CN101437977A - Antimicrobial coating methods - Google Patents

Abstract

The invention is directed to efficient methods for depositing highly adherent anti not microbial materials onto a wide range of surfaces. A controlled cathodic arc process is described, which results in enhanced adhesion of silver oxide to polymers and other surfaces, such as surfaces of medical devices. Deposition of anti-microbial materials directly onto the substrates is possible in a cost-effective manner that maintains high anti-microbial activity over several weeks when the coated devices are employed in vivo.

Description

Antimicrobial Coating Method

This application claims U.S. Provisional Application Serial No. 60/762,769 filed January 27, 2006, U.S. Provisional Application Serial No. 60/763,262 filed January 30, 2006, U.S. Provisional Application Serial No. 60/763,262 filed February 25, 2006 Provisional Application Serial No. 60/776,537, priority to US Provisional Application Serial No. 60/779,917, filed March 6, 2006, the disclosures of which are hereby incorporated by reference. This application is a continuation-in-part of U.S. Patent Application Serial No. 10/741,015, filed December 18, 2003, which claims priority to U.S. Provisional Application Serial No. 60/434,784, filed December 18, 2002 , and its disclosure is hereby incorporated by reference.

technical field

The present invention relates to a cathodic arc ion plasma (ion plasma) deposition process for the manufacture of modified metal coatings which can be used to form antimicrobial surfaces on the surfaces of devices and materials for medical applications . In particular, the present invention relates to a process for depositing silver (Ag), and other antimicrobial metals, or combinations thereof, under highly controlled conditions to form Antimicrobial coating that remains active within the segment.

Background technique

The germicidal properties of metals such as silver, zinc, niobium, tantalum, hafnium, zirconium, titanium, chromium, nickel, copper, platinum and gold have been demonstrated. Of these metals, silver in ionic or compound form is the best known and most widely used antimicrobial metal. Elemental silver has some antimicrobial benefits, but it is generally ineffective for most antimicrobial applications. The oxidized form of silver is believed to be more active as an antimicrobial, as shown in the observation that coating and ink of silver oxides results in a reduction in their reactivity and solubility.

Attempts have been made to improve silver reactivity through the use of silver oxides and combinations of silver with other materials using well-established solution-based chemistries. US Patent No. 4,828,832 describes the use of a metallic silver salt solution, such as an aqueous silver nitrate salt solution, in combination with an oxidizing agent, such as benzoyl peroxide, in the treatment of skin infections.

US Patent No. 5,824,267 discloses embedding silver metal particles and ceramic or alkali metal particles on the surface of plastic products to impart antibacterial properties to plastic products. The extremely fine silver metal particles are obtained by chemical deposition from aqueous solutions of silver metal salts.

Although solution methods for generating silver particles are able to provide silver with antimicrobial activity, there is little control over the structure of the resulting silver particles, thus these methods are limited in their applications. Also, some ionic species, such as aqueous silver nitrate solutions, are too active for most applications due to potential skin irritation and must therefore be carefully monitored and controlled. Another problem with solution-based chemistries is forming stable compositions without producing harmful by-products. Silver ions incorporated into pastes, paints, polymers, or gels tend to have short shelf lives, in part because of side reactions with the various components that occur in water-based solutions.

There is a clear need for antimicrobial surfaces capable of producing sustained release of antimicrobial metal ions. Surface ability to produce sustained release of antimicrobial ions in surgical and wound dressings and bandages, surgical sutures, catheters and other medical devices, implants, prosthetics, dental applications and tissue regeneration is particularly useful. Other devices that would also benefit from sustained release of antimicrobial materials include: medical appliances and surfaces, restaurant surfaces, face masks, clothing, door latches and other fixtures, swimming pools, hot tubs, drinking Water filters, cooling systems, porous hydrophilic materials, humidifiers and air conditioning systems.

Methods for producing sustained release of metal ions are described in US Patent No. 4,886,505. According to this method, the device is coated with a first metal, such as silver, and a second metal, such as platinum, connected to the first metal by a switch. In the presence of body fluids, the presence of silver metal and platinum metal results in a galvanic action which serves to release or release silver ions. The release of ions is controlled by a switch operated externally to the device.

Techniques for applying electrical current to silver-coated wound dressings or medical devices are also the subject of US Patent Nos. 4,219,125 and 4,411,648. Although the use of an external switch controller or an external current can increase the rate of metal ion release, such an external controller or current is not feasible for a variety of applications.

US Patent No. 6,365,220 describes a method for making an antimicrobial surface that provides a sustained release of antimicrobial ions and does not require an external electrical current to maintain the release. According to this disclosure, a multilayer metal thin film is deposited on a substrate by a sputtering or evaporation process. By applying different metal compositions to different layers and employing etching techniques to roughen or texture the surface of the layers, multiple microlayer interfaces can be created. When exposed to body fluids, multiple interfaces can provide for the release of ions through galvanic and non-galvanic effects.

US Patent No. 5,837,275 also discloses antimicrobial coatings that provide sustained release of antimicrobial ions. Coatings are produced by sputtering techniques using specific deposition parameters. The coating is described as exhibiting an "atomically haphazard" metallic film, which it says is necessary for the sustained release of metal ions.

Ordered single crystals of silver tetroxide (Ag ₄ O ₄ ) are said to be useful in the treatment of skin diseases as antibacterial agents (US Patent No. 6,258,385). However, such complexes are not practical except for topical use, and their ability to provide sustained release of antimicrobial materials over long periods of time (ie, days) has not been demonstrated.

Typically, the deposition of antimicrobial materials is limited to one of three unique methods used to prepare silver and silver oxide coatings. Each of these methods has serious drawbacks, and none has been developed to effectively produce highly adherent and uniformly distributed antimicrobial films on the surfaces of medical devices and instruments. Commonly used process conditions, such as sputtering, dipping, and ion beam assisted deposition, produce coatings with limited adhesion to flexible substrates or elastic devices. Additional layers are sometimes necessary in order to increase adhesion while spending considerable processing time.

Deposition of metallic materials on substrates by cathodic arcing in vacuum is known in the art. In contrast to other plasma evaporative deposition methods, ion plasma deposition (IPD) is capable of producing dense multi-component coatings of high purity, as described in US Patent Application Publication No. 2004/0185182. However, conventional cathodic arc deposition methods have certain disadvantages. Expensive material is wasted due to ineffective use of target material and lack of particle control. The lack of control over the material to be deposited leads to the formation of particles of different sizes, which leads to the deposition of non-uniform coatings. Typically, the cathodic arc process also requires heating the substrate surface to very high temperatures, which can damage the substrate material and severely limit substrate options.

Contents of the invention

The present invention fulfills the continuing need for an antimicrobial material that can be bonded to any surface, has a controlled release rate and lifetime, and is non-toxic in the desired application. Antimicrobial coatings with these properties can be deposited on a variety of substrate surfaces using a novel cathodic arc IPD deposition process as described in the present invention.

It is an object of the present invention to provide a method of depositing an antimicrobial material onto a substrate using an ion plasma deposition process to form a discrete layer of antimicrobial particles.

A further object of the present invention is to provide a method for preparing an antimicrobial surface on any finished product, thus eliminating the need to employ complex chemical, pulping, coating and bonding technologies.

Another object of the present invention is to provide antimicrobial surfaces which provide sustained release of antimicrobial agents at therapeutically effective levels over extended periods of time in vivo.

Another object of the present invention is to provide antimicrobial properties by impregnating or depositing dispersed metals and/or metal/metal oxides of one or more elements into a matrix for sustained release of metal ions surface.

Thus, in particularly preferred embodiments, the present invention provides for the deposition, infiltration or layering of silver and other metal ions that bond (bond) to nanoscale, ultramicroscale, and Solid-state structures of micron-sized crystalline metals and metal oxides designed as compositions of monovalent, divalent and multivalent oxides dispersed into or on surfaces. Anions can then be released by contact with pathogens due to enzymatic activity, or by addition of water or contact with body fluids.

The disclosed process can be used in the manufacture of a variety of devices requiring a controlled composition, but is particularly suitable for small to large area rolls requiring a sterilizing, sterilizing, biocidal or antimicrobial surface Manufacturing of rolls, such as bandages, or individual components, such as catheters, stems or implants. The process creates control over the amount, particle size, and energy of the ionized material to be combined with the ionized oxygen or other gas, and can be applied to monovalent, divalent, and multivalent oxides and nitrides as well as multiple layers a wide range of combinations.

This process can be used to manufacture antibacterial products or to carry out surface treatment on existing products and raw materials. The process can be used to generate small-scale energy devices to enhance antimicrobial activity or to provide power for other nanotechnology devices; for example, silver oxide batteries power micropumps, implants, galvanic surfaces ) and other devices that require energy to provide energy.

Accordingly, one aspect of the present invention is to provide a method for depositing an antimicrobial surface on a substrate comprising the steps of: placing a cathode target comprising a potentially antimicrobial metal into a vacuum chamber, powering the cathode to deposit an antimicrobial surface on the cathode An electric arc is generated that ionizes the negative metal into a plasma of ionized particles; a reactive gas such as oxygen is introduced into the vacuum chamber so that the gas reacts with the ionized plasma particles, and The deposition of plasma particles on the substrate is controlled by moving the substrate closer to or further away from the target in a controlled manner.

Further control of the deposition process can be achieved by means of controlling the arc, whereby the power supplied to the negative electrode is adjusted to vary the rate at which the arc occurs.

Another aspect of the present invention is to provide an antimicrobial surface on a substrate comprising a dispersion of metal oxide particles, wherein the metal is selected from the group consisting of silver, nickel, zinc, copper, gold, platinum, niobium, tantalum, hafnium, zirconium, titanium, Chromium, and combinations thereof.

The present invention relates to a process for depositing an antimicrobial material on a selected base material. The substrate can be any material such as metal, ceramic, plastic, glass, flexible sheet, porous paper, pottery or combinations thereof. Although the substrate may comprise any of a variety of devices, medical devices are particularly preferred. These medical devices include catheters, implants, stents, endotracheal tubes, orthopedic pins, shunts, drains, prosthetic devices, dental implants, dressings, and wound closures. However, it should be understood that the present invention is not limited to these devices, but may be extended to other devices used in the medical field, such as masks, garments, surgical tools and surfaces.

There are two important factors regarding implant infection: the introduction of bacteria during the implant procedure; and the skin opening after the procedure. Transdermal devices are the main area of infection. Bacterial contamination occurs because the device separates from the skin, creating a gap between the skin and the device.

Another aspect of the invention relates to improved and more economical methods for providing tuned antimicrobial surfaces or other compositions for use in human and veterinary medical devices and other applications.

The antimicrobial material can be any solid material or combination of materials with antimicrobial properties. Preferred materials are metals with potential antimicrobial properties and biocompatibility (ie, not damaged in the intended environment). These metals include silver, zinc, niobium, tantalum, hafnium, zirconium, titanium, chromium, nickel, copper, platinum, and gold (also referred to herein as "antimicrobial metals"). The term "potential antimicrobial properties" refers to the fact that these metals in elemental form are generally not reactive enough to be effective antimicrobials. However, when the metal is ionized it has a stronger antibacterial effect. Therefore, the antimicrobial metal has potential antimicrobial properties after metal ionization. When ionized, antimicrobial metals can also combine with various reactive gases, such as nitrogen or oxygen, to form nitrides, oxides, and/or compounds of combinations thereof.

definition

Ion plasma deposition is a method of generating a high-energy plasma by using a cathodic arc to discharge a target material.

A cathodic arc, also known as a vacuum arc, is a device used to generate plasma from solid metal. The arc strikes the metal, and the high energy density of the arc vaporizes and ionizes the metal, creating a plasma that sustains the arc. Vacuum arcs differ from high voltage arcs because the metal vapor itself is ionized rather than the ambient gas.

Colossal or macroparticles are particles larger than a single ion; nano (or small) particles are particles about 100 nanometers in size; moderately large particles are 100 nanometers to about 1 micrometer; very large particles are particles larger than 1 micrometer .

A Coulomb explosion occurs when a sufficiently strong energy destroys a group of atoms (such as a gas mass, object, or target), such that the electric field of the energy source drives some or all of the electrons away from the atom. Without electrons, the cluster of ions explodes due to Coulomb repulsion of positive charges.

Plasma Vapor Deposition (PVD) is a process of depositing thin films in the gas phase in which source materials are physically transformed onto a substrate in a vacuum without involving any chemical reactions. This type of deposition includes thermal evaporation electron beam deposition and sputter deposition. The IPD process is a subtype of physical vapor deposition.

The term "medical device" as used herein is intended to broadly extend to all devices used in the medical field, including stents, catheters, various implants, etc., regardless of the material from which they are made. References herein to medical devices and other medical references are understood to also include veterinary devices and applications.

The term "potential antimicrobial properties" refers to the situation where these metals in elemental form are generally not reactive enough to be effective antimicrobials, but may, when the metal is ionized, exhibit a stronger antimicrobial effect . Therefore, the antimicrobial metal has potential antimicrobial properties after being subjected to metal ionization in many cases. When ionized, antimicrobial metals can also combine with various reactive gases, such as nitrogen or oxygen, to form nitrides, oxides, and/or compounds of combinations thereof.

"Multiple valency" as used herein refers to one or more valence species and should be understood to refer to a charge on an ion or a charge assigned to a particular ion based on its electronic state.

Unless otherwise stated, silver oxide is defined as the singlet form of silver oxide (AgO).

The term "about" used herein is to illustrate that the specific number does not need to be precise, it can be determined by the specific process or method adopted, and the number can be higher or lower.

PEEK-Polyetheretherketone

PTFE-Polytetrafluoroethylene

EPIFE-expanded polytetrafluoroethylene

UNMWPE is Ultra High Molecular Weight Polyethylene

It should be understood that the use of "a" or "an" to define a claim is not necessarily limited to a single substance.

Description of drawings

Figure 1 is a sketch of an IPD device. 1. The target material, 2. the substrate being coated, 3. the mechanism for moving the substrate closer to or away from the target, 4. the vacuum chamber, and 5. the power supply for the target.

Fig. 2 is another embodiment of an IPD device. 1. Target material, 2. Substrate to be coated, 3. Mechanism with ability to move the substrate closer to or away from the target, 4. Vacuum chamber, and 5. Power source for the target, 6. Arc controller which determines the arc speed.

Detailed ways

The present invention offers several advantages over antimicrobial coatings in the art and other state of the art processes for depositing antimicrobial coatings, including: controlled release, embedding the coating into the matrix, lower Operating temperature, significantly improved throughput in process efficiency compared to conventional cathodic arc processes, scalability, and applicability to a wider range of substrate materials.

In addition, excellent coatings that are difficult to obtain using traditional IPD methods have been obtained, including silver oxide, copper oxide, and hafnium nitride coatings. At comparable thicknesses, these materials have higher antimicrobial activity than more expensive methods such as outlined in US Patent No. 5,454,886, which is incorporated herein by reference. Thus, by adopting the new IPD-based approach, thinner coatings with the same antimicrobial efficacy and shorter treatment times can be achieved. Higher throughputs are possible, which can lead to savings in production costs, and this is a very significant advantage especially for the pharmaceutical industry.

A factor that confers this advantage on films obtained with the disclosed process is the discovery that the new IPD process produces an increase (rather than a decrease) in macroion deposition that actually improves film quality. For technicians over the years, the most significant trend in the use of conventional cathodic arc deposition processes has been to reduce the deposition of large particles in order to produce cleaner and more uniform films. Conventional wisdom in the industry is that generally large particles are detrimental to the quality of deposited films.

The present invention relates to a process for depositing an antimicrobial material on a selected base material. The substrate can be any material such as metal, ceramic, plastic, glass, flexible sheet, porous paper, pottery or combinations thereof. Although the substrate may comprise any of a variety of devices, medical devices are particularly preferred. These medical devices include catheters, implants, stents, endotracheal tubes, orthopedic pins, shunts, drains, prosthetic devices, dental implants, dressings, and wound closures. However, it should be understood that the present invention is not limited to these devices, but extends to other devices used in the medical field, such as masks, garments, surgical implements and surfaces.

There are two important factors regarding implant infection: the introduction of bacteria during the implant procedure; and the skin opening after the procedure. Transdermal devices are the main area of infection. Bacterial contamination occurs because the device separates from the skin, creating a gap between the skin and the device.

Another aspect of the invention relates to improved and more economical methods for providing tuned antimicrobial surfaces or other compositions to human and veterinary medical devices and other applications. The antimicrobial material can be any solid material or combination of materials with antimicrobial properties. Preferred materials are metals with potential antimicrobial properties and biocompatibility (ie, not damaged in the intended environment). These metals include silver, zinc, niobium, tantalum, hafnium, zirconium, titanium, chromium, nickel, copper, platinum, and gold (also referred to herein as "antimicrobial metals"). According to the present invention, the antimicrobial metal is deposited on or into the surface of the substrate by ionizing the negative electrode of the target metal into a plasma of particulate components in vacuum. Ion plasma deposition apparatus, such as those described in International Patent Application Publication No. WO 03-044240, the contents of which are incorporated herein by reference, can be modified in accordance with the present invention and used to implement antimicrobial Controlled deposition of non-volatile materials.

A factor that confers this advantage on films obtained with the disclosed process is the discovery that the new IPD process produces an increase (rather than a decrease) in macroion deposition that actually improves film quality. For technicians over the years, the most significant trend in the use of conventional cathodic arc deposition processes has been to reduce the deposition of large particles in order to produce cleaner and more uniform films. Conventional wisdom in the industry is that generally large particles are detrimental to the quality of deposited films.

In contrast, an increase in the content of large particles has been found to form an effective route to control the antimicrobial activity of silver oxide films. For rapid release of silver into surrounding tissue, a thick pure AgO coating completely free of large particles can be used. For further tuned release, a time-release scheme is utilized.

When a cathodic arc is used to deposit a coating on a substrate, the corresponding amount of macroparticles ejected from the target can be controlled. Large particles are metal droplets (blobs) ejected from the target without being completely vaporized. These metal droplets are dense and consist of pure target material. Typically, the surfaces of these metal droplets are charged, whereas most materials are electrically neutral.

As the large particles pass through the plasma, their outer surfaces are oxidized, forming a "coated sugar"-like structure with AgO coatings on the outside of the particles and pure silver inside. This acts like a time-release capsule.

Due to the instability of the inner AgO outer "shell" and the more stable inner "shell" of sterling silver, the delayed release effect is produced. The silver oxide exterior coating releases its antimicrobial activity relatively quickly, killing any bacteria in the surrounding area. During release, the inner sterling silver is oxidized and released slowly to maintain antimicrobial activity over a period of time. The length of time is determined by the size of the macroparticle. Therefore, specific coatings of specific sized macroparticles can be designed to maintain antimicrobial activity for a selected period of time. Typically macroparticles range in size from 10 nm to 10 microns, depending on how long they need to be active.

Elution is an important factor in antimicrobial activity; however, the amount of eluted silver correlates with the antimicrobial activity of Ag/AgO-coated devices. To effectively fight infection and form biofilms, the elution rate must occur at a certain level. The minimum elution rate was about 0.005 mg Ag per square inch (0.0048 mg/square inch). The antimicrobial activity of the silver oxide coatings prepared by the methods disclosed herein will elute at this elution rate for at least 60 days. Silver/silver oxide coatings prepared by other methods did not elute at a constant rate for more than 7 days.

Another important feature of the present invention is the ability to embed the silver oxide coating on the surface of the device, thus achieving superior adhesion compared to coatings deposited by other deposition methods. The embedding process can be controlled by using arc control methods at a specific distance from the target in order to obtain embedding coatings down to 100 nm and greater for plastics and 10 nm and deeper for metals and ceramics.

A suitable apparatus for carrying out an ion plasma deposition process is shown in FIG. 1 . As shown in FIG. 1 , a cathode 1 of target material is deposited in a vacuum chamber 4 . The cathode 1 is ionized by generating an electric charge at the cathode, provided by energy supplied by the energy source 5 applied to the cathode. The plasma components are selected, controlled or directed towards the substrate by the control mechanism 3 moving the substrate 2 closer to or away from the target 1 .

Additional control of the power supply 6 may also be utilized as shown in Figure 2 to provide further control over the plasma composition by controlling the arc speed.

For example, where the desired antimicrobial metal is silver, the silver cathode and the selected substrate are placed in the vacuum chamber of an ion plasma deposition apparatus. The silver used as the cathode is preferably medical grade silver (ie, 99.99% pure) to avoid any potentially toxic substances, although lower purity silver metal can also be used.

The vacuum chamber is pumped to a suitable working pressure, typically in the range of 0.1mT to 30mT; however, the IPD process's ability to efficiently manufacture antimicrobial surfaces with sustained release rates does not depend on any specific pressure, typically in the range of 0.1mT to 30mT. work pressure. Similarly, ion plasma deposition processes are not dependent on operating temperature. Typical operating temperatures range from 25°C to 75°C, any temperature within this range is suitable for making antimicrobial surfaces.

The substrate may be rotated (eg, on a turntable) or wound through the deposition zone in any direction relative to the deposition material entry track. Electrical energy is supplied to the cathode to generate an arc at the cathode. This electrical energy is a current in the range of a few amperes to hundreds of amperes at a voltage suitable for the source material. Typically, the voltage ranges from 12 volts to 60 volts and is suitably adjusted for the size of the source material, which can be from a few inches to several feet. The arc ionizes the silver metal cathode into a plasma of silver ions, electrically neutral particles and electrons. Typically, oxygen gas is introduced into the plasma at a rate of 10 sccm to 1000 sccm, and combines with silver ions to form silver oxide particles. Depending on the desired rate of ion release and the end use of the substrate, the silver oxide particles can have a particle size ranging from less than 1 nanometer to about 50 microns.

The release rate of metal ions from the antimicrobial surface can also be controlled in order to obtain an effective release rate over a sustained period of time. This controlled release of metals is achieved by depositing a combination of oxides of various structures, including monovalent, divalent, and multivalent oxides, on the substrate. Combinations of oxides exhibit different ion release rates, which lead to control of ion concentration and sustained release of metal ions for enhanced antibacterial activity. Multivalent oxides can also form on neutral metal particles as they are oxidized in the plasma. Sustained release of the deposited material can be further enhanced by forming a composition of oxides of various sizes and valence states. The benefit of this composition is the increased release of ions over a longer period of time. Silver oxide particles are then deposited on the surface of the substrate in the form of a dispersion of silver oxide particles.

The effectiveness of an antimicrobial surface in delivering an anti-microbial is dependent on the treatment time used to form the antimicrobial surface. Longer treatment times from 5 seconds to several minutes formed antimicrobial surfaces with different antimicrobial responses.

Controlled metal release can also be obtained by depositing a combination of different metal oxides on the substrate. These compositions include silver and titanium, silver and gold, silver and copper, silver copper and gold. Other materials may be combined as co-deposited metals, alloys, or as alternating layers in various combinations. Control and adaptability of the plasma environment allows for a greater range of compositions and, correspondingly, a wide range of custom coatings.

The invention is further illustrated by the following non-limiting examples.

Example

Materials and methods

Sample Elution Test - An elution test was performed to determine the silver elution profile of the coated polypropylene coupons. The silver elution test provides a quantitative method for determining the amount of silver released from a test article over a specified period of time. The present invention is practiced in accordance with current FDA Good Laboratory Practice (GLP, Standards) 21 CFR, Part 58. Each test article was extracted from USP 0.9% NaCl solution for injection at a temperature of 37±1° C. for silver elution analysis by inductively coupled plasma spectroscopy (ICP). Each sample was placed in 10 mL of USP 0.9% NaCl for a specific period of time. The time periods used in this study were 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 24 hr, 2-7 days, 10 days, 15 days, 20 days, 25 days and 30 days. At each time point, the liquid surrounding the sample was removed into a clean glass container and fresh NaCl was added to the sample container. The liquid removed was brought up to a total volume of 50 mL with deionized water, then digested and assayed for silver content by ICP.

Specimen Zone of Inhibition (ZOI) Test - The ZOI test is an easy 24 hour test for antimicrobial activity. The test is not quantitative and only provides enough information to indicate whether serial dilution testing is permitted. This test does not provide information on tissue regeneration or necrosis.

Sample Serial Dilution Test - The serial dilution test provides an accurate measurement of the number of bacteria per unit of a given volume. This provides a quantitative measure of the activity of the antimicrobial coating when compared to a control sample.

Standard bacterial solutions were prepared from 0.5 McFarland standard. This standard was calibrated to read between 0.08 OD and 0.1 OD at 625 nm, which gave a standard bacterial count of 1.5 x ¹⁰⁸ cfu/mL.

While the following embodiments of the present invention are described in detail, modifications and adaptations to those embodiments will be apparent to those skilled in the art. It should be understood that these modifications are included within the protection scope of the present invention.

Example 1. Silver-Coated Catheters (Disclosed Method)

A solver-coated catheter was prepared using the same procedure as described in Example 6 of US Patent No. 5,454,886. Silver metal was deposited on 2.5 cm long segments of a dual lumen latex balloon catheter using magnetron sputtering. Operating conditions were implemented as closely as possible based on the disclosed examples; namely, deposition rate 200 A° per minute; argon working pressure 30 m Torr; ratio of substrate temperature to melting point of coating metallic silver (T/Tm) 0.30. In this embodiment, since the substrate is round and rough, the angle of incidence varies; that is, the angle of incidence varies around the circumference and across the sides and top of the numerous surface members within precise limits. The antibacterial effect against Staphylococcus aureus (S. aureus) was tested by zone of inhibition, (Table 1).

Table 1

Results reported in patent 5,454,886 Experimental results Zone of inhibition 0.5mm T/Tm 0.38 Zone of inhibition 16mm <1mm T/Tm 0.30 0.30

Under the same T/Tm conditions as previously disclosed, and repeating the same conditions set forth in Example 6 of patent 5,454,889, the observed zone of inhibition (ZOI) around the tube was significantly smaller than the reported ZOI. The ZOI test was performed using Staphylococcus aureus (S. aureus) as reported in Example 1 of patent 5,454,886.

Example 2. DC magnetron sputtering antimicrobial coating (published method).

The method of Example 7 in Patent 5,454,886 was followed. Under the following conditions: 0.5 kW power, 40 mTorr Ar/O ₂ , initial substrate temperature of 20 degrees Celsius, 100 mm cathode/anode distance, and a final film thickness of 300 nm, 99.99% pure silver was obtained using DC magnetron sputtering Applied on a Teflon-coated double lumen latex balloon catheter. The working gases used were commercially available Ar and 99/1 wt% Ar/ _O2 .

The antibacterial effect of the coating was tested by the zone of inhibition test. Disperse the acid hydrolyzed casein agar in a Petri dish. The surface of the agar plate was dried prior to inoculation with a lawn of Staphylococcus aureus ATCC #25923. Inoculum was prepared from Bactrol Discs (Disco, M.), which were reconstituted according to the manufacturer's instructions. Simultaneously, after incubation, the coated material to be tested was placed on the agar surface. The dishes were incubated at 37°C for 24 hrs. After incubation, the ZOI was measured and the calculation of the corrected zone of inhibition was performed as follows: corrected zone of inhibition = zone of inhibition - diameter of the test material in contact with the agar. The published results show that no zone of inhibition exists for the uncoated samples. For catheters sputtered in 99/1 wt% Ar/ _O2 at a working gas pressure of 40 mTorr, a corrected zone of inhibition of 11 mm was reported.

In Table 2 the experiments were repeated under the disclosed conditions. Small ZOIs of less than 1 mm were observed.

Table 2

In repeating the above disclosed conditions, the experimental results show a small ZOI of less than 1 mm.

Embodiment 3. Composite silver antibacterial film (disclosed method)

As found in Example 11 of patent 5,454,886, this example demonstrates the state of the art process for preparing composite antimicrobial coatings formed by reactive sputtering. Table 3 lists the published sputtering conditions and the conditions used in the comparative study (compared to the experimental results obtained by following the steps in the published method).

table 3

Open test of sputtering conditions Target 99.99% Ag 99.99% Working gas 80/20% Ar/O ₂ 80/20% ArO ₂ Working air pressure 2.5-50mTorr 40mTorr Power 0.1-2.5kW 0.5kW

Substrate temperature -5°C to 20°C 20°C Anode / cathode distance 40mm to 100mm 100mm Bottom air pressure (base P) <4×10 ⁴ Torr <4×10 ⁴ Torr ZOI 6mm-12mm 0mm-2mm

Example 4. In Vitro Testing of Silver Oxide Coated Catheters

This example demonstrates the effectiveness of antimicrobial coatings in a range of Gram-positive and Gram-negative organisms. The organisms used for the general zone of inhibition test are: Gram-positive bacteria Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus MR), and S. epidermis. Gram-negative bacteria are Escherichia coli (E. coli), K pneumoniae (K pneumoniae) and P. aerugosia.

The method used to perform the ZOI assay was a maximum of 4 days of plate-by-plate transfer. Each bacterium was plated on tryptic soy agar. Prefabricated plates were inoculated with bacteria, divided into three equal sections, and after incubation, a one inch long double lumen balloon catheter coupon coated with 200 nm silver oxide was placed in the center of each section. The samples were placed in an incubator at 37°C, and the ZOI was measured at 24 hours, 48 hours, 72 hours and 96 hours.

The total ZOI is defined as the ZOI minus the width of the specimen. For this experiment, the measurement of the total ZOI was performed and divided in two. If there is no measurable ZOI and no biofilm, and no organisms grow across or attach to the specimen, the measurement is recorded as 0.0 mm. When biofilm was observed, it was recorded as 1.0 mm. Plate-by-plate transfers were repeated until biofilm was recorded or a measurement of 0.0 mm was recorded for 2 transfers. There were three plates for each organism, with three data points per plate for the side-by-side sample and control catheters. Measurements are taken every day. The average of the three measurements for each plate was taken to obtain the plate ZOI for each day. This is done to compensate for the swipe of too heavy or too light a concentration. All recorded measurements are in mm. A measurement of 0.0 indicates that the organisms grew on the silver coupon, but did not adhere to or form a biofilm on the silver coupon conduits. All control samples without exception had biofilm from day 1 onwards. The results are shown in Table 4.

Table 4

first day

Example 5 In Vivo Testing of Silver Oxide Coated Catheters

This example demonstrates the in vivo testing of two identical segments of catheter material with a 200 nm silver oxide coating. The test device is ETO-sterilized. For each of the two lengths of catheter, four catheter antimicrobial partial segments (approximately 4 inches in length) were made. Use the test device and keep it at room temperature.

A total of eight catheter segments (four segments of each catheter material) were implanted into female New Zealand White rabbits. Prior to implantation day 1, mice were weighed and anesthetized with an intravenous injection of 0.1 mL/kg of ketamine/xylazine cocktail (87 mg/mL ketamine, 13 mg/mL xylazine). Animals were 23-25 weeks old and weighed 2.63 kg on day 1.

One week after catheter implantation, infectious (challenge) organisms (Staphylococcus aureus or Escherichia coli) were placed on the skin around each catheter entry site (two pieces of each catheter material protected by gold Staphylococcus aureus infection while the remaining two segments of each catheter material were infected with E. coli). Animals were sacrificed 48 hours after bacterial infection.

The parameters of the treatments are described in Table 5 below. Bacterial infection occurred on day 8 according to the adopted protocol.

table 5

The paraspinal area was trimmed with an electric shearer and prepared with povidone-iodine and 70% ethanol. Animals have eight implantation locations along their backs. Each location is 2.5cm-5.0cm from the midline, and the locations are about 2.5cm apart. The implantation site is identified with a permanent marker.

At each implantation site, a 16-gauge needle was pierced through the skin and into the muscle. The catheter segment is inserted into the muscle along the ID of the needle and the needle is removed so that half of the catheter segment is implanted through the skin into the muscle. One portion of catheter material is implanted at each site. Four segments of each of the same two segments, for a total of eight implants, were implanted in rabbits. Cover the exposed catheter segment with a sterile dressing. The location of the implantation site on the back of the animals is identified in Table 6.

Table 6

On day 8, a sterile dressing was removed from each exposed catheter segment. The skin around each catheter entry site received a topical instillation of 1 mL of a suspension containing 2.2 x ¹⁰⁵ CFU/mL S. aureus and 5.10 x ¹⁰² CFU/mL E. coli. One segment of each catheter material was infected with S. aureus and one segment of each catheter material was infected with E. coli. After inoculation, the catheter segment is re-covered with a sterile dressing. The inoculated organisms used for each site are listed in Table 7.

Table 7

location number side area Implanted material inoculated organism note 1 Left head 3659-16 Staphylococcus aureus Usually 1 mL of bacterial suspension 2 Left middle of skull 3659-16 N/A ¹ N/A 3 Left middle of skull 3659-17 N/A ¹ N/A 4 Left end of spine 3659-17 N/A ¹ N/A 5 right head 3659-16 N/A ¹ N/A 6 right middle of skull 3659-16 Escherichia coli Topically administer 1 mL of bacterial suspension 7 right mid caudal spine 3659-17 Escherichia coli Topically administer 1 mL of bacterial suspension 8 right end of spine 3659-17 Staphylococcus aureus Topically administer 1 mL of bacterial suspension

N/A = not applied

On day 10, animals were euthanized intravenously with a commercially available euthanasia solution according to Brain Chemistry Optimization Program protocol 01-11-21-22-02-026. Whole implants were aseptically collected and quantitative bacterial assays were performed. Surface labels are placed on the duct area of the muscle and skin. Tags were not collected in this study because multiple catheters had been withdrawn and the implanted conduit was not visible. Muscle sections surrounding the implantation marks were placed in 10% neutral buffered formalin and submitted to Colorado Histo-Prep (Fort Collins, CO) for evaluation by acclaimed veterinary pathologists. For 4 of the 8 implantation sites (Site Nos. 1, 6, 7, and 8), the internal and external portions of the implants were collected into Tryptic Soy Broth, respectively. These are sites that still have a portion of the catheter outside the skin.

Clinical observations showed that the rabbits remained healthy and showed no signs of infection, as shown in Table 8.

Table 8 Clinical Observations of Rabbit Health

explain:

G0 = Appears normal; alert, alert and responsive

S0 = normal stool

S1 = soft feces (soft)

A0 = normal amount of food consumed

For each test material, one implantation site was inoculated with Staphylococcus aureus, and one implantation site was inoculated with Escherichia coli for culture (sites 1, 6, 7, and 8). For the inoculated sites, the two implant locations identified as internal and external were evaluated for microbial growth and identification. The portion of the catheter above the skin is identified as the external implantation site, and the portion of the catheter below the skin is identified as the internal implantation site.

For the remaining four implantation sites (sites 2-5), no inoculation was performed and no implants were visible outside the skin on the day of inoculation (day 8). For these sites, the subcutaneous portion of the catheter was evaluated for growth and recognition of microorganisms.

For the site implanted with 3659-16 catheter material and infected with S. aureus (Site No. 1 ), positive growth of the infecting organism was identified at the internal and external implant sites. For the site implanted with 3659-16 catheter material and infected with E. coli (Site No. 6), there was bacterial growth identified as Staphylococcushominis at the internal implant site; this growth was attributed to environmental contamination. At this site, no growth of infectious organisms (E. coli) was recognized at the internal or external implantation site.

For the site implanted with 3659-17 catheter material and infected with S. aureus (site no. 8), positive growth of the infecting organism was identified only at the site of the external implant. For the site implanted with 3659-17 catheter material and infected with E. coli (Site No. 7), there was no growth at the internal or external implant site.

For the remaining four non-inoculated implantation sites (positions 2-5), there was no bacterial growth. See Table 9.

Table 9

Microbial growth results from implant site

N/A = not applicable

There was no overtly visible evidence of tissue reaction or infection at any implantation site. For all implant sites, there was black to gray discoloration in the subcutaneous fascia and muscle at the implant site. The results are summarized in Table 10.

Table 10

                                               

Dead body detection and observation

Group Animal Implantation Implantation Position Condition Routine ^Observation2

No. Location Material

A 17 1 3659-16 Catheter pulled from muscle No tissue reaction or infection

Visibly Visible Evidence

                                                                                                  No tissue reaction or infection

Clearly visible evidence of back out halfway

                                                                                                                                                             

Visibly Visible Evidence

                                                                     

Visibly Visible Evidence

5 3659-16 Portion of catheter still in muscle No tissue reaction or infection

Visibly Visible Evidence

                                                                                                                                           

Visibly Visible Evidence

                                                                                                                                                             

Visibly Visible Evidence

                                                                                                                            

Visibly Visible Evidence

N/A = not applied

The results show that silver/silver oxide impregnated antimicrobial catheters avoid the formation of bacteria, colonies, and biofilms. Antimicrobial efficacy was consistent across all implant sites, with the antimicrobial coating remaining effective even at day 8 after infection with E. coli or S. aureus bacteria. Necrosis was not observed. The lesions were consistent with a foreign body reaction in the muscle, with a more intense inflammatory response in the subcutaneous tissue.

Example 6 The Elution of Silver Oxide Coating

A total of twenty samples were evaluated on 1 ^cm2 of polypropylene coated with a typical silver oxide coating. Two specimens were selected from ten different specimens in each of the two experimental groups. The test was performed twice using inductively coupled plasma to determine the amount of silver present at each time point. Then for each test group, an average of the ten obtained values was taken. Elution values are shown in mg/sample, which in this case is mg/in2.

During the first 24 hours, all samples showed consistent behavior in NaCl solution. A small peak appeared around the four hour time point before the values leveled off around the 24 hour time point.

All samples had very consistent behavior. These values were fairly stable from day 1 to day 5; then peaked around the time point of day 6 and then plateaued from day 7 to day 30.

The average elution value for the coated polypropylene samples was about 0.005 mg per square inch (0.0048 mg/square inch) at all time points. Throughout the course of this study, in normal saline, the polypropylene samples showed fairly consistent silver elution using elution values and a total silver value of approximately 1.05 mg per square inch (obtained by external testing). A small peak was found at the 4 hour time point as well as after 6 days.

Example 7 In Vivo Healing Test of ePTFE Coated Substrates

Through in vivo testing, this example shows that the 200nm silver oxide coating does not cause necrosis. A 1 ^cm2 sample of ePTFE was coated with a standard 200nm silver oxide coating and implanted subcutaneously in rabbits as outlined in Example 6 above. The substrates were removed on days 9 and 22 to study the healing of the tissue surrounding the silver oxide-coated portion of the implant. The results are summarized in Table 11.

Table 11 - Historical records for 200nm silver oxide

treatment group Implantation duration, days ePTFE // visceral surface ePTFE // mesh surface Silver Particle/Particle Observation Control group uncoated mesh 9 One to several mps layers; sscs 10+ layers with ncf MF: surrounded by mps with occ gcs and with ncf mesh: populated by mps with ncf; occ pmns & baso none twenty two Properly small fibrotic response consisting of fibroblasts (spindle cells) in the collagen matrix. Macrophages and occ giant cells at the interface Fibrillation response at the ePTFE surface and sustained fibrillation response within the mesh and surrounding monofilament components none Silver oxide coated mesh sample 1200nm 9 One to several large mps layers. Fibrotic stacks suggest loss of nuclei. Nuclear hyperplasia. Obvious gcs. MF: Dec nos network of mps: Sparse cellular fibrin network. Tissue fragments. Foci of necrotic debris Obvious gcs with portions of occ larger silver grains, continuous thin layer of mps with partially-visible (vis) surface. twenty two A representative fibrotic response was observed. Dark ppts (matched with refractable fragments) were observed in responding macrophages. Refractable fragments with mps & gcs at the interface Fibrillation response on TFE surface. A large number of baso/mast cells in response. Occ black ppt (refractive fragments) was observed. Refractable fragments with mps & gcs at the interface Black ppts with mps & gcs matching the refraction fragments were observed in the fibrosis response as well as within the TFE interface.

Silver oxide coated mesh sample 2200nm 9 One to several layers of mps with moderate ncf MF: surrounded by mps with occ gcs // slightly reduced mesh: moderate ncf with mps; pronounced vascular response freq Ag particles with mps. Mostly intracellular fibrotic lamina (visible surface) - section with mps twenty two A representative fibrotic response was observed. Scattered mps (refractive fragments) with black ppt and thin layers with mps containing black ppt. TFE surface lined by mps wo fragments Fibrillation response on TFE surface. Occ scattered mps with black ppt Scattered ppt with mps with mesh response and visceral response

The abbreviations used in Table 11 are as follows:

Occ accidental

PMSs polymorphonuclear cells

Mps mucopolysaccharide

SSCs nucleated cells

MF Microfiber

Baso Basophils

Ncf Neutrophil chemotactic factor

Example 8 - Cathodic arc deposition with movable substrate

This example demonstrates how a mobile matrix affects the large particle size, thereby controlling the release of silver oxide.

The substrate (substrate one) was placed on a movable support at a distance of 30 inches from the target. Pump the chamber to a level of 5E-4 Torr. The arc was initiated with a current of 100 amps and 16 volts. Oxygen was introduced into the chamber at a rate of 200 SCCM. Bring the substrate closer to the target at a rate of one inch every 15 seconds. Continue until the substrate is 8 inches from the target.

In a comparative embodiment, the substrate (substrate two) was placed at a distance of 30 inches from the target under the same current, voltage, total time, and oxygen flow rate. This time, the substrate remains stationary.

Initial ZOI testing showed circles of the same size over a 24 hour period. Plate transfers were performed for several bacteria and the results are shown in Table 12. It can be seen that substrates that are moved towards the target during the deposition process exhibit antimicrobial activity for a longer period of time than substrates that remain stationary.

In addition to ZOI testing, cross-sections of the two substrates were also examined using SEM analysis. In sample one, the number and size of large particles increased with film thickness; that is, there were fewer and smaller large particles close to the matrix, and the number and size increased with film thickness. In contrast, the cross section in sample two had few large particles and was uniform.

Table 12

first day

Example 9 - Arc Control

This example illustrates how the arc controller is related to the size and frequency of the large particles produced. In this example, two samples were run. First, Sample Three, had no arc controller, and the substrate was placed at a distance of 12 inches from the target. The second, Sample Four, had an arc controller and also placed the substrate at a distance of 12 inches from the target. Both samples were placed in the chamber, performed different times for different runs, and pumped to 5E-4 Torr. The arc was set to start with 100 Amps for all electrical supplies. Each target had two supplies for a starting total of 200 amps. Sample three was run for five minutes without the arc controller. Sample four was run at the preferred 300 Hz current slew rate.

The switching on the target is always kept at 200amps, but each power supply will be ramped up and down, so at any time, the current on the supply source is not equal. This forces the arc to travel a specific distance at a specific time, thereby controlling the density and size of the large particles.

SEM cross-sectional analysis was performed on samples three and four. It can be observed that although the film is uniform throughout its thickness, sample 4 has a larger average value of macrograin size and density compared to sample 3. The large particles in sample three have an average size of about one micron and a density of 10 ³ /cm ² . The large particles in sample four have an average size of about three microns and a density of 10 ⁴ /cm ² .

Example 10 - In Vitro Testing of Silver Oxide on Metal

This example demonstrates the effectiveness of AgO coatings on Ti-6-4 and CoCrMo. Samples five and six were cleaned using conventional methods and placed in a vacuum chamber at a distance of 12 inches from the target. Typical silver oxide coatings were deposited on wafers and tested for ZOI over a period of three days. Sample five is Ti-6-4, and sample six is CoCrMo. The results are summarized in Table 13.

Table 13

first day

Although the present invention has been described with reference to its specific embodiments, those skilled in the art should understand that various changes, modifications, and equivalent replacements can be made without departing from the true spirit and protection scope of the present invention. In particular, it is to be understood that the chemical and pharmaceutical details of each design may have minor differences, or modifications, by one of ordinary skill in the art without departing from the scope of the invention. All such modifications are intended to come within the scope of the appended claims.

Claims (26)

1. cathode arc ion plasma deposition method that is used to prepare the antiseptic paint on matrix comprises:

Selected matrix is positioned between anode and the negative electrode target, and described target comprises ionizable metal;

The oxygen introducing is held in the vacuum chamber of described negative electrode target and described matrix, wherein, described chamber is pressurized to about 0.1mTorr to about 30mTorr;

Between described anode and described negative electrode target, produce arc-over, wherein, be fed to electric energy on the described electric arc alternatively by variable control, so that the preparation scope is at the particle of 1nm to 50 μ m; And

In arc discharge process, in a scheduled time under the temperature between about 25 ℃ to about 75 ℃, about 1 inch adjust to about 50 inches scope described matrix near or away from the motion of described target, with the thickness that has in deposition on the described matrix at about 50nm high-density, adhesivity antiseptic paint in about 5 mu m ranges extremely.

2. method according to claim 1, wherein, the described electric energy that is fed on the electric arc carries out external control by independent variable power supply or by at least two independently variable power supplies that are connected to described negative electrode target with opposite location.

3. method according to claim 2 wherein, in the process of deposition 100-200nm coating, is adjusted to about 12 volts extremely about 60 volts so that the electric current between 5 amperes to about 500 amperes to be provided with the described electric energy that is fed on the electric arc on described matrix.

4. method according to claim 1, wherein, described ionizable metal is the metal that is selected from the group of being made up of silver, gold, platinum, copper, tantalum, titanium, zirconium, hafnium and zinc.

5. method according to claim 4, wherein, described metal is a silver.

6. method according to claim 1, wherein, described matrix comprises metal.

7. method according to claim 6, wherein, described matrix is selected from by titanium, steel, chromium, zirconium, nickel, their alloy and the group formed of their combination.

8. method according to claim 1, wherein, described matrix comprises polymkeric substance or pottery.

9. method according to claim 8, wherein, described polymkeric substance is polypropylene, urethane, EPTFE, PTFE, polyimide, polyester, PEEK, UHMWPE or nylon or their combination.

10. method according to claim 9, wherein, described polymkeric substance is PEEK or polyethylene.

11. a high-adhesiveness Ag/AgO germ resistance film that is deposited on the metallic matrix, wherein, described Ag/AgO infiltrates the degree of depth that described matrix reaches about 10 nanometers.

12. a high-adhesiveness Ag/AgO germ resistance film that is deposited on the polymeric matrix, wherein, described Ag/AgO infiltrates the degree of depth that described surface reaches about 100 nanometers.

13. Ag/AgO germ resistance film according to claim 11, it deposits to and is selected from by in titanium, steel, chromium, zirconium, nickel, their combination and the metal of the group of alloy composition.

14. Ag/AgO germ resistance film according to claim 12, it deposits on the polymeric matrix that comprises the polymkeric substance that is selected from the group of being made up of polypropylene, urethane, EPTFE, PTFE, polyimide, polyester, PEEK, UHMWPE or nylon and their combination.

15. matrix according to claim 1, it comprises the device that is selected from the group of being made up of conduit, lobe, support and implant.

16. matrix according to claim 15, wherein, described device is a conduit.

17. matrix according to claim 15, wherein, described conduit, lobe, support and implant comprise polymkeric substance, metal, pottery or their combination.

18. matrix according to claim 16, wherein, described conduit comprises polymkeric substance.

19. matrix according to claim 18, wherein, described polymkeric substance is selected from by polypropylene, urethane, EPTFE, PTFE, polyimide, polyester, PEEK, UHMWPE, reaches the group that nylon is formed.

20. cathode arc ion plasma deposition method that is used for improving the anti-microbial activity of silver/silver suboxide ion plasma deposition film, comprise the distance of adjusting between matrix and the cathode arc target, and the monitoring quantity that deposits to silver in described film relevant with the distance of described matrix and described target, wherein, the reduction of the silver/silver suboxide ratio in the anti-microbial activity of the raising of described film and the described film is associated.

21. method according to claim 20 further comprises the particle size of adjusting arc speed and monitoring sedimentary silver/silver suboxide, wherein, the increase of macrobead number has improved the anti-microbial activity of described film.

22. coating by method preparation according to claim 21.

23., further comprise increasing depositing time to obtain required film thickness according to claim 20 or 21 described methods.

24. silver/silver suboxide germ resistance film that is deposited on metal, polymkeric substance or the ceramic surface, wherein, described silver/silver suboxide is embedded into described metallic surface reaches the degree of depth of about 10nm to about 10nm, described film has the thickness between about 5 μ m at about 50nm, and it can be after use reaches at least in time of 28 days and keep anti-microbial activity.

25. silver according to claim 24/silver suboxide germ resistance film, it deposits on the surface of metal, polymkeric substance or ceramic medical treatment device.

26. film according to claim 25, wherein, described medical treatment device is conduit, support, implant or lobe.

Images