CA2136454C - Process of activating anti-microbial materials - Google Patents

Abstract

Anti-microbial coatings and powders and method of forming same on medical devices are provided. The coatings are preferably formed by depositing an anti-microbial 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 vapour deposition or altered by mechanical working to produce atomic disorder are also provided. The anti-microbial effect of the coatings or powders may be further activated or enhanced by irradiating with a low linear energy transfer form of radiation such as gamma radiation.

Description

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FIELD OF THE INVENTION ;

2 The invention relates to methods of forming anti-microbial metal coatings, 3 foils and powders of biocompatihle metals which provide a s-~t~inP.d release of anti-~ r~

4 microbial metal species when in contact with an alcohol or electrolyte. ; ~' S BACKGROUND OF THE INVENTION
6 The need for an effective anti-microbial coating is wcll e~st~hli~hPd in the ' 7 medical comlllullily~ Physicians and surgeons using medical devices and ~plidnces 8 ranging from orthopaedic pins, plates and implants through to wound dressings and urinary 9 cathPtPnc must col,st~llly guard against infection. An ;~ ç~ vG anti-microbial coating 10 also finds application in medical devices used in con~umPr hP~lth~re and personal hygiene 11 products as well as in biomP~ir~l/biot~Pchni~l laboratory equipment~ The term "medical 12 device", as used herein and in the claims is meant to extend to all such products.
13 The anti-microbial effects of metallic ions such as Ag, Au, P$, Pd, Ir (i.e.
14 the noble metals), Cu, Sn, Sb, Bi and Zn are known (see Morton, H.E., Pseudomon~ in ;~
Disinfection, Ste~ili7~tion and Preservation, ed. S.S. Block, Lea and Febiger, 1977 and 16 Grier, N., Silver and Its Compounds in Di.cinfçction, St~rili7~tion and Presel vaLion, ed. S.S.
17 Block, Lea and Febiger, 1977). Of the metallic ions with anti-microbial propc;l~ies, silver 18 is perhaps the best known due to its unusually good bioactivity at low co~ ;on.~ This 19 phPnomP.n~ is termed oligodynamic action. In modern medical practice bot'n inorganic and 20 organic soluble salts of silver are used to prevent and treat microbial infçction~ While 21 these compounds are effective as soluble salts, they do not provide prolonged protection -22 due to loss through removal or comrlPY~tion of the free silver ions. They must be ~. :.'' ".'' - ~ ~ - .:

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reapplied at frequent intervals to overcome this problem. Reapplication is not always 2 practical, especially where an in-dwelling or impl~n~Pd medical device is involved.
3 Attempts have been make to slow the release of silver iocs during treatment 4 by creating silver containing complPYPs which have a lower level of solubility. For example, U.S. Patent 2,785,153 ~i~closes colloidal silver protein for this purpose. Such 6 compounds are usually formulated as creams. These compounds have not found wide 7 applicability in the medical area due to their limited efficacy. The silver ion release rate 8 is very slow. Furthermore, coatings from such compounds have been limited due to 9 ?~hesion, abrasion reCi~t~nre and shelf life problems.
The use of silver metal coatings for anti-microbial purposes has been 11 suggested. For in~t~nre, see Deitch et al., Anti-microbial Agents and Chemotherapy, Vol.
12 23(3), 1983, pp. 356 - 359 and M~r~Pen et al., Anti-microbial Agents and Chemotherapy, 13 Vol. 31(1), 1987, pp. 93 - 99. However, it is generally ~cepted that such coatings alone 14 do not provide the required level of efficacy, since ~iffil~ion of silver ions from the metallic surface is negligible.
16 A silver metal coating is produced by Spire Corporation, U.S.A. under the 17 trade mark SPI-ARGENT. The coating is formed by an ion-beam assisted deposition 18 (IBAD) coating process. The infection resistant coating is stated to be non-leaching in 19 aqueous solution.c as ~Pm()n~tr~tPd by zone of inhibition tests, thus enforcing the belief that silver metal surfaces do not release anti-microbial arnounts of silver ions.
21 Given the failure of metallic silver coatings to generate the required anti~
22 ~ ,.ubial efficacy, other l~e~he.~ have tried novel activation processes. One technique 23 is to use electrical activation of metallic silver implants (see Marino et al., Journal of 24 13iological Physics, Vol. 12, 1984, pp. 93 - 98). F.lPctric~l stim~ ti~n of metallic silver ~ . ~ . . ., - ~

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is not always practical, especially for mobile patients. Attempts to overcome this problem 2 include developing in situ electrical currents through galvanic action. Metal bands or ~ ' '~ ' 3 layers of different metals are deposited on a device as thin film coatings. A galvanic cell 4 is created when two metals in contact with each other are placed in an electrically S conducting fluid. One metal layer acts as an anode, which dissolves into the electrolyte.
6 The second metal acts as a cathode to drive the ele~ oche-llical cell. For PY~mr1P~ in the 7 case of ~lt~rn~tinp layers of Cu and Ag, the Cu is the anode, releasing Cu+ ions into the 8 electrolyte. The more noble of the metals, Ag, acts as the cathode, which does not ionize 9 and does not go into solution to any large extent. An eYPmr1~ry device of this nature is described in U.S. Patent 4,886,505 issued Dec. 12, 1989, to Haynes et al. The patent ll dicc1Oses sputtered coatings of two or more different metals with a switch affixed to one 12 of the metals such that, when the switch is closed, metal ion release is achieved.
13Previous work has shown that a film composed of thin 1~min~tçs of 14 ~1tçrn~ting, different metals such as silver and copper can be made to dissolve if the 15 surface is first etched. In this inct~n~e, the etching process creates a highly textured 16surface (see M. Tanemura and F. Okuyama, J. Vac. Sci. Technol., 5, 1986, pp 2369-2372) 17 However, the process of making such multi1~min~t~d films is time con..~ P and 18 expensive.
19Electrical activation of metallic coatings has not presented a suitable solution 20 to the problem. It should be noted that galvanic action will occur only when an electrolyte 21 is present and if an ç1Pctrir~1 connection between the two metals of the galvanic couple 22 exists. Since galvanic corrosion occurs primarily at the metallic int~rf~e between the two 23 metals, e1Pctri~1 contact is not s11ct~in~-i Thus a continnous release of metal ions over 24 an e~tPn~l~d period of time is not probable. Also, galvanic action to release a metal such ,-- ~: ...~-..:

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as silver is difficult to achieve. As in(li~t~.d above, the metal ions exhibiting the greatest 2 anti-microbial effect are the noble metals, such as Ag, Au, Pt and Pd. There are few 3 metals more noble than these to serve as cathode m~teri~ so as to drive the release of a 4 noble metal such as Ag at the anode.
A second approach to activating the silver metal surface is to use heat or 6 ch~mir~ U.S. Patents 4,476,590 and 4,615,705, issued to Scales et al. on October 16, 7 1984 and October 7, 1986, It;;,pe~;Lively, disclose methods of activating silver surface 8 coatings on endoprosthetic implants to render them bioerodible by heating at greater than 9 180~C or by contacting with hydrogen peroxide. Such treatments are limited in terms of the substrate/devices which can be coated and activated.
11 TherP is still a need for an efficacious, in~lrren~ive anti-microbial material 12 having the following properties~
13 - ucfAin~d release of an anti-microbial agent at ther~pentir~lly active levels;
14 - applicable to a wide variety of devices and m~t~ri~
- useful shelf life; and 16 - low m~mm~ n toxicity.
17 Metal coatings are typically produced as thin films by vapour deposition 18 techniques such as sputtering. Thin films of metals, alloys, semiconductors and ceramics 19 are widely used in the production of electronic colllponel.L~. These and other end uses require the thin films to be produced as dense, crystalline ~l-u~;lul~,s with minimal defects.
21 The films are often ~nnp~lrd after deposition to enhance grain growth and recryst~lli7~tion 22 and produce stable properties. Techniques to deposit metal films are reviewed by R.F.
- . ,: . ;
23 Bunshah et al., "Deposition Technologies for Films and Coatings", Noyes Public~ion.~
24 N.J., 1982 and by J.A. Thornton, "Tnfln~n-~e of Apparatus Geometry and Deposition ' 2136~4 Conditions on the Structure and Topography of Thick Sputtered Coatings", J. Vac. Sci.
2 Technol., 11(4), 666-670, 1974.
3 U.S. Patent No. 4,325,776, issued April 20, 1982 to Menzel discloses a 4 process for producing coarse or single crystal metal films from certain metals for use in integrated circuits. The metal film is formed by depositing on a cooled substrate (below -6 90~C) such that the metal layer is in an amorphous phase. The metal layer is then 7 ~nnP.~lPd by heating the substrate up to about room le,l,pel~lu,e. The end product is stated 8 to have large grain diameter and great homogeneity, p~.",;lli,.~ higher current den.~itiP.s 9 without electromigration failures.

SUMMARY OF THE INVENTION
11 The invelllul~ set out to develop an anti-microbial metal coating. They 12 discovered that, contrary to previous belief, it is possible to form metal coatings from an 13 anti-microbial metal material by creating atomic disorder in the m~tPri~l~ by vapour 14 deposition under con~ition.~ which limit diffil~ion, that is which "freeze-in" the atomic disorder. The anti-microbial coatings so produced were found to provide sust~inPd release 16 of anti-microbial metal species into solution so as to produce an anti-microbial effect.
17 This basic discovery linking "atomic disorder" to enh~nred solubility has 18 broad appliration The hlvelllol~ have d~Pmo~ dled that atomic disorder so as to produce 19 solubility can be created in other material forms, such as metal powders. The invention also has applir~tion beyond anti-microbial metals, enco.,.r~i"g any metal, metal alloy, 21 or metal compound, inr~ lin~ semiconductor or ceramic m~tPri~ , from which snst~inpd 22 release of metal species into solution is desired. For in~tanr,e, m~tPri~1~ having enhanced -.................................................................................................. ~

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or controlled metal dissolution find application in sensors, switches, fuses, electrodes, and 2 batteries.
3 The term "atomic disorder" as used herein includes high concçntr~tion.C of~
4 point defects in a crystal lattice, v~r~n~i~s, line defects such as ~icloca~ionc, intPrstiti~
atoms, amorphous regions, grain and sub grain boundaries and the like relative to its 6 normal ordered crystalline state. Atomic disorder leads to irregularities in surface 7 topography and inhomogenieties in the ~structure on a nanometre scale.
8 By the term "normal ordered crystalline state" as used herein is meant the 9 crystallinity normally found in bulk metal m~tP.ri~l.c, alloys or compounds forrned as cast, wrought or plated metal products. Such m~tPri~ contain only low conc~ iQns of such 11 atomic defects as v~c~n~ios> grain boundaries and dislocations.
12 The term "diffusion" as used herein implies diffusion OI atoms and/or 13 molecules on the surface or in the matrix of the material being formed.
14 The terms "metal" or "metals" as used herein are meant to include one or more metals whether in the form of substantially pure metals, alloys or compounds such 16 as oxides, nitrides, borides, slllrhid~Ps, halides or hydrides.
17 The i~lv~lllion, in a broad aspect extends to a method of forming a modified 18 material co~ lg one or more metals. The method comrlric~ps creating atomic disorder 19 in the material under con-lition.c which limit diffusion such that suffi~ iPnt atomic disorder is retained in the material to provide release, preferably on a smt~in~blP basis, of atoms, 21 ions, molpculps or clusters of at least one of the metals into a solvent for the m~teri~
22 Clusters are known to be small groups of atoms, ions or the like, as d~Pscrihed by R.P.
23 Andres et al., "Research O~l)ollu"i~ies on Clusters and Cluster-Assembled M~tPri~ ", J
24 Mater. Res. Vol. 4, No. 3, 1989, P. 704.

~ ' 2 13 ~'t5- ~
Specific preferred embodiments of the invention demonstrate that atomic 2 disorder may be created in metal powders or foils by cold working, and in metal coatings 3 by depositing by vapour deposition at low substrate tempelalules.
4 In another broad aspect, the invention provides a modified material compri.~ing one or more metals in a form characterized by s11fflriPnt atomic disorder such 6 that the m~teri~1, in contact with a solvent for the m~t~ri~1, releases atoms, ions, mo1.-cul~s 7 or clusters co,.~ ;l.g at least one metal, preferably on a sustainable basis, at an enh~nred 8 rate relative to its normal ordered crystalline state.
9 In preferred embodiments of the invention, the mo~ifi~d material is a metal powder which has been m~ch~nir~11y worked or colllpl~ssed, under cold working 11 con-litionc, to create and retain atomic disorder.
12 The term "metal powder" as used herein is meant to include metal particles ~ ' 13 of a broad particle size, ranging from nanocrystalline powders to flakes.
14 The term "cold working" as used herein in~ at~s that the material has been -m~ch~ni~11y worked such as by milling, grin-ling, h~mmering~ mortar and pestle or 16 compressing, at ItlllpelaLul~s lower than ~he recryst~ tion lelllpela~ul~ of the m~t~ri~1 17 This ensures that atomic disorder imparted through working is retained in the m~t.ori~
18 In another preferred embodiment, the modified material is a metal coating 19 formed on a substrate by vapour deposition l~clu~ ues such as vacuum e~ol~on, i - -sputtering, magnetron sputtering or ion plating. The matenal is formed under contlitinn~
21 which limit diffusion during deposition and which limit ~nnP~1ing or recryst~ tion 22 following deposition. The deposition condition.s preferably used to produce atomic 23 disorder in the coatings are out~side the normal range of operating con-lition.~ used to 24 produce defect free, dense, smooth films. Such normal pla~,~eS are well known ~see for - ~ ~:
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example R.F. Bunshah et al., supra). Preferably the deposition is conducted at low 2 substrate temperatures such that the ratio of the substrate to the melting point of the metal 3 or metal compound being deposited (T/Tm) is m~int~in~d at less than about 0.5, more 4 preferably at less than about 0.35, and most preferably at less than 0.30. In this ratio, the temperatures are in degrees Kelvin. The preferred ratio will vary from metal to metal and 6 i~ ases with alloy or illlpuliliy content. Other preferred deposition con~lition~ to create 7 atomic disorder include one or more of a higher than normal working gas pressure, a lower 8 than normal angle of inridenre of the coating flux and a higher than normal coating flux.
9 The temrçr~tllre of deposition or cold working is not so low that substantial ~nne~ling or recryst~ tion will take place when the material is brought to room Il L~lllpelalul~ or its intended temrPr~tllre for use (ex. body ~Ill~c;lalure for anti-microbial 12 m~tPri~lS). If the teillpela~ul~ diLrel~llli~ between deposition and ~Illpelalule of use (~T) 13 is too great, ~nn~ling results, removing atomic disorder. This ~T will vary from metal 14 to metal and with the deposition technique used. For eY~mrlP, with respect to silver, lS s~lbstr~te ~Ill?~lalulkS of -20 to 200~C are preferred during physical vapour deposition.
16 Normal or ambient working gas pressure for depoc;~ g the usually required dense, 17 smooth, defect free metal films vary according to the method of physical vapour deposition 18 being used. In general, for sputtenng, the normal working gas pressure is less than 10 Pa 19 (Pascal) (75 mT (milliTorr)), for magnetron sputtering, less than 1.3 Pa (lOmT), and for ion-plating less than 30 Pa (200 mT). Normal ambient gas plC;S~Ult;S vary for vacuum 21 i,~apolalion processes vary as follows: for e-beam or arc eva})olalion, from 0.0001 Pa 22 (0.001 mT) to 0.001 Pa (0.01 mT); for gas scatt~rin~ evapol~lion (pressure plating) and 23 reactive arc tivapolalion, up to 30 Pa (200 mT), but typically less than 3 Pa (20 mT).
24 Thus, in acco dd~-ce with the method of the present invention, in addition to using low ., , 2~6~ ~
substrate temperatures to achieve atomic disorder, working (or ambient) gas pressures 2 higher than these normal values may be used to increase the level of atomic disorder in 3 the coating.
4 Another condition discovered to have an effect on the level of atomic disorder in the coatings of the present invention is the angle of in~iden~e of the coating 6 flux during deposition. Normally to achieve dense, smooth coatings, this angle is 7 m~int~inPd at about 90~ +/- 15~. In accoldallce with the present invention, in addition to 8 using low substrate telllyelalules during deposition to achieve atomic disorder, angles of g in~idence lower than about 75~ may be used to increase the level of atomic disorder in the coating.
11 Yet another process parameter having an effect on the level of atomic 12 disorder is the atom flux to the sur ace being coated. High deposition rates tend to 13 increase atomic disorder, however, high deposition rates also tend to increase the coating 14 le-.-pelalul~. Thus, there is an optimum deposition rate that depends on the deposition technique, the coating material and other process p~r~mPt~PrS
16 To provide an anti-microbial m~ter~ the metals used in the coating or 17 powder are those which have an anti-microbial effect, but which are biocompatible (non-18 toxic for the intended utility). Preferred metals include Ag, Au, Pt, Pd, Ir (i.e. the noble 19 metals), Sn, Cu, Sb, Bi, and Zn, co---~ou--ds of these metals or alloys co~ one more of these metals. Such metals are h- ,~ ,.r~l-r referred to as "anti-microbial metals"). Most 21 preferred is Ag or its alloys and compoullds. Anti-microbial m~tP.ri~ in acco,-lallce with 22 this invention ~ ably are formed with sufficient atomic disorder that atoms, ions, 23 moiecules or clusters of the anti-iclobial material are released into an alcohol or water 24 based electrolyte on a s~ in~hlP basis. The terms " -hle basis" is used herein to ''~ ~ ''''~'''''' ,- ' ' . ' , ~

2 1 ~ 645 4 differentiate, on the one hand from the release obtained from bulk metals, which release 2 met~ ions and the like at a rate and concGIlllalion which is too low to achieve an anti~
3 microbial effect, and on the other hand from the release obtained from highly soluble salts 4 such as silver nitrate, which release silver ions virtually instantly in contact with an alcohol S or water based electrolyte. In contrast, the anti-microbial m~tP.ri~l~ of the present invention 6 release atoms, ions, mnlPc~ s or clusters of the anti-microbial metal at a s~lffi~irnt rate 7 and concelllla~on, over a snfflcipnt time period to provide a useful anti-microbial effect.
8 The term "anti-microbial effect" as used herein means that atoms, ions, 9 rnolPclllPs or clusters of the anti-microbial metal are released into the electrolyte which the material contacts in conrPntr~tion.~ snffiri~nt to inhibit bacterial growth in the vicinity of 11 the m~teri~l The most common method of mP~ming anti-microbial effect is by 12 mP~nring the zone of inhibition (ZOI) created when the material is placed on a bacterial 13 lawn. A relatively small or no ZOI (ex. less than 1 mm) in~1iratps a non-useful anti-14 microbial effect, while a larger ZOI (ex. greater than S mm) in-lir~tPs a highly useful anti-microbial effect. One pl(,ce-lult; for a ZOI test is set out in the FY~"rles which follow.
16 The invention extends to devices such as medical devices formed from, 17 inco,l,olalillg, carrying or coated with the anti-microbial powders or co~in~.~ The anti-18 microbial coating may be directly deposited by vapour deposition onto such medical 19 devices as cpth~t~r~ sutures, imp1~nt.~, burn dressings and the like. An ~hPsion layer, such as t~nt~lnm, may be applied between the device and the anti-microbial coating.
21 Adhesion may also be enh~nred by methods known in the art, for example etching the 22 substrate or forming a mixed intPrf~re between the substrate and the coating by 23 .~imlllt~nPQus sputtering and etching. Anti-microbial powders may be incollJola~d into 24 creams, polymers, ce~",ni~s, paints, or other m~trir,es, by techniques well known in the art : ~136~5~ ~

In a further broad aspect of the invention, modified m:~tPri~l.c are prepared 2 as composite metal coatings co~ hlillg atomic disorder. In this case, the coating of the 3 one or more metals or compounds to be released into solution coi.s~ Ps a matrix 4 co~llA;~ g atoms or molecules of a different m~tr.ri~l The presence of different atoms or S molecules results in atomic disorder in the metal matrix, for instance due to different sized 6 atoms. The different atoms or molecules may be one or more second metals, metal alloys 7 or metal col-ll.oul-ds which are co- or sequentially deposited with the first metal or metals 8 to be released. Alternatively the different atoms or molpclllps may be absorbed or trapped 9 from the working gas atmosphere during reactive vapour deposition. The degree of atomic 10 disorder, and thus solubility, achieved by the inrlllsion of the different atoms or molPculPs 11 varies, depending on the m~ter~ In order to retain and enhance the atomic disorder in 12 the composite m~tPri~l, one or more of the above-described vapour deposition conditions, 13 namely low substrate ~..,pe~ , high working gas pressure, low angle of incidence and 14 high coating flux, may be used in combination with the in~ ion o~ different atoms or ;. . . ~ .. :. ~, . .
15 molpculps 16 Preferred colllposil~ m~teri~lA for anti-microbial pu-~oses are formed by .: ~ ~, 17 inCl~lding atoms or molpculps co~ g oxygen, nitrogen, hydrogen, boron, sulphur or 18 halogens in the working gas atmosphere while depositing the anti-microbial metal. These ~ ~;
19 atoms or molecules are inco.~o.dted in the coating either by being absorbed or trapped in ;~
the film, or by reacting with the metal being deposited. Both of these mP~h~ during ~;
21 deposition are hp~rp~in~ft~pr referred to as "reactive deposition". Gases contAinin~ these 22 elPmPnt.~, for example oxygen, hydrogen, and water vapour, may be provided co,.lil.,~ou~ly 23 or may be pulsed for seq~l~Pnti~l deposition. ~ ~

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Anti-microbial composite m~teri~ are also preferably prepared by co- or 2 sequentially depositing an anti-microbial metal with one or more inert biocomr~tihle 3 metals selected from Ta, Ti, Nb, Zn, V, Hf, Mo, Si, and Al. Alternatively, the composite 4 m~teri~ may be formed 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 6 metals and/or the oxides, carbides, nitrides, borides, slllrhi(lp~s or halides of the inert 7 metals. Particularly preferred composites contain oxides of silver and/or gold, alone or 8 together with one or more oxides of Ta, Ti, Zn and Nb. :
9 The invention also extends to a method of activating or further Pnh~nri the anti-microbial effect of anti-microbial m~tPri~ formed with atomic disorder. Thus, "
11 anti-microbial m~t~ made i~ acco~ ce with the present invention may be irradiated 12 to further enhance the anti-microbial effect. However, it is also possible to irradiate ',',.'' '"'',',',.'S " '"L
13 m~tPri~lc initially formed with a level of atomic disorder which is inmfficiPnt to produce '~
14 an anti-l"i~i-obial effect, such that the irr~ t~P.d material has an acceptable anti-microbial effect. The process of activation comprii~Ps irradiating the material with a low linear 16 energy transfer form of radiation such as beta or x-rays, but most preferably gamma rays.
17 A dose greater than 1 Mrad is preferred. The anti-microbial material is preferably oriented 18 substantially perpendicular to the incoming radiation. The level of activation may be 19 further el-h~ ed by irr~ tin~ the material adjacent to a dielectric material such as oxides of Ta, Al and Ti, but most preferably silicon oxide.

22 As above stated, the present invention has application beyond anti-microbial 23 mItP.ri~, However, the invention is di~clospd herein with anti-microbial metals, which 13 ;

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are illustrative of utility for other metals, metal alloys and metal compounds. Preferred 2 metals include Al and Si, and the metal elPment.~ from the following groups of the periodic 3 table: IIIB, IVB, VB, VIB, VIIB, VIIIB, IB, IIB, IIIA, IVA, and VA (çxclll~ing As) in 4 the periods 4, S and 6, (see Periodic Table as published in Merck Index 10th Ed., 1983, Merck and Co. Inc., Rahway, N.J., Martha Windholz). Different metals will have varying 6 degrees of solubility. However, the creation and retention of atomic disorder in accoldallce 7 with this invention results in çMh~nced solubility (release) of the metal as ions, atoms, 8 mol~c~ s or clusters into an appropriate solvent i.e. a solvent for the particular m~t~
9 typically a polar solvent, over the solubility of the material in its normal ordered crystalline state.
11 The medical devices formed from, incorporating, carrying or coated with the 12 anti-microbial material of this invention generally come into contact with an alcohol or 13 water based electrolyte in~ln(ling a body fluid (for example blood, urine or saliva) or body 14 tissue (for example skin, muscle or bone) for any period of time such that microo.~ani~
growth on the device surface is possible. The term "alcohol or water based electrolyte"
16 also includes alcohol or water based gels. In most cases the devices are medical devices . :. :. ..,:
17 such as c~thptçrs~ impl~nt.~, tracheal tubes, orthopaedic pins, insulin pumps, wound 18 closures, drains, dressings, shunts, co~ ol ~, prosthetic devices, p~çm~b~r leads, needles, 19 surgical instruments, dental prosthesçs, ventilator tubes and the like. However, it should be understood that the illvt;~-~ion is not limited to such devices and may extend to other 21 devices useful in con.~lm~r h~lth~re, such as sterile p~ck~ginp~ clothing and footwear, 22 personal hygiene products such as diapers and sanitary pads, in biom~di~l or biotl~hnir~
23 l~hor~tory equipment, such as tables, enclosures and wall coverings, and the like. The 14 . ~
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term "medical device" as used herein and in the claims is intended to extend broadly to 2 all such devices. : .
3 The device may be made of any suitable m~teriAl, for example metals, 4 including steel, Al~ nl, and its alloys, latex, nylon, silicone, polyester, glass, ceramic, S paper, cloth and other plastics and rubbers. For use as an in-dwelling medical device, the 6 device will be made of a bioinert m~teriAl The device may take on any shape dictated by ~ ~ "
7 its utility, ranging from flat sheets to discs, rods and hollow tubes. The device may be -S
8 rigid or flexible, a factor again dictated by its intended use.
': '' '. '," -,-',, . ,' 9 Anti-Microbial Coatin~s The anti-microbial coating in accordance with this invention is deposited as 11 a thin metallic film on one or more surfaces of a medical device by vapour deposition 12 techniques. Physical vapour techniques, which are well known in the art, all deposit the 13 metal from the vapour, generally atom by atom, onto a substrate surface. The l~chl~ les 14 include vacuum or arc eva~o-alion, sputtering, magnetron sputtering and ion plating. The lS deposition is con~lct~d in a manner to create atomic disorder in the coating as defined 16 hereinabove. Various con~litionc responsible for producing atomic disorder are useful.
17 These co~ ition.~ are generally avoided in thin film deposition techniques where the object 18 is to create a defect free, smooth and dense film (see for example J.A. Thornton, supra).
19 While such con~itionc have been invçstig~ted in the art, they have not heleloÇo.G been linked to çnhqn~ed solubility of the coatings so-produced.
21 The preferred con(iition~ which are used to create atomic disorder during the ~ ~ .
22 deposition process include~

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- a low substrate temperature, that is m:lint~inin~ the surface to be coated 2 at a temperature such that the ratio of the substrate temperature to the melting point of the ;~
3 metal (in degrees Kelvin) is less than about 0.5, more preferably less than about 0.35 and . . . . :
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4 most preferably less than about 0.3; and optionally one or both of~
- a higher than normal working (or ambient) gas pressure, i.e. for vacuum 6 evaporation: e-beam or arc evàpG,a~on, greater than 0.001 Pa (0.01 mT), gas sclttP~ng 7 evaporation (pressure plating) or reactive arc evaporation, greater than 3 Pa (20 mT); for 8 sputtering: greater than 10 Pa (75 mT); for magnetron sputtering: greater than about 1.3 . ................................................................................................... ... .... ~ ~ ~
9 Pa (10 mT); and for ion plating: greater than about 30 Pa (200 mT); and - m~int~ining the angle of incid~Pnce of the coating flux on the surface to be 11 coated at less than about 75~, and preferably less than about 30~
12 The metals used in the coating are those known to have an anti-microbial 13 effect. For most medical devices, the metal must also be biocompatible. Preferred metals 14 include the noble metals Ag, Au, Pt, Pd, and Ir as well as Sn, Cu, Sb, Bi, and Zn or alloys 15 or compounds of these metals or other metals. Most preferred is Ag or Au, or alloys or 16 compounds of one or more of these metals.
17 The coating is formed as a thin film on at least a part of the surface of the 18 medical device. The film has a thi~l~nP~ no greater than that needed to provide release 19 of metal ions on a s~lst~inqhle basis over a suitable period of time. In that respect, the 20 thi~nPs5 will vary with the particular metal in the coating (which varies the solubility and 21 abrasion re~i~t~n~e), and with the degree of atomic disorder in (and thus the solubility of) 22 the coating. The thir1rnPss will be thin enough that the coating does not interfere with the 23 ~imPn.~i~n~l tolerances or flexibility of t-h-e device for its intended utility. Typically, 24 thi~knPs~P~s of less than 1 micron have been found to provide sufficieni s~st2inPd anti~

2 1 ~ 6~

microbial activity. Increased thicknpss~ps may be used depending on the degree of metal 2 ion release needed over a period of time. ThicknP~.cPs greater than 10 microns are more 3 e,~ .siv~ to produce and normally should not be needed.
4 The anti-microbial effect of the coating is achieved when the device is brought into contact with an alcohol or a water based electrolyte such as, a body fluid or 6 body tissue, thus releasing metal ions, atoms, molecules or clusters. The concelll-alion of 7 the metal which is needed to produce an anti-microbial effect will vary from metal to 8 metal. Generally, anti-microbial effect is achieved in body fluids such as plasma, serum 9 or urine atconce.ll.alions less than about0.5 - 1.5 ~,lg/ml.
The ability to achieve release of metal atoms, ions, molecules or clusters on 11 a sllct~in~hle basis from a coating is dictated by a number of factors, inrln~1in~ coating 12 cL~-Ie.;cti~s such as composition, structure, solubility and thi~lrn~s.c, and the nature of 13 the t;l-vilolllne~l in which the device is used. As the level of atomic disorder is increased, 14 the amount of metal ions released per unit time illCIt;i~SeS. For inct~n~e, a silver metal film , .. .
deposited by magnetron sputtering at T/Tm ~ 0.5 and a working gas pressure of about 0.9 16 Pa (7 mTorr) releases al~p.~ .. ately 1/3 of the silver ions that a f ilm deposited under ~ ~;
17 similar conrlition.c, but at 4 Pa (30 mTorr), will release over 10 days. Films that are 18 created with an intermediate structure (ex. lower pressure, lower angle of i"~ ce etc.) 19 have Ag release values intprrne~ ~ to these values as de t~ hlPd by bioassays. This then 20 provides a method for producing controlled release metallic coatings in âcco-dance with 21 this invention. Slow release coatings are prepared such that the degree of disorder is low 22 while fast release coatings are prepared such that the degree of disorder is high. :
23 For continuous, uniform Coating~c~ the time required for total ~ic501lltion will 24 be a function of film thir~n~$$ and the nature of the e--vi unlllent to which they are , "

~' 213S'15l exposed. The relationship in respect of thil~knP,s.~ iS al)l)r~ lately linear, i.e. a two fold 2 increase in film thicknPss will result in about a two fold increase in longevity. ~ i -3 It is also possible to control the metal release from a coating by forming a 4 thin film coating with a modulated structure. For in~t~nce, a coating deposited by S magnetron sputtering such that the working gas pressure was low (ex. 2 Pa (15 mTorr)) 6 for 50% of the deposition time and high (ex. 4 Pa (30 mTorr)) for the rçm~inin~ time, has 7 a rapid initial release of metal ions, followed by a longer period of slow release. This type 8 of coating is extremely effective on devices suc~ as urinary c~thptpr~ for which an initial 9 rapid release is required to achieve immediate anti-microbial con~Pntr~tion.~ followed by a lower release rate to sustain the concentration of metal ions over a penod of weeks. ;
11 The subst;ate ~ pt;lalult; used during vapour deposition should not be so 12 low that ~nnP.~lin~ or recryst~lli7~tion of the coating takes place as the coating warms to 13 ambient lelllpt;l~lUI~,S or the temrer~ res at which it is to be used (ex. body II ",I.e~"lu~e).
14 This allowable ~T, that the l~lllpelalul~ dirrel~lllial between the substrate tf l~ Ç~a~ e ::
during deposition and the ultimate temperature of use, will vary from metal to metal. For 16 the most preferred metals of Ag and Au, preferred substrate tPmpel.. ~ cs of -20 to 200~C
17 , more preferably -10~C to 100~C are used. : ~:
18 Atomic order may also be achieved, in acco~allce with the present19 invention, by preparing composite metal m~t~ri~l~, that is m~ter~ which contain one or more anti-llliclubial metals in a metal matrix which includes atoms or molpclllps different 21 from the anti-microbial metals.
22 Our tP~ up for preparing comro~itP material is to co- or sequentially 23 deposit the anti-microbial metal(s) with one or more other inert, biocomr~tihle metals 24 selected from Ta, Ti, Nb, Zn, V, E~, Mo, Si, Al and alloys of these metals or other metal ; ~ ;
~ . . . ~. -1~ " ~

2 ~ 3 ~ 5~

e1emçnt.~, typically other transition metals. Such inert metals have a different atomic radii - ,;: :~
2 from that of the anti-microbial metals, which results in atomic disorder during deposition.
3 Alloys of this kind can also serve to reduce atomic diffusion and thus stabilize the 4 disordered structure. Thin film deposition equipment with multiple targets for the 5 p1~em~nt of each of the anti-microbial and inert metals is preferably utilized. When 6 layers are sequentially deposited the layer(s) of the inert metal(s) should be diccontin11ous, 7 for example as islands within the anti-microbial metal matrix. The final ratio of the anti- ~-8 microbial metal(s) to inert metal(s) should be greater than about 0.2. The most preferable 9 inert metals are Ti, Ta, Zn and Nb. It is also possible to form the anti-microbial coating lO from oxides, carbides, nitrides, snlrhiAes~ borides, halides or hydrides of one or more of ll the anti-microbial metals and/or one or more of the inert metals to achieve the desired ~ ~-12 atomic disorder.
13 Another composite material within the scope of the present invention is ~
14 formed by reactively co- or sequentially depositing, by physical vapour techniques, a ~ . ,r 15 reacted material into the thin film of the anti-microbial metal(s). The reacted material is 16 an oxide, nitride, carbide, boride, sl11phide~ hydride or halide of the anti-microbial and/or 17 inert metal, formed in situ by injecting the appropriate re~ct~nt~, or gases Cc?,~l~;";llg same, 18 (ex. air, oxygen, water, nitrogen, hydrogen, boron, sulphur, halogens) into the deposition l9 chamber. Atoms or mo1~.cu1Ps of these gases may also become absorbed or trapped in the metal film to create atomic disorder. The reactant may be contin11o11s1y supplied during ~ ~ ~
21 deposition for codeposition or it may be pulsed to provide for sequential deposition. The ~ ~7 22 final ratio of anti-microbial metal(s) to reaction product should be greater than about 0.2.
23 Air, oxygen, nitrogen and hydrogen are particularly preferred reactants. ~ ;

. ~. . . .
.. : ~, .

~136~4 The above deposition techniques to prepare composite coatings rnay be used 2 with or without the conditions of lower substrate tempeldLules, high working gas ~ ;S~U1~S
3 and low angles of in~i~ence previously discussed. One or more of these con~litinn~ is 4 preferred to retain and enhance the amount of atomic disorder created in the coating.
It may be advantageous, prior to depositing an anti-microbial in accordance 6 with the present invention, to provide an n~lhPcir~n layer on the device to be coated, as is 7 known in the art. For instance, for a latex device, a layer of Ti, Ta or Nb may be first 8 deposited to enhance adhesion of the subsequently deposited anti-microbial coating.

9 Anti-Microbial Powders Anti-microbial powders, in~ 1ing nanocrystalline powders and powders ll made from rapidly solidified flakes or foils, can be formed with atomic disorder so as to 12 enhance solubility. The powders either as pure metals, metal alloys or compounds such 13 as metal oxides or metal salts, can be mech~ni~11y worked or co~ ssed to impart 14 atomic disorder. This mPch~ni-~lly illlp~Led disorder is conducted under con~lition~ of low ~ .rç~ (i.e. temperatures less than the le.,l)e,.~ ; of recrys~11i7~tion of the 16 material) to ensure that ~nnP~1ing or recryst~11i7~tion does not take place. The Ir~ u~ e 17 varies between metals and increases with alloy or impurity content.
18 Anti-microbial powders produced in accold~lce with this invention may be 19 used in a variety of forms, for instance in topical creams, paints or adherent coatings.
Alternatively, the powder may be incorporated into a polymeric, ceramic or metallic matrix 21 to be used as a material for medical devices or coatings therefor.

.~ .- '',, 213~4~1 Activation of Anti-Microbial Materials 2 Irradiation of anti-microbial m~tPri~li (powders, nanocrystalline powders, 3 foils, coatings or composile coatings of anti-microbial metals) which contain atomic 4 disorder formed by any of the above-d~P.scrihed procedures, will further activate or enhance the anti-microbial effect. Thus, even m~teri~1~ having a low level of atomic disorder may 6 be activated to an anti-microbial level.
7 Irradiation is performed with any low linear energy transfer form of 8 r~ tion~ inf~luAin~ beta, gamma and x-rays. Gamma radiation at a dose of 1 Mrad or 9 greater is preferred. Since garnma radiation is an acceptable method of st~ri1i7~tion of medical devices, activation and stPri~ tion may be achieved simultaneously through the ll irradiation process of the present invention.
12 The irradiation step is preferably conAuctPd such that the anti-microbial 13 material being irradiated is oriented generally perpPnAi~.u1~r to the incoming r~Ai~tion : --: ~ ~ .:
14 (rather than parallel). A further enh~nrPmPnt of the anti-microbial effect can be achieved lS by conducting the irr~Ai~tion step with a dielectric material adjacent to, or preferably ~ ;;
16 sandwiched around the anti-rr.icrobial m~tPri~1 FYP.mp1~ry dielectrics include oxides of 17 Si, Ti, Ta and Al. Silicon oxide surfaces are preferred. It is believed that the dielectric ;
18 material provides forward scatterin~ of electrons into the anti-microbial coating.
19 Without being bound by the same it is believed that the irradiation step is 20 causing one or more of the following changes in the anti-microbial m~tP.ri~
21 l) creating further atomic disorder, such as point defects;
22 2) ~P.nh~n--ing oxygen adsorption/c1-~-"i~o,~1ion to the surface of the anti-microbial 23 m~tPri~1;
24 3) activating trapped dopant atoms or molP.cll1P.s such as oxygen to O+ or ~i; and ~ ;

:~

2136~54 4) creating broken or dangling bonds at the surface.
2 With respect to the second and third proposed mech~ni~m.~, it is possible that oxygen 3 adsorption/chemisorption and/or activation creates a super saturated concentration Of ~2~
4 O+ or ~2- species in or on the anti-microbial metal surface, which results in the more rapid 5 dissolution of the anti-microbial metal or species thereof into an aqueous e~lviLolllllent 6 through the gP.n~r~tion of various ch~m~ species of the anti-microbial metal, inrlu(ling 7 oxides and hydroxides.
8 The invention is further ilhl.ctr~ted by the following non-limiting PY~mpl~.s g F.Y~mple 1 A medical suture material size 2/0, polyester braid was coated by magnetron 11 sputtering from 20.3 cm diameter (8 in.) planar silver and copper magnetron cat-h-odes to 12 form an Ag-Cu-alloy on the surface to a thirlrn~.ss of 0.45 microns, using either argon gas 13 working pl~,ss.lles of 0.9 Pa (7 mTorr) or 4 Pa (30 mT) at O.S KW power and a T/Tm ratio 14 of less than O.S. The total mass flow of gas was 700 sccm (standard cubic centim~ter~ per minute).
16 The anti-microbial effect of the coatings was tested by a zone of inhibition 17 test. Basal medium Eagle (BME) with Earle's salts and L-~ ",;.,f~. was modified with 18 calf/serum (10%) and 1.5 % agar prior to being ~ pçn~ed tlS ml) into Petri dishes. The 19 agar co~ Petri plates were allowed to surface dry pnor to being inocul~ted with a lawn of Staphylococcus aureus ATCCt$ 25923. The inocul~nt was prepared from Bactrol 21 Discs (Difco, M.) which were recon.~tituted as per ~e m~mlf~tnrer's dil~;Liuns.
22 Tmm~ te~y after inoculation, the m~ri~1~ or coatings to he tested were placed on the 23 surface of the agar. The dishes were in~nh~ted for 24 h at 37~C. After this incubation .... , ,~ .. ,............................. . . . , , . .. ~

-" 2 1 3 645 ~
period, the zone of inhibition was measured and a corrected zone of inhibition was 2 calculated (corrected zone of inhibition = zone of inhibition - diameter of the test material 3 in contact with the agar).
4 The results showed no zone of inhibition on the ~mro~t~Pd suture, a zone of S less than 0.5 mm around the suture coated at 0.9 Pa (7 mTorr) and a zone of 13 mm 6 around the suture coated at 4 Pa (30 mTorr). Clearly the suture coated in acco~dance with ~ A'' 7 the present invention exhibits a much more pronounced and effective anti-microbial effect.

8 FY~m~l~P. 2 ~ , "
9 This example is inc~ Pd to illustrate the surface structures which are obtained when silver metal is deposited on silicon wafers using a magnetron sputtering 11 facility and different working gas pressures and angles of inri~Pnre (i.e. the angle between 12 the path of the sputtered atoms and the snhstr~tp). All other con-litionA were as follows~
13 target was a 20.3 cm dia. planar silver magnetron cathode; power was 0.1 kW; deposition 14 rate was 200 A~/min; ratio of lt;lllpela~ul'e of substrate (wafer) to melting point of silver ; ~, (1234~K), T/Tm was less than 0.3. Argon gas plessul~s of 0.9 Pa (7 mTorr) (a normal 16 working pressure for metal coatings) and 4 Pa (30 mTorr) were used with a total mass gas 17 flow of 700 sccm. Angles of in~i~lP,nee, at each of these pl.,Ss.l-~,s were 90~ (normal 18 incidcenre), 50~ and 10~. The coat,ings had a thicknpsA of about 0.5 microns.
19 The resulting surfaces were viewed by sc~nninP electron l.lie.useope. As ';
argon gas pressure increased from 0.9 Pa (7 mTorr) to 4 Pa (30 mTorr) the grain size ' 21 decreased and void volume fficreased .~ignific~ntly. When the angle of in-i~lPnce was 22 decltiased, the grain size declt;ased and the grain boundaries became more distinct. At 0.9 23 Pa (7 mTorr) argon pressure and an angle of inl~-dPnl e of 10~, there were int~ tion~ of 2 1 3 64~
some voids between the grains. The angle of inri~enre had a greater effect on the surface 2 topography when the gas pressure was increased to 4 Pa (30 mTorr). At 90~, the grain size 3 varied from 60 - lS0 nm and many of the grains were separated by illle.~ h~ void spaces 4 which were 15 - 30 nm wide. When the angle of incidenre was decreased to 50~, the grain size decreased to 30 - 90 nm and the void volume increased substantially. At 10~, the 6 grain size was reduced to about lO - 60 nm and void volurnes were increased again.
7 The observed n~nomptre scale changes in surface morphology and 8 topography are in~iration.c of atomic disorder in the silver metal. While not being bound 9 by the same, it is believed that such atomic disorder results in an increase in the rh.~.mir~
lO activity due to increased internal stresses and surface roughness created by mi.cm~tchPd ll atoms. It is believed that the increased ch~mir~1 activity is responsible for the increased 12 level of solubility of the coatings when in contact with an electrolyte such as body fluid 13 The anti-microbial effect of the coatings was evaluated using the zone of 14 inhibition test as set out in FY~mr1e l. Each coated silicon wafer was placed on an 15 individual plate. The results were COIllp~Gd to the zones of inhibition achieved when solid 16 silver (i.e. greater than 99% silver) sheets, wires or memhr~n~s were tested. The results 17 are snmm~ri7pd in Table l. It is evident that the pure silver devices and the silver 18 sputtered coating at 0.9 Pa (7 mTorr) do not produce any biological effect. However, the 19 coatings depo.~ited at a higher than normal working gas pressure, 4 Pa (30 mTorr), 20 demonstrated an anti-microbial effect, as denoted by the substantial zones of inhibition 21 around the discs. Decreasing the angle of incidence had the greatest effect on anti-22 microbial activity when comhin~d with the bigher gas pLeSS~Ilt;S.
." ~ . ' r- 2 1 3 6 45: 4 Table I
2 ~ni U~ effectsofvarioussilverandsilvercoatedsamplesas ~ using S'. Jl~ro~f 3 aureus Sample Percent Angle of Working Gas Corrected Zone 6 Silver ~Q''pC~Qi~i~)n Pressure of Inbibition 7 Pa (mTorr) (mm) .
9 Silver Sheet~
rolled 99+
11 --:, 12 Silver wire 13 (.0045") 99+ - - <0.5 ::

Silver 16 cast 99+ - - <0.5 18 Sputtered tbin 19 film 99+ nonnal (90~) 0.9 (7) <0.5 ~ ~ :
21 Sputtered tbin 22 f~ 99+ 50~ 0.9 (7) <0.5 24 Sputtered tbin - ;~
2S film 99+ 10~ 0.9 (7) <0.5 27 Sputtered tb~
28 film 99+ normal (90~) 4 (30) 6.3 30 Sputtered tbin 31 film 99+ 50~ 4 (30) 10 '~-33 Sputteredtbin 34 film 99+ lO 4 (30) lO
..

36 FY~m~l~ 3 37 Silicon wafers were coated by magnetron S~ullt'~ using 20.3 cm dia. ~ ~ ~
38 planar silver and copper magnetron cathodes to produce an alloy of Ag and Cu (X0:20) at ~ - -39 norsnal in~ ençe at working gas p,~,~,su,~,s of 0.9 Pa (7 mTorr) and 4 Pa (30 mTorr), all .-~
40 other con~lition~ being identical to those set out in F.Y~mpl~. 2. As in FY~mrle 2, when the 41 coatings were viewed by SEM, the coatings formed at high working gas pressure had , ,.,..;, ~ ~ 3 6~
smaller grain sizes and larger void volumes than did the coatings formed at the lower 2 working gas pl~ssules.
3 Coatings which were similarly formed as a 50:50 Ag/Cu alloy were tested 4 for anti-microbial activity with the zone of inhibition test set out in F.Y~mr1P 1. The ~, S results are snmm~ri7pd in Table 2. Coatings deposited at low working gas pressure (0.9 6 Pa (7 mTorr)) showed minimal zones of inhibition, while the coatings deposited at high 7 working gas pressure (4 Pa (30 mTorr)) produced larger zones of inhibition, indicative of 8 anti-microbial activity.

9 Table 2 :~
Theanti-microbialeffectofvarioussputterdepositedsilver-copperalloysasd~ usmg~, h~ll7rQc 11 aurel~s 13 Sample Percent Angle of Working Gas Co~ected-~
14 Silver r~epoQi~ Pressure Zone of (o) Pa (mTorr) Inhibition 16 (rnm) 18 1 50 normal (90~) 1.0 (7.5) <0.5 20 2 50 normal (90~) 4 (30) 16 21 ~:~
22 3 50 10 4 (30) l9 ; ;~ ~-23 ;~

24 FY~mrl~P. 4 25 A coating in acco~ ce with the present invention was tested to ~ r~ P :~
26 the cnll~e~ Qn of silver ions released into solution over time. One cm2 silicon wafer ~: -27 discs were coated with silver as set forth in F.Y~mrlP 2 at 0.9 Pa (7 mTorr) and 4 Pa (30 : ~ ~ .
28 mTorr3 and normal inridenre~ to a thirknP.ss of 5000 A~. Using the method of Nickel et :

.

2 ~ 3 6~

al., Eur. J. Clin. Microbiol., 4(2), 213-218, 1985, a sterile synthetic urine was prepared and .. ~
2di~pçn~ed into test tubes (3.5 ml). The coated discs were placed into each test tubes and ~ ~ -3 in-~ub~t~d for various times at 37~C. After various periods of time, the discs were removed 4 and the Ag content of the filtered synthetic urine was det~.nnin~d using neutron activation . - , i, S analysis.
6The results are set forth in Table 3. The table shows the comparative 7arnounts of Ag released over time from coatings deposited on discs at 0.9 Pa (7 mTorr) ~ ~-8 or 4 Pa (30 mTorr). The coatings deposited at high pressure were more soluble than those 9 deposited at low pressure. It should be noted that this test is a static test. Thus, silver 10 levels build up over time, which would not be the case in body fluid where there is 11constant turn over. -12Table 3 13C~n~ of silver in synthetic u~ne as a function of exposure ~ne ~ . .
14Silver C ~Ig/ml ,.': , 16 ExposureTime Working Argon Working argon .
17 (Days) gas pressure gas pressure :
18 0.9 Pa (7mTorr) 4 Pa (30mTorr) lg ' ~

22 1 0.89 1.94 24 3 1.89 2.36 26 10 8.14 23.06 ...: :.... ::
28 Note: Films were deposited atnormal incidence (90~
29 1- ND (non detectable) <0.46 llghnl ...

27 :

, ' ~' . ',-':

2 1 3 6~
Example S ~ -2 This example is included to illustrate coatings in accordance with the present 3 invention formed from another noble metal, Pd. The coatings were formed on silicon ' 4 wafers as set forth in Example 2, to a thi~kn~,s.c of 5000 A~, using 0.9 Pa (7 mTorr) or 4 S Pa (30 mTorr) working gas pll;;S~Ul~s and angles of in~id~nce of 90~ and 10~. The coated 6 discs were evaluated for anti-microbial activity by the zone of inhibition test subst~nti~lly 7 as set forth in F,~mrlP 1. The coated discs were placed coating side up such that the agar 8 formed a 1 mm surface coating over the discs. The medium was allowed to solidify and 9 surface dry, after which the bacterial lawn was spread over the surface. The dishes were 10 in~ ub~tt~d at 37~C for 24 h. The amount of growth was then visually analyzed.

11 The results are set forth in Table 4. At high working gas prc,s~llre~, the ~ ' - ', ' ', 12 biological activity of the coating was much greater than that of coatings deposited at low 13 pressure. (~h~n~ing the angle of incidence (decreasing) improved the anti-microbial effect 14 of the coating to a greater extent when the gas pressure was low than when it was high. ,~
. .. ::
Table 4 16 Surface Control of ~' ,~ aureus by Sputter Deposited Palladium metal 17 -,~
18 Sample Sputtering Angle of Anti .' ~ I Control : ~ ~
19 Pressure T~er ~ " , - , 21 Pa (ml~
22 1 0.9 ~7) 9u'~ -' incidence) More than 90% of surface covered by bacterial growth 25 2 0.9 (7) 10~(~razing incidence) 2W0% of surface covered by bacterial growth 26 3 4 (30) 90~(normal incidence) Less than 10% surface covered by bacterial growth :
27 .

2~

Example 6 213 6~t54 ~ ~ ~
2 This example is included to illustrate the effect of silver deposition 3 l~lllpt;laLule on the anti-microbial activity of the coating. Silver metal was deposited on , ," ....
4 2.5 cm sections of a latex Foley catheter using a magnetron sputtering facility. Operating 5 con-~ition.~ were as follows; the deposition rate was 200 A~ per minute; the power was 0.1 6 kW; the target was a 20.3 cm diameter planar silver magnetron cathode; the argon working 7 gas pressure was 4 Pa (30mTorr); the total mass gas flow was 700 sccm; and the ratio of 8 lemp~laLul~ of substrate to melting point of the coating metal silver, T/Tm was 0.30 or 9 0.38. In this example the angles of incidence were variable since the substrate was round 10 and rough. That is the angles of incidence varied around the circumference and, on a finer 11 scale, across the sides and tops of the numerous surface features. The an~-microbial effect 12 was tested by a zone of inhibition test as outlined in F.Y~mrl~ 1.
13 The results showed corrected zones of inhibition of 0.5 and 16 mm around 14 the tubing coated at T/Tm values of 0.38 and 0.30 respectively. The sections of Foley 15 catheter coated at the lower T/Tm value were more effi~aciOIls than those coated at higher 16 T/Tm value. .

17 FY~mrlP 7 18 This example is included to ~emon~trate an anti-microbial coating formed 19 by DC magnetron sputtering on a commercial catheter. A teflon coated latex Foley :

20 catheter was coated by DC magnetron sputtering 99.99% pure silver on the surface using . .,, .- .

21 the con~lition~ listed in Table 5. The working gases used were commercial Ar and 99/1 22 wt% Ar/O2.
"' '- . .~',.',','~' 29 ~ ' ~

2 1 3 6 ~
The anti-microbial effect of the coating was tested by a zone of inhihitic~n test.
2 Mueller Hinton agar was ~li.cpenc~d into Petri dishes. The agar plates were allowed to 3 surface dry prior to being inoculated with a lawn of Staphylococcus aureus ATCC# 25923.
4 The inoculant was prepared from Bactrol Discs (Difco, M.) which were leco~ lr.d as 5 per the m~nllf~tllrer's directions. TmmP.~i~tPly after inoc~ tion~ the coated m~teri~lc to 6 be tested were placed on the surface of the agar. The dishes were incubated for 24 hr. at 7 37~C. After this incubation period, the zone of inhihition was measured and a corrected 8 zone of inhibition was c~lrul~tpd (corrected zone of inhibition = zone of inhi~jtil~n 9 diameter of the test material in contact with the agar).
10The results showed no zone of inhibition for the nnroqtPd sarnples and a corrected ~ ~ -11 zone of less than 1 mm for catheters sputtered in commercial argon at a working gas 12pressure of 0.7 Pa (5 mT). A corrected zone of inhibition of 11 mm was reported for the 13catheters sputtered in the 99/1 wt% Ar/O2 using a working gas pressure of 5.3 Pa (40 mT).
14 XRD analysis showed that the coating sputtered in 1% oxygen was a crystalline Ag film.
15 This structure clearly caused an i~ ovt;d anti-microbial effect for the coated c ~ t' 16Table s 17 Con~ of DCr~ag-: SputteringUsedfor~ Miclub;~lCoatings 19 Samples Sputtered in C C;,il Argon Samples Sputtered in 99/1 wt% Ar/O2 21 Power 0.1 kW Power O.s kW
22 Target20.3 cm dia. Ag Target 20.3 cm dia. Ag 23 Argon Pressure: û.7 Pa (s m Torr) Ar/02 Pressure: s.3 Pa (40 m Torr) ~ -24 Total Mass Flow: 700 sccm Total Mass Flow: 7ûOsccm 2S Initial Substrate T: ~ 20~C Initial SubstrateT; , 20OC
26 Cathode/AnodeDistance: 40mm Cathode/AnodeDistance: lOOmm ' 27 Film Thickness: 2s00 A Film Thickness: 3000 A

~ '''' -~1364~:4 F.Y~mrl~ 8 2 This example demonstrates silver coatings formed by arc evdpol~,tion, gas sc~ttpring 3 tvapolâ~on (pressure plating) and reactive arc evaporation. Evaporation of 99.99% silver 4 was performed onto silicon or alumina wafers at an initial substrate tell~pelalure of about 5 21~C, using the parameters as follows~
6 Bias: -100 V :
7 Current: 20 Amp-hrs 8 Angle of inc~ pnce: 90~
9 Working Gas Pressure: 0.001 Pa (0.01 mT) (arc), 3.5 Pa (26 mT) Ar/H2 96:4 (gas sc~ttering ~vapo-a~on), and 3.5 Pa (26 mT) ~2 (reactive arc eval)olalion) 11 No corrected ZOI was observed for wafers coated at vacuum (arc). Pressure plating 12 with a working gas atmosphere cont~inin~ Ar and 4 % hydrogen produced a 6 mm ZOI, 13 while a working gas ~tmosphPre of pure oxygen (reactive arc) produced an 8 mm ZOI.
14 Film thirlrnpsses of about 4000 Angstroms were produced. The results indicate that the presence of gases such as hydrogen and/or oxygen in the arc e~apvla~on ~tmosphp~re cause ~ ~.
16 the coatings to have improved anti-microbial efficacy.

,, . ~: . ' .
7 FY~mrlp 9 ; ' ~' 18 This example is included to i~ str~ composite m~t~ri~ to produce anti~
19 microbial effects. A set of coatings were produced by RF magnetron sputtering zinc oxide - ;~ii"
20 onto silicon wa~ers as outlined below. The zinc oxide coatings showed no zone of 21 inhihition 22 Coatings of Ag and ZnO were deposited to a total ~ A~ of 3300 ~' 23 Angstroms by sequ~nti~lly sputtering layers of Ag with layers of ZnO, according to the 31 ~:

~,, .,.-'- ~136~t54 conditions below, in a 75/25 wt% ratio. The coatings were demonstrated to have no zone 2 of inhibition when the zinc oxide layers were about 100 Angstroms thick. However, films 3 consieting of islands of very thin to discontinuous layers of ZnO (less than 50 Angstroms) 4 in an Ag matrix (ie. a composite film) had a 8 mm corrected zone of inhibition.
The con~lition~ used to deposit ZnO were as follows~
6 Target 20.3 cm dia. Zno; Working gas = argon; Working gas pressure = 4 Pa (30 mT);
7 Cathode-Anode distance: 40 mm; Initial Substrate Telllpelalult;; 21~C; Power: RF
8 magnetron, 0.5 kW.
9 The con~iti~n.~ used to deposit the Ag were as follows:
Traget 20.3 cm dia. Ag; Working gas = argon; Working gas pressure = 4 Pa (30 mT);
11 Cathode-Anode distance = 40 mm; Initial Substrate Telnpelalule = 21~C; Power = DC
12 magnetron, 0.1 kW.

13 Example 10 14 This example ~pmonetr~t~ps the effects of cold working and ~nnp~ g silver and gold powders on the anti-microbial efficacy ~lemonetratpd by a standard zone of 16 inhibition test. Cold working of such powders results in a deÇe~;Liv~; surface structure ~-17 co"l~;";.~ atomic disorder which favours the release of ions causing anti-microbial 18 activity. The anti-microbial effect of this defective structure can be removed by ~nnP~ling 19 Nanocrystalline silver powder (crystal size about 30 nm) was sprinklPd onto adhesive tape and tested. A zone of inhibition of 5 mm was obtained, using the method 21 set forth in PY~mrlP 7. A 0.3g pellet of the nanocl~ lline Ag powder was pressed at 22 275,700 kPa (40,000 psi). The pellet produced a 9 mm zone of inhihition when tested for 23 anti-microbial activity. Nanocyrstalline silver powder was mPch~nis~lly worked in a ball 32 ~; ''' : ~' ",~'.' ',' - 2~ ~6~
.~ :
mill for 30 sec. The resulting powder was tested for anti-microbial activity, both by 2 sprinkling the worked powder on adhesive tape and applying to the plates, and by pressing 3 the powder into a pellet at the above con~ition~ and placing the pellet on the plates. The 4 zones of inhibition observed were 7 and 11 mm lesl)e~;Lively. A pellet that had been S pressed from the worked powder was ~nn~1pd at 500~C for 1 hour under vacuum 6 conditions. A reduced zone of inhibition of 3 mm was observed for the ~nn~lPd pellet.
7These results demonstrate that nanocrystalline silver powder, while having 8 a small anti-microbial effect on its own, has an improved anti-microbial effect by 9 introducing atomic disorder by m~Gh~ni~l working of the powder in a ball mill or by 10 pressing it into a pellet. The anti-rnicrobial effect was ~ignific~ntly decreased by ~nne~lin~
11 at 500~C. Thus, conditions of mechanical working should not include or be followed by 12 con~ition.~ such as high Le,-lpe-~Lu-t;, which allow diffusion. Cold m~ch~nir~l working 13 con~itinn.c are preferred to limit diffil~ion, for example by working at room Ir~p~ e 14 or by grinding or milling in liquid nitrogen.
.': '. . '".~ :'. "'' 15Silver powder, 1 micron particle size, was tested in a manner similar to 16 above. The Ag powder sprinkl~d onto adhesive tape and tested for a zone of inhihitinn 17 No zone of inhibition was observed. The powder was worked in a ball mill for 30 seconds 18 and sprinkled onto adhesive tape. A 6 mm zone of inhibition was observed around the 19 powder on the tape. When the Ag powder (as is or after ~ chAl~ l working in the ball 20mill) was pressed into a 0.3 g pellet using 275,700 kPa (40,000 psi), zones of inhibition 21 of 5 and 6 mm l~,s~eiliv~ly were observed. A pellet which was formed from the ball 22 milled powder and which was ~nn~?l~d at 500~C for 1 hour had sigl~;r;~ ~ily reduced anti~
23 microbial activity. Initially the pellet had some activity (4.5 mm zone of inhihition) but 24 after the pellet was tested a second time, no zone of inhibition was observed. A control : . ~

~ , 21 3 6~5 ~

pellet which had not been ~nn~led continued to give a zone of inhibition greater than 4 2 mm even after 14 repeats of the test. This demonstrates that an ~nnP~1ing step, following 3 by mechanical working, limits the sustainable release of the anti-microbial silver species 4 from the powders.
Nanocrystalline gold (20 nm crystals), supplied as a powder, was tested for 6 anti-microbial effect by spnnk1ing the powder onto adhesive tape and using the zone of 7 inhibition test. No zone of inhibition was recorded for the nanocrystalline gold powder.
8 The gold powder was pressed into a 0.2 g pellet using 275,700 kPa (40,000 psi). A l0 9 mm zone of inhibition was observed. When the pressed pellets were s~1hsc~lue~,l1y vacuum annealed at 500~C for l hour and the zone of inhihiti~n was found to be 0 mm.
11 The results showed that solubility and thus the anti-microbial efficacy of 12 gold powders can be improved by a mechanical working process such as pressing a 13 nanocrystalline material into a pellet. The anti-microbial activity can be removed by 14 ~nnP~1ing Cold working is preferred.
Other gold powders in~1n-1ing a 2-5 micron and a 250 micron particle size 16 powder did not demon~trate an anti-microbial effect under the above mPc~ni~1 working 17 conditions. It is believed that the sma~ grain size of the n~loc.~ line gold powder was 18 an illll,o~ cofactor which, with the mpch~nis~l working, produced the desired anti-19 microbial effect.

FY~mr1P ll 21 This example is included to dPmonitrate a collli)o;~ile anti-microbial coating 22 formed by reactive sputtering (another example of composite films). FY~mr1~. 7 23 ~lP~mo~ s that an anti-microbial coating of silver can be obtained by spll1tPring in argon . ... . , . ~ ~ , . :

,, ., - , . .
.. ~.. . . , .. . . . .: ~ : . :

~136~4 ~ ~
and 1% oxygen (0.5 kW, 5.3 Pa (40 mTorr), 100 mm anode/cathode distance, and 20~C
2 produced a zone of inhibition of 11 mm).
3 When a working gas of argon and 20 wt% oxygen was used to sputter anti-4 microbial coatings under the con~itic)n~ listed in Table 6, the zones of inhihitinn ranged 5 from 6 to 12 mm. This in~ tps that the provision of a reactive atmosphere during vapour -. . :. ., ~
6 deposition has the result of producing an anti-microbial film over a wide range of 7 deposition process p~

8 Table 6 - Sputtering Con~iition~
9 Target 20.3 cm dia., 99.99% Ag Working Gas: 80/20 wt% Ar/O2 A ,' ~,.lI Working Gas ~lcs~ 0.3 to 6.7 Pa (2.5 to 50 mTorr) -~
12 Totial Mass Gas Flow: 700 sccm -~
13 Power: 0.1 to 2.5 kW ;
14 Substrate Ts;.llpela~u.e: -5 to 20~C
Anode/Cathode Distance 40 to 100 mm 16 Base ~Si~ul~; less than S x 104 Pa (4 x 10-6 Torr) .... .......... ..
...., ' . ,,; "',~', 17 F.Y~nrhP. 12 18 This example demon~trates that the coatings of this u~ ion have an anti- ' 19 microbial effect against a broad ~ecllulll of bacteria.
A total of 171 different bacterial samples e~o~E 18 genera and 55 -~
21 species were provide by the Provincial T ~bOIalol~ of Public Health for Northern Alberta.
22These samples had been quick frozen iD 20% skim milk and stored at -70~C for periods ' 23 ranging from several months to several years. Fastidious organisms which were unlikely 24 to grow under condition~ used in standard Kirby-Bauer susceptibility testing were not used.

~ ~

,~ .

2 1 3 6~5~
Each frozen sarnple was scraped with a sterile cotton swab to inoculate a 2 blood agar plate (BAP). The plates were incubated overnight at 35~C. The following 3 morning isolated colonies were subcultured onto fresh BAPs and incubated at 35~C
4 overnight. The next day, the organisms were subjected to Kirby-Bauer susceptibility testing as described below.
6 Four to five colonies (more if colonies were small) of the same : ~ , 7 morphological type were selected from each BAP subculture and inocul~tPd into individual 8 tubes cont~ining approAil-lately 5 mL of tryptic soy broth (TSB). The broths were ~ ~ ,~
9 incubated at 35~C for applo~ lately 2 to 3 hours. At this time, the turbidity of most of the broth cultures either equalled or eY~ee(led that of a 0.5 McFarland standard. The more 11 turbid samples were diluted with sterile saline to obtain a turbidity visually comparable to 12 that of the standard. To a d i t e visua ~se~.~mPnt of turbidity, tubes were read against 13 a white background with contrasting black line.
14 A small number of the olgdni~llls (Streptococcus and Corynebacterium) did 15 not grow well in TSB. The turbidity of these broths, after in~nhation~ was less than that ., . : : .
16 of the 0.5 McFarland standard. ~ tion~l colonies from the BAP subc~llt~res were 17 inocu1~ted to these tubes to increase the turbidity to apl)-oAi--late that of the standard.
18 Within 15 minutes of adjusting the turbidity of the bacterial suspenQ;onQ a 19 sterile cotton swab was dipped into each broth. Excess fluid was removed by rotating the 20 swab against the rim of the tube. The inoculum was applied to a Mueller Hinton (MH) 21 agar plate by streaking the swab evenly in three directions over the entire agar surface.
22 Three 1 cm x 1 cm silver coated silica wafer squares were applied to each MH plate and ~ -23 the plates were inverted and inl~uh~t~d overnight at 35~C. The coatings had been sputtered .~ , :.. ~ ..

" ; ~ '' .. .~ .. . . . .

- 2~36~5~ ~
under the following conditions, which through XRD analysis were shown to be silver/silver 2 oxide composite films~

3 Target: 20.3 cm dia, 99.99% Ag 4 Wor~ing gas: 80/20 wt % Ar/O2 Working gas pressure: 5.3 Pa (40 mT) 6 Total Mass Gas Flow: 700 sccm . ~ f 7 Power: 0.1 kW
8 Telllpelalule of Deposition 20~C
9 Base pressure 2.7 X 104 Pa (2 x 10 6 Torr) Cathode/anode distance 40 mm 11BAP cultures of control organisms were provided by the Provincial 12Laboratory and inc1~lded Staphylococcus aureus ATCC 25923; Pseudomonas aeruginosa ; ::~
13ATCC 27853; Escherichia coli: ATCC 25922; and Enterococcusfaecalis ATCC 29212 to - ~ -14 check the quality of the MH agar. These cultures were treated in a like manner to the test lS ~l~dllii IIIS except that standard antibiotic discs rather than silver coated wa ers were 16 applied to the bacterial lawns on the MH agar. These organisms demon~trated that the MH
17 agar was suitable for standard ZOI tests.
18After 16 to 18 hours of in~uh~tion at 35~C zones of inhibition around the ~:: . : ., , ": ~ .
19 silver wafers or antibiotic discs were measured to the nearest mm. Corrected zones were 20 ci~lcul~ted by subtracting the size of the wafer (1 cm) from the size of the total zone.
21Rel)reselll~ive zone of inhihition results are shown in Table 7. ~ ,,s~

, ~., ~, ' ':

" . ~............ . .

2 1 3 ~

Table 7 2 The Sensitivity of a Broad Range of Mi~-uol~ .. s to Silver* Coated Silicon Wafers ~ :
Organism Source Corrected Zone of ~ , ~
Inhibidon (mm) ' ~:
S . .~ ~. - epidermidis RC-455 blood 10 Bacillus ~ - ~ . R-2138 tibia 6 _ . CI.J sp R-594 leg 10 Usteria ~ ~o R-590 blood 5 ;
r v~o.~.. faecalis SR-113 bone 5 Sl . . bovis SR-62 blood 10 .' I Escherichia coli R-1878 urine 11 -Klebsiella ozonae R-308/90 abdomen 10 3.- r . ' cloacae R-1682 unknown 8 _~ Pro~eus vulgaris 3781 urine 4 Providencia stuar~ii U-3179 urine 8 . ~ Citrobacterfreundii U-3122190 urine 7 3 . Salmondla typhimirium ER-1154 urine 6 ;
. Serraria marcescens R-850 sputum 6 aeruginosa U-3027 urine 10 Y~ mal~ophila 90-lOB unknown 9 .
Aeromonas caviae R-1211 wound 5 ~ .
~; . L - cv-tarrhalis R-2681 unknown 12 ~J Silver teposition~ ~ :
44 FY~mrl~-. 13 This example dPmon~trates the use of tantalum as an adhesive layer for 46 coatings of this invention. Tantalum is well known as a material which, in the form of an 47 interlayer, hllplv~s a~ih~ion of thin films to substrates. In this example test sections 48 inl~lu~ing a group of stainless steel (316) (1 x 1 cm) and silicon (1.7 X 0.9 cm) coupons 49 and sections of latex tubing (S cm) were cleaned in ethanol and then half of the test sections were coated (by sputtering) with a thin layer (approx. 100 Angstroms) of Ta ;

38 ~

3 ~4 before an anti-microbial silver film was deposited on them. The second group of the test ~.
2 sections were only coated with the anti-microbial Ag film. Coating c-n(~ition.c are listed ~ ;
3 below. While all test sections had similar anti-microbial activity, the Ta coated test 4 sections had much better adhesion properties than did the untreated test sections. Adhesion S properties were detPrminPd using ASTM method D3359-87, a standard test method for ~' ' ~ . . '. !
6 mP~ rine ~tlhPsion 7 Sp ing C~
.. ~... ~
8 Target: 20.3 cm dia., 99.99% Ta 9 Working Gas: 99/1 wt% Ar/O2 Working Gas Pressure: 1.3 Pa (10 mTorr) 11 Total Mass Gas Flow: 700 sccm ~' 12 Power: 0.5 kW ~ Y
13 Cathode/Anode Distance: 100 mm 14 Substrate T~ e1G~UI~e 20~C
Target: 20.3 cm dia., 99.99% Ag 16 Working Gas: 99/1 wt% Ar/O2 17 Working Gas Pltis~ e: 5.3 Pa (40 mTorr) 18 Total Mass Gas Flow: 700 sccm 19 Power: 0.5 kW ~,' ~ ~' "'.'''!';1':
Cathode/Anode Distance: 100 mm . ~ .
21 Substrate Te-,-r,. . ~lll,~G 20~C
: :. ,~- ~ . .:

22 FY~mple 14 ~ -23 DC magnetron sputtering was used to deposit silver from a 20.3 cm dia., ~ - ~
24 99.98% pure cathode onto silicon and alumina wafers with colll-"elcial argon moi~ " ;, . d with water as the working gas at a total mass gas flow of 700 sccm. The argon was 26 moi~tllri7Pd by passing it through two flasks co~ g 3 litres of room I~IIIP~ G water 27 and one empty flask set up with glass wool to absorb any free liquid before the gas entered 28 the spll~tPllng unit.

' .:.'~ .: .

2 ~ 3 6~

The conditions of sputtering and the results of the standard zone of -, .. ~ .-2 inhihition test performed on the sputtered silver films are shown below. Silver films which 3 normally had no anti-microbial properties when deposited using argon that had not been 4 treated with water yielded a corrected zone of inhihition of up to 8 mm when sputtered - , .,; - - ~
5 using a argon/water vapour mixture as the working gas.
.' .~, , . 2, :1 6 Table 8 7 C ' - used for DC ~1zb_hu~. Sputteri~g of Anti ~ ul~;dl Caotings Working Gas Working Gas Power Suhtrate 1' ' '~ - ' Corrected .. Pressure Temperature Dist~nce ZOI ~ ?
~ Pa (rnl~

14 Conunercial Argon 1.3 (10) O.5kW -10~C 100 rnrn 0 rnrn lS Ar passed through 7 H~O 1.3 (10) 0.5kW -IO'C lOO rmn 8 rlun 18 FY~mple 15 ; ' 19 This example is included to i~ tr~te the method of activating coatings with 20 ~(1i~tion, in accold~ulce with another aspect of the present invention.
21 A series of 1.9 x 0.7 cm silicon wafers were coated with 3000 A coatings 22 of silver metal using DC magnetron sputtering under the following con~lition~
23 Sputtering Con-lition.~
24 Target 20.3 cm dia., 99.99% Ag 2S Working Gas 99fl wt% Ar/O2 26 Working Gas pressure 5.3 Pa (40 mTorr) 27 Total Mass Gas Flow 700 sccm 28 Power 0.5 kW
29 Substrate T~.. ,.p,~.,.lll.~e 21~C
Anode/Cathode Distance 100 mm ;
31 The coated wafers were divided into 4 groups and irr~ ted with varying doses of gamma ~ D~'''.
32 r~ tion - 0, 1, 2 and 4 megarad doses - from a 60Co source at Isomedix Inc., Morton . . .

~ 1 3 ~
Grove, Il., U.S.A. The samples were placed generally perpendicular to the incoming 2 radiation. After irradiation, the sarnples were tested for biological activity (anti-microbial ~ ~
3 effect) using a standard zone of inhibition test on Mueller Hinton Agar (Difco, Mi) with - - -4 S. aureus (ATCC #25923), as set out in previous eY~mplPs The results are sllmm~ri~Pd .
S in Table 9.
6 Table 9 7 Effects of Gamma Radiation on Biological Activiy of Anti-Microbial Coatings ;
8 Gamma ~ tion Dose (megarads) Corrected Zone of Tnhihitinn (mm) g O 1 1 13 The results generally show a log dose response re1~tion~hir between the 14 radiation dose and the observed biological response to the wafers. This illllct~t~s that the gamma radiation has further activated the coatings of the present invention to enhance the ;
16 anti-microbial effect. ;
17 The ~Yreriment was repeated with the anti-microbial films being oriented 18 generally parallel to the in~ominp radiation. This oripnt~tion substantially reduced the 19 level of activation of the anti-microbial coatings, such that no increase in the zone of 20 inhibition was observed relative to controls which had not been irra~i It,~

21 FY~nnrle 16 ~ ~
22 This example is included to illustrate activation of the anti-microbial 'h 23 coatings in accoLddnce with the present invention with gamma ra~i~tion using a ~iPlPctr 24 material adjacent to the material during irr~ tio~

''' ~

2 1 3 645 ~ - ~

A number of 2.5 cm x 2.5 cm pieces of high density polyethylene mesh 2 (such as used in burn wound dressings) were sputter coated with silver metal under the 3 same conditions as set forth in Example 15 with the exception that the power was 0.1 kW
4 The coated mesh was then irr~ Ated (pcrp~n~ ulAAr ori~nt~tion) as set forth in FyAmrle 15 at 4 mçgAAr~s The biological activity was then tested, as set out in Example 15.
6 Control mesh samples (silver coated, no irradiation) gave a 10mm ZOI(corrected), while 7 the irr~liAt~.d samples gave a 14 mm ZOI(corrected).
8 Further samples of the coated mesh were irradiated while s~dwi,lled 9 between two 2.5 cm x 2.5 cm silicon wafers having a 1000 A thermally grown oxide layer, as supplied by the Alberta Mi~;-uelc~llvnics Centre, F~nnonton, Alberta. This mesh sample 11 was tested for biological activity and was found to produce a 26 mm ZOI(corrected~
12 Without being bound by the same, it is believed that the silicon wafers provide a source 13 of electrons which are forward scattered to the anti-microbial coatings, further ~ hA .
14 the anti-microbial effect.
Bulk silver sheet metal was tested to dete~ -e whether it could be activated 16 to produce an anti-microbial effect by gamma irradiation. The buLk silver sheet metal 17 samples were AnnPAAl~d at 140~C for 90 minutes in air and then irradiated with a 4 megarad 18 dose. The samples were tested for biological activity, but no ZOI was produced. This 19 result appears to indicate that buLIc silver, in its normal ordered crystalline state, has too few atomic defects to be activated in accoldance with the process of the present invention.

21364~q Example 17 2 This example is included to illustrate that anti-microbial coatings cf,~ ;t,;llg 3 atomic disorder at a level that is in~nffiriP.nt to produce an anti-microbial effect can be 4 further activated by gamma irradiation, in accold~lce with the present invention.
Silver films were sputtered onto silicon wafers, as set forth in Example 15, 6 except that the gas pressure was reduced from 5.3 Pa (40 mTorr) to 0.7 Pa (5 mTorr), 7 resulting in less atomic disorder in the coatings. The silver films were then irradiated with 8 a 4 Mrad dose of garnma radiation, as in F.Y~mrkP. 15. The irr. ~i~tPd and control films 9 (not irradiated) were tested for biological activity. The control films produced only 1 mm ZOI(corrected), while the irradiated coatings produced 10 mm ZOI(corrected). This result pmQn~trates that anti-microbial m~qtt-ri~lA prepared under c-~n~itionc such that they contain 12 atomic disorder at a level in.cllffirie.nt to produce an anti-microbial effect can be activated 13 so as to be anti-microbial by irradiating with a source of gamma radiation.
14 All publications mPntionP.d in this speçifir~tion are indicative of the level of skill of those skilled in the art to which this invention pertains. All publi~tioni are 16 herein incolyu.a~d by i~re e.-ce to t~he same extent as if each individual publiration was 17 specific~lly and individually in~ir~ted to be incolyulated by ~~Çelellce.
18 The terms and expressions in this specifirati~ n are used as terms of 19 description and not of limit~tion There is no intpntion~ in using such terms and expressions, of e~rClll(linp equivalents of the features illustrated and descrihed. it being 21 recognized that the scope of the invention is defined and limited only by the claims which 22 follow.

Claims (16)

1. A method of forming an anti-microbial material containing one or more anti-microbial metals, said method comprising:
creating atomic disorder in a material containing one or more anti-microbial metals under conditions which limit diffusion for retaining atomic disorder therein to provide sustained release of atoms, ions, molecules or clusters of at least one of the metals into an alcohol or water based electrolyte at an enhanced rate relative to the material in its normal ordered crystalline state; and irradiating the material with a low linear energy transfer form of radiation to release at least one anti-microbial metal at a concentration sufficient to provide a localized anti-microbial effect.

2. The method as set forth in claim 1, wherein the anti-microbial metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn, alloys thereof and compounds thereof.

3. The method as set forth in claim 2, wherein the material is a powder or foil of one or more of the anti-microbial metals, and wherein the atomic disorder is formed by cold working of the powder or foil.

4. The method as set forth in claim 3, wherein the material is a nanocrystalline powder.

5. The method as set forth in claim 2, 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.

6. The method as set forth in claim 5, wherein the material is formed by vacuum evaporation, sputtering, magnetron sputtering or ion plating.

7. The method as set forth in claim 6, wherein the anti-microbial material is a composite coating formed by co-, sequentially or reactively depositing an anti-microbial metal in a matrix with atoms or molecules of a different material to create atomic disorder in the matrix, said different material being deposited as one or more members selected from the group consisting of oxygen, nitrogen, hydrogen, boron, sulphur or halogen absorbed or trapped in the matrix from the atmosphere of the vapour deposition; an oxide, nitride, carbide, boride, halide, sulphide or hydride of an anti-microbial metal; and an oxide, nitride, carbide, boride, halide, sulphide or hydride of an inert biocompatible metal selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al.

8. The method as set forth in claim 7, wherein the anti-microbial metal is silver and said different material is one or both of silver oxide and atoms or molecules containing oxygen trapped or absorbed in the matrix from the atmosphere of the vapour deposition.

9. The method as set forth in claim 5, wherein the coating is formed by magnetron sputtering at conditions such that the ratio of the temperature of the surface being coated to the melting point of the anti-microbial material being deposited is less than about 0.5, and the working gas pressure is greater than about 1.3 Pa (10mT).

10. The method as set forth in claim 7, wherein the coating is formed by magnetron sputtering at conditions such that the ratio of the temperature of the surface being coated to the melting point of the anti-microbial material being deposited is less than about 0.5, and the working gas pressure is greater than about 1.3 Pa (10mT).

11. The method as set forth in claim 8, wherein the coating is formed by magnetron sputtering at conditions such that the ratio of the temperature of the surface being coated to the melting point of the anti-microbial material being deposited is less than about 0.5, and the working gas pressure is greater than about 1.3 Pa (10mT).

12. The method as set forth in claim 1, 3 or 6, wherein the form of radiation is selected from gamma, beta and x-rays.

13. The method as set forth in claim 1, 3 or 6, wherein the source of radiation is gamma radiation, used at a dose of greater than about 1 Mrad.

14. The method as set forth in claim 1, 3 or 6, wherein the anti-microbial material being irradiated is oriented substantially perpendicular to the incoming radiation.

15. The method as set forth in claim 1, 3 or 6, wherein the material is placed adjacent to a dielectric material during irradiation.

16. The method as set forth in claim l, 3 or 6, wherein the material is sandwiched between silicon oxide surfaces during irradiation.