CA2134217C - Anti-microbial coating for medical devices - Google Patents

Abstract

Anti-microbial coatings and method of forming same on medical devices are provided. The coatings ace formed by depositing a biocompatible metal by vapour deposition techniques to produce atomic disorder in the coating such that a sustained release of metal ions sufficient to produce an anti-microbial effect is achieved.
Preferred deposition conditions to achieve atomic disorder include a lower than normal substrate temperature, and one or more of a higher than normal working gas pressure and a lower than normal angle of incidence of coating flux. Anti-microbial powders formed by mechanical working to produce atomic.
disorder are also provided. The invention extends to other metal coatings and powders similarly formed so as to provide enhanced solubility.

Description

w0 93/23092 PGT/CA93/00201 1 "ANTI-MICROBIAL COATING FOR MEDICAL DEVICES"

3 This invention relates to methods for preparing modified materials such as metal coatings or powders in a form such that metal species are released on a sustainable basis at an enhanced rate. In a particular aspect, the invention relates to methods of forming anti s microbial coatings and powders of biocompatible metals which provide a sustained release of '7 anti-microbial metal species when in contact with body fluids or body tissues.

The need for an effective anti-microbial coating is well established in the io medical community. Physicians and surgeons using medical devices and appliances ranging 11 from orthopaedic pins, plates and implants thmugh to wound dressings and urinary catheters 12 must constantly guard against infection. An inexpensive anti-microbial coating also finds 13 application in medical devices used in consumer healthcare and personal hygiene products as 14 well as in biomedical/biotechnical laboratory equipment. The term "medical device", as used herein and in the claims is meant to extend to all such products.
1s The anti-microbial effects of metallic ions such as Ag, Au, Pt, Pd, Ir (i.e. the 17 noble metals), Cu, Sn, Sb, Bi and Zn are known (see Morton, H.E., Pseudomonas in 18 Disinfection, Sterilization and Preservation, ed. S.S. Block, Lea and Febiger, 1977 and Grier, 19 N., Silver and Its Compounds in Disinfection, Sterilization and Preservation, ed. S.S. Block, 2 o Lea and Febiger, 1977). Of the metallic ions with anti-microbial properties, silver is perhaps 21 the best known due to its unusually good bioactivity at low concentrations.
This phenomena 2 2 is termed oligodynamic action. In modern medical practice both inorganic and organic soluble 2 3 salts of silver are used to prevent and treat microbial infections. While these compounds are 2 4 effective as soluble salts, they do not provide prolonged protection due to loss through removal or complexation of the free silver ions. They must be reapplied at frequent intervals 2 s to overcome this problem. Reapplication is not always practical, especially where an in-27 dwelling or implanted medical device is involved.
2 s Attempts have been make to slow the release of silver ions during treatment by 2 9 creating silver containing complexes which have a lower level of solubility. For example, 21 ~~~ ~)_ 1 U.S. Patent 2,785,153 discloses colloidal silver protein for this purpose.
Such compounds are 2 usually formulated as creams. These compounds have not found wide applicability in the 3 medical area due to their limited efficacy. The silver ion release rate is very slow.
Furthermore, coatings from such compounds have been limited due to adhesion, abrasion resistance and shelf life problems.
The use of silver metal coatings for anti-microbial purposes has been suggested.
7 For instance, see Deitch et al., Antimicrobial Agents and Chemotherapy, Vol.
23(3), 1983, pp. 356 - 359 and Mackeen et al., Antimicmbial Agents and Chemotherapy, Vol.
31(1), 1987, 9 pp. 93 - 99. However, it is generally accepted that such coatings alone do not provide the io required level of efficacy, since diffusion of silver ions from the metallic surface is negligible.
11 A silver metal coating is produced by Spire Corporation, U.S.A. under the 12 trade mark SPI-ARGENT. The coating is formed by an ion-beam assisted deposition (IBAD) 13 coating process. The infection resistant coating is stated to be non-leaching in aqueous 14 solutions as demonstrated by zone of inhibition tests, thus enforcing the belief that silver metal surfaces do not release anti-microbial amounts of silver ions.
16 Given the failure of metallic silver coatings to generate the required anti-17 microbial efficacy, other researchers have tried novel activation processes. One technique is is to use electrical activation of metallic silver implants (see Marino et al., Journal of Biological 19 Physics, Vol. 12, 1984, pp. 93 - 98). Electrical stimulation of metallic silver is not always 2 o practical, especially for mobile patients. Attempts to overcome this problem include 21 developing in situ electrical currents through galvanic action. Metal bands or layers of 2 2 different metals are deposited on a device as thin film coatings. A
galvanic cell is created 23 when two metals in contact with each other are placed in an electrically conducting fluid. One 2 4 metal layer acts as an anode, which dissolves into the electrolyte. The second metal acts as 2 5 a cathode to drive the electrochemical cell. For example, in the case of alternating layers of 2 6 Cu and Ag, the Cu is the anode, releasing Cu+ ions into the electrolyte.
The more noble of 2 7 the metals, Ag, acts as the cathode, which does not ionize and does not go into solution to any 28 large extent. An exemplary device of this nature is described in U.S.
Patent 4,886,505 issued 29 Dec. 12, 1989, to Haynes et al. The patent discloses sputtered coatings of two or more 3 o different metals with a switch affixed to one of the metals such that, when the switch is 31 closed, metal ion release is achieved.

I
13'O 93/23092 PCT/CA93/00201 1 Previous work has shown that a film composed of thin laminates of alternating, 2 different metals such as silver and copper can be made to dissolve if the surface is first etched.
3 In this instance, the etching process creates a highly textured surface (see M. Tanemura and F. Okuyama, J. Vac. Sci. Technol., 5, 1986, pp 2369-2372). However, the process of making such multilaminated films is time consuming and expensive.
Electrical activation of metallic coatings has not presented a suitable solution 7 to the problem. It should be noted that galvanic action will occur only when an electrolyte s is present and if an electrical connection between the two metals of the galvanic couple exists.
Since galvanic corrosion occurs primarily at the metallic interface between the two metals, 1 o electrical contact is not sustained. Thus a continuous release of metal ions over an extended 11 period of time is not probable. Also, galvanic action to release a metal such as silver is 12 difficult to achieve. As indicated above, the metal ions exhibiting the greatest and-microbial 13 effect are the noble metals, such as Ag, Au, Pt and Pd. There are few metals more noble 14 than these to serve as cathode materials so as to drive the release of a noble metal such as Ag at the anode.
1s A second approach to activating the silver metal surface is to use heat or 17 chemicals. U.S. Patents 4,476,590 and 4,615,705, issued to Scales et al. on October 16, 1984 1$ and October 7, 1986, respectively, disclose methods of activating silver surface coatings on i9 endoprosthetic implants to render them bioerodible by heating at greater than 180°C or by 2 o contacting with hydrogen peroxide. Such treatments are limited in terms of the 21 substrate/devices which can be coated and activated.
2 2 There is still a need for an efficacious, inexpensive anti-microbial material 2 3 having the following properties:
24 - sustained release of an anti-microbial agent at therapeutically active levels;
2 5 - applicable to a wide variety of devices and materials;
2 6 - useful shelf life; and 2 ~ - low mammalian toxicity.
2 8 _ Metal coatings are typically produced as thin films by vapour deposition 2 9 techniques such as sputtering. Thin films of metals, alloys, semiconductors and ceramics are 3 o widely used in the production of electronic components. These and other end uses require the 31 thin films to be produced as dense, crystalline structures with minimal defects. The films are 3 2 often annealed after deposition to enhance grain growth and recrystallization and produce 1 stable properties. Techniques to deposit metal films are reviewed by R.F.
Bunshah et al., 2 "Deposition Technologies for Films and Coatings", Noyes Publications, N.J., 1982 and by J.A.
3 Thornton, "Influence of Apparatus Geometry and Deposition Conditions on the Structure and 4 Topography of Thick Sputtered Coatings", J. Vac. Sci. Technol., 11(4), 666-670, 1974.
U.S. Patent No. 4,325,776, issued April 20, 1982 to Menzel discloses a process for 6 producing coarse or single crystal metal films from certain metals for use in integrated circuits. The 7 metal film is formed by depositing on a cooled substrate (below -90°C) such that the metal layer is 8 in an amorphous phase. The metal layer is then annealed by heating the substrate up to about room 9 temperature. The end product is stated to have large grain diameter and great homogeneity, permitting higher current densities without electromigration failures. ' 12 The inventors set out to develop an antimicrobial metal coating. They discovered 13 that, contrary to previous belief, it is possible to form metal coatings from an antimicrobial metal 14 material by creating atomic disorder in the materials by vapour deposition under conditions which limit diffusion, that is which "freeze-in" the atomic disorder. The anti-microbial coatings so 16 produced were found to provide sustained release of anti-microbial metal species into solution so 17 as to produce an anti-microbial effect.
18 This basic discovery linking "atomic disorder" to enhanced solubility has broad 19 application. The inventors have demonstrated that atomic disorder so as to produce solubility can 2 0 be created in other material forms, such as metal powders. The invention also has application 21 beyond anti-microbial metals, encompassing any metal, metal alloy, or metal compound, including 2 2 semiconductor or ceramic materials, from which sustained release of metal species into solution is 2 3 desired. For instance, materials having enhanced or controlled metal dissolution find application 2 4 in sensors, switches, fuses, electrodes, and batteries.
2 5 The term "atomic disorder" as used herein includes high concentrations of:
point 2 6 defects in a crystal lattice, vacancies, line defects such as dislocations, interstitial atoms, amorphous 2 7 regions, grain and sub grain boundaries and the like relative to its normal ordered crystalline state.
2 8 Atomic disorder leads to irregularities in surface topography and inhomogeneities in the structure 2 9 on a nanometre scale.

'"'O 93/23092 21 3 4 2 17 PCT/CA93/00201 1 By the term "normal ordered crystalline state" as used herein is meant the 2 crystallinity normally found in bulk metal materials, alloys or compounds formed as cast, 3 wrought or plated metal products. Such materials contain only low concentrations of such atomic defects as vacancies, grain boundaries and dislocations.
The term "diffusion" as used herein implies diffusion of atoms and/or molecules 6 on the surface or in the matrix of the material being formed.
'7 The terms "metal" or "metals" as used herein are meant to include one or more 8 metals whether in the form of substantially pure metals, alloys or compounds such as oxides, nitrides, borides, sulphides, halides or hydrides.
1 o The invention, in a broad aspect extends to a method of forming a modified 11 material containing one or more metals. The method comprises creating atomic disorder in 12 the material under conditions which limit diffusion such that sufficient atomic disorder is 13 retained in the material to provide release, preferably on a sustainable basis, of atoms, ions, 14 molecules or clusters of at least one of the metals into a solvent for the material. Clusters are known to be small groups of atoms, ions or the like, as described by R.P.
Andres et al., 16 "Research Opportunities on Clusters and Cluster-Assembled Materials", J.
Mater. Res. Vol.
17 4, No. 3, 1989, P. 704.
1s Specific preferred embodiments of the invention demonstrate that atomic 19 disorder may be created in metal powders or foils by cold working, and in metal coatings by 2 o depositing by vapour deposition at low substrate temperatures.
21 In another broad aspect, the invention provides a modified material comprising 22 one or more metals in a form characterized by sufficient atomic disorder such that the 2 3 material, in contact with a solvent for the material, releases atoms, ions, molecules or clusters 2 4 containing at least one metal, preferably on a sustainable basis, at an enhanced rate relative 2 5 to its normal ordered crystalline state.
2 6 In preferred embodiments of the invention, the modified material is a metal 2 ~ powder which has been mechanically worked or compressed, under cold working conditions, 2 8 to create and retain atomic disorder.
2 9 The term "metal powder" as used herein is meant to include metal particles of 3 o a broad particle size, ranging from nanocrystalline powders to flakes.
31 The term "cold working" as used herein indicates that the material has been 3 2 mechanically worked such as by milling, grinding, hammering, mortar and pestle or 1 compressing, at temperatures lower than the recrystallization temperature of the material. This 2 ensures that atomic disorder imparted through working is retained in the material.
3 In another preferred embodiment, the modified material is a metal coating formed 4 on a substrate by vapour deposition techniques such as vacuum evaporation, sputtering, magnetron sputtering or ion plating. The material is formed under conditions which limit diffusion during 6 deposition and which limit annealing or recrystallization following deposition. The deposition 7 conditions preferably used to produce atomic disorder in the coatings are outside the normal range 8 of operating conditions used to produce defect free, dense, smooth films.
Such normal practices are 9 well known (see for example R.F. Bunshah et al., su ra . Preferably the deposition is conducted at low substrate temperatures such that the ratio of the substrate to the melting point of the metal or 11 metal compound being deposited (T/T'm) is maintained at less than about 0.5, more preferably at less 12 than about 0.35, and most preferably at less than 0.30. In this ratio, the temperatures are in degrees 13 Kelvin. The preferred ratio will vary from metal to metal and increases with alloy or impurity 14 content. Other preferred deposition conditions to create atomic disorder include one or more of a higher than normal working gas pressure, a lower than normal angle of incidence of the coating flux 16 and a higher than normal coating flux.
17 The temperature of deposition or cold working is not so low that substantial 18 annealing or recrystallization will take place when the material is brought to room temperature or 19 its intended temperature for use (ex. body temperature for anti-microbial materials). If the 2 0 temperature differential between deposition and temperature of use (0T) is too great, annealing 21 results, removing atomic disorder. This DT will vary from metal to metal and with the deposition 2 2 technique used. For example, with respect to silver, substrate temperatures of -20 to 200°C are 2 3 preferred during physical vapour deposition.
2 4 Normal or ambient working gas pressure for depositing the usually required dense, 2 5 smooth, defect free metal films vary according to the method of physical vapour deposition being 2 6 used. In general, for sputtering, the normal working gas pressure is less than 10 Pa (Pascal) (75 mT
2 7 (milliTorr)), for magnetron sputtering, less than 1.0 Pa ( 10 mT), and for ion-plating less than 30 Pa 2 8 (200 mT). Normal ambient gas pressures vary for vacuum evaporation processes vary as follows:
2 9 for e-beam or arc evaporation, from 0.0001 Pa (0.001 mT) to 0.001 Pa (0.01 mT); for gas scattering 3 0 evaporation (pressure plating) and reactive arc evaporation, up to 30 Pa (200 mT), but typically less 31 than 3 Pa (20 mT). Thus, in accordance ... 6 rt~.\ . \ :i\ : t:F'!'1 Eli E..\L:IIL:', :i _ v-;~y ~ o : r~tS . -i.m;i4=J-~-3:~;s- Tq :l ti;~ -:1:~;~-i-1-~,.; . ~;_..

1 with the method of the present invention, in addition to using low substrate temperatures tn 2 achieve atomic disorder, working (or ambient) gas pressures higher than these normal values 3 may be used to increase the level of atomic disorder in the coating.
Anc~thrr condition discover to have an effect on the level of atomic disorder in the coatings of the presatt invention is the angle of incidence of the gating flux during s depos';tion. Normally to achieve dense, smooth coatings, this angle is maintained al about 90°
+I- 15°. In accordance with the present invention, in addition to using low substrate 8 temperatures during deposition to achieve atomic disordct, angles of incidence lower than 9 about 75° may be used to increax the level of atomic disorder in the tearing.
io Yet another process parameter having an effect on the Icvel of atomic disorder 11 . is the atom flux to the surface being coated. High deposition rates tend to increase atomic s2 disorder, however, high deposition rates also tend to increase the coating temperature. Thus, 13 there a an optimum deposition raft that depends on the deposition technique, the coating 14 ma.te:ial and other proccse parameters.
'fo provide an anti-microbial material, the metals used in the coating ar powder 1 & are those which have an anti-microbial effect, but which are biocompatible {nott-toxic for the I7 intended utility). Preferred metals include Ag, Au, Pt, pd, Ir {i.e. the noble nactals), Sn, Cu, Ie Sb, Bi, and Zn, compounds of these metals or alloys containing one mare of these metals.
1s Such metals arc hereinafter referred to as "anti-microbial metals"). Most preferred is Ag or 2o its alloys and compounds. Anti-microbial materials in accordartcc with this invention 21 preferably are formed with 9ufftcicnt atomic. disorder that atoms, ions, molecules or dusters z z of the anti-microbial material are released into an alcohol or water based elecuol yte on a 23 sustainable basis. The terms "sustainable basis" is used herein to differentiate, on the one 2 4 hand from the release obtained from bulk metals, which rdcase natal ions and the like at a rate and concentration which is coo Iow to achieve an anti-microbial effxt, and on the other 2 6 hand from the release obtained from highly soluble salts such as silver nitrate, which release 2'7 silver ions virtually instantly in contact with an alcohol or water based electrolyte. In 2s contrast, the anti-nucnobial materials of the present invention release atoms, ions, molecules 29 or clusters of the anti-microbial metal at a sufficient rate and concentration, over a sufficient 3 o time period to provide a useful anti-microbial effect.
31 The term "anti-microbial effect" as used herein means that atoms, ions, 3 2 molecules or clusters of tha anti-microbial metal are released info the clecwlyte which the .:Ch~~'-'~ SN~t ;~,.t.~._I,....~

21 3 421 ~!
WO 93/2309~ PCT/CA93/00201 material contacts in concentrations sufficient to inhibit bacterial growth in the vicinity of the 2 material. The most common method of measuring anti-microbial effect is by measuring the 3 zone of inhibition (ZOI) created when the material is placed on a bacterial lawn. A relatively 4 small or no ZOI (ex. less than 1 mm) indicates a non-useful anti-microbial effect, while a larger ZOI (ex. greater than 5 mm) indicates a highly useful anti-microbial effect. One procedure for a ZOI test is set out in the Examples which follow.
7 The invention extends to devices such as medical devices formed from, 8 incorporating, carrying or coated with the anti-microbial powders or coatings. The anti microbial coating may be directly deposited by vapour deposition onto such medical devices 1o as catheters, sutures, implants, burn dressings and the like. An adhesion layer, such as 11 tantalum, may be applied between the device and the anti-microbial coating.
Adhesion may 12 also be enhanced by methods known in the art, for example etching the substrate or forming 13 a mixed interface between the substrate and the coating by simultaneous sputtering and 14 etching. Anti-microbial powders may be incorporated into creams, polymers, ceramics, paints, or other matrices, by techniques well known in the art.
16 In a further broad aspect of the invention, modified materials are prepared as 17 composite metal coatings containing atomic disorder. In this case, the coating of the one or 18 more metals or compounds to be released into solution constitutes a matrix containing atoms 19 or molecules of a different material. The presence of different atoms or molecules results in 2 o atomic disorder in the metal matrix, for instance due to different sized atoms. The different 21 atoms or molecules may be one or more second metals, metal alloys or metal compounds 2 2 which are co- or sequentially deposited with the first metal or metals to be released.
2 3 Alternatively the different atoms or molecules may be absorbed or trapped from the working 24 gas atmosphere during reactive vapour deposition. The degree of atomic disorder, and thus 2 5 solubility, achieved by the inclusion of the different atoms or molecules varies, depending on 2 6 the materials. In order to retain and enhance the atomic disorder in the composite material, 2 7 one or more of the above-described vapour deposition conditions, namely low substrate 2 8 temperature, high working gas pressure, low angle of incidence and high coating flux, may 2 9 be used in combination with the inclusion of different atoms or molecules.
3 o Preferred composite materials for anti-microbial purposes are formed by 31 including atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur or 3 2 halogens in the working gas atmosphere while depositing the anti-microbial metal. These 1 atoms or molecules are incorporated in the coating either by being absorbed or trapped in the film, 2 or by reacting with the metal being deposited. Both of these mechanisms during deposition are 3 hereinafter referred to as "reactive deposition". Gases containing these elements, for example 4 oxygen, hydrogen, and water vapour, may be provided continuously or may be pulsed for sequential deposition.
6 Anti-microbial composite materials are also preferably prepared by co- or 7 sequentially depositing an anti-microbial metal with one or more inert biocompatible metals selected 8 from Ta, Ti, Nb, Zn, V, Hf, Mo, Si, and Al. Alternatively, the composite materials may be formed 9 by co-, sequentially or reactively depositing one or more of the anti-microbial metals as the oxides, carbides, nitrides, borides, sulphides or halides of these metals and/or the oxides, carbides, nitrides, 11 borides, sulphides or halides of the inert metals. Particularly preferred composites contain oxides 12 of silver and/or gold, alone or together with one or more oxides of Ta, Ti, Zn and Nb.

14 As above stated, the present invention has application beyond anti-microbial materials. However, the invention is disclosed herein with anti-microbial metals, which are 16 illustrative of utility for other metals, metal alloys and metal compounds.
Preferred metals include 17 A1 and Si, and the metal elements from the following groups of the periodic table: 1118, IVB, VB, 18 VIB, VIIB, VI)IB, IB, IIB, IZIA, IVA, and VA (excluding As) in the periods 4, 5 and 6, (see Periodic 19 Table as published in Merck Index 10th Ed., 1983, Merck and Co. Inc., Rahway, N.J., Martha 2 0 Windholz). Different metals will have varying degrees of solubility.
However, the creation and 21 retention of atomic disorder in accordance with this invention results in enhanced solubility (release) 2 2 of the metal as ions, atoms, molecules or clusters into an appropriate solvent i.e. a solvent for the 2 3 particular material, typically a polar solvent, over the solubility of the material in its normal ordered 2 4 crystalline state.
2 5 The medical devices formed from, incorporating, carrying or coated with the anti-2 6 microbial material of this invention generally come into contact with an alcohol or water based 2 7 electrolyte including a body fluid (for example blood, urine or saliva) or body tissue (for example 2 8 skin, muscle or bone) for any period of time such that microorganism growth on the device surface 2 9 is possible. The term "alcohol or water based electrolyte" also includes "". 9 1 alcohol or water based gels. In most cases the devices are medical devices such as catheters, 2 implants, tracheal tubes, orthopaedic pins, insulin pumps, wound closures, drains, dressings, 3 shunts, connectors, prosthetic devices, pacemaker leads, needles, surgical instruments, dental prostheses, ventilator tubes and the like. However, it should be understood that the invention is not limited to such devices and may extend to other devices useful in consumer healthcare, 6 such as sterile packaging, clothing and footwear, personal hygiene products such as diapers 7 and sanitary pads, in biomedical or biotechnical laboratory equipment, such as tables, enclosures and wall coverings, and the like. The term "medical device" as used herein and 9 in the claims is intended to extend broadly to all such devices.
1 o The device may be made of any suitable material, for example metals, including 11 steel, aluminum and its alloys, latex, nylon, silicone, polyester, glass, ceramic, paper, cloth 12 and other plastics and rubbers. For use as an in-dwelling medical device, the device will be 13 made of a bioinert material. The device may take on any shape dictated by its utility, ranging 14 from flat sheets to discs, rods and hollow tubes. The device may be rigid or flexible, a factor again dictated by its intended use.
16 Anti-Microbial Coatines 17 The anti-microbial coating in accordance with this invention is deposited as a 18 thin metallic film on one or more surfaces of a medical device by vapour deposition 19 techniques. Physical vapour techniques, which are well known in the art, all deposit the metal 2 o from the vapour, generally atom by atom, onto a substrate surface. The techniques include 21 vacuum or arc evaporation, sputtering, magnetron sputtering and ion plating. The deposition 2 2 is conducted in a manner to create atomic disorder in the coating as defined hereinabove.
2 3 Various conditions responsible for producing atomic disorder are useful.
These conditions are 24 generally avoided in thin film deposition techniques where the object is to create a defect free, smooth and dense film (see for example J.A. Thornton, s~ral. While such conditions have 2 6 been investigated in the art, they have not heretofore been linked to enhanced solubility of the 27 coatings so-produced.
2 s The preferred conditions which are used to create atomic disorder during the 2 9 deposition process include:
3 0 - a low substrate temperature, that is maintaining the surface to be coated at a 31 temperature such that the ratio of the substrate temperature to the melting point of the metal io 1 (in degrees Kelvin) is less than about 0.5, more preferably less than about 0.35 and most preferably 2 less than about 0.3; and optionally one or both of:
3 - a higher than normal working (or ambient) gas pressure, i.e. for vacuum 4 evaporation: e-beam or arc evaporation, greater than 0.001 Pa (0.01 mT), gas scattering evaporation (pressure plating) or reactive arc evaporation, greater than 3 Pa (20 mT); for sputtering: greater than 6 10 Pa (75 mT); for magnetron sputtering: greater than about 1 Pa ( 10 mT);
and for ion plating:
7 greater than about 30 Pa (200 mT); and 8 - maintaining the angle of incidence of the coating flux on the surface to be coated 9 at less than about 75°, and preferably less than about 30°.
The metals used in the coating are those known to have an anti-microbial effect. For 11 most medical devices, the metal must also be biocompatible. Preferred metals include the noble 12 metals Ag, Au, Pt, Pd, and Ir as well as Sn, Cu, Sb, Bi, and Zn or alloys or compounds of these 13 metals or other metals. Most preferred is Ag or Au, or alloys or compounds of one or more of these 14 metals.
1 S The coating is formed as a thin film on at least a part of the surface of the medical 16 device. The film has a thickness no greater than that needed to provide release of metal ions on a 17 sustainable basis over a suitable period of time. In that respect, the thickness will vary with the 18 particular metal in the coating (which varies the solubility and abrasion resistance), and with the 19 degree of atomic disorder in (and thus the solubility of) the coating. The thickness will be thin 2 0 enough that the coating does not interfere with the dimensional tolerances or flexibility of the device 21 for its intended utility. Typically, thicknesses of less than 1 micron have been found to provide 2 2 sufficient sustained anti-microbial activity. Increased thicknesses may be used depending on the 2 3 degree of metal ion release needed over a period of time. Thicknesses greater than 10 microns are 2 4 more expensive to produce and normally should not be needed.
2 5 The anti-microbial effect of the coating is achieved when the device is brought into 2 6 contact with an alcohol or a water based electrolyte such as, a body fluid or body tissue, thus 2 7 releasing metal ions, atoms, molecules or clusters. The concentration of the metal which is needed 2 8 to produce an anti-microbial effect will vary from metal to metal.
Generally, anti-microbial effect 2 9 is achieved in body fluids such as plasma, serum or urine at concentrations less than about 0.5 - 1.5 3 0 p g/ml .

_.

W . . \ (.~~:W I :I ' ~ \I~ tr\~ HL\ v ~ - i ~ - ;f-~ . J i, W n . ' -1 i i:i-1 _:I$-t ..Wi- T-t : ~ ti:, _~i;;; ~., ., ~ , , _ , 'Ifie ability to achieve release of metal atoms, ions, molecules or clusters on a 2 sustainable basis from a coating is dictated by a number of factors, including coating 3 ~.haracttristics such as composition, structure, solubility and thiclrness, and the nature of the envircmmcnt in which the device is used. As the level of atomic disorder is increased, the amount of metal ians rely per unit urne increases. For instance, a silver metal film 5 deposited by magnetron sputtering at TITm < 4.5 and a working gas pressure of about 0.9 7 Pa (7 mTorr) releases approximately 1/3 of the silver ions that a film deposited under similar B conditions, but at 4 Pa (30 mTorr), will release over 10 days. Films that are created with an intermediate structure (ea. lower pressure, lower angle of incidence etc.) have Ag release i o values intermediate to these values as dcrcsmined by bioassays. This then provides a method 11 for producing controlled release metallic coatings in accordance with this invention. Slow i 2 release coatings arc prepared such that the degree of disorder is low while fast release coatings 13 are prepared such that the degree of disorder is high.
14 For continuous, uniform coatings, the time required for total dissolution will be a function of film thicla~ess and the nature of the environment to which they are exposed.
16 The relationship in respect of thickness is approximately linear, i.e, a two fold increase in film ~ i ~ thickness will result in about a two fold increase in longevity.
18 It is also possible to control the metal release from a coating by forming a thin 1s film dating with a modulated structure. For instance, a dating deposited by magnetron 2 0 sputtering such that the working gas pressure was low (ez. 2 Pa (15 mTorr)) for 509 of the Z 1 deposition time and high (ea. 4 Pa (30 mTorr)) for the remaining time, has a rapid initial 2 2 release of metal ions, followed by a longcx period of slow release. This type of coating is 2 3 extremely effective on devices such as urinary catheters for which an initial rapid release. is 2 4 required to achieve immediate anti-microbial concentrations followed by a lower release talc 2 5 to sustain the concentration of metal ions over a period of weeks.
2 6 The substrate temperature used during vapour deposition should not be so low 2 7 that annealing or recrystallization of the coating takes place as the coating warms to ambient a s temperatures or the temperatures at . which it is to be used (cx. body temperaturcj. This 2 9 allowable dT, that the temperature differential betwaert the substrate temperature during 3 a deposition and the ultimate temperature of use, will vary from metal to metal. For the most 31 preferred metals of Ag and Au, preferred substrate temperatures of -20 to 2(10°C , more 32 preferably -IO°C to 100°C arc used.

r:;~~F ENDED SHEET

93/23092 21 3 4 2 17 ~ PCT/CA93/00201 1 Atomic order may also be achieved, in accordance with the present invention, 2 by preparing composite metal materials, that is materials which contain one or more and-3 microbial metals in a metal matrix which includes atoms or molecules different from the anti-4 microbial metals.
Our technique for preparing composite material is to co- or sequentially deposit 6 the anti-microbial metals) with one or more other inert, biocompatible metals selected from 7 Ta, Ti, Nb, Zn, V, Hf, Mo, Si, A1 and alloys of these metals or other metal elements, s typically other transition metals. Such inert metals have a different atomic radii from that of the and-microbial metals, which results in atomic disorder during deposition.
Alloys of this 1 o kind can also serve to reduce atomic diffusion and thus stabilize the disordered structure.
11 Thin film deposition equipment with multiple targets for the placement of each of the anti-12 microbial and inert metals is preferably utilized. When layers are sequentially deposited the 13 layers) of the inert metals) should be discontinuous, for example as islands within the anti-14 microbial metal matrix. The final ratio of the anti-microbial metals) to inert metals) should be greater than about 0.2. The most preferable inert metals are Ti, Ta, Zn and Nb. It is also 16 possible to form the anti-microbial coating from oxides, carbides, nitrides, sulphides, borides, 17 halides or hydrides of one or more of the anti-microbial metals and/or one or more of the inert 18 metals to achieve the desired atomic disorder.
19 Another composite material within the scope of the present invention is formed 2 o by reactively co- or sequentially depositing, by physical vapour techniques, a reacted material 21 into the thin film of the anti-microbial metal(s). The reacted material is an oxide, nitride, 2 2 carbide, boride, sulphide, hydride or halide of the anti-microbial and/or inert metal, formed 2 3 in situ by injecting the appropriate reactants, or gases containing same, (ex. air, oxygen, 2 4 water, nitrogen, hydrogen, boron, sulphur, halogens) into the deposition chamber. Atoms or 2 5 molecules of these gases may also become absorbed or trapped in the metal film to create 2 6 atomic disorder. The reactant may be continuously supplied during deposition for 27 codeposition or it may be pulsed to provide for sequential deposition. The final ratio of anti-2 s microbial metals) to reaction product should be greater than about 0.2.
Air, oxygen, nitrogen 2 9 and hydrogen are particularly preferred reactants.
3 0 The above deposition techniques to prepare composite coatings may be used 31 with or without the conditions of lower substrate temperatures, high working gas pressures and a~_ rtC\ . . , '~ A \11 E-:'v;CHr:'~ :.i '? - E.-:d . l Ei : t w : '~J4-4W3-~ .-49 F3:3 '>:3J~44 Eip : #I''f i iow angles of in~dence previously discussed. ~nc or mode of thcx conditions is preferred co retain and enhance the amount of atomic disorder creatai in the coating.
3 it may be advantageous, prior to depositing an anti-microbial in accordance with a the present invention, to provide an adhesion layer on the device to be coattd, as is known in the art. For instance, for a latex device, a layer of Ti, Ta or Nb may be first deposited to 6 enhance adhesion of the subsequently deposited anti-microbial caadng.
7 Anti-lvficrobial Powders a Anti-microbial powders, including aanocrystalline powders and powders made 9 from rapidly solidified flakes or foils, can be farmed with atomic disorder so as to enhance io solubility. The powders either as pure metals, metal alloys or compounds such as metal s1 oxides or metal salts, can be mechanically worked or eompnessed to impart atomic disorder.
12 This mechanically imparted disorder is conducted under conditions of low lemperaturc (i.e.
13 temperatures lrss than the ternperacure of recrystallization of the material) to ensure that 14 annealing or recrystallirttion dots not take place. The temperature varies betwten metals and increases with alloy or impurity c~ttent.
is Anti-microbial powders produced in accorda.ncc with this invention may be used s7 in a variety of forms, for instanct in topical creams, paints or adherent coatings.
18 Alternatively, the powder may be incorporated into a polymeric, ceramic or metallic matrix i9 to be used as a material for medical devices or coatings therefor.
a o The .ioyention is further illustrated by the following non-Limiting examples.
21 ~zample 1 zZ A medical suture material size 2/0, polyester braid was coated by magnetron ~ 3 sputtering an Ag-Cu-alloy onto the surface to a thickness of 0.45 microns, using either argon 2 4 gas working pressures of 0.9 Pa ('7 mTi3rr) or 4 Pa (30 mT) at 0. 5 ICW
power and a TITrn z 5 ratio of less than 0.5.
2 6 The anti-microbial effect of the coatings was tested by a zone of inhibition test.
2'; Basal medium Eagle (BME) with Farle's salts and L-g~utamine was modified with calf/serum 2 s ( 10 Se ) and I .5 ~C agar prior to being dispensed ( 15 mI) into Petri dishes. The agar 29 containing Path plates were allowed to surface dry prior to being inoculated with a lawn of ~.._~':~'E'~ SHEE':

1C\ . \ U\ Et'A 111 t: .I.HEV ai _ cu - a-i s ~. . n r 1 '-~: i:;.~ v'!.r3 ~:.i- T.; :s cs; i _a.;: ~-; .i ~ "-, _ , i , Srap~ylo~cocaeus aureus ~iTCC# 25923. The inoeulant was prepared from Bacttol Discs z (Difco, M.) which were reconstituted as per the manufacwrer's directions.
Immediately after 3 inoculation, the materials or coatings to be tested were placed on the surface of the agar. The dishes were incubated for 24 h at 37°C. After this incubation period, the zone of inhibition was measured and a oonzone of inhibition was calculated (corrected zone of inhibition 5 = zone of inhibition - diameter of the test material in contact with the agar).
The results showed no zone of inhibition on the untested suture, a z~me of less s than a.5 mm around the suture coated at 0.9 Pa (7 mTorr) and a zone of 13 mm around the 9 suture coated at 4 Pa (3Q mTorr). Clearly the suture coated in accordance with the present 1 o invention exhibits a much more pronounced and effective anti-microbial effect.
1 Z Example 2 t.2 This example is included to illustrate the surface structures which are obtained is when silver metal is deposited on silicon wafers using a magnetron spurtaing facility and 14 different working gas pressures and angles of incidence (.e. the angle between the path of the sputtered atoms and the substrate). All other conditions were as follows:
deposition raft was is 200 A°lmin; ratio of temperature of substrate (wafer) to melting point of silver (I234°I~, m TITm was less than 0.3. Argon gas pressures of 0.9 Pa (7 tnTorr) (a normal working is pressure for metal coatings) and 4 Pa (30 mTorr) were u9od. Angles of incidence at each of 1g these pressures were 90° (normal incidence), 54° and 10°. The coatings had a thickness of 2 0 about 0.5 microns.
z i The resulting surfaces were viewed by scanning electron microscope. As argon 2 z gas pressure increased from 0.9 Pa (7 mTort) to 4 Pa (30 mTorr) the grain size decreased and 2 s void volume increased significantly. When the angle of incidertcx was decreaseEi, the grain 2 4 size decreased and the grain boundaries became morn distinct. At 0.9 Pa (7 mTorr) argon z 5 pressure and an angle of incidence ~f 10°, there were indications of some voids betwean the 2 s grains. The angle of incideocx had a greater effect on the surface topography when the gas 2 ~ pressure was increased to 4 Pa (30 mTorr). At 90°, the grain size varied from 60 - ISO nm 2 s and many of the grains were separated by intergtain void spaces which were 15 - 30 n nt wide.
z 9 When the angle of incidence was decreased to 50°, the grain size decreased to 30 - 94 nm and 3 o the void volume increased substantially. At 10°, the grain size was reduced to about 10 - 60 31 nm and void volumes went increased agai>rs.

,._~;_~ct7 SHEET

:C\. \(J\ f_I-':i 11i r veli't\ ~i _ ~,-,s-3 . ~t;.tn ' ~-~_:~i~i-~:i- -ya ::;i "_t:f.!-mi~~.-, z . The observed nanometre scale changes in surface morphology and topography 2 arc indications of atomic disordar in the silver mttal. While not being bound by the same, 3 it is beiiewod that such atomic disorder results in an increase in the chemical activity due to increased internal stresses and surface mughnesa created by mismatched atoms.
it is believed that the increased chemical activity is responsible for the increased level of solubility of the 5 coatings when in contact with an electrolyrt such as body fluid.
The anti-microbial effect of the coatings was evaluated using the zone of a inhibition test as set out in Example 1. Each coated silicon wafer was placed on an individual s plate. The results were compared to the zones of inhibition achievai what solid silver (i.e.
greater than 9996 silver) sheets, wires or membranes were tested. The results are summarized 11 in Table 1. It is evident that the pure silver devices and the silver sputtered coating at 0.9 Pa 12 (7 mTorr) do not produce any bioloEical effect. However, the coatings deposited at a higher 13 than normal worlring gas pressure, 4 Pa (30 mTorr}, demonstrated an anti-microbial effect.
Z4 as denoted by the substantial zones of inhibition amund the discs.
Decreasing the angle of incidence had the greatest effect on anti-microbial activity when combined with the higher gas 1 s pressures.

___ -~T
~~ J~Ll-~

1 Table I
2 Antimicrobial effects of various silver and silver coated samples as determined using Staphylococcus aureus 4 Sample PercentAngle Working Corrected Zone of Gas SilverDepositionPressure of Inhibition 6 Pa (mTorr)(mm) Silver Sheet-9 rolled 99+ - - <0.5 11 Silver wire 12 (.0045") 99+ - - <0.5 14 Silver membrane-cast 99+ - - <0.5 17 Sputtered thin 18 film 99+ normal 0.9 (7) <0.5 (90) 2 Sputtered 0 thin 2 film 99+ 50 0.9 (7) <0.3 2 Sputtered 3 thin f Im 99+ 10 0.9 (7) <0.5 S

2 Sputtered 6 thin 2 film 99+ normal 4 (30) 6.3 7 (90~

2 Sputtered 9 thin 3 film 99+ 50 4 (30) 10 ~

3 Sputtered 2 thin 3 film 99+ 10 4 (30) 10 -i ;cv voa:>rt~,~ wt-:~:c'H~'~ a . e- ~-:~-t u, u_ . ~m~_~a~r-~~a- T~:~
_;;~:~~,~.,:,.,.:5,, r,:~

i i 3 42 7 -~

Example 3 2 Silicon wafers were coated by magnetron sputtering with an alloy of Ag and Gu 3 (80:20) at normal incidence at working gas presstuzs of 0.9 Pa (7 iriTorr) and 4 Pa (30 mTorr), all ether conditions being identical to those set out in Example 2. As in Example 2, where the coatings were viewed by SEM, the coatings formed at high working gas pressure s had smaller grain sizes and larger void volumes than did the coatings formed at the lower working gas pressures.
8 Coatings which were similarly formed from a 50:50 Ag/Gu alloy were tested 9 for anti-microbial activity with the zone of inhibition test set out in Example 1. The results l0 are summarized in Table 2. Coatings deposited at low working gas pressure (0.9 Pa (7 11 mTorr)) showed minimal zones of inhibition, while the coatings deposited at high working gas 12 pressure (4 Pa (30 m?orr)) produced Larger zones of inhibition, indicative of anti-microbial 13 activity.
14 Table 2 1 T'Ite dtoys as decenruned mdn8 S taatimicrobial ,Steph?lococcua effect of v;uiouri optuter depoaitsd silver-copper 16 arena 18 Sample Perc>fot Aa~ld of Wc>i~in~ Correetwl G~

19 Stlver Da~wcitioa Preweurs Zone of 2 (' Pa (mToa) Inhibition 21 ( Z 1 i0 normal (9ty'i .0 (7.5)< 0.5 2 2 50 normal (90~4 (30) lb 27 3 SO 10 4 (30) 19 =~v..i_~ Jfla=

se\. \U\:ct''~ vli t_W i:_ . :, _ ~._,,~ i~, . _ . _. . ~ . - ~ .. _ ..

1 Example a 2 A coating in accordance with the present invention was tested to determine the 3 concentration of silver ions released into solution over time, one cm2 silicon wafer discs were coated with silver as set forth in Example 2 at 0.9 Pa (7 rnTorr) and 4 Pa (30 mTorr) and nonnal incidence to a thickness of 5000 A°. Using the method of Nickch et al . , Eur. 1. Clin.
6 Microbiol., 4(2), 213-218, 1985, a sterile synthetic uzine was prepared and dispensed into test tubes (3.5 mi). The coated discs went placed into each test tubes and incubated for various a timrs at 37°C. After various periods of time, the discs were removed and the Ag content of 9 the Rltcrod synthetic urine was determined using neutron activation analysis.
1 o The results arc set forth in Table 3. The table shows the comparative amounts 11 of Ag released over drne from coatings deposited on discs at 0.9 pa (7 mTorr) or 4 Pa (30 1z mTorr). The coatings deposited at hiEh pressure were more soluble than those deposited at i3 Iow pressure. It should be noted that this test is a static test. Thus, silver levels build up over i 4 time, which would not be the case in body fluid where there is constant turn over.

._;~~~J s~;LFr .W 1 . \w, ~ GI .'. \)i : w.I~t_~, ;s . _ c,-;mi ~ 1~._ ~ _ - ~ ' ~ a . ~:;; _ ~ a --~ 'J ~ ;_t'J: ni W i, i I

Tabl~ 3 2 Concenustion of silver is synthetic urine as a fimrti~n of eapoxure time Silver Canceptrntion ~tsltn!

S ExpcuureTimd Woddag Anon Working argon 6 (Days) gae gressura eaa prnsaure 7 0.9 Ps (7 mTorr) 4 Pa (30 mTorr) 11 1 0.89 1.94 13 3 1.89 2.36 10 8.14 23.06 lb 17 Nute: Fllmc wet~e depolitad rt nottrwl iacideoct (90~
18 1 - ND (non dctecubln) <0.4ti ~c~lm( .._n~ED SHEET

.\. W ).~,., , '.i, :. .~~11;. ~ _ ~ ... . . ._ ~ . - - .. . _ ....

1 Example 5 This example is included to illustrate coatings in accordance with the present 3 invention formed from another noble rr~tal, Pd. The coatings were formed on silicon wafers 4 as set forth in Fxarnple 2, to a thickness of 5000 A° , using 0.9 Pa (7 mTorr) or 4 Pa (3a mTorr) working gas pressures and angles of incidence of 90° and 10°. The coated discs were evaluated for anti-microbial activity by the zone of inhibition test substantial:y as set forth in Example 1. The coated discs west placed enating side up such that the agar formod a 1 nun s surface casting over the discs. The modium was allowed to solidify and surface dry, after 9 which the bacterial lawn was sprrad over the surface. The dishes were incubated at 37°C for l0 24 h. The amount of growth was then visually analyzed.
i1 The results are set forth in 'Table 4. At high working gas pressures, the 12 biological activity of the coating was much greater than that of coatings deposited at low i 3 pressure. Changing the angle of incidence (decn~sing) improved the anti-microbial effxt of is the coating to a =realer eactent when the gas pressure was low than when it was high.

":7'1 ~ lujT~~'YYiI~.1~
~.i ~J (::: i'l: 'w ~\ . \ V ~, h:r'.\ ~.ir i: .pit" , .. _ " _ 1 Tabk 4 2 Surtacc Ccmtrot of _S~yhyly rut~c by Sputter Dapv~ited Palladium moral 4 Sample Sputteria~An~lo of Antitnierobial Control Pmretue Deposition 6 Ps (mTorr) 8 1 0.9 (?) 90'(nomutl incidence)Mare than 9096 of ~urt'ace euvurex3 by b.etn~iat growth lU 2 D.9 (7) lU(~rabn~ incidence)2a-405E of surface covered by bacterial 8rcnvth !.1 12 3 4 (30) 94(normal iacid~nca)Less tban 10 % ~urfice covered by bac;tnrsal ~tnwth 14 )Example 6 This example is includod to ilhatrate the effect of silver deposition temperature z5 on the antimicmbial activity of the coating. Silver metal was deposited on Z.S cm sections i? of a latex Foley catheter using a magnetron sputtering facility. Operating conditions were as 18 follows; the deposition late was 200 A° per minute; the argon working gas pressure was 4 Pa 15 (30 mTorr); and the ratio of temperature oC sub~ate to melting point of the coating metal z o silver, TJTm was 0.30 or 0.38. In this example the angles of incidence were variable since 21 the substrate was round and rough. That is the angles of incidence varied around the 22 circumference and, an a finer scale, across the sides and traps of the numerous surface 2 3 features. The antimicrobisl effect was tested by a zone of inhibition test as outlined in 2 4 Example 1.
The results showed corrected zones of inhibition of 0.5 and 16 mm around the 2 s tubing coated at TITm values of 0.38 and 0.30 respectively. The sections of Foley catheter 2? coated at the lower TITm value were more efficacious than those coated at higher TITm 28 value.

_ .=~i 1 Example 7 2 This example is included to demonstrate an antimicrobial coating formed by DC
3 magnetron sputtering on a commercial catheter. A Teflon coated latex Foley catheter was coated 4 by DC magnetron sputtering 99.99% pure silver on the surface using the conditions listed in Table 5. The working gases used were commercial Ar and 99/1 wt% Ar/O,.
6 The antimicrobial effect of the coating was tested by a zone of inhibition test. Mueller 7 Hinton agar was dispensed into Petri dishes. The agar plates were allowed to surface dry prior to 8 being inoculated with a lawn of Staphylococcus aureus ATCC# 25923. The inoculant was prepared 9 from Bactrol Discs (Difco, M.) which were reconstituted as per the manufacturer's directions.
Immediately after inoculation, the coated materials to be tested were placed on the surface of the 11 agar. The dishes were incubated for 24 hr. at 37°C. After this incubation period, the zone of 12 inhibition was measured and a corrected zone of inhibition was calculated (corrected zone of 13 inhibition = zone of inhibition - diameter of the test material in contact with the agar).
14 The results showed no zone of inhibition for the uncoated samples and a corrected zone of less than 1 mm for catheters sputtered in commercial argon at a working gas pressure of 0.7 Pa (5 16 mT). A corrected zone of inhibition of 11 mm was reported for the catheters sputtered in the 99/1 17 wt% Ar/OZ using a working gas pressure of 5.3 Pa (40 mT). XRD analysis showed that the coating 18 sputtered in 1% oxygen was a crystalline Ag film. This structure clearly caused an improved anti-19 microbial effect for the coated catheters.

~ .s~.

-y ; i t:: ~ _ :; ~: I i s ,.p .~ : n;
;cv . v ov : to ~,~ vrl:vcrw, a . _ ~,-a3 t ~, «:f 1 Txble S. Ccu~dit~ions of DC MeEoetron Sputtcina Used for Anti-Microbial Cnttiuas 3 Samples Spy in Coauaarial Argoa Samples buttered in 99/1 wt96 Arlt Powor 0.1 kW Paws O.S kW
6 Argon Pre~ue: 0.1 Pa (5 m~'orr) ArJO~ Fresu:c: 5.3 Pa (40 mToir) 7 laitial Sub~rata Tunpersturc: 20°C lnitixl Sut>attate ?ire: 2(~C
8 CathcxieiAnode Diamace: 40 nun C.sthodelAa~od~ Di~snco: 100mm 9 Filin Thickneu: 25110 A Film Tliicfrne~s; 3000 4 11 Example 8 ~z This example demonstrates silver coatings formed by ate evaporation, gas scattering 13 evaporation (pressure plating,) and reactive arc evaporation. Evaporation of 99.99 96 silver was 14 performed onto silicon or alumina wafers at an initial substrate temperature. of about 21°C, using the param~aers as follows:
15 Bias: -100 V
17 Current: 20 Amp-hrs 18 Angle of incidence: 90°
19 Working Gas Pressure: 0.001 Pa (0.01 mT) (arc), 3.5 Pa (26 m'I~ Arl'H~ 96:4 (gac sratterinE
z o cvaporatiotl), and 3.5 Pa (26 mTj OZ (inactive arty evaporation) 21 ~ No oo:rected ZOI was obscxved for wafers coated at vacuum (arc). Presaure plating 2 2 with a working gas atmosphere containing Ar and 4 96 hydrogen produced a 6 mm ZOI, while 2 3 a working gas atmosphere of pure oxygen (reactive arc) produced an 8 mm ZOI. Film c 4 thickncsses of about .1000 Angstroms wen produced. The results indicate that the presence a 5 of gases such as hydrogen andlor oxygen in the arc evaporation atmosphere cause the coatings 2 6 to have i~nprc>v~d anti-microbial efftcacy.

': I~i z ~ i :~ tic; r ~1 ~ ,.
vl.~ . ~ (» ~ t:~'.~ '.11 Lvl.:lt_v ai ~ _ O-:~-i ~ 1 ~~ ~ wy _ ,.. _"..,. _ .
. , Ezamplc 9 This example is included to illustrate composite materials to product anti-3 microbial effects. A set of coatings were produced by RF magnetron sputtering zinc oxide 4 onto silicon wafers as outlined below. The zinc oxide coatings showed no zone of inhibition.
s Coatings of Ag and Zn0 were deposited to a total thiclmess of 3300 Angstroms by sequaidaLly sputtering layers of Ag with layers of ZnD, according to the conditions below, 7 in a 75f25 wt96 ratio. The coatings were demonstrated to have no zone of inhibition when 8 the zinc oxide laycss were about l00 Angstroms thick. However, films consisting of islands s of very thin to discontinuous layers of ZttO (less than SO Angstroms) in an Ag matrix (ie. a 1 o composite film) had a 8 mm cornxted zone of inhibition.
i i The conditions used to deposit Zn0 were as .follows: Working gas = argon;
i2 Worlang gas pressure = 4 Pa (30 mT); Cathode-Anode distance: 40 mm; Initial Substrate 13 Temperature: 21°C; Power: RP magnetron, 0.5 kW.
~ a The conditions used to deposit the Ag were as follows:
s5 Worlong gas = argon; Workong gas pressure = 4 Pa (30 rnT); Cathode-Anode distance =
16 40 mm; Initial Substrate Temperature = 21°C; Power = DC magnetron, 0.1 kW.
1 ~ Frxample '10 This example demonstrates the effects of cold working and annealing Aver and 19 gold powders on the antinucrobial efficacy demonstratai by a standard zone of inhibition test.
2 o Cold working of such powders results in a defective aurfacc structure containing atomic 21 disorder which favours the release of ions causing antimicrobial activity.
The antimicrobial 22 effect of this defective structure can be removed by annealing.
,. ~ ._~=' SHEET

1 Nanocrystalline silver powder (crystal size about 30 nm) was sprinkled onto adhesive 2 tape and tested. A zone of inhibition of 5 mm was obtained, using the method set forth in Example 3 7. A 0.3g pellet of the nanocrystalline Ag powder was pressed at 275,700 kPa (kilopascal) (40,000 4 psi). The pellet produced a 9 mm zone of inhibition when tested for antimicrobial activity.
Nanocrystalline silver powder was mechanically worked in a ball mill for 30 sec. The resulting 6 powder was tested for antimicrobial activity, both by sprinkling the worked powder on adhesive tape 7 and applying to the plates, and by pressing the powder into a pellet at the above conditions and 8 placing the pellet on the plates. The zones of inhibition observed were 7 and 11 mm respectively.
9 A pellet that had been pressed from the worked powder was annealed at 500°C for 1 hour under vacuum conditions. A reduced zone of inhibition of 3 mm was observed for the annealed pellet.
11 These results demonstrate that nanocrystalline silver powder, while having a small 12 anti-microbial effect on its own, has an improved antimicrobial effect by introducing atomic 13 disorder by mechanical working of the powder in a ball mill or by pressing it into a pellet. The 14 antimicrobial effect was significantly decreased by annealing at 500°C. Thus, conditions of mechanical working should not include or be followed by conditions such as high temperature, 16 which allow diffusion. Cold mechanical working conditions are preferred to limit diffusion, for 17 example by working at room temperature or by grinding or milling in liquid nitrogen.
18 Silver powder, 1 micron particle size, was tested in a manner similar to above. The 19 Ag powder sprinkled onto adhesive tape and tested for a zone of inhibition.
No zone of inhibition 2 0 was observed. The powder was worked in a ball mill for 30 seconds and sprinkled onto adhesive 21 tape. A 6 mm zone of inhibition was observed around the powder on the tape.
When the Ag 2 2 powder (as is or after mechanical working in the ball mill) was pressed into a -.._>-;L\ . \ i)\ iJ!' ~ '~li ~_ ~: Uc , o _ -.~-i ~ ~" . ~ ,. _ ,... ~ . , . , 1 0.3 g pellet using 275,700 kPa (40,040 psi), zones of inhibition of 5 and 6 mm respectively 2 were observed. A pellet which was formed from the ball milled powder and which was 3 annealed at SOQ°C for 1 hour had significantly reduced antimicrobial activity. Initially the 4 pellet had some activity (4.5 mm zone of inhibition) but after the pellet was tested a second s time, no zone of inhibition was observed. A control pellet which had not been annealod s continued to give a zone of inh~ition greater than 4 mtn even after I4 repeats of the test.
7 This demonstrates that an annealing atop, following by mechanical working, limits the s sustainable release of the antimicrobi.al silver spcci.es from the powders.
s Nanocrysts.lline gold (20 nm crystals), supplied as a powder, was tested for anti-1 G microbial effect by sprinkling the powder onto adhesive tape and using the zone of inhibition 11 test. No zone of inhibition was recorded for the nanocrystaliine gold powdtr. The gold i2 powder was pressed into a 0.2 g pellet using 275,'700 kPa (40,000 psi). A
10 mm zone of 13 inhibition was observed. When the pressed pGLlets wart subsequently vacuum annealed at 14 500"C for 1 hour and the zone of inhibition was found to be 0 mm.
i5 The results showed that solubility and thus the anti-microbial efficacy of gold 1 s powders can be improved by a mechanical working process such as pressing a nanocrystalline 17 material into a pellet. The antin>icxobial activity can be removod by annealing. Cold working is is preferred.
19 Other gold powders including a 2-5 micron and a 250 micron particle size 2 o powder dial not demonstrate an anti.microbial effect under the above mechanical worming 21 conditions. It is betitvod that the small grain size of the nanocrystallinc gold powder was an 2 2 important cofactor which, with the mechanical working, produced the dcsireQ arctimicrobial 2 3 effect.

~,w~~NDED SHEET

1 Example 11 2 This example is included to demonstrate a composite antimicrobial coating formed 3 by reactive sputtering (another example of composite films). Example 7 demonstrates that an 4 antimicrobial coating of silver can be obtained by sputtering in argon and 1 % oxygen (0.5 kW, 5.3 Pa (40 mTorr), 100 mm anode/cathode distance, and 20°C - produced a zone of inhibition of 11 6 mm).
7 When a working gas of argon and 20 wt% oxygen was used to sputter antimicrobial 8 coatings under the conditions listed below in Table 6, the zones of inhibition ranged from 6 to 12 9 mm. This indicates that the provision of a reactive atmosphere during vapour deposition has the result of producing an antimicrobial film over a wide range of deposition process parameters.
11 Table 6: Sputtering Conditions 12 Target 99.99% Ag 13 Working Gas: 80/20 wt% Ar/OZ

14 Working Gas Pressure: 0.3 to 6.7 Pa (2.5 to 50 mTorr) Power: 0.1 to 2.5 kW

16 Substrate Temperature: -5 to 20C

17 Anode/Cathode Distance 40 to 100 mm 18 Base Pressure: less than 5 x 10~ Pa (4 x 10-6 Ton) 19 Example 12 2 0 This example demonstrates that the coatings of this invention have an antimicrobial 21 effect against a broad spectrum of bacteria.
2 2 A total of 171 different bacterial samples encompassing 18 genera and 55 species 2 3 were provide by the Provincial Laboratory of Public Health for Northern Alberta. These samples 2 4 had been quick frozen in 20% skim milk and stored at -70°C for periods ~'O 93/23092 1 ranging from several months to several years. Fastidious organisms which were unlikely to 2 grow under conditions used in standard Kirby-Bauer susceptibility testing were not used.
3 Each frozen sample was scraped with a sterile cotton swab to inoculate a blood 4 agar plate (BAP). The plates were incubated overnight at 35°C. The following morning isolated colonies were subcultured onto fresh BAPs and incubated at 35°C overnight. The next 6 day, the organisms were subjected to Kirby-Bauer susceptibility testing as described below.
7 Four to five colonies (more if colonies were small) of the same morphological 8 type were selected from each BAP subculture and inoculated into individual tubes containing 9 approximately 5 mL of tryptic soy broth (TSB). The broths were incubated at 35°C for 1 o approximately 2 to 3 hours. At this time, the turbidity of most of the broth cultures either 11 equalled or exceeded that of a 0.5 McFarland standard. The more turbid samples were diluted 12 with sterile saline to obtain a turbidity visually comparable to that of the standard. To aid in 13 the visual assessment of turbidity, tubes were read against a white background with contrasting 14 black line.
A small number of the organisms (Streptococcus and Corynebacterium) did not 16 grow well in TSB. The turbidity of these broths, after incubation, was less than that of the 17 0.5 McFarland standard. Additional colonies from the BAP subcultures were inoculated to 18 these tubes to increase the turbidity to approximate that of the standard.
19 Within 15 minutes of adjusting the turbidity of the bacterial suspensions a sterile 2 o cotton swab was dipped into each broth. Excess fluid was removed by rotating the swab 21 against the rim of the tube. The inoculum was applied to a Mueller Hinton (MH) agar plate 22 by streaking the swab evenly in three directions over the entire agar surface. Three 1 cm x 2 3 1 cm silver coated silica wafer squares were applied to each MH plate and the plates were 24 inverted and incubated overnight at 35°C. The coatings had been sputtered under the \ . \ U\ : l.l'.~, \Il. t_\I:HC:~~, :.> . _ ti-;I~i : 1 t; -1~, ni=r'_'a-i~-i ~:.i- r-i :j 2i'.., _.sc;;i-i ~I n ,- . ~- ; i 1 following conditions. which through XFD analysis were shown to be silv~rlsilver oxide 2 composite films:
3 Target: 99.99 96 Ag Working $as: ArIOZ SO124 Working gas pressure: 5.3 Pa (4(? mT) 0.1 kW
7 Temperature of Deposition 20°C
Base pressure 2.7 x 1~~ Pa (2 x 10~ Torr) Cathodclanode distance 44 mm 1 o BAP cultures of control organisms were provided by the Provincial Laboratory 11 and included: Staphylococcus aureus ATCC 25923; P~eudc~»ronas aencgiruua ATCC 27$53;
12 Escherirhin cull: ATCC 25922; and Eiuerocoecus juccalis ATCC 29212 to check the quality 13 of the MH agar. These cultutrs were trtatcd in a Iike manner to the test organistns except 14 that standard antibiotic discs rather than silver coatod wafers were applied to the bacterial zs lawns on the MH agac. These organisms demonstrated that the MH agar was suitable for i s standard ZOI tests.
Aftcx I6 to 18 hours of incubation at 35°C zones of inhibition around tha silver 18 wafers or antibiotic discs were measured to the nearest mm. Corrected zones were calculated 19 by subtravting the size of the wafer (1 cm) from the size of the total zone. Representative 2 a zone of inhibition results are shown in Table 7.
~~~1F_~IDED SHEET

~4 93/23092 21 3 4 2 1 7 PCT/CA93/00201 1 Table 7: 'Ihe SensitivityRange of a Broad of ll~crooc~aoiswsto Silver' Coated Si'con Wafers 3 Orgmiam Source Corrected Zone of 4 Inhibition (mm) 6 Sta~hytococcar epidtrnddiablood to -8 Badllra licheniformis tibia 6 Corynebacuriron sp R-594leg 10 12 Listtria monocytogents blood 5 14 Enttrococc~rsJatcalis bone 5 16 Strtptococcus bovis SR-62blood 10 1 Eseherichia coli R-1878 urine 11 2 Klebsitlla ozonat R-308/90abdomen10 2 Enttrobacter cloacat unknown8 2 Prottws vwlgarls 3781 urine 4 2 Providencia stWartfi urine 8 2 Citrobacttr frti U-3122/90urine 7 3 Salmonella typhimirium urine 6 3 Strraria marctscens R-850sputum 6 3 Patudomorws atraginosa urine 10 3 Xanthonbnas maltophila unknown9 6 90-lOB

3 Atromonas caviae R-121 wound 5 4 Brat~hanKlla catarrhalisunknown12 4 Silver deposition=

- 1 ;' O\ \ J\ l::-.~ \~~ L. W I1't-.'', ;i _ ; ~-s i t: . ~ n,n . +v ~:Si _: , ~ ".
", _ ",. . . _ 1 Example 13 2 This example demonsr,~tes the use of tantalum as an adhesive layer for coatings 3 of this invention. Tantalum is well known as a material which, in the form of an interlayer, 4 improves adhesion of thin films to substrates. In this example test sections including a group of stainless steal {316} (1 z 1 cm) and silicon (1.7 X 0.9 cm) coupons and sections of latex 6 tubing (5 cm) were cleaned in ethanol and then half of the test sections were coated (by '7 sputtering) with a thin layer (approx. I00 Angstroms) of Ta before an antimicrobial silver film s was deposi.bai on thcrn. The second group of the test sections were only coatod with the 9 antimictobial Ag film. Coating conditions are listed below. While all test sections had similar io antinucrobial activity, the T~a coated test sections had much better adhesion properties than did 11 the untreated test sections. Adhesion properties were deternzincd using ASTM method D3359-12 87, a standard test method for measuring adhesion, i3 Spattering Conditions 14 Target: 99.9996 Ta Working Gas: ~ 99! 1 wt 96 ArlOz 1s Working Gas Pressure: 1.3 Pay (10 mTorr) 17 Power: 0.5 kW

1s Cathode/Anode Distancx: 100 rnm 19 Substrata Temperature: 20C

2 0. Target~ 99. 99 96 Ag z1 Working Gas: 99l1 wt% ArIQ~

2 2 Working Gas Pressure: 5.3 Pa (4Q mTorr) 2 3 Power: 0.5 kW

24 CathodelAnode Distancx: 100 mm z s Substrate Temperature: 20C

2 6 Example 14 27 DC magnetron sputtering was used to deposit silver fmm a 99.9896 pure 2s cathode onW silicon and alumina wafers with commercial argon moisturized with water as the 2 9 working gas. The argon was moisturized by passing it through two flasks containing 3 litres HME~JDED S1-!EET

1 f room temperature water and one empty flask set up with glass wool to absorb any free liquid 2 before the gas entered the sputtering unit.
3 The conditions of sputtering and the results of the standard zone of inhibition test performed on the sputtered silver films are shown below. Silver films which normally had no antimicrobial properties when deposited using argon that had not been treated with water yielded 6 a corrected zone of inhibition of up to 8 mm when sputtered using a argon/water vapour mixture 7 as the working gas.
Table 8:
Conditions used for DC Magnetron Sputtering of Anti-Microbial Coatings 1 Working Working Gas Power Substrate Anode/CathodeCorrected ~ Gas 11 Pressure TemperatureDistance ZOI

12 Pa (mTorr) 14 Commercial 1.3 (10) O.SkW -10"C 100 mm 0 mm Argon Ar passed through 16 H=O 1.3 (10) 0.5kW -10"C 100 mm 8 mm 18 The terms and expressions in this specification are used as terms of description and 19 not of limitation. There is no intention, in using such terms and expressions, of excluding 2 o equivalents of the features illustrated and described, it being recognized that the scope of the 21 invention is defined and limited only by the claims which follow.
.:.Y~e."
,,

Claims (96)

Claims

1. A modified material comprising:
one or more metals in a form characterized by sufficient atomic disorder such that the material, in contact with a solvent for the material, releases atoms, ions, molecules or clusters containing at least one metal at an enhanced rate relative to its normal ordered crystalline state.

2. The material as set forth in claim 1, wherein the metal is released on a sustainable basis.

3. The material as set forth in claim 1 in the form of a powder or foil.

4. The material as set forth in claim 1 in the form of a coating.

5. The material as set forth in claim 3, wherein the material is cold world to create the atomic disorder.

6. The material as set forth in claim 4, wherein the material is formed by vapour deposition.

7. The material as act forth in claim 6, wherein the material is formed by physical vapour deposition.

8. A modified anti-microbial material comprising:
one or more anti-microbial metals in a form characterized by sufficient atomic disorder such that the material, in contact with an alcohol or water based electrolyte, releases atoms, ions, molecules and clusters of at least one anti-microbial metal into the alcohol or water based electrolyte at a concentration sufficient to provide a localized anti-microbial effect on a sustainable basis,

9. The material as set forth in claim 8, wherein the metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, and Zn or an alloy or compound thereof.

10. The material as set forth in claim 8, wherein the metal is Ag, Au or Pd or an alloy or compound of and or more of these metals.

11. The material as set forth in claim 8 in the form of a powder or foil.

12. The material as set forth in claim 8 in the form of a coating.

13. The material as set forth in claim 11 or 12, in a crystalline form,

14. A method of forming a modified material containing one or more metals, said method comprising:
creating atomic disorder in the material under conditions which limit diffusion such that sufficient atomic disorder is retained in the material to provide release of atoms, ions, molecules or clusters of at least one of the metals into a solvent for the material at an enhanced rate relative to its normal ordered crystalline state,

15. The method as set forth in claim 14, wherein the metal is released on a sustainable basis.

16. The method as set forth in claim 14 wherein the material is a powder or foil of one or more of the metals, and wherein the atomic disorder is formed by cold working of the powder or foil.

17. The method as set forth in claim 16, wherein the powder or foil is worked at a temperature below the recrystallization temperature for the powder or fail to retain atomic disorder.

18. The method as set forth in claim 17, wherein the material is a nanocrystalline powder.

19. The method as set forth in claim 17, wherein at least one of the metals is an anti-microbial metal and wherein the material is formed with sufficient atomic disorder that atoms, ions, molecules or clusters of the anti-microbial mewl are released at a concentration sufficient to provide a localized anti-microbial effect on a sustainable basis.

20. The method as set forth in claim 19, wherein at least one of the metals is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi and Zn or alloys or compounds of one or more of these metals.

21. The method as set forth in claim 19, wherein at least one of the metals is Ag, Au or Pd or an alloy or compound containing one or more of these metals.

22. The method as set forth in claim 19, wherein at least one of the metals is silver or an alloy or compound containing silver.

23. The method as set forth in claim 14. wherein the material is formed as a coating on a substrate by vapour deposition under conditions which limit diffusion during deposition and which limit annealing or recrystallization following deposition.

24. The method as set forth in claim 23, wherein the material is form by physical vapour deposition.

25. The method as set forth in claim 24, wherein the material is a coating of one or more of the metals formed on a substrate by vacuum evaporation, sputtering, magnetron sputtering or ion plating.

26. The method as set forth in claim 25, wherein tire deposition is performed under conditions such that the ratio of the temperature of the substrate to the melting point of the metal or metal compound being deposited is maintained at less than about 0.5.

27. The method as set forth in claim 26 wherein the ratio is maintained at less than about 0.3.

28. The method as set forth in claim 26, wherein the deposition is performed such that the angle of incidence of the coating flux on the substrate to be coated is lest than about 75°.

29. The method as set forth in claim 26, wherein the deposition is performed by arc evaporation at an ambient or working gas pressure of greater than about 0.001 Pa (0.01 mT).

30. The method as set forth in claim 26, wherein the deposition is performed by gas scattering evaporation at a working gas pressure of greater than about 3 Pa (24 mT).

31. The method as set forth in claim 26, wherein the deposition is performed by sputtering at a working gas pressure of greater than about 10 Pa (75 mT).

32. The method as set forth in claim 26, wherein the deposition is performed by magnetron sputtering at a working gas pressure of greater than about 1.0 Pa (10 mT).

33. The method as set forth in claim 26, wherein the deposition is performed by magnetron sputtering at a working gas pressure of at least 4 Pa (30 mT).

34. The method as set forth in claim 26, wherein the deposition is performed by ion plating at a working gas pressure of greater than about 30 Pa(200 mT).

35. The method as get forth in claim 25, wherein at least one of the metals is an anti-microbial metal and wherein the material is formed with sufficient atomic disorder that atoms, ions, molecules or clusters of the anti-microbial metal are released at a concentration sufficient to produce a localized anti-microbial effect on a sustainable basis.

36. The method as set forth in claim 26, 28 or 32, wherein at least one of the metals is an anti-microbial metal and wherein the material is formed with sufficient atomic disorder that atoms, ions, molecules or clusters of the and-microbial metal arc released at a concentration sufficient to produce a localized anti-microbial effect on a sustainable basis.

37. The method as set forth in claim 25, wherein a composite coating is formed by co-, sequentially or reactively depositing a first metal in a matrix with atoms of molecules of a different material from the first metal such that atomic disorder is created in the matrix.

38. The method as set forth in claim 37, wherein the first metal is an anti-microbial metal and wherein the different material is atoms or molecules reactively deposited into the matrix from the working gas atmosphere during deposition.

39. The method as set forth in claim 37, wherein the first metal is an anti-microbial metal and wherein the different material is atoms or molecules selected from oxides, nitrides, carbides, borides, sulphides and halides of an inert biocompatible metal.

40. A method of forming an anti-microbial coating on a device intended for use in contact with an alcohol or water based electrolyte, comprising:
depositing a coating containing an anti-microbial metal on the surface of the device by vapour deposition to provide a thin film of the metal having atomic disorder such that the coating, in contact with an alcohol or a water based electrolyte, releases ions, atoms, molecules or clusters of the anti-microbial metal into the alcohol or water based electrolyte at a concentration sufficient to provide a localized anti-microbial effect on a sustainable basis.

41. The method as set forth in claim 40, wherein the anti-microbial effect is sufficient to generate a zone of inhibition of greater than 5 mm.

42. The method as set forth in claim 40, wherein the deposition is performed by a physical vapour deposition technique selected from vacuum evaporation, sputtering, magnetron sputtering or ion plating, under conditions which limit diffusion during deposition and which limit annealing or recrystallization following deposition.

43. The method as set forth in claim 42, wherein the deposition is performed such that the ratio of the temperature of the surface being coated to the melting point of the metal is maintained at less than about 0.5.

44. The method as set forth in claim 43, wherein the deposition is performed such that the angle of incidence of the coating flux on the device to be coated is less than about 75°.

45. The method as set forth in claim 43 or 44, wherein the deposition is performed by arc evaporation at an ambient or working gas pressure of greater than about 0.001 Pa (0.01 mT).

46. The method as set forth in claim 43 or 44, wherein the deposition is performed by gas scattering evaporation at a working gas pressure of greater than about 3 Pa (20 mT).

47. The method as set forth in claim 43 or 44, wherein the deposition is performed by sputtering at a working gas pressure of greater than about 10 Pa (75 mT).

48. The method as set forth in claim 43 or 44, wherein the deposition is performed by magnetron sputtering at a working gas pressure of greater than about 1.0 Pa ( 10 mT).

49. The method as set forth in claim 43 or 44, wherein the deposition is performed by magnetron sputtering at a working gas pressure of at least 4 Pa (30 mT).

50. The method as set forth in claim 43 or 44, wherein the deposition is performed by ion plating at a working gas pressure of greater than about 30 Pa (200 mT).

51. The method as set forth in claim 43 or 44 wherein the metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, and Zn or an alloy or compound containing one or more of these metals.

52. The method as set forth in claim 43 or 44 wherein the metal is Ag, Au or Pd or an alloy or compound containing one or more of these metals.

53. A medical device intended for use in contact with an alcohol or water based electrolyte having an anti-microbial coating on its surface, comprising:
a medical device formed of a substantially bioinert structural material; and an anti-microbial coating formed on the surface of the medical device, said coating being formed from one or more anti-microbial metals and having sufficient atomic disorder such that the coating, in contact with an alcohol or water based electrolyte, releases ions, atoms, molecules or clusters of the anti-microbial metal into the alcohol or water based electrolyte at a concentration sufficient to provide a localized anti-microbial effect on a sustainable basis.

54. The medical device as set forth in claim 53, wherein the anti-microbial coating is deposited by a physical vapour deposition technique selected from vacuum evaporation, sputtering, magnetron sputtering or ion plating.

55. The medical device as set forth in claim 54, wherein the metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, and Zn or alloys or compounds containing one or more of said metals.

56. The medical device as set forth in claim 54, wherein the metal is Ag, Au or Pd or an alloy or compound containing one or more of these metals.

57. The material as set forth in claim 7, wherein the coating is a composite coating formed from at least one first metal, which is the metal to be released, in a matrix containing atoms or molecules of a different material from the first metal, the atoms or molecules of the different material creating atomic disorder in the matrix.

58. The material as set forth in claim 57, wherein the different material is selected from reacted species of the first metal or metal compound; absorbed or trapped atoms or molecules of oxygen, nitrogen, hydrogen, boron, sulphur and halogen; and a second metal.

59. The material as set forth in claim 58, wherein the fast metal is an anti-microbial metal and the different material is selected froth oxides, nitrides, hydrides, halides, borides, and carbides of an anti-microbial or a second metal; and absorbed or trapped atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur and halogen.

60. The material as set forth in claim 57, wherein the first metal is an anti-microbial metal and the different material is an oxide, nitride, boride, sulphide, halide or hydride of an inert moral selected from Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al.

61. The material as set forth in claim 57, comprising silver oxide, silver metal and optionally absorbed or trapped atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur and halogen.

62. The method as set forth in claim 23, wherein the modified material is a composite coating formed by co-, sequentially or reactively depositing a first metal in a matrix with atoms or molecules of a different material from the first metal such that atomic disorder is created in the matrix.

63. The method as set forth in claim 62, wherein the first metal is an anti-microbial metal and wherein the different material is selected from atoms or molecules containing oxygen, nitrogen, hydrogen, baron, sulphur and halogen absorbed or trapped in the matrix from the atmosphere of the vapour deposition.

64. The method as set forth in claim 62, wherein the first metal is silver and the different material is selected froth atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur and halogen.

65. The method as set forth in claim 63, wherein the first metal is an anti-microbial metal and wherein the different material is an oxide, nitride, carbide, boride, halide, sulphide or hydride of an inert metal selected from Ta, Ti, Nb, V, Hf, Zn, Mo, Si and Al.

66. The method as set forth in claim 65, wherein the first metal is silver and the different material is an oxide of Ta, Ti or Nb.

67. The medical device as claimed in claim 53, wherein the coating is a composite coating formed from the anti-microbial metal in a matrix containing atoms or molecules of a material different from the anti-microbial metal, the atoms or molecules of the different material creating atomic disorder in the matrix.

68. The medical device as set forth in claim 67, wherein the different material is one or more of (a) reacted species of the anti-microbial metal or metal compound; (b) absorbed or trapped atoms or molecules of oxygen, nitrogen, hydrogen, boron, sulphur, and halogen;
and (c) an inert metal.

69. The medical device as set forth in claim 67, wherein the different material is one or more of (a) oxides, nitrides, hydrides, halides, borides, and carbides of an anti-microbial or an inert metal; and (b) absorbed or trapped atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur, and halogen.

70. The medical device as claimed in claim 67, wherein the different material is an oxide, nitride, boride, sulphide, halide, or hydride of an inert metal selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al.

71. The medical device as claimed in claim 67, wherein the coating comprises silver oxide, silver metal, and optionally absorbed or trapped atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur, and halogen.

72. The medical device as claimed in claim 67, wherein the coating comprises silver oxide, silver oxide and optionally absorbed or trapped atoms or molecules containing oxygen.

73. The medical device as claimed in claim 53, wherein the anti-microbial metal is silver or an alloy or compound containing silver.

74. The medical device as claimed in claim 53, wherein the coating is formed by vapour deposition under conditions which limit diffusion during deposition and which limit annealing or recrystallization following deposition.

75. The medical device as claimed in claim 74, wherein the coating is formed by physical vapour deposition.

76. The medical device as claimed in claim 75, wherein the material is a coating of one or more anti-microbial metals formed on the medical device by vacuum evaporation, sputtering, magnetron sputtering or ion plating.

77. The medical device as claimed in claim 76, wherein the deposition is performed under conditions such that a ratio of the temperature of the medical device to the melting point of the metal or metal compound being deposited is maintained at less than about 0.5.

78. The medical device as claimed in claim 77, wherein the ratio is maintained at less than about 0.3.

79. The medical device as claimed in claim 77, wherein the deposition is performed such that an angle of incidence of the coating flux on the medical device to be coated is less than 75°.

80. The medical device as claimed in claim 77, wherein the deposition is performed by arc evaporation at an ambient or working gas pressure of greater than about 0.01 mT.

81. The medical device as claimed in claim 77, wherein the deposition is performed by gas scattering evaporation at a working gas pressure of greater than about 20 mT.

82. The medical device as claimed in claim 77, wherein the deposition is performed by sputtering at a working gas pressure of greater than about 75 mT.

83. The medical device as claimed in claim 77, wherein the deposition is performed by magnetron sputtering at a working gas pressure of greater than about 10 mT.

84. The medical device as claimed in claim 77, wherein the deposition is performed by ion plating at a working gas pressure of greater than about 200 mT.

85. The medical device as set forth in claim 77, wherein the deposition is performed by magnetron sputtering at a working gas pressure of greater than about 30 mT.

86. The method as set forth in claim 43 or 44, wherein the anti-microbial metal is silver or an alloy or compound containing silver.

87. The method as claimed in claim 40, wherein the coating is a composite coating formed by co-, sequentially or reactively depositing an anti-microbial metal in a matrix with atoms or molecules of a material different from the anti-microbial metal, such that the atoms or molecules of the different material create atomic disorder in the matrix.

88. The method as claimed in claim 87, wherein the different material is selected from atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur, and halogen absorbed or trapped in the matrix from the atmosphere of the vapour deposition.

89. The method as claimed in claim 87, wherein the anti-microbial metal is silver and wherein the different material is selected from atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulphur, and halogen.

90. The method as claimed in claim 87, wherein the different material is an oxide, nitride, carbide, boride, sulphide, halide, or hydride of an inert metal selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al.

91. The method as claimed in claim 87, wherein the anti-microbial metal is silver or an alloy or compound containing silver and the different material is an oxide of Ta, Ti or Nb.

92. The method as set forth in claim 87, wherein the anti-microbial metal is silver and wherein the different material comprises silver oxide and optionally absorbed or trapped atoms or molecules containing oxygen.

93. The method as set forth in claim 42, wherein the deposition is performed such that the ratio of the temperature of the surface being coated to the melting point of the metal is maintained at less than about 0.3.

94. The method as set forth in claim 43 or 44, wherein the deposition is performed by magnetron sputtering at a working gas pressure of greater than about 30 mT.

95. A medical device intended for use in contact with an alcohol or water based electrolyte having an anti-microbial coating on its surface, comprising:
a medical device formed of a substantially bioinert structural material; and an anti-microbial coating formed on the surface of the medical device, said coating being formed from one or more anti-microbial metals and having sufficient atomic disorder such that the coating, in contact with an alcohol or water based electrolyte, releases ions, atoms, molecules or clusters of the anti-microbial metal into the alcohol or water based electrolyte at a concentration sufficient to provide a localized anti-microbial effect on a sustainable basis, the atomic disorder providing irregularities in surface topography and inhomogeneities in structure on a nanometre scale and being caused by high concentrations of one or more of point defects in a crystal lattice, vacancies, and line defects comprising dislocations, interstitial atoms, amorphous regions, grain and sub grain boundaries, relative to a normal ordered, crystalline state for the anti-microbial metal.

96. The medical device as set forth in claim 95, wherein the atomic disorder is created in the coating under conditions which limit diffusion such that sufficient atomic disorder is retained in the coating to provide release of atoms, ions, molecules or clusters of the anti-microbial metal into the alcohol or water based electrolyte at an enhanced rate relative to its normal ordered crystalline state.