Coated catheter and coating method

Abstract

Coated medical devices include coated catheters. For example, the coated catheter comprises a tubular substrate, a catheter tube, and a coating thereover. The tubular substrate is made of a first polymeric material that is transparent to electromagnetic radiation in the visible light range. The coating comprises a second polymeric material affixed to the tubular substrate by chain ends of the second polymeric material impregnated into the first polymeric material with a used visible light photoinitiator. Coating methods include methods for coating medical devices, such as coated catheters. For example, the coating method includes irradiating a tubular substrate impregnated with a visible light photoinitiator with electromagnetic radiation while the tubular substrate is placed in an aqueous solution of the monomer, thereby initiating radical polymerization of the monomer and coating the tubular substrate with a coating of the second polymeric material.

Description

[Technical Field]

[0001] The present disclosure relates to coated catheters and coating methods. [Background technology]

[0002] Photoinitiated free-radical polymerization for coating medical devices such as catheters utilizes ultraviolet ("UV") light photoinitiators with relatively high absorbance in a range of UV light, such as UVC (e.g., 100-280 nm), UVB (e.g., 280-315 nm), or UVC (e.g., 315-400 nm), or narrower ranges thereof. Examples of UV light photoinitiators for such free-radical polymerization include tert-butyl peroxybenzoate and benzophenone, which have relatively strong UVC absorption peaks at 232 nm and 254 nm, respectively. While the aforementioned UV light photoinitiators can be effective in generating and transferring free radicals for chain-growth polymerization when irradiated in the range of UV light absorbed by the UV light photoinitiator, UV light itself can decompose materials, thereby limiting the choice of substrate for coated medical devices. Furthermore, UV light poses occupational risks, necessitating additional safety measures to limit worker exposure to UV light.

[0003] Disclosed are coated medical devices, methods of coating, utilizing visible light photoinitiators. Summary of the Invention

[0004] In some embodiments, a coated catheter is disclosed herein, comprising a catheter tube including a tubular substrate and a coating covering the tubular substrate. The tubular substrate is comprised of a first polymeric material that is transparent to electromagnetic radiation in the visible light range. The coating is comprised of a second polymeric material secured to the tubular substrate by chain ends of the second polymeric material impregnated into the first polymeric material. At least a portion of the chain ends comprise a spent visible light photoinitiator.

[0005] In some embodiments, the first polymeric material is a thermoplastic polyurethane that is transparent to electromagnetic radiation in the visible light range of 400 nm to 650 nm.

[0006] In some embodiments, the thermoplastic polyurethane comprises hard segments having one or more sulfur-based chain extenders.

[0007] In some embodiments, the thermoplastic polyurethane comprises a soft segment having a polycarbonate moiety.

[0008] In some embodiments, the thermoplastic polyurethane comprises a soft segment having a polyether moiety.

[0009] In some embodiments, the spent visible light photoinitiator is spent camphorquinone or a spent analog of camphorquinone.

[0010] In some embodiments, at least another portion of the chain ends of the first polymeric material comprise spent coinitiator.

[0011] In some embodiments, the spent coinitiator is a spent tertiary amine selected from ethyl-4-dimethylaminobenzoate; 4-(dimethylamino)benzonitrile; and 2-(N,N-dimethylamino)ethyl methacrylate.

[0012] In some embodiments, a coating of a second polymeric material covers either the abluminal surface or the luminal surface of the tubular substrate.

[0013] In some embodiments, a coating of a second polymeric material covers both the abluminal and luminal surfaces of the tubular substrate.

[0014] In some embodiments, the second polymeric material is a polyacrylate salt or ester.

[0015] In some embodiments, the second polymeric material is a polyacrylate salt. At least a portion of the functionalized sites of the second polymeric material are functionalized with an anionic carboxylate and a cationic therapeutic agent as the counterion.

[0016] In some embodiments, the therapeutic agent is an antibacterial agent.

[0017] In some embodiments, the therapeutic agent is chlorhexidine.

[0018] In some embodiments, at least another portion of the functionalized sites of the second polymeric material are functionalized with an anionic carboxylate and a cationic dye as the counterion, the dye providing a visual indication that a coating of the second polymeric material has coated the tubular substrate.

[0019] In some embodiments, the dye also doubles as an antifungal agent.

[0020] In some embodiments, the dye is ethyl violet.

[0021] In some embodiments, the coated catheter further includes a catheter hub and one or more extension legs, the catheter tube including a proximal end portion disposed within the catheter hub, and each extension leg of the one or more extension legs including a distal end portion disposed within the catheter hub.

[0022] Also disclosed herein are methods for producing coated catheters. The methods, in some embodiments, include steps or operations for providing a coated tubular substrate. Accordingly, the methods include obtaining an impregnated tubular substrate of a first polymeric material that is transparent to electromagnetic radiation in the visible light range. The first polymeric material is impregnated with a visible light photoinitiator. The methods also include placing the impregnated tubular substrate in an aqueous solution containing a monomer dissolved therein. The methods also include irradiating the impregnated tubular substrate with electromagnetic radiation in the visible light range through which the first polymeric material is transparent. The photoinitiator initiates radical polymerization of the monomer upon irradiation of the photoinitiator. The radical polymerization coats the impregnated tubular substrate with a coating of a second polymeric material to provide a coated tubular substrate.

[0023] In some embodiments, the method further comprises placing the unimpregnated tubular substrate in an organic solvent solution comprising a photoinitiator dissolved therein, wherein the unimpregnated tubular substrate swells in the organic solvent solution such that the photoinitiator diffuses into the first polymeric material, thereby impregnating the first polymeric material with the photoinitiator and providing the impregnated tubular substrate in its solvent-swollen form.

[0024] In some embodiments, the method further comprises placing the solvent-swollen form of the impregnated tubular substrate in water, where the organic solvent diffuses from the first polymeric material into the water, thereby shrinking the solvent-swollen form of the impregnated tubular substrate and trapping the photoinitiator in the first polymeric material.

[0025] In some embodiments, the first polymeric material is a thermoplastic polyurethane that is transparent to electromagnetic radiation in the visible range of 400 nm to 650 nm. The thermoplastic polyurethane comprises hard segments having one or more sulfur-based chain extenders and soft segments having polycarbonate moieties.

[0026] In some embodiments, the visible light photoinitiator is camphorquinone or an analogue of camphorquinone, characterized by its absorption of electromagnetic radiation in the visible light range of 400 nm to 650 nm.

[0027] In some embodiments, the impregnated tubular substrate is further impregnated with a coinitiator, wherein the coinitiator is a tertiary amine selected from ethyl-4-dimethylaminobenzoate; 4-(dimethylamino)benzonitrile; and 2-(N,N-dimethylamino)ethyl methacrylate.

[0028] In some embodiments, a coating of a second polymeric material covers either the abluminal surface or the luminal surface of the coated tubular substrate.

[0029] In some embodiments, a coating of a second polymeric material covers both the abluminal and luminal surfaces of the coated tubular substrate.

[0030] In some embodiments, the second polymeric material is a polyacrylate salt or ester.

[0031] In some embodiments, the method further comprises a step or operation to provide additional functionality to the coating of the second polymeric material. Thus, the method also comprises placing the coated tubular substrate in another aqueous solution containing a therapeutic agent, whereby protons or metal cations are exchanged with the cationic therapeutic agent as counterions to the anionic carboxylates at at least some of the functionalized sites of the second polymeric material.

[0032] In some embodiments, the therapeutic agent is an antibacterial agent.

[0033] In some embodiments, the therapeutic agent is chlorhexidine.

[0034] In some embodiments, the other aqueous solution further comprises a dye, whereby protons or metal cations are exchanged with the cationic dye as counterions to the anionic carboxylates at at least another portion of the functionalized sites of the second polymeric material.

[0035] In some embodiments, the dye also doubles as an antifungal agent.

[0036] In some embodiments, the dye is ethyl violet.

[0037] In some embodiments, the method further includes a step or operation for assembling a coated catheter. Thus, the method also includes inserting a proximal end portion of the coated tubular substrate into a catheter hub. The coated tubular substrate corresponds to the catheter tube of the coated catheter. The method also includes, for each extension leg of one or more extension legs of the coated catheter, inserting a distal end portion of the extension leg into a catheter hub.

[0038] These and other features of the concepts provided herein will become more apparent to those skilled in the art upon review of the accompanying drawings and the following description, which describe in more detail certain embodiments of such concepts. [Brief explanation of the drawings]

[0039] [Figure 1] 1 shows a coated catheter according to some embodiments. [Figure 2] 1 shows a cross-sectional view of a catheter tube of a coated catheter, according to some embodiments. [Figure 3] 1 shows a cross-sectional view of another catheter tube of a coated catheter, according to some embodiments. [Figure 4] 10A-10C show cross-sectional views of yet another catheter tube of a coated catheter, according to some embodiments. [Figure 5]10A-10C show cross-sectional views of yet another catheter tube of a coated catheter, according to some embodiments. [Figure 6] 4 provides a schematic diagram of the catheter tube of FIG. 3 having a coating affixed to the catheter tube, an antimicrobial agent ionically bonded to the coating, and a dye ionically bonded to the coating, according to some embodiments. [Figure 7] 1 illustrates a class of transparent thermoplastic polyurethanes for catheter tubing, according to some embodiments. [Figure 8] 1 illustrates another class of transparent thermoplastic polyurethanes for catheter tubing, according to some embodiments. [Figure 9] FIG. 5 provides a schematic diagram of the catheter tube of FIG. 4 showing a coating secured to the catheter tube by a spent visible light photoinitiator and a spent coinitiator, according to some embodiments. [Figure 10] 1 provides a schematic diagram illustrating a method of coating a catheter tube, according to some embodiments. [Figure 11] 1 provides a schematic illustrating a mechanism for securing a coating to a catheter tube with a spent visible light photoinitiator and a spent co-initiator, according to some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0040] Before some specific embodiments are disclosed in more detail, it should be understood that the specific embodiments disclosed herein do not limit the scope of the concepts provided herein. It should also be understood that the specific embodiments disclosed herein can have features that can be readily separated from the specific embodiment and, optionally, combined with or substituted for features of any of the other numerous embodiments disclosed herein.

[0041] Regarding the terms used herein, it should also be understood that the terms are intended to describe certain specific embodiments and do not limit the scope of the concepts provided herein. Ordinal numbers (e.g., first, second, third, etc.) are generally used to distinguish or identify different features or steps within a group of features or steps and do not provide sequential or numerical limitations. For example, "first," "second," and "third" features or steps do not necessarily have to appear in that order, and a particular embodiment including such features or steps is not necessarily limited to three features or steps. In addition, unless otherwise indicated, any of the aforementioned features or steps can include one or more additional features or steps. Labels such as "left," "right," "top," "bottom," "front," "back," etc. are used for convenience and do not imply, for example, a particular fixed position, orientation, or direction. Instead, such designations are used to reflect, for example, a relative position, orientation, or direction. The singular forms "one," "one," and "said" also include plural references unless the context clearly dictates otherwise.

[0042] "Proximal" is used to refer to a portion, section, piece, element, etc. of a medical device that is intended to be near or relatively near a clinician when the medical device is used on a patient. For example, a "proximal portion" or "proximal section" of a medical device includes a portion or section of the medical device that is intended to be near a clinician when the medical device is used on a patient. Similarly, a "proximal length" of a medical device includes the length of the medical device that is intended to be near a clinician when the medical device is used on a patient. A "proximal end" of a medical device includes the end of the medical device that is intended to be near a clinician when the medical device is used on a patient. The proximal portion, section, or length of a medical device need not include the proximal end of the medical device. In fact, the proximal portion, section, or length of a medical device may be shorter than the proximal end of the medical device. However, the proximal portion, section, or length of a medical device may include the proximal end of the medical device. Where the context does not suggest, or where deemed convenient in the detailed description below, that the proximal portion, proximal section, or proximal length of a medical device includes the proximal end of the medical device, the terms "proximal portion," "proximal section," or "proximal length" may be modified to refer to such portion, section, or length including the end portion, end section, or end length of the medical device, as opposed to the "proximal end portion," "proximal end section," or "proximal end length," respectively.

[0043] "Distal" is used to refer to a portion, section, piece, element, etc. of a medical device that is intended to be near, relatively near, or within a patient when the medical device is used on a patient. For example, a "distal portion" or "distal section" of a medical device includes a portion or section of the medical device that is intended to be near, relatively near, or within a patient when the medical device is used on a patient. Similarly, a "distal length" of a medical device includes a length of the medical device that is intended to be near, relatively near, or within a patient when the medical device is used on a patient. A "distal end" of a medical device includes an end of the medical device that is intended to be near, relatively near, or within a patient when the medical device is used on a patient. A distal portion, section, or length of a medical device need not include the distal end of the medical device. In fact, a distal portion, section, or length of a medical device may be shorter than the distal end of the medical device. However, a distal portion, section, or length of a medical device may include the distal end of the medical device. Where the context does not suggest, or where deemed convenient in the following detailed description, that the distal portion, distal section, or distal length of a medical device includes the distal end of the medical instrument, the terms "distal portion," "distal section," or "distal length" may be modified to indicate such a portion, section, or length, including the end portion, end section, or end length of the medical instrument, as opposed to the "distal end portion," "distal end section," or "distal end length," respectively, of the medical instrument.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0045] Additionally, photoinitiated free radical polymerization for coating medical devices such as catheters utilizes UV photoinitiators with relatively high absorbance in UV light ranges, such as UVC (e.g., 100-280 nm), UVB (e.g., 280-315 nm), and UVC (e.g., 315-400 nm), or narrower ranges. Examples of UV photoinitiators for such free radical polymerization include tert-butyl peroxybenzoate and benzophenone, which have relatively strong UVC absorption peaks at 232 nm and 254 nm, respectively. While the aforementioned UV photoinitiators can be effective in generating and transferring free radicals for chain-growth polymerization when irradiated in the UV light range absorbed by the UV photoinitiator, UV light itself can decompose materials, thereby limiting the choice of substrate for coated medical devices. Furthermore, UV light poses occupational risks, necessitating additional safety measures to limit worker exposure to UV light.

[0046] Disclosed herein are coated medical devices and coating methods utilizing visible light photoinitiators, thereby at least broadening substrate options for coated medical devices and reducing operational risks associated with using higher energy UV light. Coated medical devices include, but are not limited to, coated catheters, such as peripherally inserted central catheters ("PICCs"). For example, the coated catheter may include a catheter tube with a tubular substrate and a coating covering it. The tubular substrate may be comprised of a first polymeric material that is transparent to electromagnetic radiation in the visible light range. The coating may be comprised of a second polymeric material affixed to the tubular substrate by chain ends of the second polymeric material impregnated into the first polymeric material via a used visible light photoinitiator. Coating methods may include, but are not limited to, methods of coating medical devices, such as the coated catheters described above. For example, a coating method may include irradiating a tubular substrate impregnated with a visible light photoinitiator with the electromagnetic radiation described above while placing the tubular substrate in an aqueous solution of a monomer, thereby initiating radical polymerization of the monomer, and coating the tubular substrate with a coating of a second polymeric material.

[0047] medical devices A coated medical device includes any medical device having a coating as described herein on or throughout the internal portion of the medical device, the internal portion or entirety of the medical device being configured to reside within a patient for a period of time, such as during the patient's treatment. For example, a coated medical device can include a coated catheter, which can include a coated peripheral (intravenous) catheter ("PIVC") and a coated central venous catheter ("CVC"). In turn, a coated CVC can include a coated port, a coated percutaneous CVC configured for insertion through the skin into a jugular or subclavian vein, a coated rapid insertion central venous catheter ("RICC"), a coated PICC configured for insertion through the skin into a vein in the arm, and a subcutaneous or tunneled CVC having a coating as described herein.

[0048] FIG. 1 illustrates a coated catheter 100 according to some embodiments. More specifically, FIG. 1 illustrates a coated PICC according to some embodiments. However, it should be understood that the description of the coated catheter 100 is not limited to PICCs but also extends to the other coated catheters described above as well as other coated medical devices. For example, the description of the coating 110 on the catheter tube 102 described below also extends to a coating on the catheter tube of another coated catheter, such as any of the other coated catheters described above. Also, because the catheter tube 102 of the coated catheter 100 is its internal portion, the description of the coating 110 on the catheter tube 102 described below also extends to a coating on the internal portion of yet another coated medical device.

[0049] The coated catheter 100 includes, operably connected in the following order: a catheter tube 102, a catheter hub 104, and one or more extension legs 106. In effect, the catheter tube 102 includes a proximal end portion disposed within the catheter hub 104, and each extension leg of the one or more extension legs 106 includes a distal end portion disposed within the catheter hub 104.

[0050] 2-5 show cross-sectional views of a catheter tube 102 of a coated catheter 100 according to some embodiments. As shown, the catheter tube 102 includes a tubular substrate 108 and a coating 110 covering the tubular substrate 108, which in at least some embodiments corresponds to the coated tubular substrate 132 described below. The tubular substrate 108 includes at least one lumen 112 therethrough, which defines at least one luminal surface 114 of the tubular substrate 108, as well as an abluminal surface 116 of the tubular substrate 108. Additional lumens of the tubular substrate 108 are defined by one or more longitudinal partitions 118 dividing the lumens 112, as shown in FIG. 5. Each additional lumen of the additional lumens includes a corresponding luminal surface. The coating 110 can cover any one or more surfaces selected from the abluminal surface 116 and any luminal surfaces of the tubular substrate 108. In one example, the coating 110 can cover the abluminal surface 116 and each luminal surface of the tubular substrate 108, as shown in Figures 2 and 5. In another example, the coating 110 can cover the abluminal surface 116 of the tubular substrate 108, as shown in Figure 3. In yet another example, the coating 110 can cover the luminal surface 114 of the tubular substrate 108, as shown in Figure 4.

[0051] The tubular substrate 108 is made of a first polymeric material that is transparent to electromagnetic radiation in the visible light range. For example, the first polymeric material can be a thermoplastic polyurethane that is transparent to electromagnetic radiation in the visible light range of 400 nm to 650 nm, e.g., 400 nm to 550 nm, e.g., 450 nm to 500 nm, e.g., 460 nm to 470 nm. As shown in Figures 7 and 8, such a thermoplastic polyurethane can include hard segments with one or more sulfur-based chain extenders and soft segments with polycarbonate or polyether moieties. Some of the thermoplastic polyurethanes included in Figures 7 and 8, along with their preparation, can be found in the following references, each of which is incorporated herein in its entirety: 1) Rogulska et al. Chem. Pap. 2017, 71, 1195-1204; and Rogulska et al. Polym. Bull. 2018, 75, 1211-1235. However, it should be understood that the first polymeric material is not limited to the thermoplastic polyurethane of Figures 7 and 8, or even to thermoplastic polyurethane. Indeed, the first polymeric material can be any medically suitable polymeric material that is transparent to electromagnetic radiation in the aforementioned range(s) of visible light and stable to the conditions of the methods described below. In particular, the tubular substrate 108 of the first polymeric material can include one or more dyes or pigments incorporated therein, so long as the tubular substrate 108 remains transparent to electromagnetic radiation in the aforementioned range(s) of visible light.

[0052] The coating 110 is comprised of a second polymeric material secured to the tubular substrate 108 by chain ends 120 of the second polymeric material impregnated in the first polymeric material, which advantageously makes the second polymeric material coating 110 resistant to delamination. The second polymeric material is polyacrylic acid (-R in FIG. 9 ). 3is —H), polyacrylate salt, polyacrylate ester, or combinations thereof, and the functionalized site 122 of the second polymeric material is functionalized with a combination of functional groups selected from carboxy, carboxylate salt, and carboxylate ester in the aforementioned combinations. The acrylic acid or acrylate residues of the second polymeric material can be either unsubstituted or substituted with alkyl, cycloalkyl, aryl, or heteroaryl groups. The carboxylate salt, if present, includes one or more counterions selected from metal cations, cationic therapeutic agents 124, and cationic dyes 126. Furthermore, the carboxylate ester, if present, includes an organyl group (e.g., —R in FIG. 9 ) selected from alkyl, cycloalkyl, aryl, or heteroaryl groups. 3 ) is included.

[0053] Advantageously, when the second polymeric material comprises a polyacrylate salt, at least a portion of the functionalized sites 122 of the anionic carboxylate-functionalized second polymeric material can include one of the cationic therapeutic agent 124 or the cationic dye 126 as a counterion, e.g., cationic therapeutic agent 124. Additionally, at least another portion of the functionalized sites 122 of the second polymeric material can include the other of the cationic therapeutic agent 124 or the cationic dye 126 as a counterion, e.g., cationic dye 126. Such an example is shown in the schematic diagram of Figure 6, where at least a portion of the functionalized sites 122 of the second polymeric material include the cationic therapeutic agent 124 as a counterion and at least another portion of the functionalized sites 122 of the second polymeric material include the cationic dye 126 as a counterion, whereby the cationic therapeutic agent 124 and the cationic dye 126 are ionically bonded to the coating 110 or its second polymeric material. The cationic therapeutic agent 124 may include, but is not limited to, an antimicrobial agent, such as an antimicrobial small molecule, e.g., chlorhexidine, or an antimicrobial peptide, e.g., dalbavancin, daptomycin, oritavancin, teicoplanin, telavancin, or vancomycin, which may be slowly or controllably released from the coating 110 or its second polymeric material to prevent bacterial colonization, thereby combating catheter-related bloodstream infections (“CRBSIs”). The cationic dye 126 may include, but is not limited to, a triarylmethane dye, such as, but not limited to, a methyl violet dye (e.g., methyl violet 10B) or ethyl violet. The cationic dye 126 functions as a visual indicator of the presence of the second polymeric material coating 110 over the tubular substrate 108, but in some embodiments, the cationic dye 126 may also function as a therapeutic agent.For example, methyl violet 10B and ethyl violet cationic dyes 126 can each function dually as antibacterial or antifungal agents, and when both cationic therapeutic agent 124 and cationic dye 126 are ionically bonded to coating 110 or its second polymeric material, any antibacterial activity of cationic therapeutic agent 124 can be augmented with additional antibacterial activity or any antibacterial activity of cationic therapeutic agent 124 can be complemented with antifungal activity.

[0054] With respect to the second polymeric material anchored to the tubular substrate 108 by the chain ends 120 of the second polymeric material impregnated in the first polymeric material, it should be understood that the chain ends 120 are primarily initiating ends of the polymer chains of the second polymeric material, as opposed to terminal ends of the polymer chains. That is, the chain ends 120 of the second polymeric material impregnated in the first polymeric material are the ends from which the polymer chains of the second polymeric material grow. Because the tubular substrate 108 is impregnated with a photoinitiator 136 prior to initiating the radical polymerization described in the following method, at least some of the chain ends 120 of the second polymeric material impregnated in the first polymeric material comprise spent visible light photoinitiators 128 from which the polymer chains of the second polymeric material grow. Such spent visible light photoinitiators 128 may include spent camphorquinone, as shown in FIG. 9, or a spent analog of camphorquinone, such as spent carboxylated camphorquinone. Additionally, prior to initiating the radical polymerization described in the methods below, the tubular substrate 108 may be impregnated with a coinitiator 142 so that at least another portion of the chain ends 120 of the second polymeric material impregnated in the first polymeric material may contain spent coinitiators 130 from which polymer chains of the second polymeric material grew. Such spent coinitiators 130 may include spent tertiary amines selected from spent ethyl-4-dimethylaminobenzoate, 4-(dimethylamino)benzonitrile, and 2-(N,N-dimethylamino)ethyl methacrylate. Indeed, FIG. 9 illustrates the use of -R 2 Used ethyl-4-dimethylaminobenzoate where -CO2CH2CH3, and -R 2is —CN. Still further, if the tubular substrate 108 is impregnated with a polymerization accelerator prior to initiating the radical polymerization described in the methods below, at least another portion of the chain ends 120 of the second polymeric material impregnated in the first polymeric material may comprise spent polymerization accelerator. Such spent polymerization accelerator may include spent diphenyliodonium chloride, which may be indicated by the chain ends 120 of the second polymeric material comprising phenyl groups.

[0055] method The methods include methods of manufacturing coated medical devices, which include methods of coating medical devices or components thereof in the manufacture of the coated medical devices. For example, the methods of manufacturing coated medical devices include methods of manufacturing coated catheters, such as coated catheter 100, which include methods of coating catheters or components thereof in the manufacture of coated catheter 100. However, as noted above, it should be understood that the description of the method of manufacturing coated catheter 100, a PICC, is again not limited to the manufacture of PICCs, but also extends to the manufacture of other coated catheters described above, as well as the manufacture of other coated medical devices. For example, the description of coating catheter tube 102 described below also extends to coating the catheter tube of another coated catheter, such as any other coated catheter described above. Also, because the catheter tube 102 of coated catheter 100 is its internal portion, the description of coating catheter tube 102 described below also extends to coating the internal portion of yet another coated medical device.

[0056] Similar to the above description, a method for manufacturing a coated catheter 100 includes coating components of the coated catheter 100, such as the catheter tube 102, followed by assembling the coated catheter 100 with the catheter tube 102. As described below, such a method for manufacturing a coated catheter 100 includes various steps or operations beginning with a step or operation for providing a coated tubular substrate 132, as shown in FIG. 10 , which may include impregnation, coating, and functionalization operations. Optionally, such a method for manufacturing a coated catheter 100 includes various steps or operations followed by a step or operation for assembling the coated catheter 100 as a catheter tube 102 with the coated tubular substrate 132, as described above, after cutting the coated tubular substrate 132 to size and attaching a catheter tip to its distal end.

[0057] With respect to the impregnation operation, the impregnation operation can include obtaining an impregnated tubular substrate 134 of a first polymeric material impregnated with at least a visible light photoinitiator 136. Obtaining the impregnated tubular substrate 134 involves placing an unimpregnated tubular substrate 138 of the first polymeric material in an organic solvent solution 140 that includes the photoinitiator 136 dissolved in the organic solvent solution 140 by a relatively polar organic solvent or mixture of organic solvents, including a mixture of a protic organic solvent and an aprotic organic solvent, for example, a mixture of protic or aprotic organic solvents such as a mixture of 2-propanol and 2-butanone. Placing the unimpregnated tubular substrate 138 in the organic solvent solution 140 causes the unimpregnated tubular substrate 138 to swell in the organic solvent solution 140, thereby allowing the photoinitiator 136 to diffuse into the first polymeric material, which in turn impregnates the first polymeric material with the photoinitiator 136 and provides the impregnated tubular substrate 134 in its solvent-swollen form. In particular, any lumen of the unimpregnated tubular substrate 138 can be plugged or otherwise closed to prevent the photoinitiator 136 from entering the lumen and diffusing into the first polymeric material of the corresponding luminal surface prior to placing the unimpregnated tubular substrate 138 in the organic solvent solution 140, thereby providing control over which luminal surfaces of the coated tubular substrate 132 are coated. The solvent-swollen form of the impregnated tubular substrate 134 is then placed in water, allowing the organic solvent to diffuse from the first polymeric material into the water, thereby shrinking the solvent-swollen form of the impregnated tubular substrate 134 and trapping the photoinitiator 136 in the first polymeric material to provide an impregnated tubular substrate 134 of the first polymeric material impregnated with at least the photoinitiator 136.

[0058] The photoinitiator 136 can be characterized by absorption of electromagnetic radiation in the visible light range of 400 nm to 650 nm, e.g., 400 nm to 550 nm, e.g., 450 nm to 500 nm, e.g., 460 nm to 470 nm. Such photoinitiators 136 can include, but are not limited to, camphorquinone, as shown in FIG. 11, or analogs thereof, such as carboxylated camphorquinone. (See Kamoun et al. Arab. J. Chem. 2016, 9(5), 745-754.) Because initiation of radical polymerization with a visible light photoinitiator, such as camphorquinone, can benefit from a coinitiator, the organic solvent solution 140 can further include a coinitiator 142 dissolved in the organic solvent solution 140 along with the photoinitiator 136; if present in the organic solvent solution 140, the coinitiator 142 is also impregnated into the first polymeric material as described above. Such coinitiators 142 may include, but are not limited to, tertiary amines selected from ethyl-4-dimethylaminobenzoate, 4-(dimethylamino)benzonitrile, and 2-(N,N-dimethylamino)ethyl methacrylate. Indeed, FIG. 11 illustrates the -R 2 is -CO2CH2CH3, and ethyl 4-dimethylaminobenzoate, where -R 2 is -CN. Finally, because radical polymerization by a visible light photoinitiator such as camphorquinone can be accelerated with a polymerization accelerator, organic solvent solution 140 can further include a polymerization accelerator dissolved in organic solvent solution 140 along with photoinitiator 136, and if present in organic solvent solution 140, the polymerization accelerator is also impregnated into the first polymeric material as described above. Such polymerization accelerators can include, but are not limited to, diphenyliodonium chloride.

[0059] With respect to the coating operation, the coating operation may include placing the impregnated tubular substrate 134 in a suitable reactor 144 (e.g., a quartz reactor) containing an aqueous solution 146 having the monomer 148 dissolved therein, and irradiating the impregnated tubular substrate 134 with one or more lamps or light-emitting diodes ("LEDs"), thereby providing electromagnetic radiation in the visible light range through which the first polymeric material is transparent and which the photoinitiator 136 absorbs. The photoinitiator 136, which remains entrapped within the impregnated tubular substrate 134 according to the aqueous swelling-preventing solution 146 of the monomer 148, initiates radical polymerization of the monomer 148 from the impregnated tubular substrate 134 or its wall containing the photoinitiator 136 upon irradiation of the photoinitiator 136. As shown in FIG. 11 , a photoinitiator 142 containing camphorquinone as the photoinitiator 136 and ethyl-4-dimethylaminobenzoate (-R 2 is -CO2CH2CH3) or 4-(dimethylamino)benzonitrile (-R 2 When photoinitiator 136 absorbs electromagnetic radiation in the visible light range (e.g., 468 nm for camphorquinone) via an electron transfer complex (where -CN), an excited singlet state of photoinitiator 136 is formed, followed by intersystem crossing to form a triplet state of photoinitiator 136, thereby yielding a diradical of photoinitiator 136. Electron transfer between the diradical of photoinitiator 136 and coinitiator 142 results in an exciplex between the radical anion of photoinitiator 136 and the radical cation of coinitiator 142. Further, proton transfer within the exciplex forms a ketyl radical of photoinitiator 136 with the alkyl radical of coinitiator 142, both of which are capable of propagating their radicals in the radical polymerization of monomer 148. Indeed, as shown in FIG. 11 , each of the ketyl and alkyl radicals can react with a monomer 148 in an aqueous solution 146 in which the impregnated tubular substrate 134 is placed to coat the impregnated tubular substrate 134 with a second polymer material, thereby obtaining a coated tubular substrate 132 having the second polymer material fixed thereto.

[0060] As mentioned above, the second polymeric material affixed to the coated tubular substrate 132 can be polyacrylic acid, a polyacrylate salt, a polyacrylate ester, or a combination thereof. Thus, the monomer 148 dissolved in the aqueous solution 146 in which the impregnated tubular substrate 134 is disposed is acrylic acid (-R in FIG. 11 ). 3 is —H) or an acrylate ester. The acrylic acid or acrylate ester can be either unsubstituted or substituted with an alkyl, cycloalkyl, aryl, or heteroaryl group. Additionally, when an acrylate ester is present, the organyl group of the acrylate ester (e.g., —R in FIG. 11 ) can be substituted with an alkyl, cycloalkyl, aryl, or heteroaryl group. 3 ) is selected from an alkyl, cycloalkyl, aryl, or heteroaryl group.

[0061] With respect to the functionalization operation, the functionalization operation can include modifying the functionalized sites 122 of the second polymeric material, e.g., those functionalized with anionic carboxylates, to include one or more counterions as described above selected from metal cations, cationic therapeutic agent 124, and cationic dye 126. Accordingly, the functionalization operation can include placing the coated tubular substrate 132 in another aqueous solution 150 containing the metal cations, cationic therapeutic agent 124, cationic dye 126, or a combination thereof. In one example, the functionalization operation can include placing the coated tubular substrate 132 in another aqueous solution 150 containing the cationic therapeutic agent 124, thereby exchanging protons or metal cations for the cationic therapeutic agent 124 as counterions to the anionic carboxylates in at least a portion of the functionalized sites 122 of the second polymeric material. In another example, the functionalization operation can include placing the coated tubular substrate 132 in another aqueous solution 150 containing the cationic dye 126, thereby exchanging protons or metal cations as counterions to the anionic carboxylates for the cationic dye 126 in at least a portion of the functionalized sites 122 of the second polymeric material. In yet another example, the functionalization operation can include placing the coated tubular substrate 132 in another aqueous solution 150 containing both the cationic therapeutic agent 124 and the cationic dye 126, thereby exchanging protons or metal cations as counterions to the anionic carboxylates for the cationic therapeutic agent 124 in at least a portion of the functionalized sites 122 of the second polymeric material, and exchanging protons or metal cations as counterions to the anionic carboxylates for the cationic dye 126 in another portion of the functionalized sites 122 of the second polymeric material.

[0062] With respect to the assembly operation, the assembly operation may optionally include inserting a proximal end portion of the coated tubular substrate 132 into the catheter hub 104 after cutting the coated tubular substrate 132 to size and attaching a tip, as described above. Such coated tubular substrate 132 thereby corresponds to the catheter tube 102 of the coated catheter 100. Additionally, the assembly operation may include, for each extension leg of the one or more extension legs 106 of the coated catheter 100, inserting a distal end portion of the extension leg into the catheter hub 104.

[0063] Some specific embodiments have been disclosed herein, and while those specific embodiments have been disclosed in some detail, those specific embodiments are not intended to limit the scope of the concepts provided herein. Further adaptations or modifications may become apparent to those skilled in the art, and the broader aspects encompass those adaptations or modifications as well. Thus, departures from the specific embodiments disclosed herein may be made without departing from the scope of the concepts provided herein.

Claims

1. 1. A coated catheter, comprising: a catheter tube, the catheter tube comprising: a tubular substrate made of a first polymeric material that is transparent to electromagnetic radiation in the visible light range; a coating comprising a second polymeric material over the tubular substrate, the coating being secured to the tubular substrate by chain ends of the second polymeric material impregnated in the first polymeric material, at least a portion of the chain ends comprising spent visible light photoinitiator; A coated catheter comprising:

2. 10. The coated catheter of claim 1, A coated catheter, wherein the first polymeric material is a thermoplastic polyurethane that is transparent to electromagnetic radiation in the visible light range of 400 nm to 650 nm.

3. 3. The coated catheter of claim 2, A coated catheter, wherein the thermoplastic polyurethane comprises hard segments having one or more sulfur-based chain extenders.

4. 4. The coated catheter according to claim 2 or 3, A coated catheter, wherein the thermoplastic polyurethane comprises a soft segment having a polycarbonate portion.

5. 4. The coated catheter according to claim 2 or 3, A coated catheter, wherein the thermoplastic polyurethane comprises a soft segment having a polyether moiety.

6. The coated catheter according to any one of claims 1 to 5, A coated catheter, wherein the spent visible light photoinitiator is spent camphorquinone or a spent analog of camphorquinone.

7. The coated catheter according to any one of claims 1 to 6, A coated catheter, wherein at least another portion of the chain ends of the first polymeric material comprise spent coinitiator.

8. 8. The coated catheter of claim 7, A coated catheter wherein the spent coinitiator is a spent tertiary amine selected from ethyl-4-dimethylaminobenzoate; 4-(dimethylamino)benzonitrile; and 2-(N,N-dimethylamino)ethyl methacrylate.

9. The coated catheter according to any one of claims 1 to 8, A coated catheter, wherein the coating of the second polymeric material covers either the abluminal surface or the luminal surface of the tubular substrate.

10. The coated catheter according to any one of claims 1 to 8, A coated catheter, wherein the coating of the second polymeric material covers both the abluminal and luminal surfaces of the tubular substrate.

11. The coated catheter according to any one of claims 1 to 10, A coated catheter wherein the second polymeric material is a polyacrylate salt or ester.

12. 12. The coated catheter of claim 11, The coated catheter, wherein the second polymeric material is a polyacrylate salt, and at least a portion of the functionalized sites of the second polymeric material are functionalized with an anionic carboxylate and a cationic therapeutic agent as a counterion.

13. 13. The coated catheter of claim 12, A coated catheter wherein the therapeutic agent is an antibacterial agent.

14. 13. The coated catheter of claim 12, A coated catheter wherein the therapeutic agent is chlorhexidine.

15. The coated catheter according to any one of claims 12 to 14, At least another portion of the functionalized sites of the second polymeric material are functionalized with an anionic carboxylate and a cationic dye as the counterion, thereby visually indicating that a coating of the second polymeric material covers the tubular substrate.

16. 16. The coated catheter of claim 15, A coated catheter, wherein the dye doubles as an antifungal agent.

17. 16. The coated catheter of claim 15, A coated catheter, wherein the dye is ethyl violet.

18. The coated catheter according to any one of claims 1 to 17 further comprises: a catheter hub including a proximal end portion disposed within the catheter hub; one or more extension legs, each extension leg of the one or more extension legs including a distal end portion disposed within the catheter hub; A coated catheter comprising:

19. 1. A method of manufacturing a coated catheter, comprising: obtaining an impregnated tubular substrate of a first polymeric material that is transparent to electromagnetic radiation in the visible light range, said first polymeric material being impregnated with a visible light photoinitiator; placing the impregnated tubular substrate in an aqueous solution containing a monomer dissolved in the aqueous solution; irradiating the impregnated tubular substrate with electromagnetic radiation in the visible light range through which the first polymeric material is transparent, the visible light photoinitiator initiating radical polymerization of monomers upon irradiation with the visible light photoinitiator, thereby coating the impregnated tubular substrate with a coating of a second polymeric material to provide a coated tubular substrate; A method comprising:

20. The method of claim 19 further comprises: placing an unimpregnated tubular substrate in an organic solvent solution comprising the visible light photoinitiator dissolved in the organic solvent solution; wherein the unimpregnated tubular substrate is swelled in the organic solvent solution such that the visible light photoinitiator diffuses into the first polymeric material, thereby impregnating the first polymeric material with the visible light photoinitiator and providing the impregnated tubular substrate in its solvent-swollen form.

21. The method of claim 20 further comprises: placing the solvent-swollen impregnated tubular substrate in water; The organic solvent diffuses from the first polymeric material into the water, thereby shrinking the solvent-swollen impregnated tubular substrate and entrapping the visible light photoinitiator in the first polymeric material.

22. The method according to any one of claims 19 to 21, The method of claim 1, wherein the first polymeric material is a thermoplastic polyurethane that is transparent to electromagnetic radiation in the visible light range of 400 nm to 650 nm, the thermoplastic polyurethane comprising hard segments having one or more sulfur-based chain extenders and soft segments having polycarbonate moieties.

23. 23. The method of claim 22, The method wherein said visible light photoinitiator is camphorquinone or a camphorquinone analogue characterized by its absorption of electromagnetic radiation in the visible light range of 400 nm to 650 nm.

24. The method according to any one of claims 19 to 23, The method further comprises impregnating the impregnated tubular substrate with a coinitiator, wherein the coinitiator is a tertiary amine selected from ethyl-4-dimethylaminobenzoate; 4-(dimethylamino)benzonitrile; and 2-(N,N-dimethylamino)ethyl methacrylate.

25. The method according to any one of claims 19 to 24, The method wherein the coating of the second polymeric material covers either the abluminal surface or the luminal surface of the coated tubular substrate.

26. The method according to any one of claims 19 to 24, The method wherein the coating of the second polymeric material covers both the abluminal and luminal surfaces of the coated tubular substrate.

27. The method according to any one of claims 19 to 26, The method wherein the second polymeric material is a polyacrylate salt or ester.

28. The method of claim 27 further comprises: placing the coated tubular substrate in another aqueous solution containing a therapeutic agent, whereby protons or metal cations are exchanged with the cationic therapeutic agent as counterions to the anionic carboxylates at at least a portion of the functionalized sites of said second polymeric material.

29. 29. The method of claim 28, The method wherein the therapeutic agent is an antibacterial agent.

30. 29. The method of claim 28, The method wherein the therapeutic agent is chlorhexidine.

31. The method according to any one of claims 28 to 30, The other aqueous solution further comprises a dye, whereby protons or metal cations are exchanged with the cationic dye as counterions to the anionic carboxylates at at least another portion of the functionalized sites of said second polymeric material.

32. 32. The method of claim 31 , The dye functions dually as an antifungal agent.

33. 32. The method of claim 31 , The method wherein the dye is ethyl violet.

34. The method according to any one of claims 19 to 33, further comprising: inserting a proximal end portion of a coated tubular substrate into a catheter hub, the coated tubular substrate corresponding to a catheter tube of a coated catheter; for each extension leg of one or more extension legs of the coated catheter, inserting a distal end portion of the extension leg into the catheter hub; A method comprising:

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