RU2167526C2 - Antibacterial materials - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention relates to antibacterial coatings and powders, methods of their application on medicinal devices. Coatings and powders are obtained preferably in precipitation of an antibacterial biologically compatible metal by method of vacuum precipitation from vapor phase. Atomic disorderness making in coating results to the prolonged release of metal ions and attainment of antibacterial effect. EFFECT: improved method of making, antibacterial effect. 53 cl, 16 tbl, 25 ex

Description

 The invention relates to methods for creating antimicrobial metal coatings, thin films and powders which, upon contact with alcohol or an electrolyte, provide a sustained release of antimicrobial metals.

 In medicine, there has long been an urgent need for effective antimicrobial coatings. Doctors of various specializations, and especially surgeons who use numerous medical instruments in their work: from orthopedic pins, metal plates and implants to dressings and ureteral catheters placed on the wound, must constantly take care to prevent infection. Inexpensive antimicrobial coating also finds application in health care aimed at consumers in the production of personal hygiene products, as well as in the creation of biomedical / biotechnological laboratory equipment. The term "medical device" in the context of the present invention extends to all such products.

 The antimicrobial effect of metal ions such as Ag, Au, Pt, Pd, Ir, (i.e., noble metals), Sn, Sb, Cu, and Zn is well known (see Morton N.E., Pseudomonas in Disinfektion, sterilization and Preservation, Ed. SS Block. Lea and Febiger, 1977 and Grier N, Silver and Its Compounds in Disinfection, Sterilization and Preservation, Ed. SS Block, Lea and Febiger, 1977).

 Of all the metal ions with antimicrobial properties, the effect of silver is probably the best known due to the unusually high biological activity of this metal at low concentrations. This phenomenon is known as oligodynamic action. In modern medical practice, both inorganic and organic soluble silver salts are used to prevent and treat bacterial infections. Due to the fact that such compounds are effective in the form of soluble salts, they cannot provide long-term protection against infection due to the loss of free silver ions through their leaching or complexation. Therefore, to solve this kind of problem, these compounds must be reused. And repeated use is not always possible in medical practice, especially in the case of using a vital or implantable device.

 Attempts have been made to slow the release of silver ions during treatment by creating silver-containing complexes having a lower degree of solubility. For example, US Pat. No. 2,785,153 discloses a colloidal silver protein proposed for this purpose. Such compounds are usually prepared in the form of creams. However, these compounds are not widely used in the medical field due to their limited effectiveness. The release rate of silver ions in this case is extremely low. In addition, coatings prepared on the basis of such compounds have limitations associated with problems of adhesion, poor scrapability and shelf life.

 It has been proposed to use silver-containing metal coatings as antimicrobial agents. (In particular, see: Dsitch et al., Anti-mikrobial Agents and Chemotherapy, Vol. 23 (3), 1983, pp. 356-359 and Mackeen et al., Anti-mikrobial Agents and Chemotherapy, Vol. 31 ( 1), 1987, pp. 93-99). In general, however, it is generally accepted that such coatings alone do not provide the required degree of efficiency, since only a slight diffusion of silver ions from metal coatings occurs.

 Silver metal coatings are manufactured by Spire Corporation, USA (SPI-ARGENT) under the trade name SPI-ARGENT. The coating is created using an ion beam that accompanies the application process. An infection resistant coating does not penetrate into aqueous solutions, as shown by zonal inhibition tests, which once again confirms the fact that silver metal coatings do not release silver ions in the amount necessary for antimicrobial action.

 In light of the failure to use metallic silver coatings to create the desired antimicrobial efficacy, a number of other studies have paid attention to the study of new activation methods. One such technology utilizes the electrical activation of metallic silver implants (see Marino et al. Journal of Biologikal Physics, Vol. 12, 1984, pp. 93-98). Electrical stimulation of metallic silver is not always practically possible, especially in the case of mobile patients. Attempts to overcome this problem include amplification of in situ electrical processes using galvanic cells. Metal strips or layers of various metals are applied to the device in the form of thin film coatings. A galvanic cell is formed in the process of contacting with each other two metals placed in an electrically conductive liquid. In this case, one of the metal layers acts as an anode that dissolves into the electrolyte. And the second metal functions as a cathode supplying the electrochemical cell. So, for example, in the case of alternating layers of Cu and Ag, Cu plays the role of an anode that releases Cu + into the electrolyte. More noble metals, such as Ag, act as a cathode that does not undergo ionization and does not pass into solution in large quantities. An illustration of a device of this kind is the device disclosed in US Pat. No. 4,886,505 (Hfaynes et al. Issued December 12, 1989). The patent discloses coatings obtained by sputtering two or more different metals in the presence of such a switch to one of them that if the switch is closed, the release of the metal ion is achieved.

 In previous works it was shown that it is possible to obtain a film consisting of thin alternating layers of various metals, such as silver and copper, for the purpose of dissolving them if the surface was initially etched. In this case, the etching process leads to the formation of a highly textured surface (see M. Tanemura, J. Vac. Sci. Tecnol, 1986, 5, 2369-2372). It should be noted, however, that the creation of such multilayer films is a lengthy and expensive process.

 However, electrical stimulation of metal coatings does not provide an acceptable solution to the dissolution problem. It should be noted that galvanic action occurs in the case of the presence of an electrolyte and a bond between two metals in a galvanic pair. Since galvanic corrosion occurs, which occurs primarily at the separation of the boundary between two metals, the electrical contact cannot be maintained for a long time. And therefore, the constant release of metal ions over a long period of time is impossible. In addition, the galvanic action of the release of metal, such as silver, is difficult to achieve. As mentioned above, metal ions with antimicrobial activity are noble metals such as Ag, Au, Pt and Pd. There are few metals that are nobler than the ones mentioned above, which can serve as cathodes that promote the release of a noble metal, such as Ag, on the anode.

A second approach to activating a metal surface involves heating or using chemicals. US Pat. Nos. 4,467,590 and 4,615,705 to Scales et al. issued respectively on October 16, 1980 and October 7, 1986) discloses methods for activating silver surface coatings applied to implantable prostheses in order to make them resistant to biological erosion, as a result of which the latter occurs when heated above 180 ^o C and in contact with peroxide hydrogen. However, the proposed type of processing is limited to the substrate / devices that may be subjected to such a coating and further activation.

Thus, there is still a need for an effective, inexpensive antimicrobial material that has the following properties:
- prolonged release of an antimicrobial agent in therapeutically high concentrations;
- applicability in a variety of devices and materials;
- acceptable shelf life; and
- low toxicity to mammals.

 Metallic coatings are produced in the form of thin films by a vapor deposition technique, such as, for example, spraying. Thin films of metals, alloys, semiconductors and ceramics are widely used in the manufacture of components of electronic devices. For these and other types of their final application, thin films are required to be made in the form of dense, crystalline structures with a minimum number of defects. Films are often calcined after application to enhance graininess and the process of recrystallization with the creation of stable properties. A review of the technologies for applying metal films was made by Bunshah et al. and Thornton (Bunshah RF et al., "Deposition Technologies for Films and Coatings" Noyes Publication, NJ, 1982 and JA Thornton, "Influence of Apparatus Geometry and Deposition Conditions on the Structure and Topography of Thick Sputtered Coatings", J. Vac. Sci. Technol., 11 (4), 666-670, 1974.

US Pat. No. 4,325,776 (Menzel, issued April 20, 1982) discloses a method for producing a coarse-grained coating or films containing single metal crystals for use in integrated networks. Metal films are obtained by precipitation on a cooled substrate (below 90 ^° ) so that the metal layer is in an amorphous phase. Then the metal layer is annealed during heating of the substrate to about room temperature. The final product has granularity of large diameter and high homogeneity, which allows to achieve higher densities without interference in the form of electromigration.

Silver salts such as nitrate, protein derivatives, acetate, lactate and citrate have been proposed for use in antimicrobial coatings for medical devices. In many hospitals, silver nitrate is used in dressings applied to burn wounds. It is known that such salts are more effective than silver metal. The mechanism by which the high efficiency of such compounds is achieved is associated with the presence of constant ionization / dissociation, which creates an Ag ⁺ ion. The availability of silver ion is significantly reduced inside the body or in contact with fluids or tissues. Due to the high chloride content in such liquids, silver precipitates or binds in the form of insoluble silver chloride (K _sp = 1.7 • 10 ^-10 M). As a result of this process, in order to achieve the silver salt of the same efficiency as in the case of water, an excess amount of silver must be present in any media containing precipitation (mainly chloride).

 Nanocrystalline materials in the form of powders, films and flakes are single-phase or multiphase polycrystalline materials, the grain size of which in at least one dimension is several (usually <20) nanometers. Fine powders (particle size <5 microns) can be nanocrystalline or, more typically, have a size> 20 nm. Nanocrystalline materials and fine-grained powders can be prepared using numerous gas condensation methods, in which the deposited material, which is mainly in the vapor phase, in the case of, for example, evaporation or spraying, is transferred further to a relatively large volume in which it is possible to control the parameters of the medium, formed by the working gas, as well as temperature. The atoms of the deposited material collide with the atoms of the working gas, after which they quickly condense from the vapor phase to a cold substrate, such as a finger-cooled liquid nitrogen. In principle, any method that can be used to produce very fine-grained polycrystalline materials is suitable for producing nanocrystalline materials. In particular, such methods include evaporation, such as arc evaporation, vapor deposition from an electron beam, molecular beam epitaxy, ion flux, sputtering, magnetron sputtering and reactive sputtering (see, for example, Froes FH et al., " Nanocristalline Metals for Structural Applications ", JOM, 41 (1989), N 6, pp. 12-17 :, Biringer, Rainer et al.," Nanocristalline Materials - A Fist Report, Proceedings of JIMIS-4; and Gleiter H., "Materials with Ultrafine Microstructure: Retrospectives and Prospectives", Nanostructured Materials, Vol. 1992, 1, pp. 1-19 and references cited therein).

 The present invention is directed to the creation of a metal coating. It was found that, despite the previously opposite point of view, it is possible to obtain metallic coatings from an antimicrobial metallic material by creating atomic disorder in the materials during vapor deposition under conditions restricting diffusion, which allows to achieve “freezing” of atomic disorder. It was found that the antimicrobial coatings thus obtained provide a sustained release of various types of metal into the solution in order to achieve an antimicrobial effect.

 The main discovery regarding the relationship between "atomic disorder" and increased solubility has many practical applications. The present inventors have shown that atomic disorder affecting solubility can be created in other forms of materials, such as, for example, metal powders. The present invention also has applications outside of antimicrobial metals, extending to any metal, metal alloy or metal compound, including including semiconductor or ceramic materials, from which it is necessary to obtain a prolonged release of a metal in solution. So, for example, materials with increased or controlled solubility of the metal have found practical application in sensors, switches, fuses, electrodes and batteries.

 Used in the context of the present invention, the term "atomic disorder" includes the presence of high concentrations: point defects in the crystal lattice, crystal lattice vacancies, linear defects such as dislocations, intermediate atoms, boundaries between grains and inside grains, and others related to the violation of normal ordered crystalline state. Atomic disorder leads to irregularities in the surface topography and the inhomogeneity of the structure within the nanometer scale.

 The term "normal ordered crystalline state" in the context of the present invention means crystallinity normally detected in large volumes of metal materials, alloys or compounds formed by smelting, pressure treatment or electrodeposition of metal products. These materials contain only low concentrations of atomic defects such as crystal lattice vacancies, grain boundaries, and dislocations.

 The term "diffusion" in the context of the present invention includes the diffusion of atoms and / or molecules on the surface or matrix of the formed material.

 The term "metal" or "metals" in the context of the present invention refers to one or more metals, which are essentially in the form of pure metals, alloys or compounds, such as oxides, nitrides, borides, sulfides, halides or hydrides.

 The invention, in a broad aspect, relates to a method for producing a modified material containing one or more metals. Said method comprises creating atomic disorder in a material under conditions restricting diffusion, so that a sufficient level of atomic disorder is maintained in the material, capable of releasing, preferably on a long-term basis, atoms, ions, molecules or clusters of at least one metal in a solvent in which this material is located. Clusters, as you know, are small groups of atoms, ions, or others, described by Andreev et al. (R. P. Andres et al., "Research Opportunities on Cluster and Cluster-Assembled Materials", J. Mater. Res., 1989, Vol. 4, No. 3, p. 704).

 Specific preferred embodiments of the invention show that atomic disorder can be created in metal powders or thin films by cold working, and in metal coatings by vapor deposition at low substrate temperatures.

 In another broad aspect, the invention relates to a modified material comprising one or more metals in a form characterized by a sufficient degree of atomic disorder, as a result of which the material, upon contact with a solvent of this material, releases atoms, ions, molecules or clusters containing at least one metal, preferably over an extended period of time, and at a higher rate than occurs under normal conditions in an ordered crystalline state.

 In preferred embodiments of the invention, the modified material is a metal powder, which is subjected to mechanical treatment or compression in cold conditions to create and maintain atomic disorder.

 The term "metal powder" in the context of the present invention includes metal particles in a wide range of particle sizes, ranging from nanocrystalline powders to flakes.

 The term "cold working" in the context of the present invention means that the material has been machined using methods such as crushing, grinding, forging, grinding in a mortar and pestle or compression, at temperatures below the crystallization temperature of the material. Such processing provides a guarantee that the atomic disorder created during it is preserved in the material.

In another preferred embodiment, the modified material is a metal coating formed on a substrate using vapor deposition techniques, such as vacuum evaporation, sputtering, magnetron sputtering, or ion galvanization. Under such conditions, a material is obtained in which diffusion is limited during the deposition and which limits the calcination and recrystallization processes following the deposition. The preferred deposition conditions used to create atomic disorder in the coatings go beyond the commonly practiced conditions for creating defect-free, dense, smooth films. The parameters of such normal conditions are well known (see, for example, the above work, RF Bunshah). Preferably, the deposition is carried out at low substrate temperatures, so that the ratio of substrate temperature to the melting point of the deposited metal or metal compound (T / T _m ) is maintained at a level of less than 0.5, more preferably less than 0.35 and most preferably less than 0.30. In terms of the ratio, the temperature is given in degrees Kelvin. Preferably, the ratio may vary from metal to metal, increasing in alloys or in the presence of an impurity. Other deposition conditions that are preferable for creating atomic disorder include one or more gases at a pressure higher than in the case of normal working gas pressure, a lower angle of incidence of the coating stream compared to the norm, and a higher coating stream than the norm.

The temperature of deposition or cold working is not practiced so low that when transferred to room temperature or to the temperature of the expected operating conditions (for example, body temperature in the case of antimicrobial materials), significant annealing or recrystallization processes do not occur. If the deposition temperature is too different from the temperature of use (ΔТ), annealing occurs, removing the atomic disorder. This ΔT value varies from metal to metal and depends on the deposition method used. So, for example, with regard to silver, during the physical vapor deposition, it is preferable to maintain the temperature of the substrate in the range from -20 to 200 ^o C.

 The normal or ambient pressure of the working gas, usually used for deposition in the case of need for dense, defect-free metal films, varies depending on the physical vapor deposition method used. In general, for the case of sputtering, the normal pressure of the working gas is less than 10 Pa (Pascals) (75 mT (milliTorr)), for the case of sputtering with a magnetron it is less than 1.3 Pa (10 mT) and for ion galvanization it is less than 30 Pa (200 mT ) The normal values of the working gas pressure vary depending on the methods of evaporation under vacuum as follows: in the case of e-rays or arc evaporation, from 0.0001 Pa (0.001 mT) to 0.001 Pa (0.01 mT); for gas scattering evaporation (electrodeposition under pressure) and reactive arc evaporation, up to 30 Pa (200 mT), however, in a typical case, it is lower than 3 Pa (20 mT). Thus, in accordance with the method of the present invention, in addition to using low substrate temperatures to achieve atomic disorder, it is practiced to apply a working gas pressure (or ambient gas) above the normally used values to increase the level of atomic disorder in the coating.

Another parameter that has been found to affect the level of atomic disorder in the coatings of the present invention relates to the angle of incidence of the coating stream during deposition. Typically, to obtain dense, smooth films, the value of this parameter is maintained at about 90 ^o +/- 15 ^o . In accordance with the present invention, in addition to low substrate temperatures during deposition used to achieve atomic disorder, angles of incidence below 75 ^° can be practiced to increase atomic disorder in the coating.

 Another process parameter that affects the level of atomic disorder relates to the flow of atoms to the surface to be coated. At the same time, high deposition rates lead to an increase in atomic disorder, and at the same time, high deposition rates also lead to an increase in the coating temperature. Thus, the optimal deposition rate is selected, which depends on the deposition technique used, the coating material and other process parameters.

 To create an antimicrobial material, the metals used in the coating or powder are selected among those that have antimicrobial activity and, moreover, are characterized by biological compatibility (non-toxic in the field of the intended use). Preferred metals include Ag, Au, Pt, Pd, Ir (i.e., noble metals), Sn, Cu, Sb, Bi and Zn, compounds of these metals or alloys containing one or more representatives of the indicated metal group. Such metals will hereinafter be referred to as "antimicrobial" metals. Most preferred are Ag or its alloys and compounds. In accordance with the present invention, antimicrobial materials are predominantly obtained with a sufficient level of atomic disorder, as a result of which the atoms, ions, molecules and clusters of the antimicrobial material are released for a long time into an alcoholic or aqueous electrolyte. The term "for a long time" in the context of the present invention is used so that it is possible to differentiate it, on the one hand, from the release obtained from ordinary metals, during which the release of metal ions and the like occurs. at a speed and concentration that are insufficient to achieve an antimicrobial effect, and on the other hand, from the release obtained from highly soluble salts, such as silver nitrate, in which almost constant release of silver ions occurs upon contact with an alcoholic or aqueous electrolyte. In contrast, the antimicrobial materials of the present invention release atoms, ions, molecules, and antimicrobial metal clusters at a sufficient rate and concentration for a sufficient period of time to provide a useful antimicrobial effect.

 The term "antimicrobial effect" in the context of the present invention means that the atoms, ions, molecules and clusters of the antimicrobial metal are released into the electrolyte with which the material is in contact, in concentrations sufficient to inhibit bacterial growth near this material. The most common way to evaluate the antimicrobial effect is to measure the zone of inhibition (ZOI) created by material placed on a bacterial lawn. A relatively low GI or its absence (less than 1 mm) indicates an unacceptable antimicrobial effect, while a higher value of GI (more than 5 mm) indicates an acceptable antimicrobial effect. Below in the Examples section is one of the procedures for testing the ZI.

 The invention also relates to devices, in particular to medical devices that are either made from or include such materials, carry them or are coated with antimicrobial powders or coatings. Antimicrobial coatings on medical devices such as catheters, suture material, implants, burn dressings, etc. can be directly applied using vapor deposition. An adhesive layer, such as tantalum, may be placed between the device and the antimicrobial coating. Adhesion can also be enhanced using methods known in the art, for example, by etching the substrate or by forming a mixed interface between the substrate and the coating by simultaneously spraying and etching. Antimicrobial powders can be incorporated into creams, polymers, ceramics, paints or other matrices using methods known in the art.

 In another broad aspect, the invention relates to the production of modified materials in the form of composite metal coatings containing atomic disorder. In this case, the coating of one or more metals or compounds released into the solution is a matrix that contains atoms or molecules of various materials. The presence of various atoms or molecules leads to atomic disorder in the metal matrix, due, for example, to different atom sizes. Various atoms or molecules may refer to one or more secondary metals, alloys, or metallic compounds that are deposited either together or sequentially on the first metal or metals to be released. Alternatively, various atoms or molecules can be absorbed or captured from the working gas of the medium during reactive vapor deposition. The degree of atomic disorder, and hence the solubility achieved with the inclusion of various atoms or molecules, varies depending on the material. To preserve and enhance atomic disorder in a composite material, one or more of the above described vapor deposition conditions, namely, low substrate temperature, high working gas pressure, low angle of incidence, and high coating flux, can be used in combination with the inclusion of other atoms or molecules.

 Preferred composite materials used for antimicrobial purposes are formed when atoms or molecules containing oxygen, nitrogen, hydrogen, boron, sulfur or halogens are incorporated into the atmosphere of the working gas during the deposition of the antimicrobial metal. These atoms or molecules are included in the coating upon absorption or upon capture in a film or upon reaction with a deposited metal. Both of these mechanisms used in the deposition are referred to below as "reactive deposition". Gases containing such elements, for example oxygen, hydrogen, and water vapor, can be supplied continuously or in the form of pulses in the case of sequential deposition.

 A preferred method for the manufacture of antimicrobial composite materials is also the co-or sequential deposition of an antimicrobial metal with one or more inert biocompatible metals selected from Ta, Ti, Nb, Zn, V, Hf, Mo, Si and Al. Alternatively, composite materials can be prepared by co-sequentially or reactively precipitating one or more antimicrobial metals in the form of their oxides, carbides, nitrides, borides, sulfides or halides and / or oxides, carbides, nitrides, borides, sulfides or inert metal halides. Most preferred composite materials contain silver and / or gold oxides, alone or in combination with one or more of Ta, Ti, Zn and Nb.

 The present invention also relates to a method for activating or enhancing an existing antimicrobial effect of antimicrobial materials formed in the presence of atomic disorder. Thus, the antimicrobial materials obtained in accordance with the present invention can then be irradiated to enhance the antimicrobial properties. However, it is possible to irradiate materials formed initially with a level of atomic disorder insufficient for the production of the antimicrobial effect, so that the irradiated material has an already acceptable antimicrobial effect. The activation process involves irradiating the material with a low energy loss per unit path length using beta or X-ray irradiation, and most preferably gamma rays. Use of a dose above 1 Mrad is preferred. The antimicrobial material is preferably oriented in a direction substantially perpendicular to the irradiation flow. The activation level can be further enhanced by irradiating a material similar in properties to the dielectric, such as Ta, Al and Ti oxides, and most preferably silicone oxide.

The invention also relates to the manufacture of antimicrobial silver materials, which upon contact with an alcoholic or aqueous electrolyte form silver complex ions that differ in properties from Ag ⁺ , Ag ² , Ag ³⁺ . It was shown that ions of silver complexes have unexpectedly significantly greater efficiency than Ag ⁺ released from silver salts, as was known in the art. Examples of silver complex ions include Ag (CN) ₂ -Ag (CN) _ag (ion pair), Ag (NH ₃ ) ₂₊ , AgCl _2- , Ag (OH) _2- , Ag (OH) _3- , Ag ₃ ( OH) _4- and Ag (S ₂ O ₃ ) ₂ ^3- . Silver coatings, such as powders, flakes and thin films, made in accordance with the present invention in the presence of atomic disorder, are examples of silver materials that release ions of silver complexes with characteristic antimicrobial efficacy. Alternatively, silver materials can be prepared as solutions, ointments, paints or suspensions containing ions of silver complexes. Such silver materials have a wide range of applications, for example, as coatings in medical devices, in antimicrobial compositions for local use, in antifouling paints or coatings of antimicrobial filters.

In the context of another broad aspect, the present invention relates to a method for achieving an antimicrobial effect, which includes the presence of an alcoholic or aqueous electrolyte, the preparation of a silver material so that it forms silver complex ions that are different in properties from Ag ⁺ , Ag ²⁺ and Ag ³⁺ , in an amount sufficient to achieve an antimicrobial effect upon contact with an alcohol or aqueous electrolyte, which is higher than the effect exerted by an equivalent amount of silver in the form of Ag ⁺ ; then bringing the silver material into contact with the surface to be treated, alcohol or electrolyte to release silver complex ions.

 In addition, the present invention relates to fine-grained antimicrobial materials in the form of fine powder, films or flakes, which include one or more antimicrobial materials or their alloys or their compounds having a grain size of less than 200 nm, to materials in the form of fine powder, films or flakes , which is characterized by the presence of atomic disorder sufficient to ensure that upon contact of the material with an alcohol or aqueous electrolyte, a prolonged release of atoms, ions, mol molecules or clusters of at least one antimicrobial metal into the alcohol or water based electrolyte at a concentration sufficient to achieve a localized antimicrobial effect.

 Antimicrobial material can be made by introducing atomic disorder into preformed thin grains of nanocrystalline (<20 nm) powder, flakes or films of one or more antimicrobial metals by mechanical processing, for example, by compressing the material under cold working conditions. Alternatively, atomic disorder can be created through the synthesis of fine-grained nanocrystalline materials (films, flakes or powders) using the vacuum deposition technique, during which a joint, sequential or reactive deposition of an antimicrobial metal occurs on a matrix with atoms or molecules of another material under conditions that allow create and maintain atomic disorder in the matrix. Another material (or additive) is selected from inert biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulfur and halogens, as well as oxides, nitrides, carbides, borides, sulfides and halides of either or both of the antimicrobial metal or biocompatible metal. Preferred biocompatible metals include Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al. Other materials may be incorporated into the antimicrobial metal at the same or separate site, for example, at the site of Ag and / or silver oxides, which may further comprise, for example. One or tantalum oxides. Alternatively, another material may be introduced from the working gas atmosphere during vapor deposition, for example by sputtering or reactive sputtering in an atmosphere containing atoms or molecules of another material, for example oxygen.

The antimicrobial form of the silver material prepared according to the method of the present invention was physically characterized, and the following new characteristics were obtained:
- positive residual potential E _rest , measured against a standard electrode saturated with calomel (NCE (SCE)) in 1 M potassium hydroxide;
- the preferred value of the ratio of the temperature of recrystallization to the temperature of the melting point in degrees K T _rec / T _m less than about 0.33, and most preferably
- less than about 0.30;
- a preferred recrystallization temperature is less than about 140 ^° C;
- a preferred grain size is less than about 200 nm, more preferably less than 140 nm, and most preferably less than 90 nm.

 It is believed that each of the above physical characteristics, with the possible exception, perhaps, only of particle size, is the result of the presence of atomic disorder in the material. These characteristics help to identify and differentiate silver materials of the present invention from materials of the prior art in an ordered crystalline state. Preferred new antimicrobial silver materials such as essentially pure metallic silver have been characterized using methods such as X-ray diffraction (XRD), X-ray electron spectroscopy (XPS) and secondary ion mass spectrometry (SIMS) when an inert gas such as argon. However, when the working gas atmosphere contains oxygen, the materials include a matrix of substantially pure metallic silver and one or both of: silver oxide and atoms or molecules of trapped or absorbed oxygen. An additional differentiating feature of the materials of the present invention is the presence of twin crystal growth in the granular structure, which are noted by transmission electron microscopy.

 In FIG. 1 is a photograph taken by transmission electron microscopy of a silver coating deposited by the method of the present invention by sputtering, illustrating grain sizes and defects of twin growth.

 In FIG. 2 is a photograph taken by transmission electron microscopy of the film of FIG. 1, annealed, which shows an increase in grain size and the presence of twin crystals caused by annealing.

 As noted above, the present invention has uses that go beyond antimicrobial materials. However, in the present description, the invention is disclosed in relation to antimicrobial metals, which are illustrative examples of the use of other metals, metal alloys and metal compounds. Preferred metals include Al and Si, as well as metal elements from the following groups of the periodic table: IIIB, IVB, VB, VIB, VIIB, VIIIB, IB, IIB, IIIA, IVA and VA (excluding As) in periods 4, 5 and 6 (see Periodic Table published in Merck Index, 10th ed. 1983 (Merck Index 10th Ed., 1983, Merck and Co. Inc., Rahway, NJ, Martha Windholz). Different metals have different degrees of solubility. However the creation and maintenance, in accordance with the present invention, of atomic disorder leads to increased solubility (release) of the metal in the form of ions, atoms, molecules or clusters appropriate solvent, i.e. a solvent which is suitable for the material, typically in a polar solvent, in comparison with the level of solubility of the material in its normal ordered state.

 Medical devices made of the antimicrobial material of the present invention, including it, or coated with antimicrobial material, are usually brought into contact with an alcohol or aqueous electrolyte including body fluid (e.g. blood, urine, saliva) or body tissues (e.g. skin, muscles or bones) for any period of time sufficient for the growth of the microorganism on the surface of the device. The term "alcoholic or aqueous electrolyte" also includes gels based on alcohol or water. In most cases, these devices are medical devices, such as catheters, implants, tracheotomy tubes, orthopedic pins, insulin pumps, wound closure materials, drainage devices, dressings, shunts, connecting parts, prostheses, pacemakers, needles, surgical instruments, dentures, ventilation tubes, etc. However, it should be borne in mind that the present invention is not limited to such devices, but covers other devices applicable in health care. first aid to the population, such as sterile bandages, clothing and shoes, personal care products, such as diapers, or used in biomedical or biotechnical laboratory equipment, such as tables, enclosures and wall coverings, etc. The term "medical device" in the context of the present invention and the claims has a broad meaning, including all such devices.

 The device can be made of any suitable material, for example, metals, including steel, aluminum and its alloys, latex, nylon, silicone, polyester, glass, ceramics, paper, fabric and other plastic and rubber materials. For use at home, the medical device must be made of biologically inert material. The device can take any shape determined by the scope of its application, varying from flat plates to discs, rods and tubes for examining cavities. In this case, the device can be rigid or flexible, this parameter is also determined by the intended scope of application.

Antimicrobial coatings
In accordance with the present invention, an antimicrobial coating is applied in the form of a thin metal film on one or more surfaces of a medical device using a vapor deposition technique. In accordance with all methods of physical vapor deposition known in the art, metals are deposited from steam, usually an atom to an atom, on the surface of a substrate. These technologies include vacuum or arc evaporation, sputtering, magnetron sputtering, and electrodeposition of ions. Precipitation is carried out in such a way as to create atomic disorder, in accordance with the above definition. At the same time, various conditions are practiced for creating atomic disorder. Typically, such conditions are avoided by applying a thin film deposition technique, the purpose of which is to create a defect-free, smooth and dense film (see, for example, the above JA Thorton work). Previously, when studying the effect of such conditions, it was shown that they do not lead to an increase in the solubility of the coatings obtained in this process.

Preferred conditions that are used to create atomic disorder during the deposition process include:
- low temperature, which is maintained on the surface to be coated so that the ratio of the temperature of the substrate to the temperature of the melting point of the metal (in Kelvin degrees) is less than 0.5, more preferably less than 0.35 and most preferably less than 0.3, and one or both of these may not necessarily be observed of the following conditions:
- pressure increased in comparison with normal (or environmental), i.e. for vacuum evaporation - more than 0.001 Pa (0.01 mT), in case of evaporation with gas scattering (electrodeposition under pressure) or reactive arc evaporation - more than 3 Pa (20 mT); in case of spraying: more than 10 Pa (75 mT); in the case of sputtering using a magnetron: more than 1.3 Pa (10 mT); and in the case of electrodeposition of ions: more than about 30 Pa (200 mT); and
- maintaining the angle of incidence of the coating stream on the coated plane at a level of not less than 75 ^o and preferably at a level of less than 30 ^o C.

 The metals used for coating are known for their antimicrobial properties. In addition, for use in most medical devices, the metal used must also satisfy the requirement of biocompatibility. Preferred metals include the noble metals Au, Ag, Pt, Pd and Ir, as well as Sn, Cu, Sb, Bi and Zn or alloys, or compounds of these or other metals. Most preferred are Ag or Au or alloys or compounds of one or more such metals.

 The coating is formed in the form of a thin film at least on a part of the surface of the medical device. Moreover, the film has a thickness of not more than is required to ensure the sustained release of ions over an acceptable period of time. In this regard, the thickness varies depending on the type of metal in the coating (the choice of which is determined by the solubility and abrasion resistance) and the degree of atomic disorder (and, therefore, solubility) of the coating. The thickness should be small enough so that the coating does not lead to a deviation of dimensions from their nominal values, and also does not reduce the flexibility of the device in the intended scope of its use. It has been shown that in a typical case, a coating thickness of less than 1 micron provides sufficient long-term antimicrobial activity. The increase in thickness may be practiced depending on the desired degree of release of the metal ion over a period of time. However, achieving coatings greater than 10 microns is expensive and usually not required.

 The antimicrobial effect of the coating is achieved by contacting the device with an alcohol or water electrolyte, such as, for example, body fluid or body tissue, during which the release of metal ions, atoms, molecules or clusters occurs. The metal concentration required to produce an antimicrobial effect varies from metal to metal. In general, in body fluids such as plasma, blood serum, or urine, the antimicrobial effect is achieved at concentrations of less than 0.5-1.5 μg / ml.

The ability to achieve sustained release of metal ions, atoms, molecules or clusters is determined by many factors, including coating characteristics such as its composition, structure, solubility and thickness, as well as the nature of the environment in which the device will be used. Moreover, with an increase in the level of atomic disorder, the amount of metal ions released per unit time will increase. For example, a silver film in the form of a metal deposited by magnetron sputtering at a coefficient T / T _m <0.5 and a working gas pressure of about 0.9 Pa (7 mTorr) leads to the release of about 1/3 of the amount of silver ions over 10 days , which releases a film created under similar conditions, but at a pressure of 4 Pa (30 mTorr). The creation of films with an intermediate structure (for example, under reduced pressure, a reduced angle of incidence, etc.) leads to the formation of intermediate with respect to the above characteristics of the release of Ag, which are determined in biotests. Thus, in accordance with the present invention, a method for controlling the release of metal from metal coatings is provided. Moreover, in order to achieve a slow release, coatings with a low degree of atomic disorder are made, while in order to achieve a quick release it is necessary to obtain a high level of atomic disorder.

 In the case of continuous uniform coatings, the time required for dissolution is a function of the film thickness and the nature of the environment to which such coatings are exposed. In this case, the dependence on the thickness is linear, i.e., for example, a twofold increase in the film thickness leads to a twofold increase in the term of its functioning.

 In this case, it is possible to control the release of metal from the coating by creating a thin coating film with a modulated structure. For example, a coating applied by magnetron sputtering using a low working gas pressure (for example 2 Pa (15 mTorr)) for 50% of the application time and at high pressure for the remaining time period (approx. 4 Pa (30 mTorr) ) gives in the initial period a quick release of metal ions, and then a longer period of slow release sets in. This type of coating is extremely effective when used in devices such as ureteral catheters in which rapid release is first required to achieve average antimicrobial concentrations, followed by a decrease in release rate to maintain the concentration of metal ions over a period of weeks.

The temperature of the substrate during application under vacuum should not be so low that annealing or recrystallization of the coating could occur if it were transferred to warmer environmental conditions or the environment in which it will be used (for example, in an organism with a characteristic temperature ) Thus, an acceptable ΔT, in which the difference in temperature between the temperature of the substrate during deposition and the final temperature of use, will vary from metal to metal. For most preferred metals, in particular Ag and Au, the preferred temperature of the substrate is from -20 to 200 ^o C and more preferably from -10 to 100 ^o C.

 In accordance with the present invention, atomic disorder can be achieved in the manufacture of composite metallic materials, which are materials containing one or more antimicrobial metals in a metal matrix that includes atoms or molecules other than antimicrobial metals.

 The composite material manufacturing technique used in the present invention is the co-or sequential deposition of antimicrobial metal (s) together with one or more inert biocompatible metals selected from Ta, Ti, Nb, Zn, V, Hf, Mo, Si, Al and alloys of these metals or other elements - metals, which are typically transition metals. Such inert metals have atomic radii different from antimicrobial metals, which leads to the creation of atomic disorder during the deposition process. Alloys of this kind can also be used to reduce the diffusion of atoms, thereby stabilizing the disordered structure. For the manufacture of films, it is preferable to use equipment adapted for application to different target sites of each of the antimicrobial and inert metals. In the case of sequential deposition of the layers, the layer (s) of inert metal (s) should be discontinuous, representing, for example, islands inside the antimicrobial metal matrix. The value of the final ratio of the content of antimicrobial (s) metal (s) to inert (s) metal (s) should be more than 0.2. The most preferred inert metals are Ti, Ta, Nb and Zn. It is also possible to create an antimicrobial coating of oxides, carbides, nitrides, sulfides, borides, halides or hydrides of one or more antimicrobial metals and / or one or more inert metals to achieve the desired atomic disorder.

Another type of composite material falling within the scope of the present invention is made using the technique of physical evaporation in the process of reactive, joint or sequential deposition of the reacting material on a thin film of antimicrobial material (s). The reactive material is an oxide, nitride, carbide, boride, sulfide, hydride or halide of an antimicrobial and / or inert material formed in situ by injection of the appropriate reagents or gases containing the same suitable agents
(i.e. air, oxygen, water, nitrogen, hydrogen, boron, sulfur, halogens) into the chamber where the application is carried out. The atoms or molecules of these gases can also be absorbed or captured by a metal film to create atomic disorder. Reagents can be continuously fed during deposition for co-deposition or can be pulsed to achieve a consistent deposition type. The final value of the ratio of the antimicrobial (s) metal (s) to the reaction product should be higher than 0.2. The most preferred reagents are air, oxygen and hydrogen.

 The above deposition technique used for the manufacture of composite coatings may or may not be combined with the factors described above: lowering temperatures, creating a high working gas pressure and maintaining low incidence angles. It is preferable to maintain one or more of the conditions of the above list to enhance atomic disorder in the coating.

 A method may have a certain beneficial effect, including the introduction according to the method of the present invention before deposition of the antimicrobial material of the adhesive layer on the coated device in accordance with methods known in the art. For example, a Ti, Ta, or Nb layer may first be applied to the latex device to increase the adhesion of the antimicrobial coating then applied.

Antimicrobial powders
Antimicrobial powders, including nanocrystalline powders and powders based on rapidly hardening flakes or foils, can be prepared in the presence of atomic disorder in order to enhance solubility. Powders in the form of pure metals, metal alloys or their compounds, such as metal oxides or metal salts, can be mechanically processed or compressed to introduce atomic disorder into their structure. When introducing atomic disorder in such a mechanical way, it is necessary to create conditions that include low temperatures (i.e., temperatures lower than the temperature of recrystallization of the material) to ensure that neither burning nor recrystallization takes place. The temperature varies from metal to metal, while its value increases in the case of an alloy or impurity.

 Powders made in accordance with the present invention can be used in various forms, for example in the form of creams for external use, paints or adhesive coatings. Alternatively, a powder for further use as a material in medical devices or for coating them may be included in a polymer, ceramic or metal matrix.

Fine-Grained or Nanocrystalline Materials Based on Antimicrobial Metals
Methods for the preparation of fine-grained or nanocrystalline materials from the vapor phase are well known and described in the literature. For example, nanocrystalline materials can be prepared by modifying the standard method of condensation in an inert gas. The deposited material is evaporated from an electrically heated bath or crucible into an inert gas atmosphere such as argon or helium at a pressure of 5 to 7 Torr. The temperature of the bath should be high enough to maintain an acceptable level of vapor pressure of the material of interest. In the case of metals, an acceptable vapor pressure is usually achieved at a temperature of about 100 ^° C. above the melting point of the metal. Due to the presence of interatomic collisions with the atoms of the working gas, the atoms of the evaporated material lose kinetic energy and condense on a cooled finger or substrate, which are maintained at a temperature of about 77 ^o K (cooling in liquid nitrogen), in the form of loose powder, brittle flakes or films, size whose grains is less than 20 nm. In the case of powders or flakes, a deep vacuum is created (less than 5 • 10 ^-6 Pa) under which they regenerate, while the powders or flakes are separated from the chilled finger and collected in a chilled trap.

 Fine-grained materials are obtained in a similar manner during gas condensation / vapor deposition, the technique of which is also well known. The desired result is achieved by changing the temperature of the cooled finger or substrate and the gas pressure in order to allow the particles to grow to the desired size, which is preferably less than 5000 nm.

 Fine-grained / nanocrystalline antimicrobial metal powders obtained by the method known in the art were investigated, and as a result, it was revealed that their antimicrobial effectiveness was insufficient. For introducing atomic disorder into materials at a level sufficient to create an antimicrobial effect, the antimicrobial metal, alloy or compound required for coating is deposited using the technique of joint, sequential or reactive deposition on a matrix with atoms or molecules of another material (additive) under conditions allowing create and maintain atomic disorder. Such additional material is selected from inert biocompatible metals such as Ta, Ti, Nb, V, Hf, Mo, Si and Al, and most preferably Ta, Ti and Nb. Alternatively, such another material is an oxide, nitride, carbide, boride, sulfide or halide of only one of the antimicrobial metal and biocompatible metal used, or both of them. A further alternative involves the possibility of introducing another material from the atmosphere of the working gas, either by reactive deposition, or by absorbing or trapping atoms or molecules from the working gas onto the matrix. A working gas atmosphere containing oxygen, nitrogen, hydrogen, boron, sulfur and halogens may be used. Most preferred is a working gas atmosphere comprising oxygen, in which case the antimicrobial metal matrix includes either trapped oxygen, or antimicrobial metal oxides, or both components together.

 Another technology for the preparation of the antimicrobial powders of the present invention consists in applying, as described above, coatings bearing atomic disorder onto an inert, preferably biocompatible, material such as talc, bentonite, corn starch or ceramic, in particular alumina. Particles can be coated using the technique of physical vapor deposition, in the above, in part regarding antimicrobial metals, conditions that allow the creation of atomic disorder. Alternatively, the powders can be applied using an adapted vapor deposition method, for example, by passing antimicrobial material steam through a powder pore with fixed pore sizes, by fluidizing the powder layer in the antimicrobial metal vapor phase, or by creating conditions for the powder to fall through the antimicrobial vapor material. In all cases, the powder should be cooled and / or the atmosphere of the working gas should be changed in such a way as to allow the inclusion of another material (e.g. oxygen) to create the desired level of atomic disorder.

Antimicrobial Activation
Irradiation of antimicrobial materials (powders, nanocrystalline powders, foils, coatings or composite coatings of antimicrobial metals) that contain atomic disorder created using any of the above procedures will further activate or enhance the antimicrobial effect. So, the activity of even those materials that have a low level of atomic disorder can be increased until an antimicrobial effect is achieved.

 Irradiation is carried out at a low energy loss per unit path length using irradiation, including irradiation with beta, gamma or X-rays. It is preferable to carry out gamma irradiation with a dose of 1 Mrad or more. Moreover, since gamma irradiation is an acceptable method of sterilizing medical devices, using the irradiation process according to the method of the present invention, activation and sterilization can be performed simultaneously.

 The irradiation step is preferably carried out in such a way that the irradiated antimicrobial material is located generally perpendicular to the incoming irradiation (and not parallel). Further enhancement of the antimicrobial effect can be achieved by irradiation in the presence of a dielectric adjacent to or interlaying the antimicrobial material. Examples of such dielectrics include oxides of Si, Ti, Ta, and Al. Surfaces consisting of silicone oxide are preferred. It is believed that the dielectric material provides directional electron scattering into the antimicrobial coating.

Exposure is considered to cause one or more of the following changes in antimicrobial material:
1) creating further atomic disorder, such as point defects;
2) increased adsorption / chemisorption of oxygen on the surface of antimicrobial material;
3) activation of trapped atoms or impurity molecules, such as O ⁺ or O ₂ - and;
4) the creation of broken or loose bonds on the surface.

Regarding the second and third mechanisms, it can be assumed that the adsorption / chemisorption and / or activation of oxygen creates concentration supersaturation with species such as O ₂ , O ⁺ or O ₂ - inside the antimicrobial material or on its surface, which leads to accelerated dissolution of the antimicrobial metal or its forms into an aqueous environment through the formation of various chemical species of antimicrobial metal, including oxides and hydroxides.

Silver materials forming ions of silver complexes
In accordance with the present invention, silver materials are made that can form ions of silver complexes other than Ag ⁺ , Ag ²⁺ and Ag ³⁺ upon contact of the material with an alcoholic and aqueous electrolyte. Examples of silver complex ions having, as shown, an antimicrobial effect include Ag (CN) _2- , Ag (CN) _(ag) ) (ion pair)), Ag (NH ₃ ) ₂₊ , AgCl ₂ , Ag (OH ) _2- , Ag ₂ (OH) _3- , Ag ₃ (OH) _4- , Ag (S ₂ O ₃ ) _3- . Such silver materials forming complex silver ions are widely used, for example, as antimicrobial coatings in medical devices, as antimicrobial powders for medical or pharmaceutical use, as antifouling paints, coatings or compositions, antimicrobial coatings for filters, etc. d.

It should be borne in mind that the expression "silver materials that form ions of silver complexes other than Ag ⁺ , Ag ²⁺ and Ag ³⁺ ", in the context of the present description and the claims, does not exclude those materials that form upon contact of the material with an alcoholic or aqueous electrolyte, one or more of Ag ⁺ , Ag ²⁺ and Ag ³⁺ ions, in addition to ions of silver complexes. The phrase Ag ⁺ , Ag ²⁺ and Ag ³ refers to such ions in solution, including also their solvated forms. Used in the context of the present description and claims, the term "silver complex ions" does not include silver ions stabilized by strong oxidizing agents to prevent the reduction of silver ions such as persulfate or periodate.

The antimicrobial coatings, powders and foil of the present invention, when they create atomic disorder in them, as described above, demonstrate examples of silver materials that form complex silver ions other than Ag ⁺ , causing an antimicrobial effect. It is believed that ions of sulfur complexes that can form upon the contact of such silver materials with an alcohol or aqueous electrolyte are one or more negatively charged ions of Ag (OH) ₂ -, Ag ₂ (OH) _{3 -} and Ag ₃ (OH) _{4 -} .

Silver materials that form ions of silver complexes can be prepared by introducing metallic silver, a compound or its salt into an environment containing excessive amounts of cationic, anionic or neutral forms, in combination with which it is necessary to obtain silver complexes. For example, a negatively charged silver complex ion AgCl ₂ can be generated by placing a silver salt, such as AgNO ₃ , in an aqueous medium containing elevated concentrations of Cl ^- ion. Mixtures, solutions or suspensions of AgNO ₃ / NaCl or AgCl / NaCl can form AgCl ₂ ion. This AgCl ₂ ion can also be obtained from mixtures of silver powder with NaCl. Preferably, the silver powder is made in accordance with the present invention with a content of atomic disorder, while the usual form of silver can also be activated in this way. Conventional silver powder, fine-grained (<140 nm) and nanocrystalline (<20 nm) powders can also be used. Similarly, in the addition of silver salts to an excess of ammonium hydroxide in an aqueous solution, the formation of an Ag (NH ₃ ) ₂₊ ion can occur. The Ag (S ₂ O ₃ ) ₂ ^3- ion can be obtained in an aqueous solution by adding silver salts to an excess of sodium thiosulfate. The Ag (CN) _2– ion can be obtained in an aqueous solution by adding excess potassium cyanide to silver cyanide.

Silver materials forming the ions of silver complexes can be prepared in various forms, including, for example, powders, suspensions, solutions, ointments or coatings. So, for example, a pharmaceutical composition capable of generating AgCl ₂ ion can be prepared as a mixture of AgNO ₃ / NaCl salts or as a mixture of NaCl with silver powder, preferably one of these components containing atomic disorder. Such mixtures of silver material may be pre-formulated as a solution, suspension or ointment in combination with sterile aqueous or saline solution and pharmaceutically acceptable carriers, diluents, excipients, etc. Alternatively, the silver material may be presented as mixtures of silver powder / NaCl or AgNO ₃ / NaCl followed by formulation for the end user.

Physico-chemical characteristics of antimicrobial silver material
Modified metal materials obtained in accordance with the present invention, with a content of atomic disorder, which leads to an increase in the release of metal forms, are characterized by new parameters in comparison with materials having a normal ordered crystalline structure. As a result of the study of silver materials manufactured by the method of the present invention, the following new characteristics were obtained:
- positive residual potential E _rest , for example, when measured against a standard NCE electrode (SCE) in a 1M KOH solution;
- the preferred ratio of the crystallization temperature to the melting temperature is less than 0.30;
- the preferred recrystallization temperature is less than 140 ^o C; and
- a preferred grain size is less than 200 nm, more preferably less than 140 nm and most preferably less than 90 nm.

 Analysis of silver materials using X-ray diffraction, X-ray spectroscopy and mass spectrometry of secondary ions confirms the chemical nature and composition of silver films, as well as the fact that the material obtained in the presence of oxygen in the working gas atmosphere contains silver oxide or trapped oxygen, either of these components together. Transmission electron microscopy of the silver material reveals twin growth regions in it, which, at temperatures above the recrystallization temperature, turn into calcined twin regions.

 The following are non-limiting examples.

Example 1
Polyester-woven suture material 2/0 size was coated by magnetron sputtering (diameter 20.3 cm (8 inches)) of flat silver and copper magnetron cathodes with the formation of 0.45 micron thick Ag-Cu alloy using the working gas argon at a pressure of 0.9 Pa (7 mTorr) or 4 Pa (30 mTorr) at a power of 0.5 kW and a T / T _m ratio of less than 0.5. The total gas flow is 700 standard cubic centimeters per minute (art. Cm ³ / min (SCCm).

The antimicrobial effect is investigated using the test for zonal inhibition. Calf serum (10%) and 1.5% agar are added to the Eagle’s main medium (AXI (BME)) with Earle's salts and L-glutamine before being distributed (15 ml) to Petri dishes. The agar surface in Petri dishes is slightly dried before the introduction of the inoculum Staphylococcus aureus ATCC # 25923. The inoculum was prepared on the basis of Bactrol Discs (Bactrol Discs (Difco, M)), the contents of which are regenerated before use according to the attached instructions. Immediately after inoculation, the test coating materials are placed on the surface of the agar. The cups are incubated at a temperature of 37 ^o C for 24 hours. After the incubation time has passed, the inhibition zone is measured, while calculating the adjusted inhibition zone - the diameter of that part of the test material that is in contact with the agar).

 The results show the absence of inhibition on the uncovered part of the suture material, while the zone of inhibition is less than 0.5 mm around the seam covered with a pressure of 0.9 Pa (7 mTorr) and 13 mm around the seam covered with a pressure of 2 Pa (30 mTorr). In this case, the suture material coated according to the method of the present invention exhibits a significantly more pronounced antimicrobial effect.

Example 2
This example is included in the description to illustrate the role of surface structures obtained by depositing silver material on silicone wafers using a magnetron sputtering device under different working gas pressures and at different incidence angles (i.e., the angle between the direction of flow of the atomized atoms and the plane of the substrate ) Other conditions have the following meanings: the atomizer is a flat silver magnetron cathode with a diameter of 20.3 cm; power is 0.1 kW; the deposition rate is 200 A ^o / min; the ratio of the temperature of the substrate (plates) to the temperature of the melting point of silver (1234 ^o K) - T / T _m less than 0.3. Argon is used with a total mass flow rate of 700 tbsp. cm ³ / min at pressures of 0.9 Pa (7 mTorr) (this is the normal working gas pressure used for coating) and 4 Pa (30 mTorr). The values of the angle of incidence of the stream at each pressure value are 90 ^o (normal slope), 50 ^o and 10 ^o . Coatings have a thickness of about 0.5 microns.

The resulting surfaces are examined using scanning electron microscopy. As the gas pressure increases from 0.9 Pa (7 mTorr) to 4 Pa (30 mTorr), the grain size decreases, while the volume of voids increases significantly. With a decrease in the angle of incidence of the flow, the grain size also decreases, while the boundaries between the grains become more distinct. With a gas pressure of 0.9 Pa (7 mTorr) and a flow angle of 10 ^o, there are signs of voids between the grains. It was noted that the value of the angle of incidence has a greater effect on the topography of the surface with increasing gas pressure up to 4 Pa (30 mTorr). When the angle of incidence is 90 ^o, the grain size varies from 60 to 150 nm, while many of the grains are separated by empty space between grains with a width of 15 to 30 nm. With a decrease in the angle of incidence to 50 ^o, the grain size continues to decrease to 30-90 nm, and this is accompanied by a significant increase in the empty volume. When the value of the angle of incidence of 10 ^o there is a further decrease in grain size to 10-60 nm, also accompanied by an increase in the volume of voids.

 Changes in the surface morphology and topography observed on a nanometer scale indicate the presence of atomic disorder in metallic silver. It is believed that such atomic disorder leads to an increase in chemical activity due to an increase in internal stresses and the degree of surface roughness created by atomic mismatch. It is believed that it is the increase in chemical activity that leads to an increase in the solubility of coatings that come in contact with an electrolyte such as body fluid.

 The antimicrobial effect of the coatings is evaluated using the zonal inhibition test according to the method of Example 1. Each coated silicone plate is placed on a separate cup. The test results are compared with the value of the zones of inhibition obtained in the study of solid silver (i.e., when the material contains more than 99% silver) sheets, wire or membranes. The results obtained are presented in Table 1. From the data presented on it, it can be seen that pure silver devices and silver coatings applied at a pressure of 0.9 Pa (7 mTorr) do not have a biological effect, whereas coatings applied at a working gas pressure higher than normal, t. e. 4 Pa (30 mTorr) demonstrate an antimicrobial effect, as indicated by the presence of significant inhibition zones located around the discs. A decrease in the angle of incidence has the greatest effect on antimicrobial activity when such a change in parameter is combined with an increase in gas pressure.

Example 3
Spraying using a magnetron with flat silver and copper cathodes with a diameter of 20.3 cm is coated on silicone plates of an alloy of Ag and Cu (80:20), subject to the normal angle of the working gas flow under pressure of 0.9 Pa (7 mTorr) and 4 Pa (30 mTorr ), while all other conditions are maintained in accordance with the values specified in Example 2. As in Example 2, when examining the coating using scanning microscopy, it was noted that coatings obtained at high gas pressure are characterized by a smaller grain size and large its volume of voids than coatings obtained at a lower pressure of the working gas.

 Similarly, coatings obtained in the form of an alloy of 50:50 Ag and Cu are examined for the presence of antimicrobial activity using the zonal inhibition test described in Example 1. The results are summarized in table 2. It is seen that the coatings obtained by deposition under low pressure of the working gas (0.9 Pa (7 mTorr)) show minimal zones of inhibition, while coatings applied under high pressure of the working gas (4 Pa (30 mTorr)) form large zones of inhibition, which indicates the presence of antimicrobial activity.

Example 4
In the coating obtained by the method of the present invention, the concentration of silver ions released over time into the solution is determined. According to the method described in Example 2, under a pressure of 0.9 Pa (7 mTorr) and 4 Pa (30 mTorr) and a normal angle of incidence, until reaching a coating thickness of 5000 A ^o, 1 cm ^{2 of} silicone plate discs are coated with silver. According to the method of Nickel et al. (Nickel et al., Eur. J. Clin. Microbiol., 1985, 4 (2), 213-218) receive sterile synthetic urine and dispense it into test tubes (3.5 ml). Coated discs are placed in each such tube and incubated for a different period of time at a temperature of 37 ^o C. After incubation of various durations, discs are taken and the content of Ag in the filtered synthetic urine is determined using the neutron activation method.

 The test results are shown in table 3. These tables reflect the comparative amounts of Ag released over time from coatings applied to disks under a pressure of 0.9 Pa (7 mTorr) or 4 Pa (30 mTorr). High pressure coatings are more soluble than low pressure coatings. It should be noted, however, that the test described is static. So, the existing levels of Ag are created for some time, which may not correspond to the situation in the body, where it is constantly washed out.

Example 5
This example is included in the description to illustrate the coatings obtained by the method of the present invention, based on another noble metal Pd. The coatings were obtained on silicone plates in accordance with the method of example 2 until a thickness of 5000 A ^{o was} reached under a working gas pressure of 0.9 Pa (7 mTorr) and 4 Pa (30 mTorr) and with a dip angle of 90 ^o and 10 ^o . The antimicrobial activity of the coated discs is assessed using the zonal inhibition test, described in principle in Example 1. The coated discs are placed coated side on Petri dishes so that the agar protrudes 1 mm above the coated surface of the discs. Next, the medium is allowed to gradually thicken and the surface is dried, after which a bacterial inoculum is sown on the surface. The cups are incubated at a temperature of 37 ^o C for 24 hours. The magnitude of the growth is evaluated visually.

 The results are shown in table 4. At high pressure of the working gas, the biological activity of the coating is much higher than that of coatings obtained at low pressure. Changing the angle of incidence (reduction) improves the antimicrobial effect of the coating, and more significantly at low gas pressure than at high.

Example 6
This example is included in the present description to illustrate the effect of temperature maintained during the deposition of silver on the antimicrobial activity of the resulting coating. Silver metal is deposited on 2.5 cm sections of the Foley latex catheter using a magnetron sputtering device. During application, the following conditions are met: deposition rate of 200 A ^o per minute; power - 0.1 kW; the atomizer is a flat magnetron silver cathode with a diameter of 20.3 cm; argon working gas pressure is 4 Pa (30 mTorr); the total mass gas flow is 700 tbsp. cm ³ / min, and the ratio of the temperature of the substrate to the temperature of the melting point of metallic silver in the coating - T / T _m is 0.30 or 0.38. In this example, the angle of incidence varies due to the round shape and roughness of the substrate. So, the values of the angle of incidence depend on various circumstances, and at the level of the fine structure, they are determined by the direction and other parameters of the sides and vertices of the numerous formations existing on the surface. The antimicrobial effect is determined using the test for zonal inhibition, essentially described in Example 1.

The obtained results give the values of the corrected zones of inhibition of 0.5 and 16 mm located around the tubes coated with a T / T _m value of 0.38 and 0.30, respectively. Foley catheter sections coated with a lower T / T _m coefficient are more effective than those that were coated with a higher T / T _m coefficient.

Example 7
This example is included in the description to demonstrate the process of applying an antimicrobial coating using a DC magnetron to a commercial catheter. Teflon-coated Foley catheter was then coated with silver by sputtering through a DC magnetron with a purity of 99.99%, subject to the conditions listed in Table 5.

 Working gases are represented by commercial Ar and a mixture of Ar / 02 (99/1, wt%).

The antimicrobial effect of the coating is examined using a zonal inhibition test. Mueller Ainton agar is distributed over Petri dishes. Prior to inoculation of Staphylococcus aureus, ATCC # 25923 allows agar surfaces to dry. The inoculum is prepared on the basis of Bactrol disks (Bactrol Discs, Difco, M), which are regenerated before the study in accordance with the manufacturer's instructions. Immediately after inoculation, the coated coated materials are placed on the surface of the agar. The cups are incubated at a temperature of 37 ^o C for 24 hours. After the incubation time has elapsed, the inhibition zone is measured, after which the corrected inhibition zone is calculated (corrected inhibition zone = inhibition zone — diameter of the part of the test material that contacts the agar).

 The obtained results show the absence of inhibition in the case of uncovered samples and the presence of a corrected area of less than 1 mm in the case of catheters, which were spray-coated in a commercial argon atmosphere under a working gas pressure of 0.7 Pa (5 mT). In the case of catheters that were coated by spraying in an Ar / 02 mixture (99/1, wt.%) Under a working gas pressure of 5.3 Pa (40 mT), the corrected inhibition zone is 11 mm. Analysis by x-ray diffraction showed that the coating deposited by spraying in 1% oxygen, is a film of crystalline Ag. This structure clearly demonstrates an increased antimicrobial effect when using the material in catheter coatings.

Example 8
This example demonstrates silver coatings obtained by arc evaporation, vapor dispersion evaporation (electrodeposition under pressure) and reactive arc evaporation. The evaporation of silver with a purity of 99.99% is carried out on silicone or alumina plates with an initial substrate temperature of about 21 ^o C, subject to the following parameters:
Displacement: - 100 V
Current: - 20 Amp-hour
Angle of Incidence: - 90 ^o
Working gas pressure: 0.001 Pa (0.01 mT) (arc), 3.5Pa (26 mT) Ar / H ₂ , 96: 4 (evaporation during gas dissipation) and 3.5Pa (26 mT) O ₂ (reactive arc evaporation).

 In the case of plates coated under vacuum (arc), no corrected inhibition zone was noted. Electrodeposition under pressure in the atmosphere of a working gas containing Ar and 4% hydrogen leads to the formation of an inhibition zone of 6 mm in size, whereas when pure oxygen is applied in the atmosphere as a working gas (reactive arc), an inhibition zone of 8 mm is formed. The thickness of the formed film is approximately 4000 angstroms. The results show that the presence of gases, such as hydrogen and / or oxygen, in an atmosphere of arc evaporation leads to an increase in the antimicrobial efficiency of coatings.

Example 9
This example is included in the description to illustrate composite materials capable of exerting an antimicrobial effect. According to the method described below, a set of coatings is obtained by spraying zinc oxide using a high-frequency (RF) magnetron onto silicone wafers. Zinc oxide coatings do not show an inhibition zone.

 Coatings of Ag and ZnO are applied with a total thickness of up to 3300 angstroms by sequentially sputtering Ag layers together with ZnO layers (75/25,% by weight) under the following conditions. It was shown that coatings do not lead to the formation of an inhibition zone in the case when the layer thickness of zinc oxide is about 100 angstroms. However, films comprising either very thin islands or discontinuous ZnO layers (less than 50 angstroms) in an Ag matrix (i.e., a composite film) lead to the formation of a corrected inhibition zone of 8 mm.

The conditions used for applying ZnO include the following: atomizer: ZnO with a diameter of 20.3 cm; working gas - argon; working gas pressure - 4 Pa (30 mT); cathode-anode distance: 40 mm; the initial temperature of the substrate is 21 ^o C; power - high-frequency (RF) magnetron, 0.5 kW.

Applicable conditions for applying Ag include the following: atomizer: Ag with a diameter of 20.3 mm; working gas - argon; working gas pressure - 4 Pa (30mT); distance cathode - anode - 40 mm; the initial temperature of the substrate is 21 ^o C; power - magnetron, 0.1 kW.

Example 10
This example demonstrates the effect of cold working and annealing of silver and gold powders on the antimicrobial activity determined in the standard zonal inhibition test. Cold treatment of such powders leads to defects in surface structures containing atomic disorder, which promotes the release of ions that cause antimicrobial activity. The antimicrobial effect of such a defective structure can be removed by annealing.

Nanocrystalline silver powder (crystal size of about 30 nm) is sprayed onto a shallow ribbon and further examined. The method of Example 7 is used, and an inhibition zone of 5 mm is obtained. Granules nanocrystalline Ag powder (0.3 g) was compressed under a pressure 275,700 kPa (kilopascals) (40,000 lbs / ^in2). The compressed granules produce a 9 mm inhibition zone when tested for antimicrobial activity. Nanocrystalline silver powder is machined in a ball mill for 30 seconds. The resulting powder is tested for antimicrobial activity both in the case of spraying the treated powder onto an adhesive tape followed by placing it on cups, and when it is pressed into granulate subject to the above conditions, also followed by placement on cups. Marked zones of inhibition are respectively 7 and 11 mm. The granulate obtained after pressing the treated powder is annealed at a temperature of 500 ^o for 1 hour under vacuum. In this case, the zone of inhibition noted in the calcined granulate is reduced by 3 mm.

The data obtained show that nanocrystalline silver powder, without itself having a noticeable effect on the antimicrobial effect, has an increased antimicrobial effect when introducing atomic disorder by mechanical processing of the powder in a ball mill or by pressing it into granulate. The antimicrobial effect is significantly reduced during annealing at a temperature of 500 ^o C. Thus, the conditions created during or after machining should not include high temperature, which promotes diffusion. Cold machining conditions are preferred because they limit diffusion, in particular, it can be treatment at room temperature or by grinding or grinding in liquid nitrogen.

A silver powder consisting of particles of about 1 micron in size is examined in a similar manner. Ag powder is sprayed onto adhesive tape and the inhibition zone is determined. The zone of inhibition in this case is not observed. The powder is treated for 30 seconds in a ball mill and sprayed onto adhesive tape. At the same time, an inhibition zone of 6 mm in size is marked around the powder on the tape. When the Ag powder (in a normal state or after mechanical processing in the ball mill) was pressed at a pressure 275,700 kPa (40,000 pounds / ⁱⁿ²⁾ in 0.3 g of granules, the size of the zone are marked 5 and 6 mm. The granulate, which was obtained from a powder processed in a ball mill, and then calcined at a temperature of 500 ^o C, has a significantly reduced antimicrobial activity. At first, the granulate had some activity (inhibition zone 4.5 mm in size), however, in the second study, the inhibition zone was not detected. The control granulate, which was not annealed, continues to produce zones of inhibition of more than 4 mm even after 14 repetitions of the test. This result indicates that the annealing step used after machining limits the sustained release of antimicrobial forms of silver from powders.

Nanocrystalline gold in the form of a powder (crystals of 20 nm) is investigated using the test for zonal inhibition of antimicrobial activity when spraying the powder on adhesive tape. In this case, inhibition zones were noted for nanocrystalline gold powder. The gold powder was pressed at a pressure 275,700 kPa (40,000 pounds / ⁱⁿ²⁾ to 0.2 g of granulate. An inhibition zone of 10 mm is noted. Upon subsequent annealing of the pressed granulate in vacuo at a temperature of 500 ^° C. for 1 hour, the size of the inhibition zone decreases to 0 mm.

 The results show that the solubility, and therefore the effectiveness of gold powders can be significantly improved by mechanical processing, such as pressing a nanocrystalline material into granulate. In this case, antimicrobial activity may disappear after annealing. Cold treatment is preferred.

 Other gold powders, including particles of 2.5 microns and 250 microns in size, do not have antimicrobial effects under the conditions of the aforementioned cold working. It is believed that the small grain size of nanocrystalline gold powder is an important factor, which, combined with machining, contributes to the generation of the desired antimicrobial effect.

Example 11
This example is included in the description to illustrate a composite antimicrobial coating formed by reactive spraying (another example of composite films). In Example 7, it was shown that an antimicrobial coating of silver can be obtained by sputtering in an atmosphere of argon and 1% oxygen (0.5 Quatt, 5.3 Pa (40 mTorr), the anode / cathode distance is 100 mm, the temperature is 20 ^o C - this gives an inhibition zone of 11 mm).

 In the case when argon with a content of 20 wt% oxygen is used as a working gas for deposition of antimicrobial coatings, the size of the zones of inhibition varies from 6 to 12 mm. These data indicate that the creation of a reactive atmosphere during vapor deposition leads to the formation of an antimicrobial film using a wide range of deposition process parameters.

Example 12
This example shows that the coatings of the present invention exhibit antimicrobial activity against a wide range of bacteria.

A total of 171 different bacterial samples, including representatives of 18 genera and 55 species, were presented by the Northern Alberta Provincial Health Laboratory. These samples were quickly frozen in 20% skim milk and kept at a temperature of -70 ^o C for a time ranging from several months to several years. The study did not use food-demanding organisms that might not grow under the conditions created in the standard Kirby-Bauer sensitivity test.

Each frozen sample was scraped off with a cotton swab to inoculate a plate with blood agar (ChCA (BAP)). The plates were incubated overnight at a temperature of 35 ^° C. The next day, the organisms were subjected to a sensitivity test according to the Kirby-Bauer method described below.

Four to five colonies (a larger number if the colonies are small) of the same morphological type are selected from each PCA subculture and further inoculated into individual tubes containing approximately 5 ml of tryptic soy broth (TSB). The broths are incubated at a temperature of 35 ^o C for 2-3 hours. By this time, the turbidity of most of the broth cultures becomes either equal to or exceeds 0.5 McFarland Standard. More turbid samples are diluted with sterile saline to achieve a turbidity that is visually comparable to the standard. To facilitate a visual assessment of turbidity, the tubes are viewed on a white background with a contrasting black line.

 A small number of organisms (Sfreptococcus and Corynebacterium) are not able to grow well in TSB. The turbidity of these broths after incubation reaches less than 0.5 McFarland standard. To increase the turbidity to approximately the standard level, additional colonies from CCA subcultures are inoculated into these tubes.

A sterile cotton swab is immersed in each broth for 15 minutes to bring the turbidity of the bacterial suspension to the desired state. Excess fluid is removed through the edge of the tube with a swab, rotating it. The inoculum is applied to a Mueller Hinton (MX) agar plate by applying clear strips with a swab in three directions over the entire surface of the agar. Three silica wafer squares coated with silver, 1x1 cm in size, are placed on each MX cup, after which the cups are turned over and set to incubate overnight at a temperature of 35 ^o C. Coating is applied by spraying under the conditions described below, which according to the study by diffraction X-rays are composite films consisting of silver / silver oxide:
Atomizer: Diameter 20.3 cm, 99.99% Ag
Working gas: Ar / O ₂ 80/20 weight%
Working gas pressure: 5.3 Pa (40 mT)
Total mass flow: 700 st • cm ³ / min
Power: 0.1 Quatt
Precipitation temperature: 20 ^o C
Main pressure: 2.7 • 10 ^-4 Pa (2 • 10 ^-6 Torr)
Cathode / Anode Distance: 40mm
PCA (VAR) cultures of control organisms were presented by the Provincial Laboratory and included: Staphylococcus aureus ATCC 25923; Pseudomahas aerugihosa ATCC 27853; Escherichia coli: ATCC 25922; and Enterococcus faecalis ATCC 29212 for quality control of MX agar. These cultures were treated in a manner similar to test cultures, except that standard antibiotic discs were applied to bacterial lawns on MX agar rather than silver coated plates. Using these organisms, it was found that MX agar was acceptable for a standard zonal inhibition assay.

After 16-18 hours of incubation at a temperature of 35 ^° C., inhibition zones around silver plates or antibiotic discs were measured. Corrected zones were calculated by subtracting the size of the wafer (1 cm) from the size of the common zone. The results for representative zones of inhibition are shown in table 7.

Example 13
This example demonstrates the use of tantalum as an adhesive layer for use in the coatings of the present invention. Tantalum is well known as a material which, when used as an intermediate layer, improves the adhesion of thin films to a substrate. In this example, the test sections, including samples of stainless steel (316) (1 x 1 cm) and silicone (1.7 x 0.9 cm), as well as sections of latex tubes (5 cm), are washed with a standard, after which half of the test sections before applying silver films to them cover (when spraying) with a thin layer (approximately 100 angstroms) of Ta. In the second group, the studied sections are covered only with antimicrobial Ag film. Coverage conditions are given below. While the antimicrobial activity of all tested sections had close values, the experimental sections coated with Ta had much better adhesive properties than the untreated studied sections. Adhesion properties are determined using ASTM method D3359-87, which is a standard method for determining adhesion.

Atomization Conditions
Atomizer: diameter 20.3 cm, 99.99% Ta
Working gas: Ar / O ₂ , 99/1 weight%
Working gas pressure: 1.3 Pa (10 mTorr)
Total mass flow: 700 st • cm ³ / min
Power: 0.5 kW
Cathode / Anode Distance: 100mm
Substrate temperature: 20 ^o C
Atomizer: Diameter 20.3 cm, 99.99% Ta
Working gas: Ar / o ₂ , 99/1 weight%
Working gas pressure: 1.3 Pa (10 mTorr)
Total mass flow: 700 st • cm ³ / min
Power: 0.5 kW
Cathode / Anode Distance: 100mm
Substrate temperature: 20 ^o C
Example 14
DC magnetron sputtering was used to deposit silver of 99.99% purity from a cathode with a diameter of 20.3 cm on silicone and silica wafers using commercial argon moistened with water as a working gas, the total mass flow of which is 700 st • cm ³ / min. Humidification of argon is carried out by passing it through two flasks containing 3 liters of water at room temperature and through one empty flask equipped with glass wool to absorb any free liquid before supplying gas to the spray chamber.

 The spraying conditions and the results of a standard zonal inhibition test carried out on silver films deposited are presented below. Silver films, which usually do not exhibit antimicrobial properties when deposited in an argon atmosphere, are sprayed using an argon / water vapor mixture as a working gas and are characterized by values of the corrected zone inhibited to 8 mm.

Example 15
This example is included in the description to illustrate the method of activation of coatings by irradiation, which is another aspect of the present invention.

Silicone wafers with a size of 1.9 x 0.7 cm are coated with metallic silver 3000 ^o A thick by sputtering from a DC magnetron under the following conditions:
SPRAYING CONDITIONS:
Atomization: diameter 20.3 cm, 99.99% Ag
Working gas: Ar / O ₂ , 99/1 wt.%
Working gas pressure: 5.3 Pa (40 mTorr)
Total mass flow: 700 st • cm ³ / min
Power: 0.5 kW
Substrate temperature: 21 ^o C
Cathode / Anode Distance: 100mm
The coated plates are divided into 4 groups and irradiated with different doses of gamma radiation: doses of 0, 1, 2 and 4 megarods from a source of ⁶⁰ Co (Isomedics Inc., Morton Grove, USA (Isomedix Inc., Morton Grove, Il., Usa)). Samples are placed generally perpendicular to the incoming radiation. After irradiation, the samples are tested for biological activity (antimicrobial effect) using a standard zonal inhibition test on Mueller Hinton agar (Difco (Difco, Ml.)), Including the use of S.aureus (ATCC 25923), as described in the previous examples. The results obtained are summarized in table 9.

 The results indicate a logarithmic relationship between the dose of radiation and the observed biological response in the plates. This illustrates the fact that gamma radiation further activates the coatings of the present invention in order to enhance their antimicrobial effect.

 The experiment was repeated with antimicrobial films oriented mainly parallel to the incoming radiation. This orientation significantly reduces the level of activation of antimicrobial coatings so that in comparison with unirradiated control there is no increase in the inhibition zone.

Example 16
This example is included to illustrate the activation by the method of the present invention of antimicrobial coatings by gamma irradiation using a dielectric material adjacent to the material to be treated during irradiation.

 Many samples of 2.5 cm x 2.5 cm in size from high-density cellular polyethylene (such as that used for the manufacture of burn dressings) are coated with metallic silver under the conditions of Example 15, except for the power, which in this case is 0.1 kW. Then, the coated cellular material was tested according to the method described in Example 15. Control cellular samples (silver coated, not irradiated) resulted in the formation of 10 mm inhibition zones (corrected), whereas for the irradiated samples 14 mm inhibition zones (corrected) were obtained .

 Other samples of the coated cellular material were sandwiched with two silicone wafers measuring 2.5 cm x 2.5 cm carrying a thermally enhanced oxide layer (supply from the Microelectronics Center, Edmonton, Alberta (Alberta Microelectronic Center, Edmonton)). The described cellular material was examined for the presence of biological activity, and a corrected inhibition zone value of 26 mm was found. It is believed that silicone wafers are a source of electrons that are scattered on antimicrobial coatings, further enhancing the antimicrobial effect.

Sheet metal silver was examined for the possibility of its activation by gamma radiation to produce an antimicrobial effect. Sheet metal silver was annealed at a temperature of 140 ^o C for 90 mm and then irradiated with a dose of 4 megarads. Next, the samples were examined for the presence of biological activity, however, inhibition zones were not identified. This result indicates that perhaps silver in its normal ordered state has too few atomic defects that can be activated by the method of the present invention.

Example 17
This example is included in the description to illustrate the fact that antimicrobial coatings containing atomic disorder at a level not sufficient to produce an antimicrobial effect can be activated by gamma radiation in accordance with the present invention.

 Silver films are sprayed onto silicone wafers in accordance with the conditions of Example 15, except for gas pressure, which is reduced from 5.3 Pa (40 mTorr) to 0.7 Pa (5 mTorr), which leads to a decrease in atomic disorder in the resulting coatings. After that, silver films are irradiated with gamma rays at a dose of 4 Mrad according to the method of Example 15. The irradiated and control films (not irradiated) are examined for biological activity. Control films produce an inhibition zone of only 1 mm (corrected), while irradiated coatings create an inhibition zone of 10 mm (corrected). This result indicates that antimicrobial coatings made under such conditions that lead to the formation of atomic disorder at a level insufficient for the manifestation of the antimicrobial effect can be activated by irradiation from a gamma ray source, eventually acquiring antibacterial properties.

Example 18
This example demonstrates a method for forming silver complex ions other than Ag + ions, which are highly effective in generating an antimicrobial effect. The example provides comparative data on the level of diffusion and the values of inhibition zones for various silver solutions.

Solutions are prepared so that 10,000 ppm Ag is released as AgNO ₃ , Ag (NH ₃ ) ₂₊ , Ag (CN) _{2 -} and Ag (protein).

Silver solutions are prepared as follows:
1) Ag (S ₂ O ₃ ) ₂ ^3- - 2.66 g of AgCl are dissolved in 150 ml of deionized water. 17.22 g of Na ₂ (S ₂ O ₃ ) _{2 are} added and the volume is adjusted to 200 ml with deionized water.

2) Ag (CN) _2- - equal volumes of 12.5 g / l AgCN and 50 g / l KCN are mixed
3) Ag (protein) - examine two samples of silver-containing protein. Silver-containing protein powder (0.5 g, Sigma S-6767, lot 12H3437, 20% Ag) was added to 10 ml of deionized water. Silver-containing protein powder (1.25 g, Sigma S-9017, lot 33H3456, 8% Ag) was added to 10 ml of deionized water.

4) Ag (NH ₃ ) ₂₊ - silver nitrate is added to ammonium hydroxide until a black precipitate forms. An additional amount of ammonium hydroxide is added dropwise to the resulting solution until the re-dissolution of the precipitate is achieved, which leads to the transition of the Ag (NH ₃ ) _{2+ ion} into the solution.

Next, control solutions are prepared containing the same concentrations of nitrate, ammonia, cyanide and thiosulfate as in the studied solutions. The antimicrobial effect of the test solutions is determined using the zonal inhibition test. A sensitive disk (cellulose, diameter 6 mm) containing 25 microliters of each of the test solutions is placed in the middle of a plate with Müller Hinton agar (MNA) (Difco medium). Create the conditions for diffusion for 4 hours of silver or ion complexes on a cup with MNA, maintained in a thermostat at a temperature of 37 ^o . After 4 hours, a sensitive disc was removed from the dish and the silver content was determined by neutron activation analysis (HAA, University of Alberta, University of Alberta Slowpoke Reactor Facility). To measure the zones of inhibition against S.aureus, an additional series of dishes is used, taking into account the investigation of each of the silver complexes or ions present in the sensitive discs. From two sections of the cup: at the edge of the inhibition zone and under the discs, agar samples are taken. Agar samples were tested for silver using the HAA method. The study of the antimicrobial effect of control solutions showed the absence of zones of inhibition. The results are presented in table 10.

The above results show that silver salts or compounds, for which it is known that they dissociate to form an Ag + ion (e.g. silver nitrate and silver proteins), have a limited antimicrobial effect (6 mm inhibition zone). The antimicrobial effect is higher for those silver compositions that release complex ions other than Ag + (for example, Ag (NH ₃ ) ₂₊ , Ag (CN) _{2 -} and Ag (S ₂ O ₃ ) ₂ ^3- ). It is also obvious that ions of silver complexes are able to diffuse further into the agar medium than Ag +, which leads to the achievement of an antimicrobial effect at a farther distance from the silver source.

 It is believed that the Ag + ion is less effective as an antimicrobial agent, since it is easily precipitated by chloride ions present in the agar medium. On the other hand, ions of silver complexes are characterized by a higher level of antimicrobial activity and faster diffusion. The ions of silver complexes, apparently, in addition, are not precipitated by chloride ions to the same extent, which makes them more convenient for use in industrial systems or in the operation of medical and other devices that come into contact with liquids containing chloride during operation ions.

Example 19
This example provides comparative data on diffusion values and inhibition zones for a number of silver antimicrobial coatings.

 Three silver films were obtained by sputtering under the conditions indicated in table 11.

 As described in the previous examples, coatings are tested for antimicrobial activity using a zonal inhibition test. According to the method of example 18, using the HAA analysis determine the silver content after 4 hours of diffusion into the agar medium. Table 12 presents the comparative results.

In the case of the first film, which releases Ag + ions, a small zone of inhibition is formed, while silver is precipitated under the film as AgCl. In the case of film 2, a large zone of inhibition is formed (6-fold value) in the presence of silver precipitate under the plate, up to 1/4 of its amount. These data suggest that the formation of an ion of a silver complex other than Ag ⁺ occurs, which diffuses more easily. It is known that the facilitation of diffusion is determined by the nature of complex forms of silver. Film 3 releases much more silver than films 1 and 2, however, large amounts of silver are present in the form of Ag ⁺ , which precipitates under the film in the form of AgCl. However, the size of the inhibition zone indicates that, in addition to Ag ⁺ , a silver complex ion is generated that is more mobile than Ag ⁺ . Most likely, one or more negatively charged ions are formed, which are a combination of silver with hydroxyls: Ag (OH) _2- , Ag ₂ (OH) ₃ - or Ag ₃ (OH) _4- . Due to the presence of chloride in the agar medium, the formation of silver hydroxyl chloride complexes can occur.

Example 20
This example is included to illustrate the method for producing silver cyanide complex ions, as well as the antimicrobial properties of such ions.

A silver cyanide bath, commonly used in electrodeposition, is examined for the antimicrobial effect by taking 25 microliters from the bath and placing them on a sensitive disc in a standard zonal inhibition test. A silver cyanide bath contains 37 g / L silver cyanide, 45 g / L potassium cyanide and 30 g / L potassium carbonate. The resulting inhibition zones cover the entire dish, indicating that the adjusted value of the inhibition zone exceeds 94 mm. The maximum amount of silver that was available in an AgCN bath was 30000 ppm. From previous work it is known that such a concentration of silver in the form of AgNO ₃ leads to the formation of an inhibition zone of not more than 6 mm. The effect of one cyanide ion was determined by placing 25 microliters of KCN at a concentration of 45 g / l on a sensitive disc with repeating the zonal inhibition test. A value of the corrected inhibition zone of 12.5 mm was obtained. Similarly, a solution of AgCN (37 g / L) in distilled water was studied for zonal inhibition. In this case, a corrected inhibition zone value of 14 mm was obtained.

The molar ratio of silver ion to cyanide ion in the bath is 0.37: 1. It promotes the formation of a negatively charged complex of silver cyanide Ag (CN) _{2 -} or AgCN (ag) in the form of an ion pair. All these results indicate that silver complex ions are effective as antimicrobial agents and are characterized by increased mobility in the agar medium.

Thin strips of filter paper are treated with 50 microliters of either silver nitrate solution (10,000 ppm Ag) or potassium cyanide solution (6400 ppm CN ^- ). The strips were subjected to standard zonal inhibition testing using agar plates (MNA). Control strips with silver nitrate give a corrected zone of inhibition of 8 mm, while control strips with KCN do not lead to the formation of zones of inhibition. When placing strips with silver nitrate and potassium cyanide on an agar plate (MNA) and choosing the correct angle of their location relative to each other, the corrected inhibition zone is 30 mm away from the strip with silver nitrate and 22 mm from the strip with potassium cyanide.

 The result shows that the silver complex ion formed by the combination of silver nitrate and potassium cyanide in a medium has greater antimicrobial efficiency than each of them taken separately in solution.

Example 21
The present example is included to illustrate the antimicrobial efficacy of a silver complex ion from silver chloride.

Silver chloride granulate is compressed into 0.2 g of pressurized 413550 Pa (60,000 lb / ⁱⁿ²⁾ and examined by the test for inhibition of zonal on agar plates (MHA). An inhibition zone of 8 mm is obtained. A mixture of 0.15g AgCl and 0.05 g NaCl compressed into granules under pressure of 60,000 lb / ⁱⁿ² (413,550 Pa) and tested in a similar manner. As a result of testing, an inhibition zone of 24 mm is obtained.

An increase in the concentration of available chloride ion promotes the formation of an AgCl _2– silver complex ion, which, as was shown above, has improved antimicrobial efficiency compared to AgCl.

A silver nitrate solution (10,000 ppm Ag) was tested on sensitive discs (25 microliters) in a zonal inhibition test. A 6 mm inhibition zone is obtained. AgNO ₃ at the same concentration was examined on an agar plate to which 5% NaCl was added. An inhibition zone of 20 mm was obtained, which indicates an increase in antimicrobial efficacy. In a control plate with agar, in which 5% NaCl was added, there was no inhibition of bacterial growth (S.aureus).

It can be assumed that higher concentrations of chloride ion contribute to the formation of the silver complex Ag (Cl) _2– ion. This form gives a three-fold increase in antimicrobial efficacy compared to Ag ⁺ from silver nitrate.

Example 22
Animal Testing - Irritation
A study of primary skin irritation was performed on white New Zealand rabbits (NZW) using the antimicrobial coated gauze of the present invention. The coating was applied to Type VII gauze (USP (American Pharmacopoeia)) using the conditions of Example 7 in which the working gas was Ar / O ₂ , 99/1 wt.%
Coated cheesecloth is placed on scraped and scraped skin on the lateral torso of New Zealand white rabbits. After 24 hours, the gauze is removed, and the place of its application is scraped out to study the occurrence of erythema and edema 1, 24 and 48 hours after removal.

 All animals underwent research. None of the animals had erythema, edema, or infection. It was concluded that the gauze used does not cause local irritation when applied to the skin of males or females of New Zealand rabbits (NZW).

Example 23
Animal Testing - Sensitivity
The sensitivity of Hartley guinea pigs to type VII gauze (USP (American Pharmacopoeia)) coated with the antimicrobial metal coating of the present invention is examined. The gauze coating was applied according to the method of example 7 using AZO ₂ , 99/1 wt.%. For testing, the adjuvant cleavage technique is used, since the test material cannot be injected, and the application of dry ice to the induced area most closely simulates the clinical situation.

 There was no evidence that coated gauze induces erythema or edema, and no infection was observed in any of the animals studied. All animals underwent research.

 The application of coated gauze to the skin of male Hartley guinea pigs does not cause local sensitivity when tested by adjuvant cleavage.

Example 24
This example is included to illustrate that a silver powder / NaCl mixture results in an antimicrobial effect due to silver complex ions, which are likely AgCl _2- .

 Granules of silver powder (1 micron) and NaCl (25%) are passed under pressure under the following conditions. The antimicrobial effect is measured in granules using a zonal inhibition test. A comparative control study is also carried out in the form of a pressed silver powder in the zonal inhibition test. The results are presented in table 13.

Example 25
This example illustrates the structural and chemical characteristics of silver-deposited silver films that exhibit good antimicrobial activity (Corrected Inhibition Zone - CZOI) when performing the zonal inhibition test described in the previous examples. Films are obtained by sputtering from a magnetron with a flat silver sprayer with a diameter of 20.3 cm onto substrates in the form of silicone plates (100 mm from the sprayer) under the conditions indicated in Table 14. The total mass gas flow is 700 st • cm ³ / min. The ratio of the temperature of the substrate to the melting point of silver (1234 K), T / T _m , is less than 0.3, the film thickness is usually 3000 ^o A, and the angle of incidence in each case is 90 ^o (normal angle of incidence). This example describes the characteristics of precipitated silver, as well as the coating after subsequent annealing (in air at a temperature of 140 ^o C for 90 minutes). The films were characterized in terms of structure (grain size, type of defects, recrystallization) and chemical properties (impurity concentration (the impurity content being relative to atomic% O or oxide) and residual electrochemical potential). The results are summarized in tables 15 and 16.

 The concentration of impurities in the film is measured using x-ray spectroscopy and mass spectrometry of secondary ions. In the technique of X-ray electron spectroscopy, a monochromatized Al Ka X-ray beam was used as an incident beam. The Ar 4 kV ion beam is released from the solution into a 2 mm x 2 mm section to remove surface contaminants and prepare a fresh surface for X-ray spectroscopy. For research using secondary ion mass spectrometry, a positively charged cesium ion flux at 12.5 kV was used. Impurity concentrations calculated on the basis of X-ray spectroscopy and mass spectrometry data of secondary ions are shown in Tables 15 and 16, both in the films deposited and in the films after annealing. It is seen that the preferred characteristic of biologically active silver films in accordance with the present invention is the presence of an impurity. The data of X-ray electron spectroscopy and mass spectrometry of secondary ions show that the impurity, which in this case is oxygen or silver oxide and oxygen, does not chemically bind to silver atoms in the film. In addition, an impurity in the form of oxygen is included in such an amount that it allows to increase the solubility of solids in silver at room temperature.

The grain size on the deposited and annealed films is measured on images obtained by transmission electron microscopy. These data, shown in tables 10 and 11, show that the antimicrobial active silver films of the present invention have an average grain size of less than 200 nm. Active films after deposition have an average grain size of less than 140 nm. The most active films after deposition have an average grain size of less than 90 nm. In addition, high-resolution transmission electron microscopy showed that the onset of recrystallization (T _rec ) occurs at about 90 ^o C. Grain growth in such fine-grained biologically active films occurs at temperatures below 0.33 T _m , where T _m represents the melting point of silver in degrees K, in particular, below 140 ^o C. In general, recrystallization reduces antimicrobial activity. However, coatings with increased levels of silver oxide (coatings 3 and 6) retain antimicrobial activity after annealing. It is believed that the oxide captures atomic defects, thus allowing it to retain antimicrobial activity after annealing.

A study using transmission electron microscopy also indicates that biologically active silver films contain many growth twins. When annealed in air at a temperature of 140 ^o C for 90 minutes, growth twins disappear, and annealed twins appear. The latter of them are the result of the recovery, recrystallization, and grain growth, which transform the silver film into a state characterized by low energy. It is obvious that the deposited silver films, together with the growth twins accompanying them, in which such grain growth was noted, were in a state with an increased energy status. Thus, the presence of the above defects in the deposited films is a distinctive characteristic of the antimicrobial coatings of the present invention. FIG. 1 and 2 are micrographs taken by transmission electron microscopy, which show the grain size and twins observed respectively in silver films obtained after deposition and after annealing.

 The residual potential of silver films is measured in a 1M solution of potassium hydroxide (KOH) using a saturated calomel electrode (NCE) as a standard electrode. Tables 15 and 16 show that silver films exhibit antimicrobial activity only if the residual potential is positive. In the case of a negative value of the residual potential of biological activity is not observed.

 All publications cited in the present description reflect the achieved level in the technical field to which the present invention relates. However, all publications are incorporated by reference to the extent that each such publication is specifically suitable for inclusion.

 Terms and expressions of the specification are used as terms for description and are not limiting. When using such terms and expressions, equivalents of the illustrated and described materials and their characteristics are not excluded, since the scope of the invention is defined and limited only by the claims, which are given below for the present invention.

Claims (53)

 1. A method of obtaining an antimicrobial material containing one or more antimicrobial metals, characterized in that it involves the creation of atomic disorder in a material containing one or more antimicrobial metals under conditions that limit diffusion, to maintain atomic disorder in the specified material and to ensure prolonged release of atoms , ions, molecules or clusters of at least one of the metals in an alcoholic or aqueous electrolyte with an increased relative to the material in its normal order ohm crystalline state speed, and irradiating radiation material with a low linear energy transfer to release at least one antimicrobial metal at a concentration sufficient to provide a localized antimicrobial effect.  2. The method according to claim 1, where the antimicrobial metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn and their alloys and compounds.  3. The method according to claim 2, where the specified material is a powder or foil of one or more antimicrobial metals and atomic disorder is created by cold processing of said powder or foil.  4. The method according to claim 3, where the specified material is a nanocrystalline powder.  5. The method according to claim 2, where the specified material is obtained in the form of a coating on a substrate by vapor deposition under conditions that limit diffusion during the deposition process, and after deposition, limit annealing or recrystallization.  6. The method according to claim 5, where the specified material is obtained by vacuum evaporation, sputtering, sputtering using a magnetron or ion deposition of a metal.  7. The method according to claim 6, where the antimicrobial material is a composite coating formed by the joint, sequential or reactive deposition of an antimicrobial metal on a matrix with atoms or molecules of another material to create atomic disorder in the matrix, wherein said other material is one or more precipitated materials selected from the group consisting of oxygen, nitrogen, hydrogen, boron, sulfur or halogen, absorbed or trapped in a matrix from the atmosphere of the deposited vapor phase: oxy e, nitride, boride, halide, sulfide or hydride of an antimicrobial metal, and oxide, nitride, carbide, boride, halide, sulfide or hydride of an inert biocompatible metal selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo Si or Al.  8. The method according to claim 7, where the antimicrobial metal is silver, and said other material is either silver oxide, or atoms of a molecule containing oxygen, absorbed or captured into a matrix from the atmosphere of the vapor deposited phase, or both.  9. The method according to claim 5, where the said coating is obtained by sputtering using a magnetron at a ratio of the temperature of the surface to be coated with the melting point of the deposited antimicrobial material less than about 0.5 and the working gas pressure higher than about 1.3 Pa (10 mT).  10. The method according to claim 7, where the said coating is obtained by sputtering using a magnetron with a ratio of the temperature of the surface to be coated with the melting point of the deposited antimicrobial material less than about 0.5 and the working gas pressure higher than about 1.3 Pa (10 mT).  11. The method of claim 8, where the said coating is obtained by sputtering using a magnetron at a ratio of the temperature (in degrees Kelvin) of the surface to be coated with the temperature (in degrees Kelvin) of the melting of the deposited antimicrobial material less than about 0.5 and the working gas pressure higher than about 1.3 Pa (10 mT).  12. The method according to any one of claims 1, 3 or 6, where the type of radiation is selected from gamma, beta or x-ray radiation.  13. The method according to any one of claims 1, 3 or 6, where the radiation source is a source of gamma radiation used in a dose higher than about 1 Mrad.  14. The method according to any one of claims 1, 3 or 6, where the irradiated antimicrobial material is oriented generally perpendicular to the radiation flux.  15. The method according to any one of claims 1, 3 or 6, where said material is placed during irradiation next to the dielectric material.  16. The method according to any one of claims 1, 3 or 6, where the aforementioned material is placed during irradiation between the surfaces of silicon oxide. 17. A method of achieving an antimicrobial effect in an alcohol or aqueous electrolyte, which includes (a) obtaining such a silver material that forms silver complex ions other than Ag ⁺ , Ag ⁺² , Ag ⁺³ , Ag (OH) ₂ ^- , Ag ₂ (OH) ₃ ^- or Ag ₃ (OH) ₄ ^- , in an amount sufficient to achieve an antimicrobial effect upon contact with an alcohol or aqueous electrolyte, which is higher than the corresponding effect produced by an equivalent amount of silver in the form of Ag ⁺ , and (b) bringing silver material into contact with the processed alcohol or water elec trolite, which causes the release of complex silver ions. 18. The method according to 17, where said silver material forms one or more complex silver ions Ag (CN) ₂ ^- , AgCN _aq (ion pair), Ag (NH ₃ ) ₂ ⁺ , AgCl ₂ ^- and Ag (S ₂ O ₃ ) ₂ ^3- , in contact with an alcohol or aqueous electrolyte.  19. The method according to p, where the silver material is prepared in the form of a powder, solution or suspension containing one or more complex silver ions.  20. The method according to 17, where the aforementioned silver material is a fine-grained or nanocrystalline powder.  21. The method according to any one of paragraphs. 17, 18 or 19, wherein said silver material is prepared as an antimicrobial coating on a medical device.  22. The method according to any one of paragraphs.17, 18 or 19, where the aforementioned silver material is obtained in powder form for use in an antimicrobial composition for topical application. 23. The method according to 17, where said silver material forms one or more complex silver ions Ag (CN) ₂ ^- , AgCN _aq (ion pair), Ag (NH ₃ ) ₂ ⁺ , in contact with alcohol or electrolyte. 24. The method according to claim 19, where the aforementioned silver material forms one or more complex silver ions Ag (CN) ₂ ^- , AgCN _aq (ion pair), Ag (NH ₃ ) ₂ ⁺ , in contact with alcohol or electrolyte. 25. The antimicrobial form of the silver material obtained by the method according to claim 17, characterized in that the silver material is a powder, solution or suspension containing complex silver ions other than Ag ⁺ , Ag ²⁺ , Ag ³⁺ , Ag (OH) ₂ ^- , Ag ₂ (OH) ₃ ^- or Ag ₃ (OH) ₄ ^- , in an amount providing a greater antimicrobial effect upon contact with an alcohol or aqueous electrolyte than the effect produced by an equivalent amount of silver in the form of Ag ⁺ . 26. The material according A.25, where the silver material contains one or more complex silver ions Ag (CN) ₂ ^- , AgCN _aq (ion pair), Ag (NH ₃ ) ₂ ⁺ , AgCl ₂ ^- and Ag (S ₂ O ₃ ) ₂ ^3- .  27. Fine-grained antimicrobial material, characterized in that it includes one or more antimicrobial metals or their alloys, or compounds in the form of a fine-grained powder with a grain size of less than 200 nm and has atomic disorder sufficient for prolonged release upon contact of the material with an alcohol or aqueous electrolyte of atoms , ions, molecules or clusters containing at least one metal in a concentration sufficient to provide a local antimicrobial effect, while the antimicrobial metal is formed in m Atrica containing atoms or molecules of another material selected from inert biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulfur, halogen and oxides, nitrides, carbides, borides, sulfides and halides of one or both of an antimicrobial metal or an inert biocompatible metal .  28. The antimicrobial material according to item 27, where the antimicrobial metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn or their alloy, or compounds, and where the biocompatible metal is selected from a group including Ta, Ti, Nb, V, Hf, Zn, Mo, Si or Al.  29. The antimicrobial material of claim 28, wherein the antimicrobial metal is selected from Ag, Au, or Pd, and where the biocompatible metal is selected from Ta, Ti, or Nb.  30. The antimicrobial material according to item 27, containing mainly pure metallic silver, silver oxide and trapped or absorbed oxygen atoms.  31. Antimicrobial material according to any one of paragraphs. 27, 28, 29 or 30 in the form of a nanocrystalline powder having a grain size of less than about 20 nm.  32. The antimicrobial material according to any one of claims 27, 28, 29 or 30 in the form of a fine-grained powder having a grain size of less than about 140 nm.  33. The antimicrobial material according to item 27, where the antimicrobial metal is silver, or its alloy, or compound and where the material has a residual positive potential, measured with respect to the standard saturated calomel electrode in 1M NaOH, characterized by the ratio of its recrystallization temperature to its temperature melting point, in degrees K (T req. / T pl.) of less than 0.33 and, upon contact with an alcoholic or aqueous electrolyte, liberates atoms, ions, molecules or clusters containing silver in concentration ns, sufficient to provide a local antimicrobial effect.  34. The material according to p. 33, characterized in that the ratio of the temperature of its recrystallization to its melting point, in degrees K (T rek. / T pl.), Is less than about 0.3. 35. The material according to p. 33, characterized in that it has a recrystallization temperature of less than about 140 ^o C.  36. The material according to p. 35, characterized in that it has a grain size of less than about 200 nm.  37. The material according to clause 35, wherein the grain size is less than about 140 nm.  38. The material according to clause 35, wherein the grain size is less than about 90 nm.  39. The material according to clause 35 in the form of nanocrystalline powder.  40. The material according to clause 36 or 39 in the form of a mixture of essentially pure metallic silver and silver oxide.  41. The material according to clause 36 or 39 in the form of a mixture of essentially pure metallic silver and absorbed, trapped or reacted oxygen atoms or molecules.  42. The material according to paragraph 41 further comprising silver oxide.  43. A method of producing a fine-grained antimicrobial material, characterized in that one or more antimicrobial metal is deposited in the form of a powder by vapor deposition on a cooled substrate in a matrix with atoms or molecules of another material to obtain a material having atomic disorder, which ensures that the powder comes into contact with alcohol or water electrolyte prolonged release of ions, atoms, molecules or clusters of at least one of the antimicrobial metals in an alcoholic or aqueous electrolyte in concentration, d sufficient to achieve a local antimicrobial effect, while another material is selected from the group consisting of inert biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulfur, halogens and oxides, nitrides, carbides, borides, sulfides and halides and / or antimicrobial metal hydrides or inert biocompatible metal.  44. The method according to item 43, where the antimicrobial metal is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn or their alloys, or compounds of one or more of these metals and where the biocompatible metal is selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al, or alloys, or compounds of one or more of these metals.  45. The method according to item 43, where the antimicrobial metal is selected from Ag, Au, Pd and where the biocompatible metal is selected from Ta, Ti and Nb.  46. The method according to item 45, where during vapor deposition into the atmosphere of the working gas, oxygen is introduced so that oxygen atoms or molecules are captured or absorbed by the matrix.  47. The method according to item 46, where the deposited antimicrobial metal is essentially pure metallic silver or silver oxide and where oxygen can be introduced into the atmosphere of the working gas so that the deposited material comprises essentially pure metallic silver and either silver oxide or silver oxide and atoms or molecules of trapped or absorbed oxygen.  48. The method according to any one of paragraphs 43, 44 or 45, where the material is precipitated in the form of a fine powder.  49. The method according to any one of paragraphs 43, 44 or 45, where the material is precipitated in the form of nanocrystalline powder.  50. The method according to any one of paragraphs 43, 44 or 45, where the material is deposited in the form of a nanocrystalline film.  51. The method according to any one of paragraphs 43, 44 or 45, where the fine-grained antimicrobial material has a grain size of less than about 200 nm.  52. The method according to any one of paragraphs 43, 44 or 45, where the fine-grained antimicrobial material has a grain size of less than about 140 nm.  53. The method according to any one of paragraphs 43, 44 or 45, where the finely granulated antimicrobial material has a grain size of less than about 90 nm. Priority on points:
11/18/93 - according to claims 1 - 16 and 27 - 53;
02.02.94 - according to claims 17-26.

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