Coated catheter with BIO-mimicked glycocalyx structures and nitric oxide release function providing antithrombogenic and antimicrobial properties

Abstract

A catheter system may include a catheter adapter, which may include a distal end and a proximal end. The catheter system may include a catheter extending from the distal end of the catheter adapter. The catheter may include an outer surface having an active area and a passive area proximate the active area. In some embodiments, a plurality of active areas and a plurality of passive areas alternate along a length of the catheter. The active area includes one or more microbiocidal agents. The passive area includes a nitric oxide-generating compound and a glycocalyx polysaccharide matrix to simulate vascular endothelial surface. In further detail, the passive area may be superhydrophilic.

Description

COATED CATHETER WITH BIO-MIMICKED GLYCOCALYX STRUCTURES AND NITRIC OXIDE RELEASE FUNCTION PROVIDING ANTITHROMBOGENIC AND ANTIMICROBIAL PROPERTIESBACKGROUND

[0001] The disclosed invention relates to a catheter with a bio-mimicked adaptive surface for thrombus resistance and infection prevention by release of nitric oxide (NO) and glycocalyx-like surface coating. The disclosed catheter surface includes alternating patterned areas of active and passive functionality. The passive areas comprise a bio-mimicked adaptive surface to provide thrombus resistance and the active areas comprise a surface treated with one or more antimicrobial agents to provide targeted killing of microbes. The two surfaces in combination provide improved antithrombogenic and antimicrobial activity.

[0002] Indwelling medical devices include medical devices which are susceptible to bacterial colonization and infection due to prolonged contact with blood or body fluids. Examples of indwelling medical devices include, but are not limited to, catheters, such as central venous catheters (CVCs) and peripherally inserted central catheters (PICCs), urinary catheters, dialysis catheters, as well as auxiliary equipment and tubing that contacts blood, such as blood infusion equipment, plasma collection equipment, dialysis equipment, etc.

[0003] Catheters are life saving devices that have become a standard of care. Although catheters improve patient care, the longer the in-dwelling devices stay inside the patient’s body, the catheter attracts bioparticles which become deposited on catheter surfaces and can eventually lead to thrombus. Catheter related thrombosis is also associated with catheter related sepsis and further complications. Catheter related thrombosis and infections are the most common complications in catheter management in hospitals.

[0004] Catheter-related bloodstream infection (CRBSI) and central line-associated bloodstream infection (CLABSI) are caused by the colonization of microorganisms in patients with intravascular catheters and access devices. These infections are an important cause of illness and excess medical costs, as approximately 250,000 - 400,000 cases of central venous catheter (CVC) associated bloodstream infections occur annually in U.S. hospitals. In addition to the monetary costs, these infections are associated with anywhere from 20,000 to 100,000 deaths each year. Despite guidelines to help reduce healthcare associated infections (HAIs), catheter-related bloodstream infections continue to plague our healthcare system.

[0005] Multiple approaches are utilized to mitigate the occurrence of these infections - namely proper insertion site cleaning, good catheter placement practice, and use of antimicrobial agents in or on the catheter tubing to suppress microbial growth. To provide antimicrobial properties, antimicrobial agents have been immobilized into the catheter matrix or coated onto the catheter surface. These catheters, however, have given less than satisfactory results. Accordingly, there is a need in the art for catheters having improved antithrombogenic and antimicrobial capabilities.

[0006] The subject matter claimed herein is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is only provided to illustrate one example technology area where some implementations described herein may be practiced.SUMMARY

[0007] The present disclosure relates generally to a catheter having patterned areas of active and passive functionality and to related systems and methods. The areas of passive functionality contain a bio-mimicked adaptive surface to provide thrombus resistance. The areas of activefunctionality contain a surface treated with one or more antimicrobial agents to provide targeted killing of microbes. The two surfaces in combination provide improved antithrombogenic and antimicrobial activity.

[0008] In some embodiments, a catheter system may include a catheter adapter, which may include a distal end and a proximal end. In some embodiments, the catheter system may include a catheter, which may extend from the distal end of the catheter adapter. In some embodiments, the catheter system may be peripheral intravenous, central venous, midline, or arterial catheter system. In some embodiments, the catheter system may be a urinary or dialysis catheter system or another suitable type of catheter system.

[0009] In some embodiments, the catheter may include an outer surface having an active area and a passive area proximate the active area. In some embodiments, the catheter may include an inner surface forming an inner lumen, and the inner surface may have an active area and a passive area similar to the outer surface.

[0010] In some embodiments, the outer surface of the catheter has a plurality of active areas and a plurality of passive areas. In some embodiments, the plurality of active areas and the plurality of passive areas alternate along a length of the catheter.

[0011] In some embodiments, the inner surface of the catheter has a plurality of active areas and a plurality of passive areas, and the plurality of active areas and the plurality of passive areas alternate along a length of the inner lumen.

[0012] In some embodiments, the passive area comprises a nitric oxi de-generating compound and a glycocalyx polysaccharide matrix. In some embodiments, the active area comprises one or more microbiocidal agents.

[0013] In some embodiments, the passive area may be more hydrophilic than the active area to inhibit bacterial adhesion and promote bacterial adhesion at the adjacent active area. In some embodiments, the passive area may be superhydrophilic. In some embodiments, the passive area may include a superhydrophilic coating. As used herein, a superhydrophilic surface or coating has a water contact angle between 0 degrees and 10 degrees.

[0014] In some embodiments, the passive area may have lower friction than the active area. The active area may have higher friction than the passive area. The lower friction passive area has lower bacterial adhesion to the surface compared to the active area. This means that bacteria will preferentially adhere to the active area surface compared to the passive area surface. Because the active area comprises one or more microbiocidal agents, the active area provides targeted killing of microbes.

[0015] In some embodiments, the passive area comprises multicomponent surface functionalization to mimic the natural micro-environment of human vasculature for its thromboresistance. In some embodiments, the passive area surface functionalization comprises a nitric oxide-generating compound and a glycocalyx polysaccharide matrix. In some embodiments, the glycocalyx polysaccharide matrix comprises hyaluronan, heparin, or a combination hyaluronan and heparin. In some embodiments, to facilitate surface functionalization of the passive area, the passive area surface comprises a plasma polymeric allylamine coating.

[0016] In some embodiments, the nitric oxide-generating compound facilitates catalytic decomposition of endogenous or synthetic S -nitrosothiols (RSNOs) to generate nitric oxide. Nonlimiting examples of endogenous RSNOs include S-nitrosoglutathione (GSNO), S- nitroscysteine (CysNO), and S-nitrosoalbumin (AlbSNO).

[0017] In some embodiments, the nitric oxi de-generating compound comprises chelated Cu2+. In some embodiments, the chelated Cu2+comprises Cu2+chelated with DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid, also known as Tetraxetan). In some embodiments, the chelated Cu2+includes Cu2+chelated with a zeolitic imidazolate framework-8 (ZIF-8).

[0018] In some embodiments, the active area may include a microbiocidal agent. In some embodiments, the microbiocidal agent is selected from a nitric oxide donor, chlorhexidine (chlorhexidine acetate, chlorhexidine gluconate, or another suitable chlorhexidine-containing compound) copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), conjugated oligomers (COEs), and dendritic polyethylene imine (PEI).

[0019] In some embodiments, the nitric oxide donor is any physiologically compatible nitric oxide releasing compound. Non-limiting examples of a nitric oxide donor include S-nitroso-N- acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

[0020] In some embodiments, the active area may be proximal to the passive area and configured to align with an insertion site of the catheter when the catheter is indwelling in a blood vessel of a patient. In some embodiments, the catheter may include a distal tip, and the passive area may extend to the distal tip.

[0021] In some embodiments, the outer surface of the catheter may include multiple active areas and multiple passive areas. In some embodiments, the active areas and the passive areas may alternate along a length of the catheter. In some embodiments, each of the active areas proximal to the distal tip and each of the passive areas proximal to the distal tip may be cylindrical.

[0022] In some embodiments, the outer surface of the catheter comprises a plurality of active areas and a plurality of passive areas. The plurality of active areas and the plurality of passiveareas may alternate along a length of the catheter. In some embodiments, each of the plurality of active areas proximal to the distal tip and each of the plurality of passive areas proximal to the distal tip are cylindrical.

[0023] In some embodiments, the catheter comprises an inner surface forming an inner lumen and the inner surface comprises an active area and a passive area proximate the active area. Similar to embodiments discussed above, the passive area may include a nitric oxide-generating compound and a glycocalyx polysaccharide matrix and the active area may include one or more microbiocidal agents.

[0024] In some embodiments, the catheter system, the catheter includes an outer surface and an inner surface forming an inner lumen. The outer surface has a plurality of active areas and a plurality of passive areas. The plurality of active areas and the plurality of passive areas may alternate along a length of the catheter. The plurality of passive areas include a nitric oxidegenerating compound and a glycocalyx polysaccharide matrix. The plurality of active areas include a microbiocidal agent. The inner surface has a plurality of active areas and a plurality of passive areas, which alternate along a length of the inner lumen. The plurality of passive areas include the nitric oxide-generating compound and the glycocalyx polysaccharide matrix. The plurality of active areas include a microbiocidal agent.

[0025] In some embodiments, the glycocalyx polysaccharide matrix includes hyaluronan, heparin, or a combination hyaluronan and heparin.

[0026] In some embodiments, the nitric oxi de-generating compound comprises chelated Cu2+. In some embodiments, the chelated Cu2+includes Cu2+chelated with DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid). In some embodiments, the chelated Cu2+includes Cu2chelated with a zeolitic imidazolate framework-8 (ZIF-8).

[0027] In some embodiments, the nitric oxide generating compound comprises a physiologically compatible nitric oxide releasing compound doped in the polymeric material from which the catheter is fabricated. Non-limiting examples of a nitric oxide releasing compound include S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

[0028] In some embodiments, the microbiocidal agent is selected from a nitric oxide donor, chlorhexidine (chlorhexidine acetate, chlorhexidine gluconate, or another suitable chlorhexidine- containing compound) copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), conjugated oligomers (COEs), and dendritic polyethylene imine (PEI).

[0029] In some embodiments, the nitric oxide donor is selected from nitroso-N- acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

[0030] In some embodiments, the plurality of passive areas comprise a plasma polymeric allylamine coating to which the chelated Cu2+and the glycocalyx polysaccharide matrix are bound.

[0031] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed. It should be understood that the various embodiments are not limited to the arrangements and instrumentality shown in the drawings. It should also be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural changes, unless so claimed, may be made without departing from the scope of the various embodiments of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0032] Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0033] Figure 1A is an upper perspective view of an example catheter system, illustrating an example catheter having an active area and a passive area, according to some embodiments;

[0034] Figure IB is an enlarged perspective view of the catheter of Figure 1A, according to some embodiments;

[0035] Figure 1C is a cross-sectional view of the catheter of Figure 1A extending from an example catheter adapter of the catheter system, according to some embodiments;

[0036] Figure 2A is an upper perspective view of the catheter system, illustrating the catheter having multiple active areas and multiple passive areas, according to some embodiments;

[0037] Figure 2B is an enlarged perspective view of the catheter of Figure 2A, according to some embodiments; and

[0038] Figure 2C is a cross-sectional view of the catheter of Figure 2A extending from the catheter adapter of the catheter system, according to some embodiments.DESCRIPTION OF EMBODIMENTS

[0039] The disclosure relates to a catheter with antithrombogenic and antimicrobial activity. The disclosed catheter surface includes alternating patterned areas of active and passive functionality. The passive areas include a combination of a nitric oxide-generating compound and a glycocalyx polysaccharide matrix. Thus, the catheter includes a bio-mimicked adaptive surface for thrombus resistance and infection prevention by release of nitric oxide. The active areas include one or more microbiocidal agents. The passive areas comprise a bio-mimicked adaptivesurface to provide thrombus resistance and the active areas comprise a surface treated with one or more antimicrobial agents to provide targeted killing of microbes. The two surfaces in combination provide improved antithrombogenic and antimicrobial activity.

[0040] Blood vessels have an inner lining of endothelial cells. This vascular endothelial surface is coated by the glycocalyx, a ubiquitous gel-like layer composed of plasma proteins such as albumin and antithrombin. This lining has microscopic fibrous structures, made of carbohydrate / polysaccharide, with hyaluronic acid (HA), heparan sulfate (HS) and other vasoactive mediators (e.g., nitric oxide) and modulates leukocyte-endothelial interactions, thrombus formation, anti-coagulation, and other processes which contribute to thromboresistance. In the disclosed invention, the passive areas of the catheter surface include multicomponent surface functionalization to mimic the natural micro-environment of human vasculature for its thromboresistance and controlled release of nitric oxide.

[0041] Nitric oxide (NO) is able to inhibit thrombosis and bacterial growth.

[0042] Herein, a layer-by-layer grafting strategy may be used to create endothelium-like dualfunctional surface on passive area surfaces of the catheter. Typically, a nitric oxide-generating compound and a glycocalyx polysaccharide matrix molecule are sequentially immobilized on the passive area surfaces of the catheter.

[0043] The glycocalyx polysaccharide matrix may comprise hyaluronan (hyaluronic acid), heparin, or a combination hyaluronan and heparin.

[0044] In some embodiments, the nitric oxide generating compound comprises a physiologically compatible nitric oxide releasing compound doped in the polymeric material from which the catheter is fabricated. Non-limiting examples of a nitric oxide releasing compoundinclude S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

[0045] In some embodiments, the nitric oxide-generating compound is a catalyst to promote catalytic decomposition of endogenous or synthetic S-nitrosothiols (RSNOs) to release nitric oxide. Nonlimiting examples of endogenous RSNOs include S-nitrosoglutathione (GSNO), S- nitroscysteine (CysNO), and S-nitrosoalbumin (AlbSNO).

[0046] In some embodiments, the catalyst to promote catalytic decomposition of endogenous or synthetic S-nitrosothiols (RSNOs) comprises chelated Cu2+. In some embodiments, the chelated Cu2+comprises Cu2+chelated with DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid, also known as Tetraxetan). In some embodiments, the chelated Cu2+includes Cu2+chelated with a zeolitic imidazolate framework-8 (ZIF-8).

[0047] In some embodiments, the passive area surfaces of the catheter may comprise a plasma polymeric allylamine coating having amino functional groups to which the glycocalyx polysaccharide matrix and / or nitric oxide-generating compound are bound.

[0048] A layer-by-layer grafting process can enable independent control of the biomolecular density and content on each grafting layer on the passive areas of the catheter. This facilitates adjusting and control of surface functionality. A non-limiting example of a layer-by-layer grafting process is described below:

[0049] A plasma polymeric allylamine (PPAm) coating is deposited on the passive areas of the catheter surface through water-phase amidation.

[0050] A nitric oxide-generating compound comprising Cu2+chelated with DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid is immobilized on the PPAm coating.

[0051] Carboxyl groups at one side of the DOTA conjugate with amino groups of the PPAm, leaving the residual carboxyl groups on the other side of the DOTA available for a second grafting layer comprising hyaluronan (HA). To achieve high HA grafting density, polyallylamine (PAa) is employed to amplify the reaction sites by transferring the carboxyl groups into multiple amino groups.

[0052] A layer of hyaluronan is immobilized on the surface, resulting in a layer-by-layer grafted catheter passive coating with nitric oxide releasing and endothelial glycocalyx functionality. The dual -functional surface possesses typical endothelial-like properties such as nitric oxide releasing, antiplatelet, and vascular-cell preferred surface properties.

[0053] Referring now to Figures 1A-1B, in some embodiments, a catheter system 10 may include a catheter adapter 12, which may include a distal end 14 and a proximal end 16. In some embodiments, a lumen may extend between the distal end 14 and the proximal end 16. In some embodiments, the catheter system 10 may include a catheter 18, which may extend from the distal end 14 of the catheter adapter 12. In some embodiments, the catheter 18 may be tubular. In some embodiments, a needle assembly (not illustrated) may be coupled to the proximal end 16 of the catheter adapter 12 and an introducer needle of the needle assembly may extend through the catheter 18 to facilitate insertion of the catheter 18 into a blood vessel. In some embodiments, after the catheter 18 is inserted into the blood vessel, the introducer needle and the needle assembly may be removed from the catheter system 10.

[0054] Biofdms, which are surface-associated bacterial colonies, pose a significant concern for indwelling catheters and in various diseases. They represent the predominant form of bacterial existence in nature, found on both biological and non-biological surfaces. The initial phase of biofilm development involves surface adhesion, where a free-floating bacterium attaches to asurface. This adhesion is considered essential for the formation of biofilms and often becomes permanent after a period of time. Following adhesion, surface colonization occurs as the attached bacteria multiply and spread across the surface.

[0055] In some embodiments, the catheter 18 may include an outer surface 20 having an active area 22 and a passive area 24 proximate the active area 22. In some embodiments, the outer surface 20 corresponds to outer-most surface of the catheter 18 configured to contact blood when the catheter 18 is inserted into a blood vessel of a patient. In some embodiments, the passive area 24 proximate the active area 22 may facilitate preferential attachment of biofilm to the active area 22 such that the biofilm can then be destroyed in a controlled manner. In further detail, the passive area 24 may be more hydrophilic than the active area 22 to facilitate bacterial adhesion at the active area 22 compared to the passive area 24. In some embodiments, the passive area 24 may be superhydrophilic.

[0056] In some embodiments, the passive area 24 comprises a bio-mimicked adaptive surface to provide thrombus resistance and the active area 22 comprises a surface treated with one or more antimicrobial agents to provide targeted killing of microbes. The two surfaces in combination provide improved antithrombogenic and antimicrobial activity.

[0057] In some embodiments, the passive area 24 comprises a nitric oxide-generating compound and a glycocalyx polysaccharide matrix. In some embodiments, the active area 22 comprises one or more microbiocidal agents.

[0058] In some embodiments, the passive area 24 comprises multicomponent surface functionalization to mimic the natural micro-environment of human vasculature for its thromboresistance. In some embodiments, the passive area surface functionalization comprises a nitric oxide-generating compound and a glycocalyx polysaccharide matrix. In some embodiments,the glycocalyx polysaccharide matrix comprises hyaluronan, heparin, or a combination hyaluronan and heparin. In some embodiments, to facilitate surface functionalization of the passive area, the passive area surface comprises a plasma polymeric allylamine coating.

[0059] In some embodiments, the nitric oxi de-generating compound facilitates catalytic decomposition of endogenous or synthetic S-nitrosothiols (RSNOs) to generate nitric oxide. Nonlimiting examples of endogenous RSNOs include S-nitrosoglutathione (GSNO), S- nitroscysteine (CysNO), and S-nitrosoalbumin (AlbSNO).

[0060] In some embodiments, the nitric oxi de-generating compound comprises chelated Cu2+. In some embodiments, the chelated Cu2+comprises Cu2+chelated with DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid, also known as Tetraxetan). In some embodiments, the chelated Cu2+includes Cu2+chelated with a zeolitic imidazolate framework-8 (ZIF-8).

[0061] In some embodiments, the active area 22 may include a microbiocidal agent. In some embodiments, the microbiocidal agent is selected from a nitric oxide donor, chlorhexidine (chlorhexidine acetate, chlorhexidine gluconate, or another suitable chlorhexidine-containing compound) copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), conjugated oligomers (COEs), and dendritic polyethylene imine (PEI).

[0062] In some embodiments, the nitric oxide donor is any physiologically compatible nitric oxide releasing compound. Non-limiting examples of a nitric oxide donor include S-nitroso-N- acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

[0063] In some embodiments, the passive area 24 is a hydrophobic glycocalyx mimicked surface containing nitric oxide release factors which simulates natural endothelial vascular tissue and possesses antithrombogenic and antimicrobial properties. Moreover, due to the passive area24 being hydrophilic or superhydrophilic, it is difficult for bacteria to adhere to the passive area24.

[0064] Bacteria have surface sensing mechanisms to search for favorable environments for cell adhesion. When the passive area 24 is blocked by the glycocalyx mimicked surface, bacteria may preferentially choose to adhere to the active area 22, which may be proximate the passive area 24. In some embodiments, the active area 22 may include one or more microbiocidal agents such that the bacteria adhered to the active area 22 may be destroyed. Thus, in some embodiments, the catheter system 10 may provide a two-prong approach to infection prevention: 1) disrupting the mechanism of microbial attachment at the passive area 24, and 2) disinfecting attached microbes using biocides.

[0065] In some embodiments, the microbiocidal agent may include a nitric oxide donor. In some embodiments, the microbiocidal agent may include silver sulfadiazine or another suitable silver-containing compound. In some embodiments, the microbiocidal agent may include chlorhexidine acetate, chlorhexidine gluconate (CHG), or another suitable chlorhexidine- containing compound. Other non-limiting examples of suitable microbiocidal agents may include polyhexamethylene biguanide (PHMB), conjugated oligomers (COEs), and dendritic polyethylene imine (PEI) modified not to be toxic to animal cells.

[0066] In some embodiments, the microbiocidal agent may be included in the active area 22 according to any suitable method known in the art. In some embodiments, the microbiocidal agent may be a coating. In some embodiments, the microbiocidal agent may be incorporated into a polymer matrix of a material of a wall forming the catheter 18. In some embodiments, the microbiocidal agent may be impregnated into the material of the wall during manufacturing andreleased over time. In some embodiments, the passive area 24 may not include the microbiocidal agents or any microbiocidal agents.

[0067] In some embodiments, the microbiocidal agent may act according to one or more of the following: 1) inhibition of cell wall synthesis, 2) inhibition of protein synthesis, 3) inhibition of nucleic acid synthesis, 4) affects cell membrane sterols, and 5) inhibition of unique metabolic steps. Non-limiting examples of microbiocidal agents that inhibit cell wall synthesis include chlorhexidine, penicillin, and vancomycin. Non-limiting examples of microbiocidal agents that inhibit protein synthesis include silver ions, nitric oxide, and tetracyclines such as minocycline. Non-limiting examples of microbiocidal agents that inhibit nucleic acid synthesis include sparfloxacin, quinolones, nitric oxide, and rifampin. Non-limiting examples of microbiocidal agents that affect cell membrane sterols include silver ions, triclosan, antimicrobial peptides, and antifungal agents such as amphotericin. Non-limiting examples of microbiocidal agents that inhibit unique metabolic steps include nitrofuran, triclosan, bacteriophages, and sulfonamide. In some embodiments, the microbiocidal agent may eliminate bacteria after they have attached to a surface and / or may not prevent adhesion of the bacteria to the surface.

[0068] In some embodiments, the passive area 24 may have lower friction than the active area 22, which may further facilitate bacteria binding to the active area 22 instead of the passive area 24. The passive area 24 being a low friction surface or having lower friction than the active area 22 can reduce mechanical interlocking or attachment of bacteria, especially in a blood vessel where there is flow, and may allow bacteria to slide over the passive area 24 more easily. In some cases, the bacteria may slide to the adjacent active area 22. In some embodiments, the passive area 24 may be a low friction surface and / or the active area 22 may be a high friction surface. In someembodiments, the hydrophilic or superhydrophilic characteristics of the passive area 24 may cause the passive area 24 to be low friction due to the hydration layer.

[0069] In some embodiments, the passive area 24 may be superhydrophilic such that a water contact angle is between 0 degrees and 10 degrees or between 0 degrees and 5 degrees, which may facilitate bacterial adhesion at the active area 22 compared to the passive area 24.

[0070] In some embodiments, the active area 22 may be proximal to the passive area 24 and configured to align with an insertion site of the catheter 18 when the catheter 18 is indwelling in the blood vessel of the patient. In these and other embodiments, a distal end of the active area 22 may be disposed about half-way between the distal end 14 of the catheter adapter 12 and a distal tip 26 of the catheter 18. In some embodiments, the active area 22 may extend proximally to the distal end 14 of the catheter adapter 12, which may facilitate bacteria moving away from the patient. Providing the active area 22 or a zone of disinfection at or near the insertion site of the catheter 18 may help prevent bacteria from migrating further quickly and may help provide a controlled zone of attack against infection rather than uncontrolled treatment of an entire catheter.

[0071] In some embodiments, the catheter 18 may include the distal tip 26 that may be proximate an aperture providing access to an inner lumen of the catheter 18, and the aperture may have a tendency to accumulate bacteria in a way that occludes the catheter 18. In some embodiments, the passive area 24 may extend to the distal tip 26, which may reduce a risk of occlusion of the catheter 18 at the aperture.

[0072] Referring now to Figure 1C, in some embodiments, the active area 22 and the passive area 24 may extend from the outer surface 20 to an inner surface 28 of the catheter 18. In these embodiments, the active area 22 and the passive area 24 may provide antithrombogenic and antimicrobial activity within the catheter 18. In some embodiments, the inner surface 28 may forman inner lumen 30 of the catheter 18, which may be in fluid communication with the lumen of the catheter adapter 12.

[0073] Referring now to Figures 2A-2B, in some embodiments, the outer surface 20 of the catheter 18 may include multiple active areas 22 and multiple passive areas 24. In some embodiments, the active areas 22 and the passive areas 24 may alternate along a length of the catheter 18, which may facilitate movement of bacteria from the passive areas 24 to the active areas 22 nearby. In some embodiments, due to weak adhesion to the passive areas 24, bacterial flow may be propelled forward and eventually reach one of the active areas 22 and be destroyed by the antimicrobial agents. In some embodiments, the active areas 22 and the passive areas 24 may alternate along an entire length of the catheter 18 from the distal tip 26 to the distal end 14 of the catheter adapter 12. In some embodiments, a particular passive area 24 may be flanked on both sides by a first particular active area and a second particular active area.

[0074] The specific pattern of active areas 22 and passive areas 24 may be obtained through the use of masks to the catheter surface. For example, the active areas 22 may be prepared using conventional dip coating or spay coating techniques. Thereafter, the active areas 22 can be masked and the layer-by-layer preparation for the passive areas 24 can be prepared as disclosed herein. Thereafter, the mask is removed from the active areas.

[0075] In some embodiments, each of the active areas 22 proximal to the distal tip 26 and each of the passive areas 24 proximal to the distal tip 26 may be cylindrical, which may provide annular protection from bacteria. In some embodiments, the distal tip 26 may taper inwardly in a distal direction, which may facilitate insertion of the distal tip 26 through skin and the blood vessel of the patient.

[0076] Referring now to Figure 2C, in some embodiments, the active areas 22 and the passive areas 24 may extend from the outer surface 20 to the inner surface 28 of the catheter 18. In these embodiments, the active areas 22 and the passive areas 24 may antithrombogenic and antimicrobial activity within the catheter 18. In some embodiments, the inner surface 28 may form the inner lumen 30 of the catheter 18, which may be in fluid communication with the lumen of the catheter adapter 12.

[0077] Reference throughout this specification to “one embodiment,” “certain embodiments,” “one or more embodiments” or “an embodiment” means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases such as “in one or more embodiments,” “in certain embodiments,” “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0078] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention include modifications and variations that are within the scope of the appended claims and their equivalents.

Claims

CLAIMS1. A catheter system, comprising: a catheter adapter comprising a distal end and a proximal end; and a catheter extending from the distal end of the catheter adapter, wherein the catheter comprises an outer surface having an active area and a passive area proximate the active area, wherein the passive area comprises a nitric oxide-generating compound and a glycocalyx polysaccharide matrix and the active area comprises a microbiocidal agent.

2. The catheter system of claim 1, wherein the glycocalyx polysaccharide matrix comprises hyaluronan, heparin, or a combination hyaluronan and heparin.

3. The catheter system of claim 1, wherein the nitric oxide-generating compound comprises chelated Cu2+.

4. The catheter system of claim 3, wherein the chelated Cu2+comprises Cu2+chelated with DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid).

5. The catheter system of claim 1, wherein the microbiocidal agent is selected from a nitric oxide donor, chlorhexidine (chi orhexi dine acetate, chlorhexidine gluconate, or another suitable chlorhexidine-containing compound) copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), conjugated oligomers (COEs), and dendritic polyethylene imine (PEI).

6. The catheter system of claim 5, wherein the nitric oxide donor is selected from nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

7. The catheter system of claim 1, wherein the microbiocidal agent comprises chlorhexidine, chlorhexidine acetate, or chlorhexidine gluconate.

8. The catheter system of claim 1, wherein the passive area comprises a plasma polymeric allylamine coating to which the nitric oxide-generating compound and the glycocalyx polysaccharide matrix are bound.

9. The catheter system of claim 1, wherein the active area is proximal to the passive area and configured to align with an insertion site of the catheter when the catheter is indwelling in a blood vessel of a patient.

10. The catheter system of claim 1, wherein the catheter comprises a distal tip, wherein the passive area extends to the distal tip.

11. The catheter system of claim 1, wherein the outer surface of the catheter comprises a plurality of active areas and a plurality of passive areas, wherein the plurality of active areas and the plurality of passive areas alternate along a length of the catheter.

12. The catheter system of claim 11, wherein the catheter comprises a distal tip, wherein the passive area extends to the distal tip and each of the plurality of active areas proximal to the distal tip and each of the plurality of passive areas proximal to the distal tip are cylindrical.

13. The catheter system of claim 1, wherein the catheter further comprises an inner surface forming an inner lumen, wherein the inner surface comprises an active area and a passive area proximate the active area, wherein the passive area comprises a nitric oxide-generating compound and a glycocalyx polysaccharide matrix and the active area comprises a microbiocidal agent.

14. A catheter system, comprising: a catheter adapter comprising a distal end and a proximal end; and a catheter extending from the distal end of the catheter adapter, wherein the catheter comprises: outer surface having a plurality of active areas and a plurality of passive areas, wherein the plurality of active areas and the plurality of passive areas alternate along a length of the catheter, wherein the plurality of passive areas comprise a nitric oxidegenerating compound and a glycocalyx polysaccharide matrix and the plurality of active areas comprise a microbiocidal agent; and an inner surface forming an inner lumen, wherein the inner surface has a plurality of active areas and a plurality of passive areas, wherein the plurality of active areas and the plurality of passive areas alternate along a length of the inner lumen, wherein the plurality of passive areas comprise the nitric oxide-generating compound and the glycocalyx polysaccharide matrix and the plurality of active areas comprise a microbiocidal agent.

15. The catheter system of claim 14, wherein the glycocalyx polysaccharide matrix comprises hyaluronan, heparin, or a combination hyaluronan and heparin.

16. The catheter system of claim 14, wherein the nitric oxide-generating compound comprises chelated Cu2+.

17. The catheter system of claim 16, wherein the chelated Cu21comprises Cu21chelated with DOTA (l ,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid).

18. The catheter system of claim 14, wherein the microbiocidal agent is selected from a nitric oxide donor, chlorhexidine (chlorhexidine acetate, chlorhexidine gluconate, or another suitable chlorhexidine-containing compound) copper, silver (ionic), silver nanoparticles, triclosan,polyhexamethylene biguanide (PHMB), conjugated oligomers (COEs), and dendritic polyethylene imine (PEI).

19. The catheter system of claim 18, wherein the nitric oxide donor is selected from nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and mixtures thereof.

20. The catheter system of claim 14, wherein the plurality of passive areas comprise a plasma polymeric allylamine coating to which the nitric oxide-generating compound and the glycocalyx polysaccharide matrix are bound.

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