CA2136456C - Novel anti-microbial materials - Google Patents

Abstract

Anti-microbial coatings 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. Novel anti-microbial silver materials are defined, characterized by having a positive rest potential, a T rec/Tm less than 0.33, and a grain size less than 200 nm. Anti-microbial fine grain or nanocrystalline materials are provided, together with methods of preparation, wherein the anti-microbial metal if deposited in a matrix with atoms or molecules of a different material such as other biocompatible metals (ex. Ta), trapped or absorbed oxygen, or compounds of anti-microbial metals or biocompatible metals (ex. Ag0 or TaO).

Description

:' . ~- .
FIELD OF THE INVENTION
2The invention relates to methods of forrning anti-microbial metal coatings, 3 foils and powders which provide a s ~st~impd release of anti-microbial metal species when ~., ~. - . -:
4 in contact with an alcohol or electrolyte.
~ . - , SBACKGROUND OF THE INVENTION
6The need for an effective anti-microbial coating is well established in the ..~ ~. . .
7medical community. Physicians and surgeons using medical devices and appliances ~ ~
. ;,.: ~ .. ;.
8ranging from orthopaedic pins, plates and impl~nt.Q. through to wound dressings and urinary . .
9catheters must cons~all~y guard against infection. An i~YI~el~Qive anti-microbial coating '.
10 also finds application in medical devices used in consuiller hP~lthc~re and personal hygiene . ., . ~ . ,.~
11 products as well as in biompdi~ bio~echni~l laboratory equipm~nt The term llmedical 12device", as used herein and in the claims is meant to extend to all such products. ~ ' 13The anti-microbial effects of metallic ions such as Ag, Au, Pt, Pd, Ir (i.e.
14 the noble metals), Cu, Sn, Sb, Bi and Zn are known (see Morton, H.E., Pse~l~omon~Q in 15Disinfection, Sterili7~tion and Preservation, ed. S.S. Block, Lea and Febiger, 1977 and 16 Grier, N., Silver and Its Compounds in Disinfection, StPrili7~tion and ~c~Sel ~ion, ed. S.S.
17 Block, Lea and Febiger, 1977). Of the metallic ions with anti-microbial properties, silver 18 is perhaps the best known due to its unusually good bioactivity at low concentrations. This ,.~. :~ .'~..
19 phPnomPn~ is termed oligodynamic action. In modern medical practice both inorganic and 20 organic soluble salts of silver are used to prevent and treat microbial infections. While - ~ ~ '. .. :
21 these colllpoullds are effective as soluble salts, they do not provide prolonged protection 22 due to loss through removal or comI~lPY~tion of the free silver ions. They must be '~ ~ '' ' ', '~, "~

213 6~5 ~ ~
.~,, reapplied at frequent intervals to overcome this problem. Reapplication is not always 2 practical, especially where an in-dwelling or imrl~ntpd medical device is involved.

3 Attempts have been make to slow the release of silver ions during treatment 4 by creating silver co~ i"E complexes which have a lower level of solubility. For S ex~m~le, 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 7~(lhç~ion, abrasion re.ci~t~nce and shelf life problems.
10 ~ 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 ~r~en et al., Anti-microbial Agents and Chemotherapy, 13 Vol. 31(1), 1987, pp. 93 - 99. However, it is generally accepted that such coatings alone 14 do not provide the required level of efficacy, since diffusion of silver ions from the 15 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 solntion~ as lletnon~trated by zone of inhibition tests, thus enforcing the belief that silver metal surfaces do not release anti-microbial amounts of silver ions.
, ~ ~
21 Given the failure of metallic silver coatings to generate the required anti-22 microbial efficacy, other researchers have tried novel activation processes. One technique 23 is to use electrical activation of metallic silver impl~nt.~ (see Marino et al., 30urnal of 24 Biolosical Physics, Vol. 12, 1984, pp. 93 - 98). 131ectncal shmulahon of metsllic silver ~ ' . ~ ;'', .

is not always practical, especially for mobile patients. Attempts to overcome this problem 2 include developing in situ electr~cal currents through galvanic action. Metal bands or 3 layers of different metals are deposited on a device as thin film co~ting~. A galvanic cell 4 is created when two metals in contact with each other are placed in an electrically S condn~ting fluid. One metal layer acts as an anode, which dissolves into the electrolyte.
6 The second metal acts as a cathode to drive the electrochemical cell. For e~r~mrlP, in the 7 case of ~ltPrn~ting 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 eY~mpl~ry device of this nature is 10described in U.S: Patent 4,886,505 issued Dec. 12, 1989, to Haynes et al. The patent closes 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 l~min~t~s of 14 ~ltl~rn~ting, different metals such as silver and copper can be made to dissolve if the 15 surface is first etched. In this inAt~nce, the etching process creates a highly textured 16surface tsee M. Tanemura and F. Okuyama, J. Vac. Sci. Technol., 5, 1986, pp 2369-2372 17 However, the process of making such mnltil~min~ted films is time con.~uming 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 electrical conn~ction between the two metals of the galvanic couple 22 exists. Since galvanic corrosion occurs primarily at the metallic intP~ e between the two 23 metals, electrical contact is not snst~in~l Thus a continuous release of metal ions over 24 an extentied period of time is not probable. Also, galvanic action to release a metal such ~ .. ~ - . . . --. -.

~13~45~
as silver is difficult to achieve. As indicated above, the metal ions exhibiting the greatest ~ ~ ;
,:: - . . , 2 anti-microbial effect are the noble rnetals, such as Ag, Au, Pt and Pd. There are few ~ .
. . . ,:::;~ ;.
3 metals more noble than these to serve as cathode rn~teri~l~ 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 chPmi~lc. U.S. Patents 4,476,590 and 4,615,705, issued to Scales et al. on October 16, -; ~ , : .:
7 1984 and October 7, 1986, respectively, disclose methods of activating silver surface '~
.. .:. ~. .:
8 coatings on endoprosthetic impl~nt~ to render them bioerodible by heating at greater than 9 180~C or by cont~rtin~ with hydrogen peroxide. Such tre~tmPnts are limited in terms of , ~ .....
10 the ~ubslldle/devices which can be coated and activated.
11 There is still a need for an efficacious, inPyrencive anti-microbial material '':
12 having the following properties~
, , 13 - su.~tz~inPd release of an anti-microbial agent at thel,-l eulir~lly active levels;
14 - applicable to a wide variety of devices and m~teri~
:, . . ,::
- 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, semicontillrtQr.~ and ceramics 19 are widely used in the production of electronic compollel.~. These and other end uses require the thin films to be produced as dense, crystalline ~luclules with minimal defects. ~ -21 The films are often ~nnr~lrd after deposition to enhance grain growth and recryst~11i7~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 ~lh1ir~tion~
24 N.J., 1982 and by J.A. Thornton, "Tnllnenre of Apparatus Geometry and Deposition S '.
'~ .~''".,.

2136~
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 5 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 annealed by heating the substrate up to about room l~;mp~ldlule. The end product is stated 8 to have large grain diameter and great homogeneity, pe~"~ g higher current ~n.~iti~s 9 withoutelectromigration failures.
Nanocrystalline m~t~ri~l~ in the forms of powders, films and flakes are 11 m~te.ri~lc which are single-phase or multi-phase polycrystals, the grain size of which is in 12 the order of a few (typically ~20) n~nometer.c in at least one dimension. Fine grain 13 powders (particle size <5 mircons) may be nanocrystalline, or more typically have grain 14 sizes ~20 nm. Nanocrystalline m~tpr~ and fine powders may be prep~ed by a number 15 of modified gas conden.s~tion methods, wherein the material to be is deposited is generated 16 in the vapour phase, for example by evaporation or sputtering, and is transported into a 17 relatively large volume in which the working gas atmosphere and temperature is controlled.
18 Atoms of the material to be deposited collide with atoms of the working gas atmosphere, 19 lose energy and are rapidly condensed from the vapour phase onto a cold snbstr~t~, such 20 as a liquid nitrogen cooled finger. In prinrirl~., any method capable of producing very fine 21 grain sized polycrystalline m~t~ri~ can be used to produce nanocrystalline m~teri~
22 These methods include, for e~r~mpl~, eval)olalion such as arc evaporation, electron beam 23 vapor deposition, molecular beam epitaxy, ion beam, sputtering, magnetron sputtering and 24 reactive sputtering (see for eY~mrle, Froes, F.H. et al., "Nanocrystalline Metals for ' ~ . ., ~
, .

~ 1 3 ~4~ 6 Structural Applications", JOM, 41 (198~), No. 6., pp 12 - 17; Birringer, Rainer et al., 2"Nanocrystalline Mzlteri~ - A First Report, Proceefl-ng~ of JIMIS-4; and Gleiter, H.
3"Mzltrristl.~ with Ultrafine Microstructures: Retrospectives and Perspectives, 4NanoStructured M~zlteristl.~, Vol. 1, pp 1-19, 1992, and n;~lences cited therein).

SSUMMARY OF THE INVENTION ~ -6The i~venlol~ set out to develop an anti-microbial metal coating. They 7discovered that, contrary to previous belief, it is possible to form metal coatings from an 8anti-microbial metal material by creating atomic disorder in the mzttP.rizll~ by vapour :;
9deposition under con~ition~ which limit diffusion, that is which "freeze-in" the atomic ; ~: ;

10. disorder. The anti-microbial coatings so produced were found to provide sn.st~inPd release 11of anti-microbial metal species into solution so as to produce an anti-microbial effect. ~ ' .;, .
12This basic discovery linking "atomic disorder" to enhz~nred solubility has .~ ' 13broad appliration The inventors have demonstrated that atomic disorder so as to produce ' ~ ;
14solubility can be created in other material forms, such as metal powders. The invention ' .
~ ~ .
15also has applicz~tion beyond anti-microbial metals, enro",p~c.cit-g any metal, metal alloy, ~-16 or metal compound, in~ ing semiconductor or ceramic m~tPri tl.~, from which 5n~tZ~inpd 17release of metal species into solution is desired. For inAtZ~nre~ mzttPtizt1S having enhz~nr,ed '~
,. ,~.
18or controlled metal ~i~solntion find appliration in sensors, switches, fuses, electrodes, and ~ ~
. ..
19bZltt~pr 20The term "atomic disorder" as used herein includes high con~P.ntrz~tion.~ of~
21 point defects in a crystal lattice, vacz~nriPs, line defects such as ~iSlocatir)nA~ intP.r.~titiz~
22 atoms, amorphous regions, grain and sub grain boundaries and the like relative to its , ,', ',':,.. ',~'',;

- . .. . . . . .1 -............. .

2 1 3 ~

normal ordered crystalline state. Atomic disorder leads to irregularities in surface 2 topography and inhomogenieties in the structure on a nanometre scale.
3 By the term "normal ordered crystalline state" as used herein is meant the 4 crystallinity normally found in bulk metal m~tPri~ , alloys or colllpoullds formed as cast, wrought or plated metal products. Such m~tPri~ls contain only low concentrations of such 6 atomic defects as v~c~ncies, grain boundaries and dislocations.
7 The term "diffusion" as used herein implies diffusion of atoms and/or 8 molecules on the surface or in the matrix of the material being formed.
9 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 1I as oxides, nitrides, borides, snlI-hides, halides or hydrides.
12 The inventionl in a broad aspect extends to a method of forming a modified 13 material cont~ining one or more metals. The method compri.~P.s creating atomic disorder 14 in the material under conAi~ion.~ which limit diffusion such that snffl~iPnt atomic disorder is retained in the material to provide release, preferably on a snst~in~l 1P basis, of atoms, 16 ions, molecules or clusters of at least one of the metals into a solvent for the m~tP.ri~
17 Clusters are known to be small groups of atoms, ions or the like, as ~escrihed by R.P.
18 Andres et al., "Research Ol,~ollulli~es on Clusters and Cluster-Assembled M~teri~ ", J
19 Mater. Res. Vol. 4, No. 3, 1989, P. 704.
Specific preferred embodiments of the invention dPm~n~tr~tP that atomic 21 disorder may be created in rnetal powders or foils by cold working, and in metal coatings 22 by deposi~ g by vapour deposition at low substrate le~ e~ s.
23 In another broad aspect, the invention provides a modified material 24 comprising one or more metals in a form ch~cle~ ;7Pd by snffi~iP.nt atomic disorder such .... ........ .. . ... .. . . .. .. . . . .. . .. .... . . . .

2 ~3 6~

that the m:ltPri~l, in contact with a solvent for the msl~eri~l releases atoms, ions, molecules 2 or clusters con~ g at least one metal, preferably on a sustainable basis, at an enh~n~ed 3 rate relative to its normal ordered crystalline state.
4 In preferred embodiments of the invention, the modified material is a metal powder which has been mpch~nic~lly worked or compressed, under cold working 6 cnn~ition.C, to create and retain atomic disorder.
7 The term "metal powder" as used herein is meant to include metal particles 8 of a broad particle si~e, ranging from nanocrystalline powders to flakes.9 The term "cold working" as used herein in~i~atps that the material has been mPch~ni~ally worked such as by milling, grintlin~, h~mmPring, mortar and pestle or 11 compressing, at le~ )elalul~s lower than' the recrystallization ~lllpeldlule of the m~tPr~

12 This ensures that atomic- disorder imparted through working is retained in the m~teri~l 13 In another preferred embodiment, the modified material is a metal coating 14 formed on a substrate by vapour deposition lechni.lues such as vacuum e~apolation, sputtering, magnetron sputtering or ion plating. The material is formed under con~ition~
16 which limit diffusion during deposition and which limit ~nnP~ling or recrys~ tion 17 following deposition. The deposition con~ition.~ preferably used to produce atomic 18 disorder in the coatings are outside the normal range of operating conl~itions used to ..,. ~ .: . -19 produce defect free, dense, smooth films. Such normal practices are well known (see for ' ~ -example R.F. Bunshah et al., ~). Preferably the deposition is conducted at low ;~
21 s"~ P le-nl)el~lul~s such that the ratio of the substrate to the melting point of the metal 22 or metal compound being deposited (T/Tm) is m~int~in~d at less than about 0.5, more 23 preferably at less than about 0.35, and most preferably at less than 0.30. In this ratio, the ' .:. ~ "
24 tempelalul~s are in degrees Kelvin. The preferred ratio will vary from metal to metal and . .''".-'"' ." .
9 , ~

2 ~ 5 ~

increases with alloy or UllpU[i~iy content. Other preferred deposition conditions to create 2 atomic disorder include one or more of a higher than normal working gas pressure, a lower 3 than normal angle of inri~nre of the coating flux and a higher than normal coating flux.
4 The l~n~ eldtule of deposition or cold working is not so low that substantial S ~nn.~,~ling or recryst~ tion will take place when the material is brought to room 6 te.llpe~a~ul~ or its intended ~ lper~ule for use (ex. body eemperature for anti-microbial 7 m~t~.ri~ ). If the telllpela~ulc~ dirr~ ial between deposition and temperature of use (~T) . , 8 is too great, ~nn~ling results, removing atomic disorder. This ~T will vary from metal 9 to metal ~and with the deposition technique used. For eY~mpl~, with respect to silver, substrate ~elllpeld~u~s of -20 to 200~C are preferred during physical vapour deposition.
11 Norrnal or ambient working gas pressure for deposi~ g the usually required 12 dense, smooth, defect free metal films vary according to the method of physical vapour 13 deposition being used. In general, for spllt~erin~ the normal working gas pressure is less 14 than 10 Pa (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 pl~S;~IleS vary for 16 vacuum evaporation p~c~sscs vary as follows: for e-beam or arc evaporation, from 17 0.0001 Pa (0.001 mT) to 0.001 Pa (0.01 mT); for gas sC~t~er~ng evaporation (pressure 18 plating) and reactive arc evaporation, up to 30 Pa (200 mT), but typically less than 3 Pa 19 (20 mT). Thus, in accol.l~lce with the method of the present invention, in addition to using low substrate temperatures to achieve atomic disorder, working (or ambient) gas 21 pn~s~ es higher than these normal values may be used to increase the level of atomic 22 disorder in the coating.
23 Another condition discovered to have an effect on the level of atomic 24 disorder in the coatings of the present invention is the angle of in~ nce of the coating 1 0 ' ' ~ ' ' ' : ~:

-r- ~ 2 1 3 6L~5 Ç~

flux durin~ deposition. No~nally to achieve dense, smooth coatings, this angle is 2 m~int~in~.d at about 90~ +/- 15~. In accordance with the present invention, in addition to 3 using low substrate tempel~lw~s during deposition to achieve atomic disorder, angles of 4 inci~i~nce lower than about 75~ may be used to increase the level of atomic disorder in the 5 coating.
6 Yet another process parameter having an effect on the level of atomic 7 disorder is the atom flux to the surface being coated. High deposition rates tend to 8 increase atomic disorder, however, high deposition rates also tend to increase the coating 9 temperature. Thus, there is an op~ lulll deposition rate that depends on the deposition : technique, the coating material and other process parameters.
11 - To provide an anti-microbial m~t~ri~l, the metals used in the coating or 12 powder are those which have an anti-microbial effect, but which are biocompatible (non~
13 toxic for the int~n~ed utility). Preferred metals include Ag, Au, Pt, Pd, Ir (i.e. the noble 14 metals), Sn, Cu, Sb, Bi, and Zn, compounds of these metals or alloys containing one more of these metals. Such metals are hereinafter referred to as "anti-microbial metals"). Most 16 pr0ferred is Ag or its alloys and compounds. Anti-microbial m~t~.ri~ in acconlance with 17 this-invention preferably are formed with snffir;~n~ atomic disorder that atoms, ions, 18 molecules or clusters of the anti-microbial material are released into an alcohol or water 19 based electrolyte on a snst~in~hle basis. The terms "s~l~t~in~hlP- basis" is used herein to dirr~r~ iate, on the one hand from the release obtained from buLk metals, which release 21 metal ions and the like at a rate and concenL-~lion which is too low to achieve an anti~
22 microbial effect, and on the other hand from the release obtained from highly soluble salts 23 such as silver nitrate, which release silver ions virtually instantly in contact with an alcohol 24 or water based electrolyte. In contrast, the anti-microbial m~teri~ of the present invention ,, ~.".,,.,~ ,., ~-~' 2~36~
:.' release atoms, ions, molecules or clusters of the anti-microbial metal at a snffi~iPnt rate ~;
2 and concentration, over a snf~lciPnt time period to provide a useful anti-microbial effect.
3 The term "anti-microbial effect" as used herein means that atoms, ions, 4 molecules or clusters of the anti-microbial metal are released into the electrolyte which the S material contacts in concentrations snffl~i~Pnt to inhibit bacterial growth in the vicinity of 6 the mAteri~l The most common method of mp~Asllrine anti-microbial effect is by ~ ;~
7 me~Snrin~ the zone of inhihition (ZOI) created when the ma~erial is placed on a bacterial ~ ~ -,. . :
8 lawn. A relatively small or no ZOI (ex. less than 1 mm) infli~AtP~ a non-useful anti-9 microbial effect, while a larger ZOI (ex. greater than 5 mm) in~icAtPS a highly useful anti-: :-microbial effect. One procedure for a ZOI test is set out in the Fy~mrlps which follow.
11 The invention extends to devices such as medical devices forrned from, 12 ~ inco.l,o~ lg, carrying or coated with the anti-microbial powders or coatings. The anti-13 microbial coating may be directly deposited by vapour deposition onto such medical 14 devices as c~th~terS, sutures, implAnt.~, burn dressings and the like. An ~h~ion layer, 15 such as t~lnt~lum, may be applied between the device and the anti-microbial coating.

16 Adheslon may also be çnh~nced by methods known in the art, for example etching the 17 su~strAt~ or forming a mixed inte.rf~e. between the substrate and the coating by 18 ~imllltAn-~.oUS sputtering and etching. Anti-microbial powders may be incorporated into 19 crearns, polymers, ceramics, paints, or other mAtri~es, by techniques well known in the art.
In a further broad aspect of the invention, modified m~t~.riAl~ are prepared 21 as composite metal coatings c~ g atomic disorder. In this case, the coating of the 22 one or more metals or compounds to be released into solution con.~titutes a matrix '~3 co~ ;.,;"g atoms or molecules of a dirrelelll m~teri~l The presence of different atoms or 24 molecules results in atomic disorder in the metal matrix, for instance due to different sized ,, ~. ~.,.'.,"'~,.

~ ~ 3 ~
atoms. The different atoms or molecules may be one or more second metals, metal alloys 2 or metal compounds which are co~ or sequentially deposited with the first metal or metals 3 to be released. Alternatively the different atoms or mol~c~ s may be absorbed or trapped 4 from the working gas atmosphere during reactive vapour deposition. The degree of atomic S disorder, and thus solubility, achieved by the inclusion of the different atoms or molecules 6 varies, depending on the m~teri~l.e In order to retain and enhance the atomic disorder in 7 the composite m~t~.ri~l, one or more of the above-described vapour deposition conl1ition.e, 8 namely low substrate temperature, high working gas pressure, low angle of incidence and 9 high coating flux, may be used in combination with the inclusion of different atoms or 10 molecules.
11 Preferred composite m~teri~le for anti-microbial pul~oses are formed by }2 inc~ ing atoms or molecules c~ g oxygen, nitrogen, hydrogen, boron, sulphur or 13 halogens in the working gas atmosphere while depositing the anti-microbial metal. These 14 atoms or molecules are incorporated in the coating either by being absorbed or trapped in 15 the film, or by reacting with the metal being deposited. Both of these mechanisms during 16 deposition are herein&r~er refened to as "reactive deposition". Gases cont~ining these 17 PlemPnt.e, for example oxygen, hydrogen, and water vapour, may be provided continuously 18 or may be pulsed for sequential deposition.
19 Anti-microbial composite m~t~.ri~l.e are also preferably prepared by co- or 20 sequentially depositing an anti-microbial metal with one or more inert biocompatible 21 metals selected from Ta, Ti, Nb, Zn, V, Hf, Mo, Si, and Al. Alternatively, the composite 22 m~teri~ls may be formed by co-, selue~Lially or reactively depositing one or more of the 23 anti-microbial metals as the oxides, carbides, nitrides, borides, slllphirles or halides of these 24 metals and/or the oxides, carbides, nitrides, borides, slllrhides or halides of the inert ',"'.~

~36~5~

metals. Particularly preferred composites contain oxides of silver and/or gold, alone or 2 together with one or more oxides of Ta, Ti, Zn and Nb.
3 The invention further extends to fine grain anti-microbial m~t~rials in a fime 4 powder, film or flake form, compri.~in~ one or more anti-microbial metals or alloys or S compounds thereof, having a grain size less than 200 nm, in a fine powder, flake or film 6 form, char~ctPri7:Pd by sllffi~iPnt atomic disorder such that the m~tPri~l, in contact with an 7 alcohol or a water based electrolyte, provides a sustained release of the atoms, ions, 8 molecules or clusters of at least one anti-microbial metal into the alcohol or water based 9 electrolyte at a concentration sllfflcient to provide a loca1i~Pd anti-microbial effect.
The anti-microbial material may be prepared by introducing the atomic 11 disorder into a pre-formed fine grain or nanocrystalline (<20 nm) powder, flakes or films 12 of one or more of the anti-microbial metals by mPch~nic~l working, for example by 13 compressing the m~tPri~l, under cold working conditions. Alternatively, the atomic 14 disorder may be created during the synthesis of fine grain or nanocrystalline m~teri~ls (films, flakes or powders) by vapour deposition techniques in which the anti microbial 16 metal is co-, seqllP.ntin1ly or reactively deposited in a matrix with atoms or mo1PclllPs of 17 a different material under con~litif~ns such that atomic disorder is created and retained in 18 the matrix. The different material (or dopant) is selected from inert. biocomratihle metals, 19 oxygen, nitrogen, hydrogen, boron, sulphur, and halogens, and oxides, nitrides, carbides, borides, sulphides and halides of either of both of an anti-microbial metal or a21 biocomr~tiklP metal. Preferred biocomp~tihl~ metals include Ta, Ti, Nb, B, Hf, Zn, Mo, 22 Si and Al. These different m~ter~ may be included with the anti-microbial metal in the 23 same or separate target, for example a target of Ag and/or silver oxides, which may further 24 contain, for P.Y~rnI~1P~ Ta or t~nt~hlm oxides. Allelllalively, the different material may be -' ~ 1 3 fi 4~
introduced from the working gas atmosphere during vapour deposition, for example by ~ -2 sputtering or reactive sputtering in an atmosphere containing atoms or molecules of the 3 differen~ material such as oxygen.
4 The anti-microbial form of silver mateIial prepared in accordance with the S process of the present invention has been physically ch~.acL~ ed and hâs been found to 6 have the following novel characteristics~
7 - a positive rest potential, E,,~, when measured against a salu.~led calomel 8 reference electrode (SCE), in 1 M potassium hydroxide;
9 - preferably a ratio of temperature of recryst~lli7~tion to its melting point, in degrees K, (TrJTm), of less than about 0.33, and most preferably less than about 0.30;
11 - preferably a temperature of recryst~lli7~tion less than about 140 ~C;
12 - preferably, a grain size less than about 200nm, preferably less than 140 13 nm and most preferably less than 90 nm. ~ ' .
14 ~ Each of these physical char:lcteriAtics, with perhaps the exception of grain 15 size, is believed to be the result of the presence of atomic disorder in the m~t~ri~l The 16 char~cteri~tirs are of ~c~ nce. in identifying and distinguishing the silver m~t~ri~l~ of the 17 present invention from prior art m~t~ri~l~ or m~teri~ls in their nonnal ordered crystalline 18 state. The preferred novel anti-microbial silver m~t~ri~l~ have been char~cteri~d, for 19 example by XRD, XPS and SIMS analysis, as co.,.r~ici..~ s~bst~nti~lly pure silver metal, 20 when deposited in an inert atmosphere such as argon. However, when the working gas 21 atmosphere contains oxygen, the m~teri~li comprise a matrix of ~ubs~llially pure silver 22 metal and one or both of, silver oxide and atoms or molecules of trapped or absorbed 23 oxygen. A further distinguishing feature of the m~teri~l~ of the present invention is the 24 presence of growth twins in the grain structure, visible from TEM analysis.
,. ~ .
;~ ' ~ 4~

BRIEF DESCRIPTION OF THE DRAWINGS
2 Figure 1 is a TEM micrograph of a sputter deposited silver coating in 3 accordance with the invention, illustrating grain size and growth twin defects.
4 Figure 2 is a TEM micrograph of the film of Figure I after ~nnP~ling, ~;
showing larger grain size and the presence of ~nnP~ling twins.
~ ~

'~:
6 DESC RIPTlON OF THE PREFERRED EMBODIMENTS
7 As above stated, the present invention has appli~a~i()n beyond anti-microbial 8 m~tPri~lA However, the invention is ~ clos~Pd herein with anti-microbial metals, which 9 ~ are illustrative of utility for other metals, metal- alloys and metal compounds. Preferred 10 metals include Al and Si, and the metal elPmPntc from the following groups of the periodic 11 table: IIIB, IVB, VB, VIB, VIIB, VIIIB, IB, IIB, IIIA, IVA, and VA (eY~ ng As) in ;~ ; -12 the periods 4, 5 and 6, (see Periodic Table as published in Merck Index 10th Ed., 1983, 13 Merck and Co. Inc., Rahway, N.J., Martha Windholz). Different metals will have varying 14 degrees of solubility. However, the creation and retention of atomic disorder in accor-lance with this invention results in enh~n~ed solubility (release) of the metal as ions, atoms, '~
16 molecules or clusters into an appropriate solvent i.e. a solvent for the particular m~teri~
17 typically a polar solvent, over the solubility of the material in its normal ordered crystalline 18 state. ~ ~.
19 The medical devices formed from, illcO~ ing, carrying or coated with the : ' 20 anti-microbial material of this invention generally come into contact with an alcohol or 21 water based electrolyte inrhl~ing a body fluid (for example blood, urine or saliva) or body 22 tissue (for example skin, muscle or bone) for any period of time such that microorgar~ism -., ~ .
23 growth on the device surface is possible. The term "alcohol or water based electrolyte"

'.' '-.~:: .' .. ". ' .,., ~",,.".....
: ~ - .;

2~ 36~6 also includes alcohol or water based gels. In most cases the devices are medical devices 2 such as c~th~ter.e, implants, tracheal tubes, orthopaedic pins, insulin pumps, wound 3 closures, drains, dressings, shunts, connectors, prosthetic devices, p~cçm~kPr leads, needles, 4 surgical instruments, dental prosthP.ses, ventilator tubes and the like. However, it should S be understood that the invention is not limited to such devices and may extend to other 6 devices useful in consumer hP~lthcare, such as sterile pack~P;ng, clothing and footwear, 7 personal hygiene products such as diapers and sanitary pads, in biomP~lir~l or biotechnic~
8 laboratory equipment, such as tables, enclosures and wall coverings, and the like. The 9 term "medical device" as used herein and in the claims is intPndPd to extend broadly to 10 all such devices.
11 The device may be made of any suitable m~t~ri~l, for example metals, 12 inclurlin~ steel, al"".inl.,.. and its alloys,-latex, nylon, silicone, polyester, glass, ceramic, 13 paper, cloth and other plastics and rubbers. For use as an in-dwelling medical device, the 14 device will be made of a bioinert material. The device may take on any shape dictated by 15 its utility, ranging from flat sheets to discs, rods and hollow tubes. The device may be 16 rigid or flexible, a factor again dictated by its intended use.

17 Anti-Microbial Co~tin,~
18 The anti-microbial coating in accordallce with this invention is deposited as 19 a thin metallic film OD one or more surfaces of a medical device by vapour deposition 20 tec~ s. Physical vapour techniques, which are well known in the art, all deposit the 21 metal from the vapour, generally atom by atom, onto a substrate surface. The techniques 22 include vacuum or arc evaporation, sputtering, magnetron sputtering and ion plating. The 23 deposition is conducted in a manner to create atomic disorder in the coating as defined 2~ 36?~5~ ~
hereinabove. Various conditions responsible for producing atomic disorder are useful.
2 These conditions are generally avoided in thin film deposition techniques where the object ~;
3 is to create a defect free, smooth and dense film (see for example J.A. Thornton, supra).
4 While such conditions have been investip~ted in the art, they have not heretofore been 5 linked to ~nh~nced solubility of the coatings so-produced.
6 The preferred conditions which are used to create atomic disorder during the 7 deposition process include~
8 - a low substrate l~ p~l~lul~, that is m~int~inin~ the surface to be coated 9 at a lenlpel~lul~ such that the ratio of the substrate l~lllpelalu~ to the melting point of the ~:
metal (in degrees Kelvin) is less than about 0.5, more preferably less than about 0.35 and 11 most preferably less than about 0.3; and optionally one or both of:
12 - a higher than normal working (or ambient) gas pressure, i.e. for vacuum 13 ev~l)oldlion: e-beam or arc evaporation, greater than 0.001 Pa (0.01 mT), gas sc~ttPring 14 evaporation (pressure plating) or reactive arc evaporation, greater than 3 Pa t20 mT); for sputtering: greaterthan 10 Pa (75 mT); formagnetron sp~ g greater than about 1.3 16 Pa (10 mT); and for ion plating: greater than about 30 Pa (200 mT); and -17 - m~int~ining the angle of incid~.n~e of the coating flux on the surface to be 18 coated at less than about 75~, and preferably less than about 30~
19 The metals used in the coating are those known to have an anti-microbial 20 effect. For most medical devices, the metal must also be biocompatible. Preferred metals 21 include the noble metals Ag, Au, Pt, Pd, and Ir as well as Sn, Cu, Sb, Bi, and Zn or alloys -~
22 or compounds of these met~s or other met~s. Most preferred is Ag or Au, or alloys or 23 colllpounds of one or more of these metals. - ' '.~' '~'' ' '' -'.'' '.

. ~., ~ . .

3 6~5 ~
The coating is formed as a thin film on at least a part of the surface of the 2 medical device. The film has a thicknpss no greater than that needed to provide release 3 of metal ions on a snst~in~hle basis over a suitable period of time. In that respect, the 4 thir~n~ will vary with the particular metal in the coating twhich varies the solubility and S abrasion reQiQt~nce), and with the degree of atomic disorder in (and thus the solubility of) 6 the coating. The thickn~ss will be thin enough that the coating does not interfere with the 7 dimen~ional tolerances or flexibility of the device for its intended utility. Typically, 8 thickn~ çs of less than 1 micron have been found to provide sufficient sustained anti~
9 microbial activity. Increased thirknps~es may be used depending on the degree of metal 10 ion release needed over a period of time. Thirkn~cces greater than 10 microns are more 11 expensive to produce and normally should not be needed.
12 The an~i-microbial effect of the coating is achieved when the device is 13 brought into contact with an alcohol or a water based electrolyte such as, a body fluid or 14 body tissue, thus releasing metal ions, atoms, molecules or clusters. The concentration of 15 the metal which is needed to produce an anti-microbial effect will vary from metal to 16 metal. Generally, anti-microbial effect is achieved in body fluids such as plasma, serum 17 or urine at concentrations less than about 0.5 - 1.5 ~g/ml.
18 The ability to achieve release of metal atoms, ions, molecules or clusters on 19 a sll~t~in~hl~ basis from a coating is dictated by a number of factors, inrhl-lin~ coating 20 cl,ala~ tirS such as composition, structure, solubility and thi~knrss, and the nature of 21 the e-lviro~ ent in which the device is used. As the level of atomic disorder is increased, 22 the amount of metal ions released per unit time i.l~leases. For in.~t~nre, a silver metal film 23 deposited by magnetron sputtering at T/Tm < 0.5 and a working gas pressure of about 0.9 24 Pa ~7 mTorr) releases approxim~tPly 1/3 of the silver ions that a film deposited wlder ,,,.,..~

' -'.' ~.,." ", - .... .. ....

2 ~ 5 ~

similar conditions, but at 4 Pa (30 mTorr), will release over lO days. Films that are 2 created with an intP.rm~Pdi~tP structure (ex. lower pressure, lower angle of incidence etc.) 3 have Ag release values intennPdi~tP to these values as determined by bioassays. This then 4 provides a method for producing controlled release metallic coatings in acco~dance with ~
-S this invention. Slow release coatings are prepared such that the degree of disorder is low 6 while fast release coatings are prepared such that the degree of disorder is high.
7 For continuous, uniform coatings, the time required for total ~ so1ntion will 8 be a function of film thirknpss and the nature of the ellvilol~ P~nt to which they are 9 exposed. The relationship in respect of thicknPs~ is al)plv~ t~ply linear, i.e. a two fold increase in film thicknPss will result in about a two fold increase in longevity.
l l It is also possible to control the metal release from a coating by forming a 12 thin film coating with a modulated structure. For in.~t~nce, a coating deposited by 13 magnetron sputtering such that the working gas pressure was low teX. 2 Pa (lS mTorr)) 14 for 50% of the deposition time and high (ex. 4 Pa (30 mTorr)) for the rem~inin~ time, has ' ~ ~ ' lS a rapid initial release of metal ions, followed by a longer period of slow release. This type 16 of coating is extremely effective on devices such as urinary c~th~t~rs for which an initial ~ : ~
17 rapid release is required to achieve immediate anti-microbial concentrations followed by .' ~ ' 18 a lower release rate to sustain the conce~ a~ion of metal ions over a period of weeks. ~ ~
l9 The substrate temperature used during vapour deposition should not be so ; - -low that ~nn~1in~ or recryst~11i7atiQn of the coating takes place as the coating warms to 21 ambient t~-mr~ u~es or the t~mrerat11res at which it is to be used (ex. body teml-erat11re).
22 This allowable ~T, that the temperature differential between the ~ub;~lla~e l~ elal~e ' '.
23 during deposition and the ultimate temperature of use, will vary from metal to metal. For . . ~.,.' :-..... .. .....

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

2 ~ 3 6~5 ~
the most preferred metals of Ag and Au, preferred substrate temrer~tl-res of -20 to 200~C
2 , more preferably -10~C to 10û~C are used.
3 Atomic order may also be achieved, in accordance with the present 4 invention, by preparing composite metal m~t~Pr~ , that is m~tP,riP.l,~ which contain one or 5 more anti-microbial metals in a metal matrix which includes atoms or moleclllPs different 6 from the anti-microbial metals.
7 Our technique for preparing composite material is to co- or sequentially 8 deposit the anti-microbial metal(s) with one or more other inert, biocompatible metals 9 selected from Ta, Ti, Nb, Zn, Y, Hf, Mo, Si, Al and alloys of these metals or other metal 10 : ~plpment~ typically other transition metals. Such inert metals have a different atomic radii 1 I from that of the anti-microbial metals, which results in atomic disorder during deposition.
12 Alloys of this kind can also serve to reduce atomic diffusion and thus stabilize the 13 disordered structure. Thin film deposition equipment with multiple targets for the 14 pl~r~Pm~Pnt of each of the anti-microbial and inert metals is preferably utilized. When 15 layers are sequentially deposited the layer(s) of ~he inert metal(s) should be t1i~ccontinllous 16 for example as islands within the anti-microbial metal matrix. The final ratio of the anti-17 microbia meta (s) to inert meta (s) should be greater than about 0.2. The most preferable 18 inert metals are Ti, Ta, Zn and Nb. It is also possible to form the anti-microbial coating 19 from oxides, carbides, nitrides, s--lphi~-s, borides, halides or hydrides of one or more of 20 the anti-microbial metals and/or one or more of the inert metals to achieve the desired 21 atomic disorder.
22 Another composite material within the scope of the present invention is 23 formed by reactively co- or sequentially depositing, by physical vapour techni~ues, a 24 reacted material into the thin film of the anti-microbial metal(s). The reacted material is .~' -'.''',''.'..''',', ''' "~

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

2136~5~
an oxide, nitride, carbide, boride, sulphide, hydride or halide of the anti-microbial and/or 2 inert metal, formed in situ by injecting the appropriate react~nt.c, or gases c.)~ g same, 3 (ex. air, oxygen, water, nitrogen, hydrogen, boron, sulphur, halogens) into the deposition 4 chamber. Atoms or molecules of these gases may also become absorbed or trapped in the S metal film to create atornic disorder. Ihe reactant may be continuously supplied during 6 deposition for codeposition or it may be pulsed to provide for sequential deposition. The 7 final ratio of anti-microbial metal(s) to reaction product should be greater than about 0.2 8 Air, oxygen, nitrogen and hydrogen are particularly preferred reactants.
9 The above deposition techniques .o prepare composite coatings may be used with or without the con~1ition.~ of lower substrate temllerahlres~ high working gas l)~s~ules ,.: . .
11 and low angles of incidence previously discucce~ One or more of these con-lition.~ is ';
12 - preferred to retain and enhance the amount of atomic disorder created in the coating.
13 It may be advantageous, prior to depositing an anti-microbial in accordd~lce ;
: ~: . , 14 with the present invention, to provide an adhesion layer on the device to be coated, as is ' 15 known in the art. For inst~nce~ for a latex device, a layer of Ti, Ta or Nb may be first 16 deposited to enhance adhesion of the subsequently deposited anti-microbial coating. ; ~ ' ., ..,.,, - .

. : ~ .,.. ~. :
17 Anti-Microbial Powders 18 Anti-microbial powders, inc~ ing nanocrystalline powders and powders 19 made from rapidly solidi~ed flakes or foils, can be formed with atomic disorder so as to 20 enhance solubility. The powders either as pure metals, metal alloys or compounds such 21 as metal oxides or metal salts, can be m~ch~nir~lly worked or colllpl~sscd to impart ~ .
22 atomic disorder. This m~ch7.ni(~11y imparted disorder is cnn(l~cted under conditic)n.~ of - -23 low ~elllpeldlule (i.e. temperatures less than the temperature of recryst~lli7~ti~n of the . . ..., ~ .
'~ "''''"' 2~3~5~ ~
material) to ensure that ~nnr~ling or recryst~lli7~tion does not take place. The ~ elalule 2 varies between metals and increases with alloy or impurity content. ~
;
3 Anti-microbial powders produced in accordance with this invention may be ;
' 4 used in a variety of forms, for instance in topical creams, paints or adherent coatings.
S Alternatively, the powder may be incorporated into a polymeric, cerarnic or metallic matrix 6 to be used as a material for medical devices or coatings therefor. -, :.:., .,- ~
:',,: ' ' ',' "''' 7 Fine Grain or NanocrYstalline Materials of Anti-Microbial Metals 8 Methods of forming fine grain or nanocrystalline m~ter~ c from the vapour 9 phase are well known and docum~n~ed in the literature. For in.ct~n~e, nanocrystalline 10 m~t~ l.c may be formed by a modified standard inert-gas con~len~c~ti~n technique. The 11 material to be deposited is evalJo~àl~d from an electrically heated boat or crucible into an ~ -12 inert gas atmosphere such as argon or helium with a pressure of about ~ to 7 Torr. The . ~ ~
13 temperature of the boat has to be high enough to obtain a s~lbst~nti~l vapour pressure oi 14 the material of interest. For metals, a le-llpel~Lul~ about 100~C above the melting point '' 15 of the metal will typically provide an adequate vapour pressure. Due to h~ a~OIllic 16 ct-lli.cion.c with the working gas atmosphere atoms, the ~v~poldl~d atoms of the material ;
17 lose their kinetic energy and con(l~.n.ce onto a cold finger or substrate held at about 77 K ~ -18 (liquid nitrogen cooled) in the form of a lose powder or friable flakes or film, the grain - ' 19 size of which is less than about 20 nm. With respect to powders or flakes, a high vacuum -~
20 (less than 5 x 10-6 Pa) is restored and the powder or flakes are stripped off from the cold 21 fimger and coll~ct~.d in a cold trap.
22 Fine grain m~t~ri:~lc are produced analogously in gas con~enc~tion/vapour 23 deposition processes, as is known in the art. This is typically achieved by altering the cold : .:

:, " ' ' ,.

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

213~L~5~
finger or substrate temperature and the gas pressure to allow the particle to coarsen to the 2 desired size which is preferably under 5000 nm.
3 Fine powders/nanocrystalline powders of anti-microbial metals pleL)ared in 4 accordance with the known prior art processes have been tested and found not to have S sufficient anti-microbial efficacy. In order to introduce atomic disorder into the m~tP.ri~ls 6 at a level which is suffici~nt to produce an anti-microbial effect, the anti-microbial metal, 7 alloy or compound to be deposited is co-, sequentially or reactively deposited in a matrix 8 with atoms or molecules of a different material (dopant) under cnn~ition~ such that atomic 9 disorder is created and retained in the matrix. The different material is selected from inert .:: ..: ... ~
10 ~ biocompatible metals, such as Ta, Ti, Nb, B, Hf, Zn, Mo, Si and Al, most preferably Ta, 11 Ti and Nb. Alternatively the dirr~r~ material is an oxide, nitride, carbide, boride, ; -' 12 sulphide or halide of either or both of an anti-microbial metal or of the biocomp~tihle 13 metal. A further alternative is to introduce the different material from the working gas : ' :
14 atmosphere, either by reactive deposition or by absorbing or trapping atoms or molecules 15 from the working gas into the matrix. Working gas ~tmospheres COnl~lnillg oxygen, 16 nitrogen, hydrogen boron, sulphur and halogens may be used. Worhng gas atmospheres : .
17 inr~ ing oxygen are most preferred, such that the matrix of anti-microbial metal includes 18 either or both of trapped oxygen and oxides of the anti-microbial metal.
19 A further technique for forming anti-microbial powders of the present .. ;
invention is to form coatings COI~Ail~ g atomic disorder in the manner set out above onto ;
21 an inert, preferably biocompatible, particulate material such as talc, bentonit~, col,.sl~
22 or ceramics such as alumina. The particles may be coated by physical vapour deposition . . ~ . .
23 techniques under conditions to create atomic disorder, as set forth above in respect of the - ~ -24 anti-microbial metal coatings. Alternatively, the powders can be coated by adapting a 24 ''~

~' ' "''' ''' ~ 213~6 ~ :' vapour deposition process, for instance by passing a vapour of the anti-microbial material .
2 through a fixed porous bed of the powders, by flni~ ine the powder bed in the anti~
3 microbial metal vapour phase, or by letting the powder fall through a vapour of the anti- ' . ~ . .
4 microbial material In all cases, the powder could be cooled and/or the working gas ~ '.. ; .'.
atmosphere could be altered to include a different material (ex. oxygen), in order to 6 produce the desired degree of atomic disorder. ,~

7 PhYsical/Chemi~al CharArtP.ristics of Anti-Microbial Silver Material ~ .: ' ' .
B ~ .... The modified metal matP.ri~ formed in accordance with the present ':
',,: ,.,~:
9 invention so as to contain atomic disorder which leads to çnh~nced release of the metal 10 species have novel physical cl~ e~ ti~s when compared with mate.ria1.~ in their normal 11 ordered crystalline state. Silver matpri-als made in accordance with the present invention .. ~ ' 12 have been ch~t ~lr-~;~.Pd as having the following novel characteri.~tic~
13 .. - a positive rest potential, E~ for exatnrl~ when measured against a SCE . . : . . ' .
14 reference electrode in a 1 M KOH solution;
- preferably a ratio of temperature of recrysta1li7-atiQn to melting temperature ... .. - .
16 less than 0.33, and most preferably less than 0.30; ~' ~. .... .. ' ~' 17 - preferably a l~nlpel~lure of recryst~lli7~tion less than about 140 ~C; and ;.. ~; .. .'.
18 - preferably a grain size less than about 200nm, more preferably less than 19 140nm and most preferably less than 90nm.
Analysis of the silver m~teri~ by XRD, XPS and SIMS techniques ~.
21 confirm.~ the ch~mi~l nature and content of the film as silver metal, and in the event that 22 the material is formed with oxygen in the working gas atmosphere, one or both of silver 23 oxide and trapped oxygen. TEM analysis reveals growth twins in the silver m~teri~l,: ~ .

~ .

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

- 2 ~. 3 ~1t5 ~

which are converted to annealed twins when the m~te.ri~ls are annealed above the 2 le~ )el~ule of recry~t~lli7~tinn 3 The invention is further illnstr~tpd by the following non-limiting eY~mrl~Ps ~ ~ :

4 FY~rnrlP 1 .,'., ::,',.''"'".
A medical suture material size 2/0, polyester braid was coated by magnetron -:
6 ~.llle~ g from 20.3 cm diameter (8 in.) planar silver and copper magnetron c~thod~Ps to 7 form an Ag-Cu-a~oy on the surface to a thicknP.~ of 0.45 microns, using either argon gas ; ' 8 working pressures of 0.9 Pa (7 mTorr) or 4 Pa (30 mT) at O.S KW power and a T/Tm ratio ' ' 9 . of less than O.S. The total mass gas flow was 700 sccm (standard cubic centimptpr~ per ' -- ' minute). ' ' , .: .:
11 - The anti-microbial effec~ of the coatings was tested by a zone of inhibition 12 test. Basal medium Eagle (BME) with Earle's salts and L-g~ P was modified with 13 calf/serum (10%) and l.S % agar prior to being dispensed (lS ml) into Petri dishes. The ':: , . ',. ,.:
î4 agar co~ g Petri plates were allowed to surface dry prior to being inoculated with a . ~
...... ~,. ~
lawn of Staphytococcus aureus ATCC# 25923. The inocul~nt was pr~al~d from Bactrol 16 Discs (Difco, M.) which were reco~ ed as per the m~n~lf~ct~lrer~s directions 17 TmmP.~i~tP.ly after inoculation, the m~tP.ri~ or coatings to be tested were placed on the 18 surface of the agar. The dishes were incllh~t~pd for 24 h at 37~C. After this inCu~ati()n 19 period, the zone of inhihition was measured and a corrected zone of inhihition was 20 c~l~nl~tP.d (corrected zone of inhihition = zone of inhibition - diameter of the test material 21 in contact with the agar).
~ The results showed no zone of inhihition on the nnro~ted suture, a zone of 23 less than O.S mm around the suture coated at 0.9 (7 mTorr) and a zone of 13 mm around :~ .'' ~ ' .' 2 1 3 6 ~
the suture coated at 4 Pa (30 mTorr). Clearly the suture coated in accordance with the 2 present invention exhibits a much more pronounced and effective anti-microbial effect.
:'',''" ,'''~.'.~',.~.

3 ~Y~mrlP 2 ' ~
4 This exarnple is included to illustrate the surface structures which are ' -. . ~ .
obtained when silver metal is deposited on silicon wafers using a magnetron sputtering 6 facility and different working gas pressures and angles of incid~Pnr,e (i.e. the angle between 7 the path of the sputtered atoms and the substrate). All other cQn~lition~ were as follows~
8 target was a 20.3 cm dia. planar silver magnetron cathode; power was 0.1 kW; deposition 9 '~ rate was 200 A~/min; ratio of tempt;la~urt; of ~ub~LIdl~ (wafer) to melting point of silver (1234~K), T/Tm was less than 0.3. Argon gas ~l~S~Ul'~S of 0.9 Pa (7 mTorr) (a normal 11 working pressure for metal coatings) and 4 Pa (30 mTorr) were used. Angles of incidence 12 at each of these pressures were 90~ (normal inri~1enr,e), 50~ and 10~. The coatings had a 13 thir~n~ss of about 0.5 microns.
14 The resulting surfaces were viewed by scanninE electron micluscope. As argon gas pressure increased from 0.9 Pa (7 mTorr) to 4 Pa (30 mTorr) the grain size 16 decreased and void volume increased .~iEnific~nt1y. When the angle of inci(lpnce was 17 dec~ascd, the grain size decreased and the grain boundaries became more distinct. At 0.9 18 Pa (7 mTorr) argon pressure and an angle of inci~Pnre of 10~, there were in~icatiûns of 19 some voids between the grains. The angle of incidPnre had a greater effect on the surface topography when the gas pressure was increased to 4 Pa (30 mTorr). At 90~, the grain size 21 varied frorn 60 - 150 nm and many of the grains were sep~ratPd by i~ hl void spaces 22 which were 15 - 30 nm wide. When the angle of lnCi~pnce was decreased to 50~, the grain ~ 1 ~ 6~5~ ~:

size decreased to 30 - 90 nm and the void volume increased substantially. At 10~, the . .
2 grain size was reduced to about 10 - 60 nm and void volumes were increased again. ~; ' 3 The observed nanometre scale changes in surface morphology and 4 topography are in~ic~tions of atomic disorder in the silver meta . While not being bound ~ ~ ' S by the same, it is believed that such atomic disorder results in an increase in the chemical 6 activity due to increased internal stresses and surface roughness created by mi~m~t~h~d - - ' 7 atoms. It is helieved that t e ~Icl~ased chemica ac ivity is responsible for the increased ' ' ' 8 level of solubility of the coatings when in contact with an electrolyte such as body fluid.
9 The anti-microbial effect of the coatings was evaluated using the zone of ~ . ' inhibition test as set out in F.Y~mrl~ 1. Each coated silicon wafer was placed on an 11 individual plate. The results were compared to the zones of inhihition achieved when solid ; . " "
12 silver (i.e. greater than 99% silver) sheets, wires or membranes were tested. The results ;
13 are sllmm~ri~ed in Table 1. It is evident that the pure silver devices and the silver '~ ' 14 sputtered coating at 0.9 Pa (7 mTorr) do not produce any biological effect. However, the ~ :' 15 coatings deposited at a higher than normal working gas pressure, 4 Pa (30 mTorr), 16 demonstrated an anti-microbial effect, as denoted by the sukst~nti~l zones of inhibition 17 around the discs. Decreasing the angle of inci(lenre had the greatest effect on anti~
18 microbial activity when combined with the higher gas pres~ules. ;~

;'' '" '''.'''' 28 ~ ~ ~

~13~al56 Table I
2 Anti ~,b;dl effects of various silver and silver coated samples as ~ r~ d using S~ hJl ~ccc 3 al~reus :

S Sample Percent Angle of Working GasCorrected Z;one .
6 Silver ]~ep~!~~ n Pressure of Inhibition' .
7 Pa (mTorr) (mm) .
9 Silver Sheet- S
0 rolled 99+ - - <0 5 12 Silver wi~e 3 (.0045") 99+ - - <0.5 Silver 16 cast 99+ - - <0.5 ; i~
18 SputteIed thin - -19 f~lm 99+ normal (90~) 0.9 (7) <0.5 . - ~ ' 21 Sputtered thin 223 911m 99+ 50~ 0.9 (7) <0.5 :
24 Sputtered thin film 99+ 10~ 0.9 (7) <0.5 27 Sputter~d tbin 28 film 99+ normal (90~) 4 (30) 6.3 ~ ;::
Sputtered thin 31 film 99+ 50~ 4 (30) 10 ~ :
32 i:
33 Sputtered thin 34 film 99+ 10 4 (30) lO : ':
' ' .~ , .
.. ~: ' 36 FY~mplP. 3 : m 37 Silicon wafers were coated by magnetron spu~ i.,g using 20.3 cm dia.
38 planar silver and copper magnetron cathodes to produce an alloy of Ag and Cu (80:20) at 39 normal inri~pnce at working gas pressu,~s of 0.9 Pa (7 mTorr) and 4 Pa (30 mTorr), all other con~ition.~ being i~Pn~ir~1 to ~hose set out in F.Yamrle 2. As in ~Y~mrlP 2, when the 41 coatings were viewed by S~M, the coatings formed at high working gas pressure had :~ - - : : . . :
:: : : ~ :

:

smaller grain sizes and larger void volumes than did the coatings forrned at the lower 2 working gas pressures. ~: ~
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 FY~mI~lA 1. The ;:;
S results are s~lmm~ri7rd 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 Table2 : : :::;;' 10 The anti-microbial effect of various sputter deposited silver-copper alloys as t ~t - ~ using ~
11 al~reus . -12 ~ ' 13 Sample Percent Angle of Working Gas Co~rected 14 Silver De~oci~ Pressu~e Zone of (o) Pa (mTorr) Inhibition 16 (mm) 18 1 50 normal (90~) 1.0 (7.5) <0.5 19 '''" ~
2 50 normal (90~) 4 (30) 16 22 3 50 10 4(30) 19 ~
24 FY~mrle 4 A coating in accordance with the present invention was tested to detPrmin~
26 the col~cenllalion of silver ions released into solution over time. One cm2 silicon wafer '~
27 discs were coated with silver as set forth in F~ml~le 2 at 0.9 Pa (7 mTorr) and 4 Pa (30 -28 mTorr) and normal incidence to a thickn~ of 5000 ~. Using the method of Nickel et al., 2~'~6~f56 ;: ~' Eur. J. Clin. Microbiol., 4(2), 213-218, 1985, a sterile synthetic urine was prepared and .: , 2 ~ pen.~ed into test tubes (3.5 ml). The coated discs were placed into each test tubes and ; ' 3 incubated for various times at 37~C. After various periods of time, the discs were removed 4 and the Ag content of the ~lltered synthe~ic urine was ~letermin~d using neutron activation analysis. ~ ' 6 The results are set forth in T~ble 3. The table shows the comparative ;
7 amounts 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 11 constant turn over.
12 - Table 3 13 c of silver in synthetic urine as a funcaon of exposure ame 14 Silver C~ Jg/ml 16 Exposure Time Working Argon Working argon 17 (Days) gas pressure gas pressure 18 0.9 Pa (7mTorr) 4 Pa (30mTorr) 21 ;~
22 1 0.89 1.94 23 ' 24 3 1.89 2.36 :
26 10 8.14 23.06 .
: . : .::

28 Notei: Films were deposited at no~al incidence (909 29 1 - ND (non detectable) <0.46 llg/ml . ~:

~ . i E~cample 5 2 This example is included to illustrate coatings in accordance with lhe present - ;
3 invention formed from another noble metal, Pd. The coatings were formed on silicon: . . i '~
. ~ .... ~ . .
4 wafers as set forth in F.~mrllP 2, to a thi~npss of 5000 ~, using 0.9 Pa t7 mTorr) or 4 Pa (30 mTorr) working gas pressures and angles of inci~Pn~e of 90~ and 10~. The coated 6 discs were evaluated for anti-microbial activity by the zone of inhibition test sl~bSt~nti~lly 7 as set forth in F~r~m~ , 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 ~ incubated 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 pressures, the , , :
- 12 biological activity of the coating was much greater than that of coatings deposited at low 13 pressure. C~h~n~in~ 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 S' ,~ L n ~ureus by Sputter Deposited Palladium metal -:
17 '~
18 Sample Sr_'' ' g Angleof Anti-microWalControl . ::
19 Pressure Deposition Pa (mT) 22 1 0.9 (7) 9~ - ) More than 90% of suIface covered by bacterial growtb : ~ -24 2 0.9 (7) 10~(grazing incidence) 20-40% of surface covered by bacterial growtb ~ ~ .
26 3 4 (30) 90~(normal incidence) Less than 10% surface coveredby bacterial growth . - . ~ ~, 32 - :

~' 7~3~ 6 ~
Example 6 ~ ~
2 This example is included to illustrate the effect of silver deposition ; - ~:
3 temperature 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 conditions 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 dia. planar silver magnetron cathode; the argon working gas 7 pressure was 4 Pa ~30mTorr); the total mass gas flow was 700 sccm; and the ratio of ~ ' 8 te,llpeldLul~ 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 inci~lenre were variable since the substrate was round ;
and rough. That is the angles of inril1~nce varied around the cil.;ulllfelt;llce and, on a finer 11 scale, across the sides and tops of the numerous surface features. The anti-microbial effect 12 was tested by a zone of inhibition test as outlined in F.Y~rnrlP 1. ~ "
13 The results showed corrected zones of inhihition 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 ~:
catheter coated at the lower 'r/Tm value were more efficacious than those coated at higher 16 T/Tm value. ; -,'', ~;';;,'''~'' ,' 17 FY~mrllR 7 18 This example is inrln~led to demonstrate an anti-microblal coating formed ~ ~;
19 by DC magnetron sputt~ring on a commercial catheter. A teflon coated latex Foley 20 catheter was coated by DC magnetron spulL~ lg 99.99% pure silver on the surface using 21 the conflition~ listed in Table 5. The working gases used were commercial Ar and 99/1 22 wt% Ar/O2.
' ~',',.',i,.4''' 33 ~

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

2 ~
The anti-microbial ef~eet of the coating was tested by a zone of inhibition test.
2 Mueller Hinton agar was dispensed into Petri dishes. The agar plates were allowed to ."
3 surface dry prior to being inoc~ tPd with a lawn of Staphylococcus aureus ATCC# 25923.
4 The inoculant was prepared from Bactrol Dises (Difco, M.) which were recQn.~tit~t~d as S per the m~nllfarturer's directions. TmmP~i~tPly after inoculation, the coated m~tP.ri~ to 6 be tested were placed on the surface of the ag~r. The dishes were incubated for 24 hr. at 7 37~C. After this incubation period, the zone of inhibition was measured and a eorreeted :
8 zone of inhibition was cal~ tPd (corrected zone of inhibition = zone of inhibition ~
9 diameter of the test material in contaet with the agar). ~ ~ ;
' The results showed no zone of inhibition for the nneo~t~d sarnples and a eorreeted . .:
11 zone of less than 1 mm for eatheters sputtered in commercial argon at a working gas 12 pressure of 0.7 Pa (5 mT). A corrected zone of inhihition of 11 mm was reported for the 13 eatheters 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 eoating sputtered in 1% oxygen was a erystalline Ag film. ' 15 This strueture elearly eaused an improved anti-mierobial effeet for the eoated e~thPt~r.s.

16 Table S :
17 Cc- " ' of DC rla~ b S~ ~ ' Used for Anti ~i~lUI ~ ~ Coatings ~ :
18 ~ ' 19 Samples Spu~ered in C ~ ~ Argon Samples Sputtered in 99/1 wt% Ar/O2 21 Power o.l kW Power o.s kW ; ;
22 Target 20.3 cm dia. Ag Target 20.3 cm dia. Ag 23 Argon Pressure: 0.7 Pa (5 m Torr) . Ar/O2 Pressure: s.3 Pa (40 m Torr) 24 Total Mass Flow: 700 sccm Total Mass Flow: 700sccm Initial Substrate T; ~ Ci. 200C Initial Substrate TC~ c~dt~ ~i. 20~C
26 Cathode/Anode Distance: 40 mm Cathode/Anode Distance: lOOmm ~ :
27 Film Tl ' ~ 2500 A Film T~ cc- 3000 A

~3~ g ~xample 8 2 This example demonstrates silver cQatings formed by arc evaporation, gas sc~tt~ring 3 evaporation (pressure plating) and reactive arc evaporation. Evaporation of 99.99% silver :
4 was performed onto silicon or alumina wafers at an initial substrate l~l-lpel~lurd of about ~ ~' 21~C, using the parameters as follows: : ;
6 Bias: -100 V
7 Current: 20 Amp-hrs - . .: .
8 Angle of in~i-lence: 90~
.
9 Working Gas Pressure: 0.001 Pa (0.01 mT) (arc), 3.5 Pa (26 mT) Ar/H2 96:4 (gas ~ - ;
scattering evaporation), and 3.5 Pa (26 mT) ~2 (reactive arc ev~ol~lion) 11 No corrected ZOI was observed for wafers coated at vacuum (arc). Pressure plating ~. ~
12 with a working gas atmosphere containing Ar and 4 % hydrogen produced a 6 mm ZOI, ' ~ ;
13 while a working gas atmosphere of pure oxygen treactive arc) produced an 8 mm ZOI.
14 Film thirl~nes.~es of about 4000 Angstroms were produced. The results indicate that the presence of gases such as hydrogen and/or oxygen in the arc evaporation atmosphere cause :
16 the coatings to have i~np~,d anti-microbial efficacy.
., i, 17 FY~mrl~ 9 :~ :
18 This example is included to illustrate C()lllpOSi~t: m~t~.ri~ to produce anti-19 microbial effects. A set of coatings were produced by RF magnetron syullefillg zinc oxide onto silicon wafers as outlined below. The zinc oxide coatings showed no zone of21 inhibition.
22 Coatings of Ag and ZnO were deposited to a total thi~kn~ s of 3300 .
23 Angstroms by sequentially sputtering layers of Ag with layers of ZnO, according to the . -~ .

2 ~ 3 ~
conditions below7 in a 75/25 wt% ratio. The coatings were demonstrated to have no zone 2 of inhibition when ~he zinc oxide layers were about 100 Angstroms t-h-ick. However, films 3 COI~SiSlillg 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 inhihition The con~lition.s used to deposit ZnO were as follows~
6 Target 20.3 cm dia. Zno; Working gas = argon; Working gas preissure = 4 Pa (30 mT); .
7 Cathode-Anode distance: 40 mm; Initial Substrate Tempel~lure; 21~C; Power: RF
8 magnetron, 0.5 kW. ~ ' 9 The con~lition.~ used to deposit the Ag were as follows: , ';
10 - - Target 20.3 cm dia. Ag; Working gas = argon; Working gas pressure = 4 Pa (30 mT); : ~
11 Cathode-Anode distance = 40 mm; Initial Substrate Temperature = 21~C; Power = DC ' 12 magnetron, 0.1 kW.
: '', '''~''~
13 F~i~mple 10 14 This 0xample demon~qtr~tes the effects of cold working and ~nnP~Iing silver ; ~ '~
15 and gold powders on the anti-microbial efficacy ~emon~trated by a standard zone of 16 inhibition test. Cold working of such powders results in a defective surface structure ; -' 17 Co~ i"ill~ atomic disorder which favours the release of ions causing anti-microbial -:
18 activity~ The anti-microbial effect of this defective stmcture can be removed by ~nn~ling 19 Nanocrystalline silver powder (crystal size about 30 nm) was spr~nkl~.d onto ;~
adhesive tape and tested. A zone of inhibition of 5 mm was obtained, using the method '' ~ ; ' 21 set forth in F.Y~mrle 7. A 0.3g pellet of the nanocrystalline Ag powder was pressed at -- ' 22 275,700 kPa (40,000 psi). The pellet produced a 9 mm zone of inhibition when tested for 23 anti-microbial activity. Nanocyrstalline silver powder was m~ck~niri~lly worked in a ball ~ -... . . ~ , . . ~

2 ~
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~itinnC and p:lacing the pellet on the plates. The 4 zones of inhibition observed were 7 and 11 mm fes~e~ilively. A pellet that had been 5 pressed from the worked powder was ~nn~lP.d at 500~C for 1 hour under vacuum 6 conditions. A reduced zone of inhibition of 3 mm WilS observed for the ~nnP~lPd pellet.
7 These 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 mPçh~nir~l working of the powder in a ball mill or by 10 pressing it into a pellet. The anti-microbial effect was si~nifl~ntly decreased by ~nnP~1in~
11 at 500~C. Thus, con~litionc of mechanical working should not include or be followed by 12 conditions such as high lelllpela~ult;, which allow diffusion. Cold mpch~nic~l working 13 con~ition.~ are preferred to limit diffusion, for example by working at room temperature 14 or by grinding or milling in liquid nitrogen.
Silver powder, 1 micron particle size, was tested in a manner similar to 16 above. The Ag powder sprinklPd onto adhesive tape and tested for a zone of inhibition.
17 No zone of inhibition was observed. The powder was worked in a ball mill for 30 seconds 18 and sprinklPd 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 mPch~nic~l working in the ball mill) was pressed into a 0.3 g pellet using 275,700 kPa (40,000 psi), zones of inhibition ~ : :
21 of 5 and 6 mm respectively were observed. A pellet which was formed from the ball ;
22 milled powder and which was ~nne~lP.d at 500~C for 1 hour had .~i~nifir~ntly 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 5 ~
pellet which had not been ~nne~lPd continued to give a zone of inhibition greater than 4 2 mm even after 14 repeats of the test. This demonstrates that an ~nne~linE step, following 3 by mpch~nical working, limits the sustainable release of the anti-microbial silver species 4 from the powders.
S Nanocrystalline gold (20 nm crystals), supplied as a powder, was tested for : - .
6 anti-microbial effect by sprinklin~. 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 (40,000 psi). A 10 mm 9 zone of inhibition was observed. When the pressed pellets were subse~luenlly vacuum ~nnealPd at 500~C ior 1 hour and the zone of inhibition 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 mech~ni~l working process such as pressing a 13 nanocrystalline material into a pellet. The anti-microbial activity can be removed by 14 ?~nnP~ling Cold working is preferred.
Other gold powders inclll~ing a 2-5 micron and a 250 micron particle size 16 powder did not demonstrate an anti-microbial effect under the above mPcll~nic~l working 17 cnn~ition.~. It is believed that the small grain size of the nanocrystalline gold powder was . . . - ,, .
18 an inlpu~ cofactor which, with the mechanical working, produced the desired anti- ' 19 microbial effect.

20 PY~mrlP 11 21 This example is inclu~ed to demonstrate a composite anti-microbial coating 22 formed by reactive sputtering (another example of composite films). FY~mplP 7 23 ~P~mon~ctrates that an anti-microbial coating of silver can be obtained by sputtering in argon : ; - ;.' ~13~5~
and 1% oxygen (0.5 kW, 5.3 Pa (40 mTorr), 100 mm anode/cathode ~i~t~nce, and 20~C -2 produced a zone of inhibition of 11 mm).
3When a working gas of argon and 20 wt% oxygen was used to sputter anti-4microbial coatings under the contlitionc listed in Table 6, the zones of inhihiti~n ranged -Sfrom 6 to 12 mm. This in~1ic~tes 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 parameters.
8Table 6 - Sputtering Con(lition.~ ~
9 Target 20.3 cm dia., 99.99% Ag '.
Working Gas: 80/20 wt% Ar/O2 11 Working Gas Pl~ss,llt;; 0.3 to 6.7 Pa (2.5 to 50 mTorr) 12 Total Mass Gas Flow: 700 sccm 13 Power: 0.1 to 2.5 kW - ;~
14 Substrate Temperature: -5 to 20~C
Anode/Cathode Distance 40 to lOO mm 16 Base Pressure: less than 5 x 10 4 Pa (4 x 10 6 Torr) 17 RY~mpl~. 12 18This example demon~ales that the coatings of this invention have an anti-19 microbial effect against a broad S~JeCIlUIII of bacteria.
, ~:
A total of 171 different bacterial samples enco,.,~ i.. g 18 genera and 55 21 species were provide by the Provincial Laboratory of Public Health for Northern Alberta 22 These samples had been quick frozen in 20% skim milk and stored at -70~C for periods 23 ranging from several months to several years. Fastidious olgd~ lllS which were unlikely 24 to grow under con~itiQn.~ used in standard Kirby-Bauer susceptibility testing were not used.
Each frozen sample was scraped with a sterile cotton swab to inoc~ t~. a 26 blood agar plate (BAP). The plates were incubated overnight at 35~C. The following 27 morning isolated colonies were s~hc~lltllred onto fresh BAPs and in~ bated a~ 35~C

2 11 3 ~
overnight. The next day, the organisms were subjected to Kirby-Bauer susceptibility 2testing as described below. - ~ ' . ~.
3Four to five colonies (more if colonies were small) of the same '~
4 morphological type were selected from each BAP subculture and inocul~t~.d into individual 5tubes col~lA;~ g appl.~Ahllately 5 mL of tryptic soy broth (TSB). The broths were '~
6 incubated at 35~C for approxim~t~ly 2 to 3 hours. At this time, the turbidity of most of 7 the broth cultures either equalled or çxree-led that of a 0.5 McFarland standard. The more .: .~ ,:, - .
8 turbid samples were diluted with sterile saline to obtain a turbidity visually comparable to : , ~ .
9 ~ that of the standard. To aid in the visual ~ses~m~nt of turbidity, tubes were read against 10 ' a white bacl~luulld with co~ lillg black line.
..: ..
11A small number of the û~dlliSIllS (Streptococcus and Corynebacterfum) did ~ ' 12not grow well in TSB. The turbidity of these broths, after incllb~tion~ was less than that ~ ' ..., ~
13 of the 0.5 McFarland standard. Additional colonies from the BAP s~hcllltnres were 14 inocul~t~.d to these tubes to increase the turbidity to approxi-llate that of the standard.
15Within 15 minutes of adjusting the turbidity of the bacterial s1l~pens;on~ a 16- sterile cotton swab was dipped into each broth. Excess fluid was removed by rotating the ~
17swab against the rim of the tube. The inoculum was applied to a Mueller Hinton (MH) ;
18 agar plate by streaking the swab evenly in three directions over the entire agar surface.
19 Three 1 cm x 1 cm silver coated silica wafer squares were applied to each MH plate and 20 the plates were inverted and incubated overnight at 35~C. The coatings had been sputtered .. ~ .....
21under the following con-lition.~, which through XRD analysis were shown to be silver/silver - ~ ~
.. . i, 22 oxide composite films~
~: .- ' .

- .: ~ .-;

. .. , ~,, ' !

2 ~ 3 ~ 6 Target: 20.3 cm dia., 99.99% Ag ~ ~ -2 Working gas: 80l20 wt % Ar/O2 ~ ~
3 Working gas pressure: 5.3 Pa (40 mT) ~ ~-4 Total Mass Gas Flow: 700 sccm '~' S Power: 0.1 kW
6 Te~lre~ e of Deposition 20~C
7 Base pressure 2.7 X 104 Pa (2 x 10-6 Torr) 8 Cathode/anode distance 40 mm ~ ':
9 BAP cultures of control organisms were provided by the Provincial ' ~"
Laboratory and in~.lu(led Staphylococcus aureus ATCC 25923; Pseudomonas aeruginosn 11 ATCC 27853; Escherichia coli: ATCC 25922; and Enterococcus faecalis ATCC 29212 to 12 check the quality of the MH agar. These cultures were treated in a like manner to the test ~;
13 OrgdlliSIllS except that standard antibiotic discs rather than silver coated wafers were 14 applied to the bacterial lawns on the MH agar. These organisms demonctr~ted that the MH
~15 agar was suitable for standard ZOI tests.
16 After 16 to 18 hours of incllbation at 35~C zones of inhibition around the ~ ' 17 silver wafers or antibiotic discs were measured to the nearest mm. Corrected zones were ' 18 calculated by subtracting the size of the wafer (1 cm) from the size of the total zone.
19 Replcsell~a~i~re zone of inhi~iiion results are shown in Table 7.

. ~

:' ''' '~....'....
- .
....: ... .: .
,'. '' ' '''"'''' 41 : ~ ~
'''...,.'.'.' ,,'.

.~

~13~C~5~
Table 7 2 The Sensitivity of a Broad Range of Microorganisms to Silver* Coated Silicon Wafers ~- Organism Source Corrected Zone of :~
4 Inhibition (mm) -epidermidis RC-455 blood 10 . .
Il 8acillus l ' ~ . ' R-2138 tibia 6 _;. C~ , sp R-594 leg 10 _, :: ~ :
_ J Listeria ~ ~.Jt.g~ . R-590 blood 5 _'~ r ,),.o.,~u~faecalis SR-113 bone 5 .
_i~ : ~:
St,.. t. bovis SR-62 blood 10 ; '; Escherichia coli R-1878 urine 11 ,; Klebsiella ozonae R-308190 abdomen 10 _' r s~ cloacae R-1682 unknown 8 .
:' Proteus vulgaris 3781 urinc 4 :
,~ Providencia stuarSii U-3179 urine 8 ,' Ci~robac~erfreundii U-3122/90 udne 7 J; Salmonella IJ,." ' ' ER-1154 urinc 6 .: -;
J l : ' _~ Serraria matcescens R-850 sputum 6 : :
~ ..... .
J~ F, '( aetuginosa U-3027 urinc 10 Y ' . mallophila 90-lOi3 unknown 9 ~etomonas caviae R-1211 wound 5 :
,~ catarthalis R-2681 unknown 12 . - -~J Silvcr deposition~
:' .
44 F.lr~mple 13 45This example demonstrates the use of t~nt~ m 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, improves adhesion of thin films to substrates. In this example test sections 48 incll,~in~ 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 (5 cm) were cleaned in ethanol and then half of the test 50 sections were coated (by sputtering) with a thin layer (approx. 100 Angstroms) of Ta ..
42 ; ~

. ..: . : ~.

before an anti-microbial sllver film was deposited on tnem. The second group of the test 2 sections were only coated with the anti-microbial Ag film. Coating con~ition.~ 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 section.~. Adhesion S properties were dete~,rnined using ASTM metnod D3359-87, a standard test metnod for 6 mç~uring ~h~ion 7 Sputtering C~ ;" .
8 Target: 20.3 cm dia., 99.99% Ta ~ -~
9 Working Gas: 99/1 wt% Ar/02 ~ . '' Working Gas Pressure: 1.3 Pa tlO mTorr) : - ' ' 11 Total Mass Gas Plow: 700 sccm 12 Power: 0.5 kW ' -13 Cathode/Anode Distance: 100 mm 14 Substrate Te.llpela~ure: 20~C
Target: 20.3 cm dia., 99.99% Ag 16 Working Gas: 99/1 wt% Ar/O2 17 Working Gas Pressure: 5.3 Pa (40 mTorr) 18 Total Mass Gas Flow: 700 sccm 19 Power: 0.5 kW
Cathode/Anode Distance: 100 mm 21 Substrate Temperature: 20~C

22 ~ 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 cc,llllllel~;ial argon moi~tnri~d ;~
with water as tne working gas at a total mass gas flow of 700 sccm. The argon was - ' -26 moi~tllri7~d by passing it through two flasks cq~ ;n;.lg 3 litres of room L~lllpefaLul~: water '~
27 and one empty flask set up with glass wool to absorb any free liquid before the gas entered .
28 the spuLLelillg unit.
:' ;"''~'''"

21 36~5 ~
~ .
The conditions of spu~tering and the results of the standard zone of ~ :
2 inhibition 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 ~u~ d : ....
5 using a argonlwater vapour mixture as the working gas.
:: ., 6 Tabl~ 8 8 Crm~litin~~~ used for DC Magnetron Sputtering of Anti ~ ul/;dl Caotings f'~ Wo~king Gas Working Gas Power Substratc Anode/Cathoda Corrected ~ ~ :
Pressure Tempcrature Distancc ZOI :~ -- ::
1;. Pa (mT) :: :
1 ~ .
13 Commercial Argon 1.3 (10) 0.5kW -IO~C lOO mm O mm 14 Ar passed through ~110 1.3 (10) 0.5kW IO'C 100 mm 8 nun i .

17 RY~mplç 15 18 This example illll5trat~5 the structural and ch~miç~l cha~a(~le~ lies of sputter 19 deposited silver films that exhibit good anti-microbial activity (corrected zone of inhihition, CZOI) using the zone of inhihition test as set forth in previous eY~mrles. The films were ;;; -::
21 produced by sputtering of a solid 20.3 cm dia. planar silver mangetron target onto silicon 22 wafer substrates (100 mm from the target) under the conflitinn.~ snmm~ri7Pd in Table 9.
23 The total mass gas flow was 700 sccm. The ratio of substrate temperature to melting point .
24 of silver (1234K), T/Tm~ was less t-h-an 0.3, the 11lir~ lle~.~ of the film was nomin~lly 3000,~
....- ~ . ~, -.
and the angle of inri(l~nre in each case was 90~ (normal in~ nre3. The C~ tir~ -26 of as deposited silver as well as those that were subsequently annealed (in air at 140~C for i 27 90 minutes) are described in this eY~m~ The films were characteri~ed in terms of ~ -~
28 structural (grain size, type of defects, recrystallization) and çh~mi5a1 properties (dopant , . . .- .~

~ c~ 5~

concentration (wherein dopant refers to atomic %O or oxide content), and electrochemical 2 rest potential). The results are snmmAri~-d in Tables 10 and 11.
3 The dopant concentration in $he film was measured using x-ray4 photoelectron spectroscopy (XPS) and secondary ion mass spe~;LIull~etry (SIMS). In the XPS technique a monochromatized Al Ka x-ray beam was used as the incident beam. A
6 4kV Ar ion beam was rastered over a 2 mm x 2 mm area in order to remove surface 7 co~ .,.in~ ; and expose a fresh surface for XPS analysis. A positive cesium ion beam 8 at 12.5 kV was employed for the SIMS analysis. The dopant concentration computed from 9 XPS and SIMS data is snmm~n~d in Tables 10 and 11 for both as deposited and ann~ d films. It can be seen that one preferred characteristic of biologically active silver films in 11 accoldance with the invention is the presence of a dopant. The XPS and SIMS data 12 further showed that the dopant, which in the present case was oxygen or both silver oxide 13 and oxygen, was not çh~mic~lly bound to the silver atoms in the buLk film. Moreover, the 14 dopant as oxygen was incoll.ola~ed in such amounts as to exceed the room temrer~tllre solid solubility in silver.
16 The grain size of as deposited and ~nn~ d films was measured from 17 images taken with a tr~n~mi.~ion electron micloscope (TEM). These data, reported in 18 Tables 10 and 11, demonstrate that anti-microbial active silver films of this invention have '.. '.:
19 an average grain size smaller than 200 nm. Active films, as deposited, had an average 20 grain size less than about 140 nm. The most active films, as deposited, had an average 21 grain size less than 90 nm. In ~d~ition~ high resol~ltion tr~n.~mi.~.~ion electron microscopy 22 showed that the onset of reclyst~lli7~tion (Trec) comm~n~ed at about 90~C. Grain growth 23 of these fine grained, biologically active films, occurred at tempel~ es well below 0.33 24 Tm~ where Tm is the melting point of silver in degrees K, in particular below 140~C. In .: . , ,. ~
~' ~," . '. ...

2 1 ~ ~ 4~
general, recrystAl1i7;~tiQn ~i",il~isl1~d anti-rnicrobial activity. However, coatings with higher 2 levels of silver oxide (coatings 3 and 6) retained anti-microbial activity after ~nnP.~1ing 3 It is believed that the oxide pins s~lffi~iP~nt atomic defects so as to retain anti-lllicrobial 4 activity after ~nnP.~1in~
SThe TEM analysis further in~ t~d that biologically active silver films 6contained a number of growth twins. Upon ~nnP~1ing in air at 140~C for 90 minutes these 7 growth twins disappeared and ~nn~1ing twins appeared. These latter twins were, however, 8 the result of lecovel~, recryst~11i7:~tion and grain growth which transformed the silver film 9 into a lower energy state. Evidently, these deposited silver films, along with the as~soci~t~d l0 growth twins that underwent such grain growth, were in a higher energy state. Thus, the ll presence of these aforementioned defects in the as deposited films is a distinguishing 12 char~teri.~tic of anti-microbial coatings in accordance with this invention. Figures l and 13 2 are TEM micrographs showing the grain sizes and twins observed in as deposited and 14 ~nnP~1~d silver films l~,Dpe~iliv~ly.
15The rest potential of the silver films was measured in one molar (lM) 16 potassium hydroxide (KOH) solution using a saturated calomel electrode (SCE) as the 17 reference electrode. Tables l0 and ll show that the silver films exhibited anti-microbial 18 behaviour only when the rest potential was positive. No biological activity was observed l9 when the rest potential was negative.

: . . ~. .

,, ., ,.. . -'"'" ' "''''''i .. :,~, i,.

46 :-~::
213~5~
Table 9 . ~
2Growt'n Conditions for Sputte~ Deposited Silver Anti-microbial Coabngs : :
3 :
4 ID Nr,mber GROWTH CONDITIONS
Gas C .; Presslu~e Pa (mTorr) Power(kW) : ~
6 1 99% Ar, 1% 0 1.3 (10) 0.10 . ::
7 2 99% Ar, 1% 0 1.3 (10) 0.50 8 3 99% Ar, 1% 0 5 3 (40) 0 05 :
9 4 99% Ar, 1% 0 5.3 (40~, 0.10 - :~
99% Ar, 1% 0 5 3 (40) 0 50 : ~ :
11 6 80% Ar, 20% 0 5.3 (40) 0.10 : . : ~:

13 Table 10 14 - ~ St;uctural l~h .,. ~ h ~ of Sputter Deposited Silver ~ ~ ' Jl,ial Coaangs . ~ ..
_ ~ Growt'n Condition :.
ID Number . As Dc7,x7sited . ~
Grain Sizc Dopant Rest Potential Defects C Z O I ~ ' R

'~1 (nm) C~ ~ mV (mm~
Atomic 9toO (vs SCE~
,,. 1 37 5.5 ~125 Growt'n lwios 9 2 148 0 -342 ~ 2 ~ 3 21 20.0~ +150 Growth twins 10 _~ 4 19 8.0 l 135 Growth twins 7 ~,~ 5 41 3.4 +131 Growt'n twins 9 .:
_~, 6 22 58.0~ +146 - 8 :. :.'~
~ulk Sllvor ~200 0 -170 as Ag20 ~ These values are sub~,ect to vatiability of :i:20 mV . .
31 - not measured . . :: ~:::, . .;

.... .
':,''~,~'- :','.
..:: :::. i:i:

,""., ..1,", ii" .' i . ,, ~ -.. .:

47 :.i~.-:., . ~ ~, .. .
.. .''. :~: . , ''.'.'..

2 1 3 6 4~
... ...
Table 11 : -2 Struc~ral ch~ t ~ ;rs of Annealed Silver Anti-microbial Coatings ~ ;

Grow~ Condition - .
ID Numcer Annealed at 140~C, 90 Minutes n Grain Si~o Dopant Rest Potential Defeds C Z O I : ::
'' , '-(nm) r. . DnV (mm) : ' atonic ~OO (vs SCE) 91 - -6 Annealing twins 1 .; .
_ ~) 2 135 0 -224 Anncaling twins 0 _ ... 3 130 16.0~ +121 Anncaling twins 10 - S
__ 4 73 0.8 +33 Anncaling twins 8 _~ 5 132 0.7 -29 Anncaling tWiDs 0 .
_~ 6 - 31.0~+127 - 8 ~.' ::
_ ~i3ulk Silvcr ~200 0 -170 - d ~ : : :. . ' :'~
~ .:: . :: . .::
_ ~~ as Ag2O
18 ~ These values are subject to variability of +20 mV
19 - not measured All publications m~ntion~d in this sperifi~tion are indicative of the level '.
;. :.: .;
21 of skill of those skilled in the art to which this invention pertains. All pnhlil~tion~ are 22 herein incorporated by ~ererellce to the same extent as if each individual pnblic~tion was 23 spec-ifir~lly and individually indicated to be inco~ordted by reference. ' . "':. . .
~: . . .
.; :: ::., : .
24 The terms and expressions in this s~eC;ricfilion are used as terms of ... ' .. ...~ :~
description nd not of limit~tion. here is no intrnti~n, in using such terms and .'.. ''' 26 expressions, of e~clu~ing equivalents of the features illustrated and describe~ it being ... ' ' ~ ' 27 recognized that the scope of the in~tention is defined and limited only by ~e claims which 28 follow. . :. ' .

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

.

Claims (27)

1. A fine grain anti-microbial material, comprising:
one or more anti-microbial metals, or alloys or compounds thereof in the form of a fine grain powder, having a grain size less than 200 nm, characterized by sufficient atomic disorder such that the material, in contact with an alcohol or a water based electrolyte, provides a sustained release of atoms, ions, molecules or clusters containing at least one metal at a concentration sufficient to provide a localized anti-microbial effect, wherein the anti-microbial metal is formed in a matrix with atoms or molecules of a different material, the different material being selected from inert biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulphur, halogen, and oxides, nitrides, carbides, borides, sulphides and halides of either or both of an anti-microbial metal or an inert biocompatible metal.

2. The anti-microbial material 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, and Zn or an alloy or compound thereof, and wherein the biocompatible metal is selected from the group consisting of Ta, Ti, Nb, B, Hf, Zn, Mo, Si, and Al.

3. The anti-microbial material as set forth in claim 2, wherein the anti-microbial metal is selected from Ag, Au or Pd, and wherein the biocompatible metal is selected from Ta, Ti or Nb.

4. The anti-microbial material as set forth in claim 1, comprising substantially pure silver metal, silver oxide and trapped or absorbed atoms of oxygen.

5. The anti-microbial material as set forth in claim 1, 2, 3, or 4 in the form of a nanocrystalline powder having a grain size less than about 20 nm.

6. The anti-microbial material as set forth in claim 1, 2, 3, or 4 in the form of a fine grain powder having a grain size less than about 140 nm.

7. The anti-microbial material as set forth in claim 1 wherein the anti-microbial metal is silver, or an alloy or compound thereof and wherein the material is characterized as having a positive rest potential, when measured against a saturated calomel reference electrode, in 1M potassium hydroxide and having a ratio of its temperature of recrystallization to its melting temperature, in degrees K, (Trec/Tm), less than 0.33, and which, in contact with an alcohol or a water based electrolyte, releases atoms, ions, molecules or clusters containing silver or a sustained basis at a concentration sufficient to provide a localized anti-microbial effect.

8. The material as set forth in claim 7, wherein the material is further characterized in that the ratio of its temperature of recrystallization to its melting temperature, in degrees K, (T rec/Tm), is less than about 0.3

9. The material as set forth in claim 7, wherein the material is further characterized in that it has a temperature of recrystallization less than about 140°C.

10. The material as set forth in claim 9, wherein the material is further characterized in that it has a grain size less than about 200nm.

11. The material as set forth in claim 9, wherein the material is further characterized in that it has a grain size less than about 140nm.

12. The material as set forth in claim 9, wherein the material is further characterized in that it has a grain size less than about 90nm.

13. The material as set forth in claim 9, in the form of a nanocrystalline powder.

14. The material as set forth in claim 10 or 13, in the form of a mixture of substantially pure silver metal and silver oxide.

15. The material as set forth in claim 10 or 13, in the form of substantially pure silver metal and absorbed, trapped, or reacted atoms or molecules of oxygen.

16. The material as set forth in claim 15, which further includes silver oxide.

17. A method of producing a fine grain anti-microbial material, comprising:
depositing one or more anti-microbial metals in a matrix with atoms or molecules of a different material, in a powder form, by vapour deposition onto a cooled substrate, to provide a material having atomic disorder such that the powder, in contact with an alcohol or a water based electrolyte, provides a sustained release of ions, atoms, molecules or clusters of at least one of the anti-microbial metals into the alcohol or water based electrolyte at a concentration sufficient to provide a localized anti-microbial effect, wherein the different material is selected from the group consisiting of inert, biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulphur, halogens, and oxides, nitrides, carbides, borides, sulphides and halides of an anti-microbial metal or an inert, biocompatible metal.

18. The method as set forth in claim 17, wherein the anti-microbial metal 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, and wherein the biocompatible metal is selected from the group consisting of Ta, Ti, Nb, B, Hf, Zn, Mo, Si and Al or alloys or compounds of one or more of these metals.

19. The method as set forth in claim 17, wherein the anti-microbial metal is selected from Ag, Au, and Pd, and wherein the biocompatible metal is selected from Ta, Ti, and Nb.

20. The method as set forth in claim 19, wherein oxygen is included in the working gas atomosphere during vapour deposition such that atoms or molecules of oxygen are trapped or absorbed in the matrix.

21. The method as set forth in claim 20, wherein the anti-microbial metal which is deposited is substantially pure silver metal or silver oxide and wherein oxygen may be included in the working gas atmosphere such that the deposited material includes substantially pure silver metal, and one or both of silver oxide and atoms or molecules of trapped or absorbed oxygen.

22. The method as set forth in claim 17, 18, or 19, wherein the material is deposited as a fine grain powder.

23. The method as set forth in claim 17, 18, or 19, wherein the material is deposited as a nanocrystalline powder.

24. The method as set forth in claim 17, 18, or 19, wherein the material is deposited as a nanocrystalline film.

25. The method as set forth in claim 17, 18, or 19, wherein the fine grain anti-microbial material has a grain size less than about 200nm.

26. The method as set forth in claim 17, 18, or 19, wherein the fine grain anti-microbial material has a grain size less than about 140nm.

27. The method as set forth in claim 17, 18, or 19, wherein the fine grain anti-microbial material has a grain size less than about 90nm.