Abstract:
A method for producing an antimicrobial coating on a surface. The method includes mixing a parylene dimer and an antimicrobial agent to form a mixture, heating the mixture to sublimate the parylene dimer and suspend the antimicrobial agent within the sublimated parylene dimer, pyrolyzing the sublimated parylene dimer to form a parylene monomer while the antimicrobial agent is suspended within the parylene monomer, and condensing the parylene monomer and the antimicrobial agent together on the surface to polymerize the parylene monomer and form a coating containing a parylene polymer and the antimicrobial agent.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims priority to Provisional Application No. 62/191,347, filed Jul. 11, 2015, which is herein incorporated by reference in its entirety. 
     
    
     TECHNICAL FIELD 
       [0002]    The present invention relates to preventing infections associated with medical devices. More specifically, the invention relates to coatings and methods for coating medical devices with antimicrobial agents to prevent infections. 
       BACKGROUND 
       [0003]    Medical procedures, and the medical devices employed in the procedures, may expose a patient to a risk of a nosocomial (e.g., hospital-acquired) infection. For example, the average nosocomial infection rate associated with the implantation of pacemakers and implantable cardioverter defibrillators is approximately 3%. In some cases of infection, the implantable medical device, including a device housing and any associated electrical leads or catheters, must be completely removed. Following removal, the infection must be cured and the patient must heal enough to tolerate implantation of a replacement medical device. The costs of such infections are significant, not only intrinsically, but also in terms of the physical and emotional stress suffered by the patient. 
         [0004]    Despite infection control practices, such as sterilizing devices, infectious microorganisms may be transmitted from the skin of patients or from a hospital or clinic environment to a medical device. Medical devices in the hospital environment may include for example, catheters, implantable cardio-defibrillators, pacemakers, implantable electrical leads, medical tools, and diagnostic equipment surfaces such as touch pads and displays. 
         [0005]    What is needed is a way to prevent nosocomial infections which may result from infectious microorganisms transferred from contaminated medical devices to a patient. 
       SUMMARY 
       [0006]    Example 1 is a method for producing an antimicrobial coating on a surface. The method includes mixing a parylene dimer and an antimicrobial agent to form a mixture, heating the mixture to sublimate the parylene dimer and suspend the antimicrobial agent within the sublimated parylene dimer, pyrolyzing the sublimated parylene dimer to form a parylene monomer while the antimicrobial agent is suspended within the parylene monomer, and condensing the parylene monomer and the antimicrobial agent together on the surface to polymerize the parylene monomer and form a coating containing a parylene polymer and the antimicrobial agent. 
         [0007]    In Example 2, the method Example 1, wherein the parylene dimer is selected from the group consisting of [2,2]-paracyclophane, dichloro-[2,2]-paracyclophane, tetrachloro-[2,2]-paracyclophane, and octafluoro-[2,2]-paracyclophane. 
         [0008]    In Example 3, the method any of Examples 1-2, wherein the antimicrobial agent is present in the mixture in an amount from about 0.0001 wt. % to about 10 wt. %. 
         [0009]    In Example 4, the method any of Examples 1-3, wherein mixing the parylene dimer and the antimicrobial agent includes mixing the parylene dimer and a plurality of antimicrobial nanoparticles, the antimicrobial nanoparticles having an average diameter less than or equal to about 100 nanometers. 
         [0010]    In Example 5, the method of Example 4, wherein the antimicrobial nanoparticles have an average diameter greater than or equal to about 20 nanometers and less than or equal to about 60 nanometers. 
         [0011]    In Example 6, the method any of Examples 4-5, wherein the antimicrobial nanoparticles include at least one of metallic gold, metallic silver, metallic copper, and combinations thereof. 
         [0012]    In Example 7, the method any of Examples 4-6, wherein the antimicrobial nanoparticles include at least one of gold salt, a silver salt, a copper salt, and combinations thereof. 
         [0013]    In Example 8, the method of any of Examples 1-7, further including treating the coating with an oxygen-containing plasma. 
         [0014]    Example 9 is a device including an antimicrobial coating produced by any of the methods of Examples 1-8, the device including a first surface, a second surface, and an antimicrobial coating covering at least a portion of the first surface and at least a portion of the second surface. The coating includes a parylene polymer distributed throughout the coating, and a plurality of inorganic antimicrobial particles distributed throughout the coating. 
         [0015]    In Example 10, the device of Example 9, wherein the second surface is not parallel to the first surface, and wherein a concentration of the inorganic antimicrobial particles in the coating does not differ by more than about 1% between the portion of the first surface and the portion of the second surface. 
         [0016]    In Example 11, the device of any of Examples 9-10, wherein the inorganic antimicrobial particles have diameters between about 10 nanometers and about 1 millimeter. 
         [0017]    In Example 12, the device of any of Examples 9-11, wherein the inorganic antimicrobial particles include a plurality of inorganic antimicrobial nanoparticles and a plurality of agglomerations of the nanoparticles, wherein the nanoparticles have an average diameter greater than or equal to about 20 nanometers and less than or equal to about 60 nanometers. 
         [0018]    In Example 13, the device of any of Examples 9-12, wherein the inorganic nanoparticles have an average diameter of about 40 nanometers. 
         [0019]    In Example 14, the device of any of Examples 9-13, wherein the inorganic antimicrobial particles include at least one of metallic gold, metallic silver, metallic copper, and combinations thereof. 
         [0020]    In Example 15, the device of any of Examples 9-14, wherein the inorganic antimicrobial particles include at least one of gold salt, a silver salt, a copper salt, and combinations thereof. 
         [0021]    Example 16 a method for producing an antimicrobial coating on a surface. The method includes mixing a parylene dimer and an antimicrobial agent to form a mixture, heating the mixture to sublimate the parylene dimer and suspend the antimicrobial agent within the sublimated parylene dimer, pyrolyzing the sublimated parylene dimer to form a parylene monomer while the antimicrobial agent is suspended within the parylene monomer, and condensing the parylene monomer and the antimicrobial agent together on the surface to polymerize the parylene monomer and form a coating containing a parylene polymer and the antimicrobial agent. 
         [0022]    In Example 17, the method of Example 16, further including treating the coating with an oxygen-containing plasma. 
         [0023]    In Example 18, the method of any of Examples 16-17, wherein the parylene dimer is selected from the group consisting of [2,2]-paracyclophane, dichloro-[2,2]-paracyclophane, tetrachloro-[2,2]-paracyclophane, and octafluoro-[2,2]-paracyclophane. 
         [0024]    In Example 19, the method of any of Examples 16-18, wherein the antimicrobial agent is present in the mixture in an amount from about 0.0001 wt. % to about 10 wt. %. 
         [0025]    In Example 20, the method any of Examples 16-19, wherein mixing the parylene dimer and the antimicrobial agent includes mixing the parylene dimer and a plurality of antimicrobial nanoparticles, the antimicrobial nanoparticles having an average diameter less than or equal to about 100 nanometers. 
         [0026]    In Example 21, the method of Example 20, wherein the antimicrobial nanoparticles have an average diameter greater than or equal to about 20 nanometers and less than or equal to about 60 nanometers. 
         [0027]    In Example 22, the method of any of Examples 20-21, wherein the antimicrobial nanoparticles include at least one of metallic gold, metallic silver, metallic copper, and combinations thereof. 
         [0028]    In Example 23, the method of Example 22, wherein the antimicrobial nanoparticles consist of metallic silver. 
         [0029]    In Example 24, the method of any of Examples 20-21, wherein the antimicrobial nanoparticles include at least one of gold salt, a silver salt, a copper salt, and combinations thereof. 
         [0030]    In Example 25, the method of Example 24, wherein the antimicrobial nanoparticles are selected from a group consisting of silver nitrate, silver chloride, and combinations thereof. 
         [0031]    Example 26 is a device including an antimicrobial coating. The device includes a first surface, a second surface that is not parallel to the first surface, and an antimicrobial coating covering at least a portion of the first surface and at least a portion of the second surface. The coating includes a parylene polymer distributed throughout the coating, and a plurality of inorganic antimicrobial particles distributed throughout the coating. A concentration of the inorganic antimicrobial particles in the coating does not differ by more than about 1% between the portion of the first surface and the portion of the second surface. 
         [0032]    In Example 27, the device of Example 26, wherein the parylene polymer is selected from the group consisting of poly(p-xylylene), poly(monochloro-p-xylylene), poly(dichloro-p-xylylene), and poly(tetrafluoro-p-xylylene). 
         [0033]    In Example 28, the device of Example 27, wherein the parylene polymer is poly(monochloro-p-xylylene). 
         [0034]    In Example 29, the device of any of Examples 26-28, wherein the inorganic antimicrobial particles have diameters between about 10 nanometers and about 1 millimeter. 
         [0035]    In Example 30, the device of any of Examples 26-29, wherein the inorganic antimicrobial particles include a plurality of inorganic antimicrobial nanoparticles and a plurality of agglomerations of the nanoparticles, wherein the nanoparticles have an average diameter greater than or equal to about 20 nanometers and less than or equal to about 60 nanometers. 
         [0036]    In Example 31, the device of Example 30, wherein the inorganic nanoparticles have an average diameter of about 40 nanometers. 
         [0037]    In Example 32, the device of any of Examples 26-31, wherein the inorganic antimicrobial particles include at least one of metallic gold, metallic silver, metallic copper, and combinations thereof. 
         [0038]    In Example 33, the device of Example 32, wherein the inorganic antimicrobial particles include metallic silver. 
         [0039]    In Example 34, the device of any of Examples 26-33, wherein the inorganic antimicrobial particles include at least one of gold salt, a silver salt, a copper salt, and combinations thereof. 
         [0040]    In Example 35, the device of Example 34, wherein the inorganic antimicrobial particles are selected from a group consisting of silver nitrate, silver chloride, and combinations thereof. 
         [0041]    While multiple embodiments are disclosed, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative embodiments of the invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not restrictive. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0042]      FIG. 1  is a schematic view of a system for producing an antimicrobial coating on surfaces of devices in accordance with embodiments of the present invention. 
           [0043]      FIGS. 2A, 2B, and 2C  are views of a device including a surface having an antimicrobial coating in accordance with embodiments of the present invention.  FIG. 2A  is a perspective view.  FIGS. 2B and 2C  are enlarged schematic cross-sectional views of portions of the surface of the device in  FIG. 2A . 
           [0044]      FIG. 3  is a micrograph of an antimicrobial coating on a surface in accordance with embodiments of the present invention. 
       
    
    
       [0045]    While the invention is amenable to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and are described in detail below. The intention, however, is not to limit the invention to the particular embodiments described. On the contrary, the invention is intended to cover all modifications, equivalents, and alternatives falling within the scope of the invention as defined by the appended claims. 
       DETAILED DESCRIPTION 
       [0046]      FIG. 1  is a schematic view of a system for producing an antimicrobial coating on surfaces of devices in accordance with embodiments of the present invention.  FIG. 1  shows a deposition system  10  may include a vaporizer  12 , a furnace  14 , a deposition chamber  16 , a cold trap  18 , and a pump  20 . The vaporizer  12  may include a removable boat  22 . The vaporizer  12  may be a vacuum chamber which may be heated and maintained at a desired temperature. The furnace  14  may be another vacuum chamber which may also be heated and maintained at a desired temperature different from the temperature of the vaporizer  12 . The deposition chamber  16  is yet another vacuum chamber. The cold trap  18  may be a device employing cooling to condense materials within. The cold trap  18  may be cooled by refrigeration or by a cryogenic gas, such as liquid nitrogen. The pump  20  may be a mechanical vacuum pump, for example, a rotary vane vacuum pump. As shown in  FIG. 1 , the vaporizer  12 , the furnace  14 , and the deposition chamber  16  may all be fluidly connected. The vacuum pump  20  may be fluidly connected to the deposition chamber  16  through the cold trap  18 . The deposition system  10  may be a commercially available system, such as a Specialty Coating Systems™ PDS 2035CR Parylene Deposition System from Specialty Coating Systems, Inc. of Indianapolis, Ind.; or a Para Tech™ Model 4000V Parylene Coating System from Para Tech Coating, Inc. of Aliso Viejo, Calif. 
         [0047]    Also shown in  FIG. 1  are exemplary devices  24 ,  26  having surfaces to be coated with an antimicrobial coating. In some embodiments, the devices  24 ,  26  each have at least a first surface and a second surface in which the second surface is not parallel to the first surface as described below in reference to  FIGS. 2A-2C  for device  24 . While device  24  is illustrated as a cylinder and device  26  is illustrated as a cube, it is understood that embodiments include other shapes, for example, pyramids, spheres, ovoids, ellipsoids, and other three-dimensional shapes or combinations of three-dimensional shapes including surfaces that are not parallel to each other. The devices  24 ,  26  may be, for example, catheters, implantable cardio-defibrillators, pacemakers, implantable electrical leads, medical tools, and diagnostic equipment surfaces, including touch pads and displays, or any combination of these devices. In some embodiments, devices  24 ,  26  may be a device for use in a hospital operating room. 
         [0048]    Also shown in  FIG. 1  is a mixture  28  including a parylene dimer  30  and an antimicrobial agent  32 . The mixture  28  may be formed by mixing the parylene dimer  30  and the antimicrobial agent  32 . In some embodiments, the antimicrobial agent  32  may be present in the mixture  28  in an amount as little as about 0.0001 weight percent (wt. %), about 0.0005 wt. %, about 0.001 wt. %, about 0.005 wt. %, or about 0.01 wt. %, or as great as about 0.1 wt. %, about 0.5 wt. %, about 1 wt. %, about 5 wt. %, or about 10 wt. %, or may be present within any range defined between any pair of the foregoing values. In exemplary embodiments, the antimicrobial agent  32  may be present in the mixture  28  in an amount from about 0.0001 wt. % to about 10 wt. %, from about 0.0005 wt. % to about 5 wt. %, from about 0.001 wt. % to about 1 wt. %, from about 0.005 wt. % to about 0.5 wt. %, or from about 0.01 wt. % to about 0.1 wt. %. In some exemplary embodiments, the antimicrobial agent  32  may be present in the mixture  28  in an amount of about 0.05 wt. %. 
         [0049]    In some embodiments, the parylene dimer  30  may be [2,2]-paracyclophane according to Formula I below, also referred to as parylene N dimer. In other embodiments, the parylene dimer  30  may be dichloro-[2,2]-paracyclophane according to Formula II below, also referred to as parylene C dimer. In some embodiments, the parylene dimer  30  may be tetrachloro-[2,2]-paracyclophane according to Formula III, also known as parylene D dimer. In some embodiments, the parylene dimer  30  may be octafluoro-[2,2]-paracyclophane according to Formula IV, also known as parylene AF-4 dimer. The parylene dimer  30  may be available in the form of a solid, such as a powder. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0050]    In some embodiments, the antimicrobial agent  32  may be a plurality of antimicrobial particles having an average diameter less than about 1 millimeter. In other embodiments, the antimicrobial particles may have an average diameter less than about 0.5 millimeters, less than about 0.2 millimeters, less than about 0.05 millimeters, less than about 0.02 millimeters, less than about 0.01 millimeters, less than about 5,000 nanometers, less than about 2,000 nanometers, less than about 1,000 nanometer, or less than about 500 nanometers. 
         [0051]    In some embodiments, the plurality of antimicrobial particles may include a plurality of antimicrobial nanoparticles having an average diameter less than or equal to about 100 nanometers. In some embodiments, the nanoparticles may have an average diameter as little as about 5 nanometers, 10 nanometers, about 20 nanometers, or about 30 nanometers, or as great as about 50 nanometers, about 60 nanometers, about 70 nanometers, or about 100 nanometers, or may have an average diameter within any range defined between any pair of the foregoing values. In exemplary embodiments, the nanoparticles may have an average diameter from 5 to 100 nanometers, 10 to 70 nanometers, from 20 to 60 nanometers, or from 30 to 50 nanometers. In some embodiments, the nanoparticles may have an average diameter of about 40 nanometers. 
         [0052]    In some embodiments, the antimicrobial particles may be inorganic antimicrobial particles. In some embodiments the inorganic antimicrobial particles may include at least one of metallic silver, metallic gold, metallic copper, and combinations thereof. Metallic silver, metallic gold, and metallic copper mean silver, gold, and copper in the form of metal ions metallically bonded to other metal ions. In some embodiments, the inorganic antimicrobial particles may include metallic silver. Alternatively or additionally, in some embodiments the inorganic antimicrobial particles may include at least one of a silver salt, a gold salt, a copper salt and combinations thereof. A silver salt, a gold salt, and a copper salt mean silver, gold, and copper in the form of metal ions ionically bonded to non-metal ions (e.g. chloride, nitrate). In some embodiments, the inorganic antimicrobial particles may include a silver salt, for example, silver nitrate, silver chloride, and combinations thereof. In some embodiments, the inorganic antimicrobial particles may be antimicrobial nanoparticles as described above. 
         [0053]    In operation, the devices  24 ,  26  may be placed within the deposition chamber  16  as shown in  FIG. 1 . The mixture  28  may be placed within the removable boat  22 , and the removable boat  22  placed within the vaporizer  12 . Air may be removed from the vaporizer  12 , the furnace  14 , and the deposition chamber  16  through the cold trap  18  by one or more vacuum pumps, such as vacuum pump  20 . The furnace  14  may then be heated to a temperature sufficient to pyrolize the parylene dimer  30 . The temperature sufficient to pyrolize the parylene dimer  30  may depend on which type of parylene dimer is employed. For example, if the parylene dimer  30  is parylene C, the pyrolization temperature may be between about 680° C. and about 685° C. In other embodiments, the pyrolization temperature may be as low as about 550° C., about 615° C., or about 680° C., or as high as about 690° C., about 695° C., or about 700° C., or within any range defined between any pair of the foregoing values. In exemplary embodiments, the pyrolization temperature may be from about 550° C. to about 700° C., from about 615° C. to about 695° C., or from about 680° C. to about 690° C. In some exemplary embodiments, the pyrolization temperature may be about 685° C. In some embodiments, the pyrolization temperature may increase as the absolute pressure in the furnace  14  increases. 
         [0054]    As the furnace  14  approaches the pyrolization temperature and the deposition system  10  has reached a base pressure, the vaporizer  12  may be heated to a temperature sufficient to sublimate or vaporize the parylene dimer  30 . In some embodiments, the vaporization temperature may be as low as about 110° C., about 130° C., or about 145° C., or as high as about 155° C., about 160° C., or about 170°, or within any range defined between any pair of the foregoing values. In exemplary embodiments, the vaporization temperature may be from about 110° C. to about 170° C., from about 130° C. to about 160° C., or from about 145° C. to about 155° C. In some exemplary embodiments, the vaporization temperature may be about 150° C. 
         [0055]    As the parylene dimer  30  sublimates, the antimicrobial agent  32  may be carried along or suspended within the vaporized parylene dimer  30 . In some embodiments, the sublimation of the parylene dimer  30  may increase the pressure within the vaporizer  12  relative to the pressure in the furnace  14 , and drive a flow of the vaporized parylene dimer  30  and the suspended antimicrobial agent  32  into the furnace  14 . 
         [0056]    Within the furnace  14 , the parylene dimer  30  may pyrolize, or cleave, into a parylene monomer. The antimicrobial agent  32  remains suspended and is carried along with the parylene monomer. In some embodiments, the parylene monomer may be according to Formula V below if the parylene dimer  30  is parylene N dimer. In other embodiments, the parylene monomer may be according to Formula VI below if the parylene dimer  30  is parylene C dimer. In some embodiments, the parylene monomer may be according to Formula VII below if the parylene dimer  30  is parylene D dimer. In some embodiments, the parylene monomer may be according to Formula VIII below if the parylene dimer  30  is parylene AF-4 dimer. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0057]    The parylene monomer and the suspended antimicrobial agent  32  flow from the furnace  14  into the deposition chamber  16  where the parylene monomer and the antimicrobial agent  32  condense onto surfaces at about room temperature (e.g. about 25° C.). The devices  24 ,  26  may be at about room temperature, so the parylene monomer and the antimicrobial agent condense onto all exposed surfaces of the devices  24 ,  26 . Once condensed onto a surface, the parylene monomer polymerizes to form an antimicrobial coating  34  including a parylene polymer  36  and the antimicrobial agent  32  as described below in reference to  FIG. 2 . 
         [0058]    In some embodiments, the parylene polymer  36  may be poly(p-xylylene) according to Formula IX below, also referred to as parylene N, if the parylene dimer  30  is parylene N dimer. In other embodiments, the parylene polymer  36  may be poly(monochloro-p-xylylene) according to Formula X below, also referred to as parylene C, if the parylene dimer  30  is parylene C dimer. In some embodiments, the parylene polymer  36  may be poly(dichloro-p-xylylene) according to Formula XI below, also referred to as parylene D, if the parylene dimer  30  is parylene D dimer. In some embodiments, the parylene polymer  36  may be poly(tetrafluoro-p-xylylene) according to Formula XII below, also referred to as parylene AF-4, if the parylene dimer  30  is parylene AF-4 dimer. 
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         [0059]    The pump  20  pumps away reaction products and any air that may leak into the deposition system  10  to maintain a pressure gradient across the deposition system  10 . In some embodiments, the absolute pressure within the vaporizer  12  may be as low as about 13 Pa (0.1 Torr), or about 40 Pa (0.3 Torr), or as high as about 107 Pa (0.8 Torr), or about 133 Pa (1 Torr), or within any range defined between any pair of the foregoing values. In exemplary embodiments, the absolute pressure within the vaporizer  12  may be from about 13 Pa (0.1 Torr) to about 133 Pa (1 Torr), or from about 40 Pa (0.3 Torr) to about 107 Pa (0.8 Torr). In exemplary embodiments, the absolute pressure within the vaporizer  12  may be about 67 Pa (0.5 Torr). In some embodiments, the absolute pressure within the deposition chamber  16  may be as low as about 1.3 Pa (0.01 Torr), about 2.7 Pa (0.02 Torr), or about 6.7 Pa (0.05 Torr), or as high as about 13 Pa (0.1 Torr), about 27 Pa (0.2 Torr), or about 67 Pa (0.5 Torr), or within any range defined between any pair of the foregoing values. In exemplary embodiments, the absolute pressure within the deposition chamber  16  may be from about 1.3 Pa (0.01 Torr) to about 67 Pa (0.5 Torr), from about 2.7 Pa (0.02 Torr) to about 27 Pa (0.2 Torr), or from about 6.7 Pa (0.05 Torr) to about 13 Pa (0.1 Torr). In exemplary embodiments, the absolute pressure within the deposition chamber  16  may be about 9.3 Pa (0.07 Torr). The pressure within the deposition chamber  16  may increase as the parylene monomer and the suspended antimicrobial agent  32  flow from the furnace  14  into the deposition chamber  16 . The absolute pressure in the deposition chamber  16  may be lower than the absolute pressure within the vaporizer  12 . The cold trap  18  may condense any reaction products (e.g. parylene monomer) escaping from the deposition chamber  16  to protect the pump  20 . 
         [0060]    Portions of the devices  24 ,  26  may be masked (not shown) such that parylene monomer and the suspended antimicrobial agent  32  condense on the mask, and not on the masked portions. Portions of the deposition chamber  16  and instrumentation (not shown) for the deposition chamber  16  may be heated to prevent condensation of the parylene monomer and the antimicrobial agent  32  on those portions/instruments. 
         [0061]      FIGS. 2A, 2B, and 2C  are views of the device  24  including the antimicrobial coating  34  on the surface in accordance with embodiments of the present invention.  FIG. 2A  is a perspective view of the device  24 .  FIGS. 2B and 2C  are enlarged schematic cross-sectional views of portions of the surface of the device  24 . In  FIG. 2A , the device  24  is shown is after deposition of the antimicrobial coating  34  described above in reference to  FIG. 1 . As shown in  FIG. 2A , the device  24  may be cylindrical in shape and may have a surface including a first surface  38 , a second surface  40 , and a third surface  42 . The first surface  38  may be a flat surface at one end of the device  24 , the third surface  42  may be another flat surface at an axially opposite end of the device  24 , and the second surface  40  may be a cylindrical surface connecting the first surface  38  to the third surface  42 . The second surface  40  may not be parallel to the first surface  38 . 
         [0062]    In some embodiments, the third surface  42  may be a surface of the device  24  upon which the device  24  rests within the deposition chamber  16  during deposition of the antimicrobial coating  34 , and may not be an exposed surface upon which the parylene monomer and the antimicrobial agent  32  condense. Thus, in some embodiments little, if any, antimicrobial coating forms on the third surface  42 . 
         [0063]      FIG. 2B  shows a schematic cross-section of a portion of the first surface  38  covered by the antimicrobial coating  34 . As shown in  FIG. 2B , the antimicrobial coating  34  includes the parylene polymer  36  and the antimicrobial agent  32 . The antimicrobial agent  32  may be a plurality of inorganic antimicrobial particles as described above in reference to  FIG. 1 . The parylene polymer  36  and the antimicrobial agent  32  may be distributed throughout the antimicrobial coating  34  on the first surface  38 . 
         [0064]      FIG. 2C  shows a schematic cross-section of a portion of the second surface  40  covered by the antimicrobial coating  34 . As shown in  FIG. 2C , the antimicrobial coating  34  includes the parylene polymer  36  and the antimicrobial agent  32 . The antimicrobial agent  32  may be a plurality of inorganic antimicrobial particles as described above in reference to  FIG. 1 . The parylene polymer  36  and the antimicrobial agent  32  may be distributed throughout the antimicrobial coating  34  on the second surface  40 . 
         [0065]    In some embodiments, the antimicrobial agent  32  may be present in the antimicrobial coating  34  in an amount as little as about 0.0001 wt. %, about 0.0005 wt. %, about 0.001 wt. %, about 0.005 wt. %, or about 0.01 wt. %, or as great as about 0.1 wt. %, about 0.5 wt. %, about 1 wt. %, about 5 wt. %, or about 10 wt. %, or may be present within any range defined between any pair of the foregoing values. In exemplary embodiments, the antimicrobial agent  32  may be present in the antimicrobial coating  34  in an amount from about 0.0001 wt. % to about 10 wt. %, from about 0.0005 wt. % to about 5 wt. %, from about 0.001 wt. % to about 1 wt. %, from about 0.005 wt. % to about 0.5 wt. %, or from about 0.01 wt. % to about 0.1 wt. %. In some exemplary embodiments, the antimicrobial agent  32  may be present in the antimicrobial coating  34  in an amount of about 0.05 wt. %. 
         [0066]    In contrast to some deposition processes, for example, sputter deposition, or e-beam evaporation in which the deposition may be directional, the deposition process for the antimicrobial coating  34  described above in reference to  FIG. 1  is a non-directional gas phase deposition process. In this deposition process, the antimicrobial coating  34  may deposit substantially evenly on all exposed surfaces, regardless of the relative orientation of the surfaces. That is, the concentration of the antimicrobial agent  32  in the antimicrobial coating  34  may be substantially the same between the first surface  38  and the second surface  40 , even though the surfaces may have different relative orientations because the second surface  40  may not be parallel to the first surface  38 . In some embodiments, the concentration of the antimicrobial agent  32  in the antimicrobial coating  34  may not differ between the portion of the first surface  38  and the portion of the second surface  40  by more than as little as about 0.1%, about 0.2%, or about 0.5%, or as much as about 2%, about 5%, or about 10%, or may not differ by more than any amount within any range defined between any pair of the foregoing values. In exemplary embodiments, the concentration of the antimicrobial agent  32  in the antimicrobial coating  34  may not differ between the portion of the first surface  38  and the portion of the second surface  40  by more than from about 0.1% to about 10%, from about 0.2% to about 5%, or from about 0.5% to about 2%. In exemplary embodiments, the concentration of the antimicrobial agent  32  in the antimicrobial coating  34  may not differ between the portion of the first surface  38  and the portion of the second surface  40  by more than about 1%. For example, if the concentration of the antimicrobial agent  32  in the antimicrobial coating  34  on the first surface  38  as shown in  FIG. 2B  is about 1 wt. %, then the concentration of the antimicrobial agent  32  in the antimicrobial coating  34  on the second surface  40  as shown in  FIG. 2C  may be within about 1% of the 1 wt. %, or from 0.99 wt. % to 1.01 wt. %. 
         [0067]    In some embodiments, the antimicrobial agent  32  may include a plurality of antimicrobial nanoparticles as describe above in reference to  FIG. 1 , and a plurality of agglomerations of the antimicrobial nanoparticles. In some embodiments, the agglomerations may be as much as about 10,000 times larger than the individual nanoparticles. For example, embodiments employing inorganic antimicrobial nanoparticles having an average diameter of about 100 nanometers may form agglomerations of the antimicrobial nanoparticles as large as 1 millimeter in diameter. In another example, embodiments employing inorganic antimicrobial nanoparticles having an average diameter of about 40 nanometers may form agglomerations of the antimicrobial nanoparticles as large as 0.4 millimeters in diameter. 
         [0068]    In some embodiments, after the antimicrobial coating  34  is formed as described above, the antimicrobial coating  34  may be treated with an oxygen containing plasma. It has been found that treating the antimicrobial coating  34  with the oxygen-containing plasma can expose more of the antimicrobial agent  32 . Exposing more of the antimicrobial agent  32  may increase the antimicrobial efficacy of the antimicrobial coating  34 . In some embodiments, the oxygen-containing plasma is an isotropic plasma, treating the antimicrobial coating  34  across all exposed surfaces. 
         [0069]    Embodiments described above provide an antimicrobial coating on medical devices to prevent a transfer of infectious microorganisms from medical devices to a patient. By mixing the antimicrobial agent with the parylene before loading the deposition system, embodiments may employ a commercially available deposition system requiring few, if any, modifications to support the process. Because the antimicrobial coating may be of uniform composition across all exposed surfaces, a desired level of antimicrobial efficacy may be achieved across all exposed surfaces to help prevent nosocomial infections. 
       EXAMPLES 
       [0070]    The present invention is more particularly described in the following examples that are intended as illustrations only, since numerous modifications and variations within the scope of the present invention will be apparent to those of skill in the art. Unless otherwise noted, all parts, percentages, and ratios reported in the following examples are on a weight bases, and all reagents used in the examples were obtained, or are available, from the chemical suppliers described below, or may be synthesized by conventional techniques. 
       Example 1 
     Deposition of Parvlene C and 100 Nanometer Silver Nanoparticles 
       [0071]    A mixture was prepared from 100 nanometer diameter silver nanoparticles in dispersion (Sigma-Aldrich, 0.02 mg/mL in aqueous buffer containing sodium citrate as a stabilizer, #730777) and parylene C dimer powder (Specialty Coating Systems, Inc., SCS DPX-C). Approximately 0.10 to 0.15 milliliters (2 to 3 drops) of the silver nanoparticle dispersion was manually mixed with 1.5 grams of the parylene C dimer powder. 
         [0072]    The mixture was placed in a removable boat and placed within a vacuum chamber to drive off any liquid. The mixture was then placed within a vaporizer of a parylene deposition system. Air was evacuated from the deposition system, including the vaporizer, and the mixture was heated to 150° C. in the vaporizer to sublimate the dimer and the silver nanoparticles. Then the sublimated dimer was heated to 685° C. to pyrolize the dimer before the pyrolized dimer (monomer) and the silver nanoparticles were deposited on a substrate surface at room temperature to form an antimicrobial coating on the substrate. 
         [0073]      FIG. 3  is a micrograph of the deposited antimicrobial coating. The micrograph was taken at a magnification of 10 times under a combination of white and ultraviolet lights. As shown in  FIG. 3 , some of the 100 nanometer nanoparticles have agglomerated to form particles as large as about 1 millimeter in diameter. Agglomerations smaller than about 0.02 millimeters, and any individual 100 nanometer nanoparticles, are not visible in the micrograph. As also shown in  FIG. 3 , the inorganic antimicrobial particles are integrated into the parylene polymer and distributed throughout the coating. 
       Example 2 
     Deposition of Parvlene C and 40 Nanometer Silver Nanoparticles 
       [0074]    A mixture was prepared from 40 nanometer diameter silver nanoparticles in dispersion (Sigma-Aldrich, 0.02 mg/mL in aqueous buffer containing sodium citrate as a stabilizer, #730807) and parylene C dimer powder (Specialty Coating Systems, Inc., SCS DPX-C). Approximately 0.10 to 0.15 milliliters (2 to 3 drops) of the silver nanoparticle dispersion was manually mixed with 1.5 grams of the parylene C dimer powder. 
         [0075]    The mixture was placed in a removable boat and placed within a vacuum chamber to drive off any liquid. The mixture was then placed within a vaporizer of a parylene deposition system. Air was evacuated from the deposition system, including the vaporizer, and the mixture was heated to 150° C. in the vaporizer to sublimate the dimer and the silver nanoparticles. Then the sublimated dimer was heated to 685° C. to pyrolize the dimer before the pyrolized dimer (monomer) and the silver nanoparticles were deposited on a substrate surface at room temperature to form an antimicrobial coating on the substrate. 
         [0076]    The antimicrobial coating was viewed at a magnification of 50 times under ultraviolet light. Some of the 40 nanometer nanoparticles had agglomerated to form particles as large as about 0.1 millimeter in diameter. The agglomerations were integrated into the parylene polymer and appeared to be distributed throughout the coating. 
         [0077]    Various modifications and additions can be made to the exemplary embodiments discussed without departing from the scope of the present invention. For example, while the embodiments described above refer to particular features, the scope of this invention also includes embodiments having different combinations of features and embodiments that do not include all of the described features. Accordingly, the scope of the present invention is intended to embrace all such alternatives, modifications, and variations as fall within the scope of the claims, together with all equivalents thereof.