Antimicrobial catheter coatings with passive antifungal properties

Abstract

The present invention relates to a medical device resistant to Candida albicans and antimicrobial activity comprising a medical device surface having a copolymer coating of an antifungal moiety and an ion binding moiety. The copolymer coating is prepared by reacting an antifungal monomer selected from the group consisting of tricyclodecane dimethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate, and mixtures thereof, and an antifungal monomer selected from the group consisting of acrylic acid, acrylic acid, acrylic acid, and mixtures thereof. Ionic binding monomers of methyl acrylate and mixtures thereof are copolymerized. The coating may be loaded with an elutable antimicrobial substance bound to an ion binding moiety. The antimicrobial substance may be a cationic type, such as a cationic dye, such as ethyl violet chloride, a cationic drug, such as chlorhexidine diacetate, a cationic peptide, such as a cecropin, a clawed toad antibacterial peptide, a porcine antibacterial peptide, and a bovine antibacterial peptide, or ionic silver. The medical device may be a catheter having a luminal inner surface and a luminal outer surface, and a copolymer coating disposed on the luminal inner surface and the luminal outer surface.

Description

Technical Field

[0001] This disclosure relates to antifungal coatings for medical devices. This disclosure also relates to medical device coatings having both antimicrobial and passive antifungal properties. The covalently linked coating includes structural portions having passive resistance to the yeast strain *Candida albicans*. The coating is combined with an ion-bound pharmaceutical active ingredient (API) for elution. The API can be selected to provide antimicrobial activity against both Gram-positive and Gram-negative bacteria. Background Technology

[0002] Medical devices may include catheters having coatings on the inner and outer surfaces of the lumen, the coatings having antifungal and antimicrobial properties.

[0003] The medical devices disclosed herein include those that are susceptible to bacterial and fungal colonization and infection due to prolonged contact with blood or bodily fluids. Examples of medical devices include, but are not limited to, catheters such as central venous catheters (CVCs) and peripherally inserted central venous catheters (PICCs), urinary catheters, dialysis catheters, and blood-contacting auxiliary devices and lines such as blood transfusion equipment, plasma collection equipment, and dialysis equipment.

[0004] Catheters are life-saving devices and have become a standard of care. Catheter-related bloodstream infections (CRBSI) and central catheter-related bloodstream infections (CLABSI) are caused by the colonization of microorganisms in patients with intravascular catheters and access devices. These infections are a significant cause of illness and additional medical costs, with approximately 250,000–400,000 cases of central venous catheter (CVC)-related bloodstream infections occurring annually in U.S. hospitals. In addition to monetary costs, these infections are associated with 20,000 to 100,000 deaths each year. Despite guidelines to help reduce healthcare-associated infections (HAI), CVBI continues to plague our healthcare system.

[0005] Several methods have been used to mitigate these infections, including proper cleaning of the insertion site, good catheter placement practices, and the use of antimicrobial agents in or above the catheter line to inhibit microbial growth.

[0006] Most commercially available catheters currently in use do not have any antimicrobial or antifungal properties.

[0007] To provide antimicrobial and antifungal properties, active agents need to be immobilized in a matrix or coated onto the surface of the catheter. However, these catheters have yielded less than satisfactory results.

[0008] Therefore, there is a need in the field for medical devices such as catheters that have antifungal and antimicrobial properties.

[0009] The subject matter claimed herein is not limited to embodiments that address any disadvantages or operate only in environments such as those described above. Rather, this background art is merely provided as an example technical field to illustrate some of the embodiments described herein that can be practiced. Attached Figure Description

[0010] The exemplary embodiments will be described and explained in further specific and detailed manner using the accompanying drawings, in which:

[0011] Figure 1 Table showing five acrylate and diacrylate monomers M1-M5 that exhibit passive resistance to Candida albicans yeast strains.

[0012] Figure 2 The mechanism of UV light-induced free radical formation using benzophenone photoinitiator was disclosed.

[0013] Figure 3 This is a flowchart outlining the procedure for testing surface coatings prepared from M1-M5 antifungal monomers.

[0014] Figure 4 The layout of the assay plate used for MBEC studies of the tested monomers is shown.

[0015] Figure 5 The figure for the MBEC study results shows the logarithmic reduction of each surface coating relative to the growth control produced by different combinations of monomers M1-M5. Detailed Implementation

[0016] This disclosure relates to a method for preparing antifungal coatings on medical devices using UV-induced free radical polymerization. This method can be used to prepare covalently bonded intraluminal and extraluminal coatings on catheters. For example... Figure 1 As shown, coatings incorporating antifungal monomers with structural motifs M1-M5 exhibit excellent passive resistance to clinically relevant Candida albicans yeasts, such as ATCC 90027. Antifungal monomers can be combined with one or more ion-binding eluting monomers to allow the active pharmaceutical ingredient (API) to be ionically bound to the surface for elution. The APIs disclosed herein possess antimicrobial activity and are effective against Gram-positive Staphylococcus aureus strains such as ATCC 33592 and Gram-negative Pseudomonas aeruginosa strains such as ATCC 27853.

[0017] The method for forming a covalently bonded coating uses a photoinitiator capable of generating free radicals upon exposure to UV light to covalently bond a certain proportion of the anti-Candida copolymer to the surface of a medical device. The copolymer graft containing ion-binding monomers can subsequently be loaded with antimicrobial cationic substances, including but not limited to cationic dyes such as methylene blue and ethyl violet chloride, cationic drugs such as chlorhexidine diacetate, cationic peptides such as cecropins, macainins, protegrins, and bactenicins, or ionic silver.

[0018] U.S. Patent No. 8,920,886 discloses catheter coatings that aim to use carboxylic acids containing acrylate groups (e.g., acrylic acid (CAS No. 79-10-7) and methyl acrylate (CAS No. 96-33-3)). In contrast, the antifungal coatings for medical devices disclosed herein replace all or part of conventional acrylate monomers with acrylate and diacrylate monomers comprising cyclic hydrocarbons, esters, tert-butyl structural moieties, and non-aromatic hydrocarbon structural moieties that exhibit resistance to Candida albicans. Non-limiting examples of antifungal monomers exhibiting passive resistance to *Candida albicans* include M1: tricyclodecanedimethyl diacrylate (CAS No. 43048-08-4), M2: 4-tert-butylcyclohexyl acrylate (CAS No. 84100-23-2), M3: neopentyl glycol diacrylate (CAS No. 2223-82-7), M4: trimethylcyclohexyl methacrylate (CAS No. 7779-31-9), and M5: isobornyl acrylate (CAS No. 5888-33-5), such as... Figure 1 As shown in the figure. Polymer coatings prepared from these monomers, including mixtures of these monomers, possess passive antifungal activity. The polymer coatings may be loaded with one or more elutable antimicrobial substances to provide antimicrobial activity.

[0019] The disclosed antifungal coating for medical devices utilizes free radical polymerization to graft copolymer monomer reagents onto the catheter surface. Surface graft polymerization using ultraviolet (UV) light is an efficient and convenient method for modifying polymer surfaces. A common strategy for surface graft polymerization uses photoinitiators that generate free radicals when exposed to UV light. These then react with monomers to initiate polymer chain growth. More specifically, photoinitiators generate a class of free radicals upon exposure to UV light that extract hydrogen atoms from the polymer surface, thereby generating surface-bound free radicals capable of initiating graft polymerization of monomers in solution. Non-limiting examples of photoinitiators include benzophenone (BP), 2,2-dimethoxy-2-phenylacetophenone (DPA), and related molecules.

[0020] In this process, the mechanism of UV light-induced free radical formation by benzophenone photoinitiator is as follows: Figure 2 As shown in Gutiérrez-Villarreal, MH, and JG Guzmán-Moreno. “Surface graft polymerization of N-vinylcaprolactam onto polylactic acid film by UVirradiation.” Journal of Polymer Research 20.6 (2013): 1-6. The photoinitiator enters a radicalized state after exposure to a UV-A to UV-C radiation spectrum of approximately 100 nm to 400 nm. The excited electrons then undergo intersystem crossing and enter a highly reactive triplet state, generating a diradical. This diradical then extracts hydrogen atoms from surrounding molecules (grafted monomers or co-initiators). This diradical propagates in solution to surrounding monomers to create a covalently bonded coating on the surface of the medical device.

[0021] The disclosed surface graft polymerization reaction can be carried out in a grafting reactor containing a polymerizable aqueous solution of monomers, which polymerize to form a polymer or copolymer coating grafted onto the surface of a medical device. The monomer solution comprises an antifungal monomer selected from tricyclodecanediethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate, and mixtures thereof. In some embodiments, the monomer solution comprises two or more antifungal monomers.

[0022] In some embodiments, the monomer solution further comprises an ion-bound monomer. In some embodiments, the ion-bound monomer is selected from acrylic acid, methyl acrylate, and mixtures thereof.

[0023] The grafting reactor may include a UV-transmissive wall made of glass or a material that transmits UV light. A UV light assembly positioned outside the grafting reactor allows UV light to pass through the wall and irradiate the interior of the reactor. The UV light can be in the range of approximately 100 nm to approximately 400 nm. This includes UVA (315-400 nm), UVB (280-315 nm), and UVC (100-280 nm). In this manner, medical devices such as catheters can be immersed in a polymerizable solution and simultaneously exposed to UV light to induce a polymerization reaction and form an antifungal coating.

[0024] Copolymer grafts containing ion-binding monomers can be exposed to a solution containing one or more antimicrobial substances, selected to provide antimicrobial activity against Gram-positive and Gram-negative bacteria, including but not limited to Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. In some embodiments, the antimicrobial substance is cationic, including but not limited to cationic dyes such as methylene blue and ethyl violet chloride, cationic drugs such as chlorhexidine diacetate, cationic peptides such as silkworm antimicrobial peptides, Xenopus antimicrobial peptides, porcine antimicrobial peptides, and bovine antimicrobial peptides, or ionic silver.

[0025] Antifungal coatings for medical devices are produced via a photochemical reaction catalyzed by UV radiation. In some embodiments, the medical device is a catheter having an inner and outer lumen surface. Free radical polymerization can be used to graft copolymers simultaneously from both the inner and outer lumen surfaces of the catheter. The graft copolymers can be prepared from a monomer mixture containing monomers with passive and active elution structural moieties in a specific ratio. These copolymers are covalently bonded to the catheter. They can then be loaded with a cationic pharmaceutically active ingredient (API) for elution. The API can be selected to provide antimicrobial activity against both Gram-positive and Gram-negative bacteria. This method extends the prior art of catheter coatings by disclosing coatings made from a unique group of monomers that are effective against Candida albicans, which can be loaded with one or more antimicrobial agents to provide broad-spectrum antimicrobial and antifungal activity.

[0026] Therefore, in addition to the controlled release of antimicrobial substances with active antimicrobial effects against Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, the disclosed catheter coating also exhibits passive resistance to Candida albicans. The same principle can be applied to other catheter materials with unique physical and chemical properties.

[0027] Other features and advantages of the disclosed invention will become apparent from the following embodiments. These embodiments illustrate different aspects and embodiments of the invention and how they can be made and practiced. These embodiments do not limit the claimed invention. Although similar or equivalent methods and materials to those described herein can be used in the practice of the invention, suitable methods and materials are described below. Based on this disclosure, those skilled in the art will be able to identify and use other components and methodologies that can be used in the practice of the invention.

[0028] Example 1

[0029] Preparation of five acrylate and diacrylate monomers (M1-M5); Figure 1 The resulting surface coating, and its passive resistance to Candida albicans confirmed using a standard MBEC (Minimum Biofilm Clearance Concentration) assay, was analyzed. The surface coating was prepared using a photoinitiator, 2,2-dimethoxy-2-phenylacetophenone (DPA), with the chemical structure shown below.

[0030]

[0031] MBEC assay is a high-throughput screening assay used to determine the biofilm efficacy of antimicrobial agents against a variety of microorganisms. The MBEC assay biofilm inoculum consists of a plastic cap with 96 pins and a corresponding receiving plate.

[0032] To assess the effectiveness of monomers against clinically relevant strains, a surface coating was polymerized onto pins of an assay device and transported for MBEC testing. This allowed pathogens to establish themselves on the pins under intermittent conditions with gentle mixing, and then be transferred to another receiving plate with various selected reactor conditions to test biofilm or yeast viability. This study tested resistance to adhesion and Candida albicans formation. For this purpose, the surface-coated pins were cultured in their respective pathogens, transferred to receiving plates and sonicated, followed by further serial dilutions and plating, then pathogen colony counting and log reduction calculation. Figure 3 This is a flowchart outlining the procedure for testing surface coatings prepared from M1-M5 antifungal monomers.

[0033] A surface coating was prepared on nails using a 50 / 50 v% / v% monomer mixture / dioxolane ratio and a total solution concentration of 5% w% / v% photoinitiator 2,2-dimethoxy-2-phenylacetophenone. 200 μL of each polymerization solution was prepared and added to the corresponding nail receiver reservoir. The nails were immersed in the solution and placed in a UV reactor oven supplied with a nitrogen blanket. When the oxygen content measured in the oven was less than 200 ppm, the samples were subjected to UV curing from a UVA lamp for 10 minutes.

[0034] refer to Figure 4A surface coating solution was prepared such that the nails in rows AE and columns 1-5 were surface-coated with acrylate monomers M1-M5 in a 50 / 50 ratio, and this was repeated in columns 6-10. That is, row AE corresponds to a surface coating using monomers from M1-M5, and columns 1-5 and 6-10 correspond to monomers from M1-M5. Therefore, each nail was prepared with a surface coating comprising a mixture of two monomers, but... Figure 4 Except for the diagonal peg positions (A1, B2, C3, D4, E5, A6, B7, C8, D9, and E10), which are prepared from solutions of a single monomer. This allows for two tests of the surface coating for each monomer (MX / MX, indicated by the diagonal peg positions) and four replicates of the 50 / 50 ratio monomer solution pair variation (MX / MY). Pegs in column 11 are retained for immersion / adjustment in the reagent blank test control of dioxolane in the solvent system, column 12 is retained for the reagent blank + %5% photoinitiator control, and row FH is retained as a blank for the MBEC procedure pathogen growth control (GC) standard and yeast growth test (BGC).

[0035] In the following text Figure 4 A diagram of the board is provided. Figure 4 The layout of the assay plate used for the MBEC study of the tested monomers is shown. Various ratios and placements of the monomers used in the surface coating solutions described in the preceding sections are also shown.

[0036] The MBEC study results showed that several variants of surface coatings prepared from single monomers and combinations of M1-M5 produced a 4-Log reduction (99.99% reduction) in Candida albicans formation relative to the growth control recovery data, as shown in... Figure 5 As can be seen in the text. Figure 5 The figure shows the results of the MBEC study, illustrating the logarithmic reduction of various surface coatings produced by different combinations of monomers M1-M5 relative to the growth control. Several variants of surface coatings utilizing these new monomers produced satisfactory 4-Log reductions and showed general pathogen resistance to clinically relevant Candida albicans. Surface coatings produced from M1-M5 exhibited a 3-Log reduction (99.9% reduction) in general resistance to Candida albicans.

[0037] Implementation Plan

[0038] Various embodiments are listed below. It should be understood that the embodiments listed below can be combined with all aspects of the invention and other embodiments.

[0039] Implementation Scheme 1. A method for preparing an antifungal coating on a medical device, comprising: obtaining a medical device including a surface of the medical device, wherein the surface of the medical device contains a photoinitiator that generates free radicals upon exposure to UV light; exposing the surface of the medical device to a monomer solution containing an antifungal monomer; irradiating the photoinitiator with UV light to cause free radical polymerization; grafting the antifungal monomer onto the surface of the medical device; and forming an antifungal coating.

[0040] Implementation Scheme 2. The method of Implementation Scheme 1, wherein the antifungal monomer is selected from tricyclodecanediethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate and mixtures thereof.

[0041] Implementation Scheme 3. The method of Implementation Scheme 2, wherein the monomer solution contains two or more antifungal monomers.

[0042] Implementation Scheme 4. The method of any of the foregoing embodiments, wherein the medical device includes a catheter having an inner lumen surface and an outer lumen surface, and wherein the surface of the medical device includes an inner lumen surface and an outer lumen surface.

[0043] Implementation Scheme 5. The method of any of the foregoing embodiments, wherein the monomer solution further comprises an ion-binding monomer, and wherein the step of irradiating the photoinitiator with UV light causes free radical polymerization of the antifungal monomer and the ion-binding monomer to form a copolymer coating having antifungal and ion-binding structural portions.

[0044] Implementation Scheme 6. The method of Implementation Scheme 5, wherein the ion-binding monomer is selected from acrylic acid, methyl acrylate and mixtures thereof.

[0045] Implementation Scheme 7. The method of Implementation Scheme 5 or 6, further comprising exposing the copolymer coating to an antimicrobial substance bonded to the ion-bonded structural portion.

[0046] Implementation Scheme 8. The method of Implementation Scheme 7, wherein the antimicrobial substance is a cationic antimicrobial dye.

[0047] Implementation Scheme 9. The method of Implementation Scheme 8, wherein the cationic antimicrobial dye is selected from methylene blue and ethyl violet.

[0048] Implementation Scheme 10. The method of Implementation Scheme 7, wherein the antimicrobial substance is chlorhexidine diacetate.

[0049] Implementation Scheme 11. The method of Implementation Scheme 7, wherein the antimicrobial substance is ionic silver.

[0050] Implementation Scheme 12. The method of Implementation Scheme 7, wherein the antimicrobial substance is a cationic peptide selected from silkworm antimicrobial peptides, Xenopus antimicrobial peptides, porcine antimicrobial peptides and bovine antimicrobial peptides.

[0051] Implementation Scheme 13. The method of any of the foregoing embodiments, wherein the photoinitiator is a radical-generating substance selected from 2,2-dimethoxy-2-phenylacetophenone, benzophenone or related substances and mixtures thereof.

[0052] Implementation Scheme 14. A medical device having antifungal and antimicrobial activity, comprising: a medical device surface having a copolymer coating comprising an antifungal structural portion and an ion-binding portion, wherein the copolymer coating is obtained by copolymerizing an antifungal monomer and an ion-binding monomer, said antifungal monomer being selected from tricyclodecanediethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate, and mixtures thereof, said ion-binding monomer being selected from acrylic acid, methyl acrylate, and mixtures thereof; and an antimicrobial substance ionically bound to the ion-binding structural portion.

[0053] Implementation Scheme 15. The medical device of Implementation Scheme 14, wherein the medical device includes a catheter having an inner lumen surface and an outer lumen surface, and wherein a copolymer coating is disposed on the inner lumen surface and the outer lumen surface.

[0054] Implementation Scheme 16. The medical device of Implementation Scheme 14 or 15, wherein the antimicrobial substance is a cationic antimicrobial dye.

[0055] Implementation Scheme 17. The medical device of Implementation Scheme 16, wherein the cationic antimicrobial dye is selected from methylene blue and ethyl violet.

[0056] Implementation Scheme 18. Medical devices according to Implementation Scheme 14 or 15, wherein the antimicrobial substance is chlorhexidine diacetate.

[0057] Implementation Scheme 19. Medical devices according to Implementation Scheme 14 or 15, wherein the antimicrobial substance is ionic silver.

[0058] Implementation Scheme 20. The medical device according to Implementation Scheme 14 or 15, wherein the antimicrobial substance is a cationic peptide selected from silkworm antimicrobial peptides, Xenopus antimicrobial peptides, porcine antimicrobial peptides and bovine antimicrobial peptides.

[0059] Implementation Scheme 21. The medical device of Implementation Scheme 14 or 15, wherein the antimicrobial substance is selected from cationic antimicrobial dyes, chlorhexidine diacetate, ionic silver, cationic peptides and combinations thereof.

[0060] Throughout this specification, references to "one embodiment," "some embodiments," "one or more embodiments," or "implementation" mean that a particular feature, structure, material, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the appearance of phrases such as "in one or more embodiments," "in some embodiments," "in one embodiment," or "in an embodiment" throughout this specification does not necessarily refer to the same embodiment of the invention. Furthermore, in one or more embodiments, a particular feature, structure, material, or characteristic may be combined in any suitable manner.

[0061] Although the invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and apparatus of the invention without departing from the spirit and scope thereof. Therefore, the invention is intended to include modifications and variations within the scope of the appended claims and their equivalents.

Claims

1. A method for preparing an antifungal coating on a medical device comprising: obtaining a medical device comprising a medical device surface, wherein the medical device surface comprises a photoinitiator; exposing the medical device surface to a monomer solution comprising an antifungal monomer; and irradiating the photoinitiator with UV light to cause free radical polymerization and grafting of the antifungal monomer to the medical device surface and formation of an antifungal coating.

2. The method of claim 1, wherein the antifungal monomer is selected from the group consisting of tricyclodecanedimethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate, and mixtures thereof.

3. The method of claim 2, wherein the monomer solution comprises two or more antifungal monomers.

4. The method of claim 1, wherein the medical device comprises a catheter having an inner luminal surface and an outer luminal surface, and wherein the medical device surface comprises the inner luminal surface and the outer luminal surface.

5. The method of claim 1, wherein the monomer solution additionally comprises an ion- binding monomer, and wherein the step of irradiating the photoinitiator with UV light causes free radical polymerization of the antifungal monomer and ion-binding monomer to form a copolymer coating having antifungal and ion-binding moieties.

6. The method of claim 5, wherein the ion-binding monomer is selected from the group consisting of acrylic acid, methyl acrylate, and mixtures thereof.

7. The method of claim 5, further comprising exposing the copolymer coating to an antimicrobial substance that binds to the ion-binding moieties.

8. The method of claim 7, wherein the antimicrobial substance is a cationic antimicrobial dye.

9. The method of claim 8, wherein the cationic antimicrobial dye is selected from the group consisting of methylene blue and ethyl violet.

10. The method of claim 7, wherein the antimicrobial substance is chlorhexidine diacetate.

11. The method of claim 7, wherein the antimicrobial substance is ionic silver.

12. The method of claim 7, wherein the antimicrobial substance is a cationic peptide selected from the group consisting of Cecropin peptides, Magainin peptides, Prophenin peptides, and Brevin peptides.

13. The method of claim 1, wherein the photoinitiator is a free radical generating species selected from the group consisting of 2,2-dimethoxy-2-phenylacetophenone, benzophenone, and mixtures thereof.

14. A medical device having antifungal and antimicrobial activity comprising: a medical device surface having a copolymer coating comprising antifungal moieties and ion-binding moieties, wherein the copolymer coating is obtained by copolymerizing an antifungal monomer selected from the group consisting of tricyclodecanedimethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate, and mixtures thereof; and an ion-binding monomer selected from the group consisting of acrylic acid, methyl acrylate, and mixtures thereof; and a medical device surface having a copolymer coating comprising antifungal moieties and ion-binding moieties, wherein the copolymer coating is obtained by copolymerizing an antifungal monomer selected from the group consisting of tricyclodecanedimethanol diacrylate, 4-tert-butylcyclohexyl acrylate, neopentyl glycol diacrylate, trimethylcyclohexyl methacrylate, isobornyl acrylate, and mixtures thereof; and an ion-binding monomer selected from the group consisting of acrylic acid, methyl acrylate, and mixtures thereof; and antimicrobial substance ionically bound to the ionically binding moiety.

15. The medical device of claim 14, wherein the medical device comprises a catheter having an inner luminal surface and an outer luminal surface, and wherein the copolymer coating is disposed on the inner luminal surface and the outer luminal surface.

16. The medical device of claim 14, wherein the antimicrobial substance is a cationic antimicrobial dye.

17. The medical device of claim 16, wherein the cationic antimicrobial dye is selected from the group consisting of methylene blue and ethyl violet.

18. The medical device of claim 14, wherein the antimicrobial substance is chlorhexidine diacetate.

19. The medical device of claim 14, wherein the antimicrobial substance is ionic silver.

20. The medical device of claim 14, wherein the antimicrobial substance is a cationic peptide selected from the group consisting of Cecropin peptides, Magainin peptides, Prophenin peptides, and Brevin peptides.

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