyethers, polyorganosiloxanes, polysulfones, polytetrafluoroethylene, polysiloxanes and their combinations. In one respect, the device is a medical device selected from the group consisting of dressings, sutures, scaffolds, fracture fixation devices, catheters, endoprostheses, implants, tubes, rods, prostheses, electrodes, endoscopes, heart valves, pacemakers, dental implants, and surgical, medical, or dental instruments. According to one aspect, a medical device is provided that is manufactured by the method described in this description. According to one aspect, an initiator station is provided for applying an initiator to a first side of a device wall, the initiator station comprising: a tank for containing the initiator; a support to hold the device so that, in use, it comes into substantial contact with the initiator only on one side of the wall. In one aspect, the device comprises a lumen defined by the wall, wherein the first side of the wall is oriented away from the lumen and the second side of the wall is oriented towards the lumen. In one aspect, the method further comprises an aspirator for aspirating the initiator into the lumen. According to one aspect, a system is provided for grafting a polymeric coating onto a first side of a device wall; the system comprises: the initiator station described herein; and a grafting station comprising: a grafting tank for applying a polymerizable solution to the first side of the wall; and a UV light source for exposing the device to UV light. Other features and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given only for illustrative purposes, since various changes and modifications within the spirit and scope of the invention will be evident to those skilled in the art from said detailed description. DESCRIPTION OF THE FIGURES The present invention shall be further understood from the following description with reference to the Figures, wherein: Figure 1 shows a front view of a system as described in this description. DETAILED DESCRIPTION This description outlines, in part, novel methods for coating medical devices, typically those comprising a lumen, such as catheters. In conventional methods, a polymeric device, such as a catheter, is immersed in an initiator solution so that both sides of one wall of the device (the wall facing the lumen and the wall facing outwards) are coated with the initiator. The device is then immersed in a coating composition and subsequently subjected to graft polymerization. It was previously believed that, to achieve effective graft polymerization on both sides of the device wall, both sides of the device wall would need to be pre-treated with the initiator.However, it has now been discovered that devices can be coated with initiator on only one wall, introduced into a coating composition, and subsequently undergo graft polymerization to achieve efficient grafting of the coating composition onto both sides of the wall. For example, in some cases, the initiator is drawn only into the device lumen, and therefore, contact with substantially only the lumen-facing device wall is sufficient to achieve graft polymerization of the coating onto the outward-facing wall. This improves efficiency and reduces the volume of initiator required to effectively graft polymerize the coating composition onto one or both sides of the device wall. Definitions For the purposes of this application, the terms "a," "an," "the," and "said" are intended to designate that there is one or more of the elements. Additionally, the term "comprising" and its derivatives, as used herein, are intended to be open-ended terms that specify the presence of the stated characteristics, elements, components, groups, wholes, and / or stages, but do not exclude the presence of other unstated characteristics, elements, components, groups, wholes, and / or stages. The foregoing also applies to words with similar meanings, such as the terms "includes," "has," and their derivatives. It should be understood that any aspect described as comprising certain components may also consist of or essentially consist of (or vice versa), where "consisting of" has a closed or restrictive meaning and "consisting essentially of" means that it includes the specified components but excludes other components except for materials present as impurities, unavoidable materials present as a result of the processes used to provide the components, and components added for a purpose other than achieving the technical effects described herein. For example, a composition defined by the phrase "consisting essentially of" encompasses any known pharmaceutically acceptable additives, excipients, diluents, carriers, and the like.Typically, a composition consisting essentially of an assembly of components will comprise less than 5% by weight, typically less than 3% by weight, plus typically less than 1% by weight of unspecified components. It should be understood that any component defined in this description as included may be explicitly excluded by means of a negative condition or limitation, such as any specific compound or method step, whether implicitly or explicitly defined in this description. Furthermore, all intervals given in the present description include the end of the intervals and also any intermediate points of the intervals, whether explicitly in a stage or not. Finally, terms of degree such as "substantially" and "approximately," as used herein, signify a reasonable amount of deviation from the modified term such that the result does not change significantly. These terms of degree may be interpreted as including a deviation of at least ±5% from the modified term if this deviation does not negate the meaning of the modifying term. Coating methods This description outlines methods for grafting a polymer coating onto a first side of a device wall, such as a polymer medical device. The method comprises applying an initiator substantially only to a second side of the wall; applying a coating composition to the first side of the wall; and grafting the coating composition. It should be understood that the coating composition can also be applied to the second side of the wall before the polymerization stage if both sides of the device wall are to be coated. Without intending to impose any theory, it appears that applying the initiator to one wall is sufficient to allow graft polymerization to occur on both walls, wherever the coating composition is present. It is believed that the photoinitiator migrates through the wall and that this migration may be facilitated by the solvent in which the photoinitiator is dissolved. The coating composition can be applied to the entire device or only to the parts of the device that are to be coated. Typically, the device is immersed in the coating composition so that both the first and second sides of the wall are coated with it. Typically, the device comprises a lumen defined by the wall, where the first side of the wall faces away from the lumen and the second side faces the lumen. Thus, applying the initiator substantially only to the second side of the wall involves applying the initiator to the lumen, for example, by aspiration. The initiator may be allowed to drain from the lumen or may be actively expelled from it. The device is typically made of a material selected from the group consisting of polyurethanes, polyamides, polyesters, polycarbonates, polyureas, polyethers, polyorganosiloxanes, polysulfones, polytetrafluoroethylene, polysiloxanes, and combinations thereof. Typically, the device is a medical device selected from the group consisting of dressings, sutures, scaffolds, fracture fixation devices, catheters, endoprostheses, implants, tubing, rods, prostheses, electrodes, endoscopes, heart valves, pacemakers, dental implants, and surgical devices, medical instruments, or dental instruments. The initiator is typically applied to the device for a period of approximately 1 second to approximately 30 minutes, such as approximately 1, 5, 10, 15, 30, or 45 seconds, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes to approximately 5, 10, 15, 30, or 45 seconds, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 minutes, such as approximately 30 seconds, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 minutes. Typically, the initiator is applied to the device for approximately 1 minute. Applying the initiator substantially only to one side of the device wall is typically achieved by spraying, aspirating, dipping, or otherwise applying the initiator in a way that exposes substantially only the second side of the wall. For example, when the initiator is aspirated into the lumen of a device such as a catheter, the catheter tip may be placed in a solution of the initiator, which is then aspirated into the catheter lumen. It should be understood that a small amount of initiator may come into contact with the first side of the device wall when the tip is inserted into the solution, so that effective aspiration can be achieved. Once the initiator is applied substantially only to the second side of the device wall, the device is typically placed in the coating composition immediately afterward, such as without first drying the device. Typically, the initiator is a photoinitiator and is selected, for example, from the group consisting of a perester, an α-hydroxyketone, a benzyl ketal, a benzoin, their derivatives, and mixtures thereof. Typically, the photoinitiator is selected from tere-butyl peroxybenzoate and / or benzophenone. The initiator is typically in solution in an organic solvent, such as an alcohol, for example, ethanol. The initiator is typically present in the organic solvent in a sufficient quantity to initiate the polymerization of the coating composition. This is typically from approximately 10 mM to approximately 250 mM, such as approximately 10 mM, 25 mM, 50 mM, 75 mM, 100 mM, 150 mM, or 200 mM to approximately 25 mM, 50 mM, 75 mM, 100 mM, 150 mM, 200 mM, or 250 mM, such as approximately 50 mM. The coating composition may be any known coating composition capable of polymerizing onto the surface of a polymeric device. For example, the coating composition may be the coating composition described in U.S. Patent Nos. 6,808,738, 8,840,927, 8,877,256, 8,697,112, 8,746,168, 8,920,886, and / or 8,967,077 and / or U.S. Patent Application Publication No. 2018 / 029673713, each of which is incorporated herein by reference in its entirety. Typically, the one or more monomers comprise at least one vinyl carboxylic acid monomer and at least one neutral monomer. For example, the vinyl carboxylic acid monomer is selected from the group consisting of acrylic acid, 2-bromoacrylic acid, 2-(bromomethyl)acrylic acid, 2-carboxyethyl acrylate, 2-ethylacrylic acid, itaconic acid, methacrylic acid, 2-propylacrylic acid, sodium acrylate, sodium methacrylate, 2-(trifluoromethyl)acrylic acid, 4-vinylbenzoic acid, and combinations thereof. For example, the neutral monomer is selected from the group consisting of acrylates, such as methyl acrylate, methacrylates, such as methyl methacrylate, acrylamides, vinyl compounds, and combinations thereof. Typically, vinyl carboxylic acid comprises acrylic acid and the neutral monomer comprises methyl acrylate. Specifically, at least one neutral monomer has a lower glass transition temperature (Tg) than an acrylic acid homopolymer (approximately 105 °C) when in its homopolymeric form. It has been found that choosing a neutral monomer with a lower Tg than an acrylic acid homopolymer, such as less than approximately 105 °C or, more typically, less than approximately 100 °C, softens the mechanical properties of the coating (relative to a pure polyacrylic acid homopolymer, for example), allowing for some expansion, such as during the inflation of a Foley catheter balloon, with little or no cracking and / or delamination.Therefore, copolymers made using neutral monomers described herein with a homopolymeric Tgh below that of polyacrylic acid possess sufficient flexibility to allow the expansion of inflatable materials with minimal or no cracking or delamination. In certain respects, therefore, at least one neutral monomer has a glass transition temperature that is less than approximately 105 °C or, more specifically, less than approximately 100 °C, 90 °C, 80 °C, 70 °C, 60 °C, 50 °C, 40 °C, 30 °C, 20 °C or 10 °C in homopolymeric form. Thus, a copolymer formed from the polymerization of at least one vinyl carboxylic acid monomer and at least one neutral monomer typically has a glass transition temperature that is less than approximately 100 °C, such as less than approximately 90 °C, 80 °C, 70 °C, 60 °C, 50 °C, 40 °C, 30 °C, 20 °C, or 10 °C. It should be understood that the vinyl carboxylic acid monomer may be present in the coating composition and / or the polymer coating in any amount, typically from approximately 20% to approximately 90% by weight, such as from approximately 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70% or 75% to approximately 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75% or 80% by weight. In additional or alternative aspects, the vinyl carboxylic acid monomer may be present in the coating composition and / or the polymer coating in amounts from approximately 100 mM to approximately 500 mM, such as approximately 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM or 450 mM to approximately 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM or 500 mM, such as approximately 300 mM. Similarly, the neutral monomer may be present in the coating composition and / or the polymer coating in any amount, typically from approximately 10% to approximately 80% by weight, such as from approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70% or 75% up to approximately 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75% or 80% by weight. In additional or alternative aspects, the neutral monomer may be present in the coating composition and / or the polymer coating in quantities from approximately 10 mM to approximately 250 mM, such as approximately 10 mM, 25 mM, 50 mM, 75 mM, 100 mM, 150 mM or 200 mM to approximately 25 mM, 50 mM, 75 mM, 100 mM, 150 mM, 200 mM or 250 mM, such as approximately 50 mM. The vinyl carboxylic acid and the neutral monomer can be present in the coating composition in various ratios, such as from approximately 1:50 to approximately 50:1, such as from approximately 1:50, 1:40, 1:30, 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2 or 1:1 to 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1 or 50:1. The coating composition may comprise additional excipients as understood by someone skilled in the art. Typically, after the coating composition is applied to one or more walls of the device as desired, the coating is polymerized onto the device by applying UV light for a time of approximately 10 seconds to approximately 30 minutes, such as approximately 10, 15, 30 or 45 seconds, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 25 minutes to approximately 15, 30 or 45 seconds, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30 minutes, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 minutes. In typical aspects, UV light is applied to the device for approximately 3 minutes with or without stirring, while the device is immersed in carboxylic acid vinyl monomers and neutral monomer solution. The polymerization stage typically involves purging or bubbling an inert gas, such as nitrogen, through the monomers before and / or during the UV light application stage. The gas is typically bubbled before the UV light is applied and typically for a period of time ranging from approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes to approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 minutes, or approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. Typically, the gas bubbles for about 6 minutes. Typically, carboxylic acid vinyl monomers and neutral monomers are present in the same solution; however, it is envisaged that the initiator could be applied to the desired wall of the device, followed by application and / or introduction into one monomer solution and then into the other, after which polymerization is effected. Typically, after the coating polymerizes, it is washed with alcohol, such as ethanol, for a short period of time, such as approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes, or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 minutes. In typical cases, the device comprising the coating is immersed in ethanol, with or without agitation, for approximately 6 minutes. After washing with alcohol, the coating is typically ionized by applying a basic solution to it. The basic solution typically has a pH greater than approximately 7.0, 7.5, 8.0, 8.5, or 9.0. The basic solution can be any known basic solution but is typically selected from the group consisting of TRIZMA base, disodium tetraborate, sodium carbonate, and hydroxides such as ammonium hydroxide, calcium hydroxide, sodium hydroxide, and mixtures thereof, for example. Typically, ionizing the coating involves immersing the device in the base solution for a period of approximately 1 minute to approximately 30 minutes, such as approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes. Typically, the device comprising the coating is immersed in the base solution with or without agitation for approximately 6 minutes. Once the coating is ionized, a therapeutic agent can be applied to the coating, typically by immersing the device in a solution comprising the therapeutic agent for a period of approximately 1 to approximately 30 minutes, such as approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes. Typically, the device comprising the ionized coating is immersed in a solution comprising the therapeutic agent, with or without agitation, for a period of approximately 3 to approximately 5 minutes. The therapeutic agent in some respects is an antimicrobial agent, which includes one or more antibacterial agents, and / or one or more antifungal agents, and / or one or more antiviral agents, and / or one or more antiseptic agents, and / or combinations thereof. In typical terms, the antimicrobial agent is an antibacterial agent. Although any antibacterial agent may be used in the polymer coatings described herein, some illustrative, but not limited to, antibacterial agents include those classified as aminoglycosides, beta-lactams, quinolones or fluoroquinolones, macrolides, sulfonamides, sulfametaxozoles, tetracyclines, streptogramins, oxazolidinones, lincomycins, rifamycins, glycopeptides, polymyxins, lipopeptide antibiotics, metallic salts, as well as pharmacologically acceptable sodium salts, pharmacologically acceptable calcium salts, pharmacologically acceptable potassium salts, lipid formulations, derivatives, and / or analogues thereof. In other respects, the antimicrobial agent includes an antifungal agent. Some illustrative classes of antifungal agents include imidazoles or triazoles such as clotrimazole, miconazole, ketoconazole, econazole, butoconazole, omoconazole, oxiconazole, terconazole, itraconazole, fluconazole, voriconazole (UK document 109,496), or posaconazole; polyene antifungals such as amphotericin B, liposomal amphotericin B, natamycin, nystatin, and lipid formulations of nystatin; cell wall-active cyclic lipopeptide antifungals, including echinocandins such as caspofungin, micafungin, anidulfungin, and cilofungin; LY 121019; LY303366; and the allylamine group of antifungals such as terbinafine.Other non-limiting examples of antifungal agents include naftifine, tolnaftate, mediocidin, candicidin, trichomycin, hamicin, aurefungin, ascosin, ayfattin, azacolutin, trichomycin, levorin, heptamycin, candimycin, griseofulvin, BF-796, MTCH 24, BTG-137586, pradimycins (MNS 18184), benanomycin; ambisome; nikkomycin Z; flucytosine or perimycin. In other respects, an antimicrobial agent includes an antiviral agent. Non-limiting examples of antiviral agents include cidofovir, amantadine, rimantadine, acyclovir, ganciclovir, penciclovir, famciclovir, foscarnet, ribavirin, and valacyclovir. In some respects, an antimicrobial agent is an innate immune peptide or protein. Some illustrative classes of innate immune peptides or proteins are transferrins, lactoferrins, defensins, phospholipases, lysozyme, cathelicidins, serprocidins, bactericidal permeability-enhancing proteins, amphipathic alpha-helical peptides, and other antimicrobial amino acids, peptides, or synthetic proteins. In other respects, the polymeric coatings described in this description may comprise at least one anticoagulant such as heparin, hirudin, EGTA, EDTA, urokinase, streptokinase or hydrogen peroxide, etc. In typical aspects, the polymer coating comprises an antimicrobial agent selected from the group consisting of chlorhexidine, octenidine, ethonium, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, fluoroquinolones, beta-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof. More typically, the antimicrobial agent comprises silver ions, which are typically derived from a silver salt selected from the group consisting of silver phosphate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver sulfate, silver palmitate, and mixtures thereof. Polymeric coatings may comprise additional agents and / or excipients as understood by a person skilled in the art. For example, when silver ions are chosen as the antimicrobial agent, a colorant and / or complexed silver, such as a photostabilizer (e.g., brilliant green) and / or pyrrolidone carboxylic acid, may be applied to the device, as described in U.S. Patent No. 8,877,256, which is incorporated herein by reference in its entirety. Typically, these agents are applied by immersing the device in a solution comprising the agents, with or without stirring for a period of time such as approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 25 minutes to approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30 minutes, such as approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 minutes. After applying the antimicrobial agent to the device, the device is typically washed in a basic solution that has a pH greater than approximately 7.0, 7.5, 8.0, 8.5, or 9.0. The basic solution can be any known basic solution but is typically selected from the group consisting of TRIZMA base, disodium tetraborate, sodium carbonate, and hydroxides such as ammonium hydroxide, calcium hydroxide, sodium hydroxide, and mixtures thereof, for example. In other respects, after washing the device in ethanol, the method comprises protonating the coating. The coating is typically protonated by applying an acidic solution to the coating, wherein the acidic solution has a pH of less than approximately 7.0, such as less than approximately 6.5, less than approximately 6.0, less than approximately 5.5, less than approximately 5.0, less than approximately 4.5, or less than approximately 4.0, or from approximately 4.0 to approximately 7.0, such as from approximately 5.0 to approximately 6.5, or from approximately 5.0 to approximately 6.0. The acid solution can be any known acid solution; however, specific examples include acid solutions comprising an acid selected from the group consisting of HCl, HBr, HI, HClO4, H2SO4, HNO3, sodium hydrogen sulfide, sulfonic acid, acetic acid, phosphoric acid, phosphorous acid, sulfurous acid, trichloroacetic acid, salicylic acid, italic acid, nitrous acid, lactic acid, hydroiodic acid, formic acid, citric acid, tartaric acid, and combinations thereof. Typically, the acid solution comprises HCl. The acid solution can be applied to the coating for any period of time, but typically, the device comprising the coating is immersed in the acid solution for a period of approximately 1 minute to approximately 30 minutes, such as approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes. In typical cases, the device comprising the coating is immersed in the acid solution with or without agitation for approximately 6 minutes. Once the coating is protonated, an antimicrobial agent can be further added to the coating by immersing the device comprising the coating in a solution comprising the antimicrobial agent, as explained above. In this way, the device will be intrinsically antimicrobial, but will also elute an antimicrobial agent. As mentioned previously, the device is typically washed in ethanol for a short period of time after polymerization. This washing can help remove residual photoinitiator from the device and coating. After the polymerization, protonation, and ionization steps are completed, and after the desired agents, such as antimicrobial agents, are added to the coated device, the device is typically washed in deionized water for a period of approximately 1 to approximately 30 minutes, such as from approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 minutes to approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 minutes, or approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. Typically, the device comprising the device is immersed in deionized water, with or without agitation, for a period of approximately 6 to approximately 10 minutes. After washing in deionized water, the coated device is typically air dried and optionally sterilized and packaged. The method described above can be fully manual, fully automated, or partially automated. In particular, the method is substantially carried out using the system described in International Patent Application Publication No. WO 201 1 / 038483, which is incorporated herein by reference in its entirety, wherein the photoinitiator station described therein is modified to apply the initiator substantially only to one side of a device wall, such as by aspiration into the lumen of a device, as described herein. The methods and compositions described above are typically used to form polymer coatings. These polymer coatings comprise a graft-polymerized copolymer from at least one water-soluble vinyl carboxylic acid monomer, as described above, and at least one water-soluble neutral monomer, as described above. Specifically, the vinyl carboxylic acid monomer is protonated in the polymer coating. This is typically achieved by immersing the polymer coating in an acidic solution. Protonation of the vinyl carboxylic acid monomer has been found to provide a coating that is inherently antimicrobial, optionally exhibiting a reduction greater than approximately 2-log in microbes within approximately 24 hours, such as a reduction greater than approximately 2-log, 3-log, 4-log, or 5-log in microbes within approximately 5 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours, or 24 hours. In alternative or additional aspects, the polymer coating is inherently antithrombogenic, optionally showing a reduction greater than approximately 80%, such as a reduction greater than approximately 85%, 90%, 95%, 96%, 97%, 98%, or 99%, relative to an uncoated surface. In alternative or additional aspects, the polymer coating releases few or no particles, optionally releasing fewer particles than an uncoated surface; the polymer coating is lubricating; the polymer coating has high resistance to cracking when it expands or swells; and / or the polymer coating has high resistance to delamination, as demonstrated by the maintenance of hydrophilicity after exposure to high shear stress. In some aspects, one or more of these characteristics are improved compared to a polyacrylate (AA) coating. In certain respects, exposing the polymer coating to a modified pH environment, such as an acidic or basic environment—typically an acidic environment to reprotonate the surface—restores its inherent biological activity, such as antimicrobial activity, antithrombogenicity, low or no particle release, lubricity, crack resistance, and / or maintenance of hydrophilicity. In some respects, one or more of these characteristics are improved compared to a polyacrylate (AA) coating. The polymeric coatings described herein are typically polymerized by grafting onto the surface of a medical device. The medical device itself is typically polymeric and made of a material such as polyurethanes, polyamides, polyesters, polycarbonates, polyureas, polyethers, polyorganosiloxanes, polysulfones, polytetrafluoroethylene, polysiloxanes, or combinations thereof. Although not exhaustive, a medical device is typically a device for internal or external use on wounds, for example. Thus, in particular, a medical device is selected from the group that includes dressings, sutures, scaffolds, fracture fixation devices, catheters, endoprostheses, implants, tubes, rods, prostheses, electrodes, endoscopes, heart valves, pacemakers, dental implants, and surgical, medical, or dental instruments. Typically, the device comprises a lumen and is, for example, a catheter, an endoprosthesis, or a tube. Coating systems Systems for coating devices are also described herein. Such systems may comprise one or more stations for coating different reagents onto devices and polymerizing coatings onto the devices. Illustrative systems are described in U.S. Patent Nos. 8,746,168; 8,920,886; and 8,967,077, each of which is incorporated herein by reference in its entirety. The individual stations within the system are also described. For example, an initiator station is described herein and shown in Figure 1. The initiator station 10 comprises a tank 12 for holding the initiator 14 and a holder 16, in this case a syringe, which also functions as an aspirator. The holder 16 holds a device 18 in place above the initiator 14. In this case, the device 18 comprises a lumen 20 that is defined by a wall 22. The wall 22 has a first side that faces outward from the lumen 20 and is not in direct contact with the initiator 14. The wall 22 has a second side that faces into the lumen 20 and comes into contact with the initiator 14 when aspirated into the lumen 20. As shown, the holder 16 holds the device 18 such that substantially only the second side of the wall 22 comes into contact with the initiator.There may be some minor contact with the first side of wall 22, where the end of device 18 is slightly inserted into or touches the surface of initiator 14, so that it can draw initiator 14 into lumen 20. A grafting station as described in U.S. Patents 8,746,168, 8,920,886, and 8,967,077 may also be included. The grafting station typically comprises a grafting tank for applying a polymerizable solution to the first side of the wall and a UV light source for exposing the device to UV light. Many other stations as described in these U.S. patents may also be included. Although only a single device is shown, connected to a hand syringe as an aspirator, it should be understood that this method can be expanded to accommodate any desired number of devices simultaneously and can transfer devices from one tank to the next. The aspirator could be a fully integrated vacuum system. Furthermore, the device need not be as shown, and the system could be modified to accommodate other types of devices, as described herein, for example. The system and method described above can be fully automated, partially automated, or entirely manual. The foregoing description generally describes the present invention. A more complete understanding can be obtained by referring to the following specific examples. These examples are described for illustrative purposes only and are not intended to limit the scope of the invention. Changes in form and the substitution of equivalents are contemplated as circumstances may suggest or make it convenient. Although specific terms have been employed in the present description, such terms are intended in a descriptive sense and not for the purpose of limitation. EXAMPLES Example 1 - Coated polyurethane catheter The inner and outer surfaces of a polyurethane vascular catheter (Chronoflex) (5 Fr) were coated with a grafted copolymer layer according to the following method. A photoinitiator complex solution was prepared by dissolving benzophenone and tert-butyl peroxybenzoate (50 mM each) in ethanol. A syringe was attached to one end of the catheter, while the other end was immersed in the photoinitiator solution. A volume of photoinitiator solution was aspirated into the catheter lumen using the attached syringe and held in place for 1 minute. The luminal solution was then expelled, and the treated catheter was immersed in an aqueous monomer solution composed of acrylic acid and methyl acrylate (300 mM and 50 mM, respectively). Nitrogen gas was bubbled into the monomer solution for 19 minutes, followed by exposure to UV light (350 nm) for 3 minutes.Next, the catheter is rinsed by immersing it in deionized water for 6 minutes. The presence of a grafted copolymer layer on the inner and outer surfaces of the device was confirmed by exposing the catheter to a solution of the cationic dye, Brilliant Green (1.6 mM) 5 for 1 min. Both the inner and outer surfaces of the catheter were stained green, indicating the presence of the coating. The foregoing description generally describes the present invention. Although specific terms have been used in this description, such terms are intended for descriptive purposes and not for limitation. All publications, patents, and patent applications mentioned in this description are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application indicated individually and specifically were incorporated by reference in its entirety. Although preferred embodiments of the invention have been described in detail herein, those skilled in the art will understand that variations may be made to them without departing from the spirit of the invention or the scope of the appended claims.

Claims

1. A method for grafting a polymeric coating onto a first side of a device wall, the method comprising: applying an initiator substantially only to a second side of the wall; applying a coating composition to the first side of the wall; and grafting the coating composition.

2. The method of claim 1, further comprising applying the coating composition to the second side of the wall before the polymerization stage.

3. The method of claim 1 or 2, wherein the device comprises a lumen defined by the wall, wherein the first side of the wall is oriented away from the lumen and the second side of the wall is oriented towards the lumen.

4. The method of claim 3, wherein the application of the initiator substantially only to a second side of the wall comprises aspirating the initiator into the lumen and subsequently expelling the initiator from the lumen.

5. The method of any one of claims 1 to 4, wherein the application of the initiator substantially only to a second side of the wall is for a time from approximately 1 second to approximately 30 minutes, such as from approximately 10 seconds to approximately 10 minutes, such as approximately 1 minute.

6. The method of any one of claims 1 to 5, wherein the initiator is a photoinitiator.

7. The method of claim 6, wherein the photoinitiator is selected from the group consisting of a perester, an α-hydroxyketone, a benzyl ketal, a benzoin, their derivatives and mixtures thereof.

8. The method of claim 7, wherein the photoinitiator is selected from tere-butyl peroxybenzoate and / or benzophenone.

9. The method of any one of claims 1 to 8, wherein the initiator is in solution in an organic solvent such as alcohol, such as ethanol.

10. The method of any one of claims 1 to 9, wherein the application of the coating composition to the first side of the wall comprises applying the coating composition to the first and second sides of the wall.

11. The method of claim 10, wherein the application of the coating composition to the first and second sides of the wall comprises introducing the device into the coating composition.

12. The method of any one of claims 1 to 11, wherein the coating composition comprises one or more monomers.

13. The method of claim 12, wherein the one or more monomers comprise at least one vinyl carboxylic acid monomer and at least one neutral monomer.

14. The method of claim 13, wherein the vinyl carboxylic acid monomer is selected from the group consisting of acrylic acid, 2-bromoacrylic acid, 2-(bromomethyl)acrylic acid, 2-carboxyethyl acrylate, 2-ethylacrylic acid, itaconic acid, methacrylic acid, 2-propylacrylic acid, sodium acrylate, sodium methacrylate, 2-(trifluoromethyl)acrylic acid, 4-vinylbenzoic acid and combinations thereof.

15. The method of claim 13 or 14, wherein the neutral monomer is selected from the group consisting of acrylates, such as methyl acrylate, methacrylates, such as methyl methacrylate, acrylamides, methacrylamides, vinyl compounds and combinations thereof.

16. The method of any one of claims 13 to 15, wherein the vinyl carboxylic acid comprises acrylic acid and the neutral monomer comprises methyl acrylate.

17. The method of any one of claims 13 to 16, wherein the composition comprises the vinyl carboxylic acid monomer in an amount of approximately 20% to approximately 95% by weight and / or in an amount of approximately 100 mM to approximately 500 mM, such as approximately 300 mM.

18. The method of any one of claims 13 to 17, wherein the composition comprises the neutral monomer in an amount of approximately 5% to approximately 80% by weight and / or in an amount of approximately 10 mM to approximately 250 mM, such as approximately 50 mM.

19. The method of any one of claims 1 to 18, wherein the graft polymerization step comprises applying UV light to the device.

20. The method of claim 19, wherein the UV light is applied to the device for approximately 1 to approximately 10 minutes, such as approximately 3 minutes.

21. The method of claim 19 or 20, wherein the graft polymerization step further comprises bubbling an inert gas such as nitrogen through the composition, before and / or during the UV light application step to the device.

22. The method of claim 21, wherein the bubbling of the inert gas is from approximately 1 to approximately 10 minutes, such as approximately 6 minutes.

23. The method of any one of claims 1 to 22, further comprising ionizing the coating after the polymerization step.

24. The method of claim 23, wherein the ionization of the coating comprises applying a basic solution to the coating.

25. The method of claim 24, wherein the basic solution has a pH greater than approximately 8.

0.

26. The method of claim 24 or 25, wherein the basic solution is selected from the group consisting of TRIZMA base, disodium tetraborate, sodium carbonate and hydroxides such as ammonium hydroxide, calcium hydroxide, sodium hydroxide and mixtures thereof.

27. The method of any one of claims 24 to 26, wherein the ionization of the coating comprises immersing the device in the basic solution for a time of approximately 1 minute to approximately 30 minutes, such as approximately 6 minutes.

28. The method of any one of claims 24 to 27, further comprising applying an antimicrobial agent to the coating after the coating ionization step.

29. The method of claim 28, wherein the step of applying the antimicrobial agent comprises immersing the device in a solution comprising the antimicrobial agent for a time of approximately 1 to approximately 30 minutes, such as approximately 3 to approximately 5 minutes.

30. The method of claim 28 or 29, wherein the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, ethonium, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, fluoroquinolones, beta-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

31. The method of claim 30, wherein the antimicrobial agent comprises silver ions.

32. The method of claim 31, wherein the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver sulfate, silver palmitate, and mixtures thereof.

33. The method of claim 31 or 32, wherein the method further comprises applying a photostabilizer such as brilliant green and / or pyrrolidone carboxylic acid to the device.

34. The method of claim 33, wherein the device is immersed in a solution comprising the photostabilizer, pyrrolidone carboxylic acid, and silver ions.

35. The method of any one of claims 28 to 34, wherein the method further comprises washing the device in a basic solution after the antimicrobial agent application step.

36. The method of any one of claims 1 to 35, further comprising protonating the coating after the polymerization step.

37. The method of claim 36, wherein the protonation of the coating comprises applying an acidic solution to the coating.

38. The method of claim 37, wherein the acid solution comprises an acid selected from the group consisting of HC1, HBr, HI, HC1C, H2SO4, HNO3, sodium hydrogen sulfide, sulfonic acid, acetic acid, phosphoric acid, phosphorous acid, sulfurous acid, trichloroacetic acid, salicylic acid, italic acid, nitrous acid, lactic acid, hydroiodic acid, formic acid, citric acid, tartaric acid and combinations thereof.

39. The method of claim 37 or 38, wherein the step of applying the acid solution to the coating for a time of approximately 1 to approximately 30 minutes, such as approximately 6 minutes.

40. The method of any one of claims 1 to 39, comprising a step of washing the device in ethanol immediately after the polymerization step for a time of approximately 1 minute to approximately 30 minutes, such as approximately 6 minutes.

41. The method of any one of claims 1 to 40, comprising a final stage of washing the device in deionized water and / or an alcohol such as ethanol for a time of approximately 1 minute to approximately 30 minutes, such as approximately 6 to approximately 10 minutes, such as approximately 6 minutes.

42. The method of any one of claims 1 to 41, further comprising air-drying the device.

43. The method of any one of claims 1 to 42, further comprising sterilizing the device.

44. The method of any one of claims 1 to 43, wherein the coating: a) is inherently antimicrobial, optionally exhibiting a reduction greater than approximately 2-log in microbes within approximately 24 hours, such as a reduction greater than approximately 2-log, 3-log, 4-log, or 5-log in microbes within approximately 5 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours, or 24 hours; b) is inherently antithrombogenic, optionally exhibiting a reduction greater than approximately 80%, such as a reduction greater than approximately 85%, 90%, 95%, 96%, 97%, 98%, or 99%, relative to an uncoated surface; c) releases few or no particles, and optionally releases fewer particles than an uncoated surface; d) is lubricating; e) has high resistance to cracking when expanded or inflated;and / or) has a high resistance to delamination, as demonstrated by the maintenance of hydrophilicity after exposure to a high shear force.; 45. The method of any one of claims 1 to 44, wherein exposure of the polymer coating to a modified pH environment restores its inherent biological activity, such as antimicrobial activity, antithrombogenicity, low or no particle release, lubricity, crack resistance and / or maintenance of hydrophilicity.

46. ​​The method of any one of claims 1 to 45, wherein the device is made of a material selected from the group consisting of polyurethanes, polyamides, polyesters, polycarbonates, polyureas, polyethers, polyorganosiloxanes, polysulfones, polytetrafluoroethylene, polysiloxanes and combinations thereof.

47. The method of any one of claims 1 to 46, wherein the device is a medical device selected from the group consisting of dressings, sutures, scaffolds, fracture fixation devices, catheters, endoprostheses, implants, tubes, rods, prostheses, electrodes, endoscopes, heart valves, pacemakers, dental implants, and surgical, medical, or dental instruments.

48. A medical device manufactured by the method of any one of claims 1 to 47.

49. An initiator station for applying an initiator to a first side of a wall of a device, the initiator station comprising: a tank for containing the initiator; a support for holding the device so that, in use, only a second side of the wall comes into substantial contact with the initiator.

50. The initiator station according to claim 49, wherein the device comprises a lumen defined by the wall, wherein the first side of the wall is oriented away from the lumen and the second side of the wall is oriented towards the lumen.

51. The initiator station according to claim 50, further comprising an aspirator for aspirating the initiator into the lumen.

52. A system for grafting a polymer coating onto a first side of a device wall, the system comprising: the initiator station of any one of claims 49 to 51; and a grafting station comprising: a grafting tank for applying a polymerizable solution to the first side of the wall; and a UV light source for exposing the device to UV light.