HK1032883A - Anti-microbial coatings having indicator properties and wound dressings - Google Patents

Description

Antimicrobial coatings and wound dressings with indicator properties

Technical Field

The present invention relates to antimicrobial coatings formed from one or more antimicrobial metals and to multilayer laminated wound dressings.

Background

Burns and related wounds present serious problems in infection control. Precious metal ions such as silver and gold ions are known to have antimicrobial activity and have been used in medical care for many years to prevent and treat infections. Water soluble silver nitrate is widely used as an astringent and as a strong antimicrobial solution. For example, a 10% silver solution formulation is applied directly to the oral ulcer; dressings wetted with 0.5% silver nitrate solution are used to cover second and third degree burns, in particular to protect against infection by gram-negative bacteria; 1% silver nitrate solution eye drops are still a legal treatment for the prevention of neonatal ophthalmia in many parts of the world.

The antimicrobial effect of these known silver nitrate solutions is apparently directly related to the concentration of silver ions. Unfortunately, the water-soluble silver nitrate solution provides very low residual activity due to the reactivity of silver ions with chloride ions and the like in body fluids. To compensate for this life deficiency, water-soluble silver solutions, such as silver nitrate, are used at concentrations (2 to 5mg/L) much higher than required for bacterial control (3000 to 3500mg/L) in an effort to extend the period of antimicrobial efficacy. As a result, the solution may have a stimulating and astringent effect on the wound. For example, a 1% solution for the prevention of neonatal ophthalmia must be rinsed with 0.85% sodium chloride immediately within a few seconds to prevent conjunctivitis. Present fever for second degree burnWound treatment uses a 0.5% silver nitrate solution, but it must be added frequently throughout the day (usually 12 times a day) to replenish active Ag⁺Ions. Also in use is silver sulfadiazine cream which requires frequent re-application and scraping to remove debris and chemical barriers, and which may also cause sensitivity or sensitization to the sulfonamide component.

Effective improvement schemes that minimize side effects were sought from the beginning of this century. Some attempts have been made to focus on the use of colloidal solutions of poorly ionized insoluble salts, such as oxide complexes with proteins, to reduce the release rate of silver ions. Other attempts have focused on producing the silver in an activated form, for example by depositing it on porous carbon to provide a slower release of silver ions, or by activating the deposited silver, for example by treatment with a strong oxidizing agent. In addition, there have been other attempts involving electro-activation of the silver coating to drive the release of silver, or deposition of more noble metals of different electrochemical potentials, which use bimetallic current action as the driving force to release silver ions. Improvements in antimicrobial agents derived from antimicrobial metals such as silver and wound treatment procedures using them have heretofore been sought to improve the antimicrobial efficacy of the metal ions, reduce the frequency of use of the antimicrobial agents, and improve infection control in wound treatment. Also needed are visual indicators of antimicrobial activity and effectiveness in order to minimize over-application of antimicrobial agents and unwanted wound dressing removal, thus improving patient comfort and minimizing sensitive reactions to antimicrobial metals.

Applicants have developed antimicrobial materials that provide effective and durable antimicrobial effects. These materials are described, for example, in US5,454,886 issued by Burrell et al on 3.10.1995. These materials are powders, foils, flakes, coatings or films formed from one or more antimicrobial metals so as to contain atomic disorder.

Summary of The Invention

In carrying out the work of the present inventors on the improvement of the atomic disordered antimicrobial materials described in the aforementioned patent applications, the present inventors have made several surprising discoveries. First, the inventors have discovered that a thin film of antimicrobial metallic material on a reflective base coating, such as a reflective silver coating, can produce interference colors. By varying the refractive index and/or the thickness of the top layer, a visually different interference color is produced. Secondly, the inventors have found that if the top antimicrobial metal layer is in an atomically disordered form, which produces an antimicrobial effect when exposed to alcohol or electrolyte, a clearly visible interference colour is produced, providing a useful indicator of the activity (release of ions etc.) of a medical device or the like bearing such a coating. Even minor dissolution or compositional changes in the top layer of the coating, such as fingertip contact, were found to cause a detectable color change. Third, the inventors have discovered that it is possible to produce an atomic disordered antimicrobial metal monolayer with an initial color that changes upon contact with alcohol or electrolyte, thereby producing an interference color that is different from the initial color. Without being limited thereto, it is believed that contact with the atomically disordered material forms a thin layer (hereinafter referred to as an "in situ generated top layer") on top of the material, which has a sufficiently different composition than the underlying base layer, and thus is capable of forming an interference color. Thus, the present invention extends to a method of indicating exposure of a multilayered antimicrobial material in an atomic disordered state to an alcohol or electrolyte by utilizing an interference color.

In one broad aspect, the present invention provides a multi-layered antimicrobial material comprising a) a base layer of partially reflective material capable of producing an interference color when covered with a partially reflective, partially light transmissive top layer; and b) a top layer formed on said base layer, said top layer being a partially reflective, partially light transmissive film containing at least one antimicrobial metal and having a thickness that produces an interference color, said top layer having a refractive index different from that of the base layer and the antimicrobial metal being in a sufficiently atomic disorder such that upon contact with the alcohol or water-based electrolyte, the top layer continuously releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte at a concentration sufficient to provide a localized antimicrobial effect. The invention extends to antimicrobial materials in which the top layer is formed on the base layer by a technique such as vapor deposition, and to materials having an in situ generated top layer.

The base layer may be a partially reflective substrate (e.g., a medical device) such that it provides an interference color when covered with a partially reflective, partially transmissive top layer. Preferably, the base layer is formed of a metal selected from the group consisting of Ag, Au, Pt, Pd, Cu, Ta and Al, with Au, Ag, Pt, Pd and Cu being most preferred. Both the top and base layers are preferably formed from an antimicrobial metal in an atomic disordered state. The top layer is most preferably formed of Au or Ag.

Most preferably, the top layer is a composite material formed by depositing the anti-bio-metal in a matrix containing atoms or molecules of different materials, wherein the different materials provide atomic disorder in the matrix. The different material may be a biocompatible metal such as Ta, Ti, Nb, V, Hf, Zn, Mo, Si or Al, or an oxide, nitride, carbide, boride, halide, sulfide or hydride of these biocompatible metals. In addition, the different material may be an atom or molecule, including oxygen, nitrogen, hydrogen, boron, sulfur, or a halogen, that is absorbed or trapped from the atmosphere used in the vapor deposition process. Alternatively, the different material may be an oxide, nitride, carbide, boride, halide, sulfide or hydride of the antimicrobial metal. Most preferably, the top layer is formed of Ag as the base metal and one or both of silver oxide and absorbed or trapped oxygen as a different material.

When provided as a coating on a substrate, the base layer is preferably at least 25nm, and more preferably at least 60nm, thick. If formed from an atomically disordered antimicrobial metal, the base layer is preferably about 300nm to 2500nm in thickness to provide a prolonged antimicrobial effect after dissolution of the top layer. The top layer is preferably less than 400nm thick and more preferably between 5 and 210nm thick. Most preferably, the top layer has a thickness of between 40 and 160 nm.

The present invention also includes a method of making a multilayer antimicrobial material capable of indicating exposure to an alcohol or aqueous-based electrolyte. The method comprises a) providing a base layer of partially reflective material capable of producing interference colors when covered with a partially reflective, partially light transmissive top layer; and b) providing a top layer formed on said base layer, said top layer being a partially reflective, partially light transmissive film containing at least one antimicrobial metal and having a thickness that produces an interference color, said top layer having a refractive index different from that of the base layer, and the antimicrobial material being in a sufficiently atomic disorder such that, upon contact with the alcohol or water-based electrolyte, the top layer continuously releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte at a concentration sufficient to provide a localized antimicrobial effect. The top layer may be formed by depositing it on the base layer, for example by vapour deposition, or the top layer may be provided as an in situ generated top layer. In either approach, a color change occurs upon contact with an alcohol or water-based electrolyte, thereby indicating activation of the material.

The inventors have also discovered that when using wound dressing materials, multiple layers of wound dressings can be laminated together using ultrasonic welding at several points of discontinuity, resulting in a wound dressing that can be conveniently cut to size without causing separation between the different layers and without the need to use seams or adhesives to join the different layers together. The presence of an ultrasonically welded spot at several points of discontinuity on the dressing is surprisingly superior to a stitched dressing or the use of an adhesive, because an ultrasonically welded dressing has excellent comfort properties (i.e. is able to conform to the contours of the wound and skin). In wound dressings having one or more porous layers that are permeable to fluids, it has also been found that the ultrasonic welds only minimally affect the penetrating properties of the dressing. Importantly, when a wound dressing is coated with an antimicrobial metal coating of the present invention, i.e., a coating comprising one or more layers of an antimicrobial metal in an atomic disordered state in the dressing, the laminate of the ultrasonically welded wound dressing does not inhibit antimicrobial activity. When the material is heated, atomic disorder in the material can be easily removed because the heat can eliminate crystal defects.

Accordingly, in another broad aspect, the invention provides a multilayer laminated wound dressing comprising:

a first wound-facing layer formed of a porous, non-adhesive material;

a second layer laminated on the first layer and formed of an absorbent material;

an optional third layer laminated to one or both of the first and second layers;

at least one of the first, second and optional third layers is formed of plastic; and

the first, second and optional third layers are laminated together by ultrasonic welding at several discrete points on the dressing so that the dressing can be cut to size without delamination.

The wound dressing is preferably formed of an antimicrobial coating, most preferably a multi-layered antimicrobial material as mentioned above, to provide an interference color indicator of activation upon contact with an alcohol or water-based electrolyte.

As used herein and in the claims, the following terms and phrases have the following meanings.

"metal" includes one or more metals in the form of substantially pure metals, alloys, or compounds, such as oxides, nitrides, borides, sulfides, halides, or hydrides.

An "antimicrobial metal" is a metal whose ions have an antimicrobial effect. Preferably, the metal is also biocompatible. Preferred antimicrobial metals include Ag, Au, Pt, Pd, Ir (i.e., noble metal), Sn, Cu, Sb, Bi, and Zn.

"biocompatible" means non-toxic for the intended application. Thus, for use in humans, biocompatible means non-toxic to humans or human tissues.

By "antimicrobial effect" is meant that ions, atoms, molecules, or clusters of antimicrobial metals (hereinafter "species" of antimicrobial metals) are released into an alcohol or water-based electrolyte in contact with the material at a concentration sufficient to substantially inhibit the growth of bacteria (or other microorganisms) in the vicinity of the material. The most common method of measuring antimicrobial effect is by the zone of inhibition (ZOI) produced when the material is placed in a bacterial lawn. A relatively small or no ZOI (e.g., less than 1mm) indicates no useful antimicrobial effect, while a larger ZOI (e.g., greater than 5mm) indicates a highly useful antimicrobial effect. The ZOI test procedure is given in the examples below.

"sustained release" or "sustainable basis" is used to define the sustained release of atoms, molecules, ions or clusters of antimicrobial metals over an assay of hours or days, and is therefore clearly distinguished from the release of these metal species from bulk metals which, when contacted with an alcohol or electrolyte, release these species at too low a rate and concentration to achieve an antimicrobial effect, and also from the release of highly soluble salts of antimicrobial metals such as silver nitrate which, when contacted with an alcohol or electrolyte, release silver ions virtually immediately, but not continuously.

"atomic disorder" includes high concentrations of: lattice point defects, vacancies, line defects such as dislocations, interstitial atoms, amorphous regions, grain and sub-grain boundaries, and the like, relative to their normally ordered crystalline state. Atomic disorder leads to surface topography irregularities and structural non-uniformities on the nanometer scale.

"normally ordered crystalline state" refers to crystallinity typically seen in cast, wrought, or plated bulk metallic materials, alloys, or compounds. These materials contain only a low concentration of atomic defects such as vacancies, grain boundaries and dislocations.

"diffusion," when used to describe conditions that limit diffusion in a process that creates and preserves atomic disorder, i.e., freezes atomic disorder, refers to diffusion of atoms and/or molecules within or on the surface of the matrix of the material being formed.

By "substrate" is meant any surface, typically the surface of a medical device, which is itself partially reflective, or which may be coated with a partially reflective metallic coating by, for example, vapor deposition, including evaporation or physical vapor deposition techniques. In this application, it should be understood that when reference is made to the formation of a reflective base layer on a substrate, it does not mean that each substrate needs to have such a layer formed thereon, but includes inherently reflective substrates, such as reflective plates or devices formed of polymers, metals or dielectrics, so that it can provide an interference color.

"medical device" means any device, instrument, clip, fiber, fabric, or material used for medical, health care, or personal hygiene purposes, including, but not limited to, orthopedic nails, plates, implants, endotracheal tubes, catheters, insulin pumps, wound closures, drainage tubes, shunts, dressings, connectors, prostate devices, pacemaker leads, needles, dentures, respiratory tubes, surgical instruments, wound dressings, incontinence pads, sterile packaged cloth footwear, personal hygiene products such as diapers and hygiene pads, and biomedical/or biotech laboratory equipment such as tables, wraps, and wall coverings, and the like. The medical device may be made of any suitable material, such as metals, including steel, aluminum and alloys thereof, latex, nylon, silicone, polyester, glass, ceramics, paper, cloth, and other plastics and rubbers. For in vivo (indwelling) medical devices, the device is made of a biologically inert or biocompatible material. The device may be of any shape depending on its use, and may be in the form of a flat sheet or a disc, a rod or a hollow tube. The device may be rigid or flexible, depending on its intended use.

An "alcohol or water-based electrolyte" is intended to include any alcohol or water-based electrolyte into which the antimicrobial material of the present invention can come into contact to activate (i.e., cause the release of antimicrobial metal species). This term is intended to include alcohols, water, gels, fluids, solvents, and water-containing tissues, including bodily fluids (e.g., blood, urine, or saliva), and bodily tissues (e.g., skin, muscle, or bone).

"color change" is intended to include changes in light intensity under monochromatic light as well as changes in color of white light containing more than one wavelength.

An "interference color" is produced when light is shone on two or more partially reflective surfaces separated by a distance related to the wavelength of the light to be removed by destructive interference.

"partially reflective" when used to describe a base or top layer material means that the material has a surface that reflects a portion of incident light, but it also transmits a portion of incident light. Reflection occurs when an incident beam of light encounters a boundary or interface characterized by a change in refractive index between two media. For the top layer of the antimicrobial material of the present invention, the interface is with air. For the base layer, the interface is with the top layer. The reflectance of the base and top layers is balanced, thereby producing interference colors.

"partially light transmissive" when used to describe a film of topsheet material means that the film is capable of transmitting at least a portion of incident visible light into the film.

"visually detectable", when used to describe a color change, means that a shift in the dominant wavelength of reflected light is observed, whether the change is detected by an instrument such as a spectrometer, or by the naked eye. The dominant wavelength is the wavelength that determines the color observed.

"wound" refers to a cut, injury, burn or other trauma to human or animal tissue in need of a wound dressing.

"wound dressing" refers to a covering for a wound.

Description of the drawings

FIG. 1 is a schematic cross-sectional view showing a colored antimicrobial coating of the present invention producing an interference color;

figure 2 is a schematic cross-sectional view of a three-layer wound dressing of the present invention.

Description of the preferred embodiments

1. Multilayer antimicrobial material with interference colors

The present invention provides an antimicrobial material comprised of at least two layers, a base layer and a top layer, to produce a interference color one. Both layers are partially reflective; the top layer is partially light transmissive. The top layer is a thin film containing at least one antimicrobial metal in a sufficiently atomic disordered state such that the top layer, when contacted with an alcohol or aqueous-based electrolyte, releases ions, atoms, molecules, or clusters of the antimicrobial metal continuously at a concentration sufficient to provide a topical antimicrobial effect. In this way, the top layer will undergo a change in optical path length upon contact with an alcohol or electrolyte, either due to some dissolution resulting in a change in thickness or due to a change in the composition of the newly formed thin layer on the top layer resulting in a change in the refractive index of the top layer. One or both of these results is sufficient to cause a detectable color change, thus providing an indicator that the topsheet has been activated.

The generation of interference colors is known in the art of decorative effects, diffraction gratings, and diagnostic assays, and thus the balance of the various properties of the at least two layers of material necessary to generate the interference colors, i.e., the reflectance, transmission, thickness, and refractive index of these layers, is generally well known in the art. The prior art generally teaches anodizing metals to produce a thin layer of a generally transparent oxide on a reflective base metal (see, e.g., US5,124,172 to buttel et al, published on 23.6.1992). Other prior art teaches the use of sputtering of certain reflective metals with oxides of the same or different metals to produce interference colors (see, for example, US 4,702,955 to Allred et al, published on month 10 and 27 of 1987). However, not all metals are easily anodized. Furthermore, the prior art has considered it impossible to sputter plate these important antimicrobial metal oxides, such as silver oxide, without decomposition (see, for example, U.S. Pat. No. 8, 4,728,323 to Matson, published on 3/1/1988). Thus. Presented herein are novel methods of making antimicrobial materials capable of producing interference colors and producing indications of antimicrobial effects.

The generation of the antimicrobial material and interference colors of the present invention is illustrated in fig. 1. The material comprises a base layer 2 and a top layer 4 on the base layer 2. The base and top layers 2, 4 are typically formed on the surface of a substrate 6, such as a medical device. However, if the substrate itself is partially reflective, the substrate may serve as a base layer. The base layer 2 and the top layer 4 are formed from a partially reflective material. In this way, at least part of the incident light is reflected by the surface of the layer, while another part is transmitted into the layer. The top layer 4 is partially light transmissive, allowing incident light to reach the interface with the base layer 2. Thus, the top layer 4 cannot be about 100% reflective, as is the case with pure Al or Ag, otherwise no disturbing colors can be produced, as is well known in the art. The materials of the layers 2, 4 should be balanced in their reflectivity in order to produce interference colors. Typically, the top layer 4 is deposited in the form of a thin film, the thickness of which is such that sufficient transmission is maintained in order to produce interference colours. Furthermore, the refractive indices of the materials in the layers 2, 4 are different, being achieved by differences in their actual or effective composition. For example, different materials in the two layers will result in materials having different actual refractive indices. However, if it is desired to make the layers 2, 4 from the same material, the two layers may be deposited with different porosities or different levels/types of atomic disorder to obtain different effective compositions and thus different refractive indices.

In this way, in fig. 1, incident light a is reflected off the interface 7 of the base layer 2 and the top layer 4. Incident light B reflects from the interface 8 of the top layer 4 with air and interferes with the light reflected off the interface 7, thus producing an "interference color" C. The particular colour produced and its brightness depend on the properties of the layers 2, 4 and above all on the composition of the two layers, which determines their transmission and absorption properties and their refractive index, and also on the thickness of the two layers. Generally, it is desirable to minimize the number of internal reflections by limiting the thickness of the base and top layers to produce primary and secondary interference colors. The first and second interference colors are generally brighter than the third and fourth, etc., colors, making them more aesthetically pleasing, more reproducible to manufacture, and more readily detectable as color changes due to thickness variations caused by small amounts of dissolution of the top layer 4.

The property determining the particular color produced is the effective optical thickness of the top layer 4, i.e. the product of the refractive index of the material of the top layer and the thickness of the top layer 4. Thus, the desired color can be varied by varying the actual thickness of the top layer 4 or its refractive index.

According to the invention, the base layer 2 is a partially reflective material, which is capable of producing interference colours when covered with a partially reflective, partially transmissive top layer 4. Reflective materials such as polymers, dielectrics or metals may be used in the base layer. To achieve the desired level of reflectivity, the base layer 2 may be coated with additional layers (not shown) to vary its reflectivity. For example, the reflective plastic sheet may be coated with a thin discontinuous (island-like) or continuous coating of a reflective metal such as silver, resulting in a base layer whose average reflectance can be better balanced with the top layer to produce the desired interference color effect. Preferably, the material in the base layer 2 is a reflective metal. These metals are known in the art and include, for example, one or more noble metals, e.g., Ta, Nb, Ti, Zr, and Hf, and transition metals such as Au, Ag, Pt, Pd, Sn, Cu, V, W, and Mo, or the metal Al. More preferably, the binder is formed of Ag, Au, Pt, Pd, Cu, Ta and Al. The use of a metal such as tantalum as the base layer 2 may cause reduction of the oxide-containing material in the top layer 4. To avoid this, a barrier layer (not shown) should be included on the tantalum layer, such as tantalum oxide formed by anodizing at least a portion of the top surface of the Ta metal. Preferred metals for the base layer 2 are the antimicrobial metals Au, Ag, Pt, Pd, Sn and Cu in partially reflective form, more preferably Au, Pt and Ag.

The base layer 2 may be formed by a known technique such as a vapor deposition technique of evaporation or physical vapor deposition. Preferably, the substrate 2 is formed as a thin film of atomic disorder by physical vapor deposition, as set forth hereinafter and in the inventor's aforementioned patent application, e.g., US5,454,889, to produce a sustained antimicrobial effect upon ultimate exposure of the substrate to an alcohol or water-based electrolyte. The thickness of the base layer 2 is generally not critical as long as it is partially reflective. The preferred thickness may vary widely depending on the composition of the material and the desired color. However, where layer 2 is a thin film formed by physical vapor deposition techniques, it should be at least about 25nm thick in order to produce a useful color. To produce primary and secondary interference colors and to produce antimicrobial effects according to preferred aspects of the invention, the base layer 2 should be greater than 60nm thick, more preferably 300 to 2500nm thick, and most preferably 600 to 900nm thick.

The top layer 4 is formed from a partially reflective, partially light transmissive film containing at least one atomic disordered antimicrobial metal in order to produce a sustainable antimicrobial effect and a resulting color change when exposed to an alcohol or water-based electrolyte. The antimicrobial metal is preferably one or more of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi and Zn in a partially reflective, partially transmissive form. More preferably, the antimicrobial metal is Ag, Au, Pt, Pd or Cu. The thickness of the top layer 4 formed of these metals is preferably less than 400nm to maintain a preferred level of light transmission. The desired thickness depends on the composition of the top layer 4 and on the desired final color and color variation. The thickness is typically less than about 400nm for primary and secondary interference colors. More preferably, the thickness is in the range of 5 to 210nm, more preferably 10 to 100 nm.

The top layer 4 may be a thin layer of a base material with a different refractive index, for example by varying the deposition conditions to vary the voidage, composition and/or degree of atomic disorder in the layers 2, 4.

When the base layer 2 itself is formed of an atomic disordered state antimicrobial metal, the top layer 4 may be a top layer generated in situ by virtue of its thickness and/or compositional change upon contact with an alcohol or aqueous-based electrolyte so as to produce an interference color that is different from the initial color of the base layer 2.

Most preferably, the top layer 4 is a thin film of a composite material obtained by co-deposition, sequential deposition or reactive deposition of an antimicrobial metal in the manner given belowIn a matrix with atoms or molecules of different materials, atomic disorder is generated in the matrix to form. The different material is selected from a) a biocompatible metal, b) oxygen, nitrogen, hydrogen, boron, sulfur or a halogen, or c) an oxide, nitride, carbide, boride, halide, sulfide or hydride of one or both of the antimicrobial metal or biocompatible metal. More preferably, the top layer material is a composite material containing silver and silver oxide and either or both of atoms trapped or absorbed in the silver matrix or molecules containing oxygen. The term "silver oxide" is meant to include any silver oxide or mixture of oxides. However, the top layer 4 is preferably made of more than AgO and/or Ag₂O formation, because the solubility of these materials is low, is insufficient to provide a useful antimicrobial effect according to the present invention. A) Antimicrobial materials containing atomic disorder

At least the top layer 4, and preferably also the base layer 2, is formed of an atomically disordered crystalline form of the antimicrobial metal in order to produce an antimicrobial effect. Atomic disorder produced by physical vapor deposition techniques is described in the aforementioned patent applications, including US5,454,886, and is summarized below.

The antimicrobial metal is deposited as a thin metal film on one or more surfaces of a substrate, typically a medical device, using vapor deposition techniques. Physical vapor techniques are well known in the art and deposit metals from vapor, usually as atoms, one after the other, onto a substrate surface. These techniques include vacuum or arc evaporation, sputtering, magnetron sputtering or ion plating. The deposition is carried out in such a way as to create atomic disorder in the coating as defined above. Various conditions are useful in connection with creating atomic disorder. These conditions are generally those that have been taught to avoid use in thin layer deposition techniques, since most thin film depositions are aimed at producing defect-free, smooth, and compact films (see, e.g., j.a. tornton, supra). Although these conditions have been studied in the art, they have not been linked to an improvement in the solubility of the coatings thus produced until the present application.

Preferred conditions for creating atomic disorder during this deposition process include:

low substrate temperature, i.e. keeping the surface intended to be coated at a temperature such that the ratio of the substrate temperature to the melting point (in K) of the metal is below about 0.5, more preferably below about 0.35 and most preferably below about 0.3; and optionally one or both of

Higher than normal working (or ambient) gas pressure, i.e. for vacuum evaporation: electron beam or arc evaporation, greater than 0.01mT, gas scattering evaporation (pressure plating) or active arc evaporation, greater than 20 mT; for spraying: greater than 75 mT; for magnetron sputtering: greater than 10 mT; and for ion plating: greater than about 200 mT; and

-keeping the angle of incidence of the coating stream on the intended coating surface less than about 75 °, and preferably less than about 30 °.

The metals used in the coating are metals known to release ions or the like having an antimicrobial effect, such as those given above. For most medical devices, the metal must also be biocompatible. Preferred metals include the noble metals Ag, Au, 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 of these metals.

The film is formed on at least a portion of the surface of the substrate/medical device. For economic reasons, the thickness of the film is not greater than that required for sustained release of the metal ions and generation of the desired interference color over a suitable period of time. Within the preferred ranges given above for the thickness, the thickness depends on the particular metal in the coating (which differs in their solubility and wear resistance) and on the degree of atomic disorder in the coating (and its solubility). The thickness should be sufficiently thin so that the coating does not interfere with dimensional tolerances or flexibility of the intended use of the medical device.

When the coated substrate is contacted with an alcohol or water-based electrolyte, such as a body fluid or body tissue, metal ions, atoms, molecules or clusters are released, thereby obtaining the antimicrobial effect of the material so produced. The concentration of the metal species required to produce the antimicrobial effect will vary from metal to metal. Generally, antimicrobial effects are achieved at concentrations below about 0.5-5 micrograms/ml in bodily fluids such as plasma, serum, or urine.

The ability to obtain a sustained release of metal atoms, ions, molecules or clusters from the coating is determined by a number of factors, including coating characteristics such as composition, structure, solubility and thickness, and the nature of the environment in which the appliance is used. As the level of atomic disorder increases, the amount of metal species released per unit time increases. For example, a silver metal film deposited by magnetron sputtering at a T/Tm < 0.5 and an operating pressure of about 7 mTorr releases approximately 1/3 releasing silver ions within 10 days of a film deposited under the same conditions but at 30 mTorr. As determined by biological assays, films produced with intermediate structures (e.g., low pressure, low angle of incidence, etc.) have Ag release values in between these values. This provides a method of making the controlled release metallic coating of the present invention. Slow release coatings are made with a low degree of disorder, while fast release coatings are made with a high degree of disorder.

For a continuous uniform coating, the time required for complete dissolution will be a function of the film thickness and the nature of the environment to which it is exposed. The relationship with thickness is approximately linear, i.e., a doubling of the film thickness results in an approximately 2-fold increase in lifetime.

It is also possible to control the release of metal from the coating by forming the coating film with a modulated structure. For example, a coating deposited by magnetron sputtering such as a low operating gas pressure (e.g., 15 mtorr) for 50% of the deposition time, a high operating gas pressure (e.g., 30 mtorr) for the remainder of the time, initially releases metal ions quickly, followed by a slow release for a longer period of time. This type of coating is extremely effective in devices such as urinary catheters, where an initial rapid release is required to achieve the antimicrobial concentration immediately followed by a lower release rate to maintain the metal ion concentration for periods of up to several weeks.

During vapor deposition, the substrate temperature used should not be too low so that annealing or recrystallization of the coating does not occur when the coating is warmed to room temperature or the temperature at which it is used (e.g., body temperature). The allowed Δ T, i.e., the temperature difference between the substrate temperature and the final temperature used during deposition, will vary from metal to metal. For the most preferred metals Ag and Au, the substrate temperature preferably employed is from-20 to 200 deg.C, more preferably from-10 to 100 deg.C.

Atomic disorder may also be obtained in one or both of the base and top layers 2, 4 according to the present invention by preparing a composite metal material, i.e. a material containing one or more antimicrobial metals in a metal matrix comprising atoms or molecules other than antimicrobial metals.

Our preferred method of preparing the composite is to co-or sequentially deposit one or more antimicrobial metals together with one or more other inert biocompatible metals selected from Ta, Ti, Nb, Zn, V, Hf, Mo, Si, Al and alloys of these metals or other metallic elements, typically other transition metals. These inert metals have an atomic radius different from that of the antimicrobial metal, resulting in atomic disorder during deposition. This type of alloy may also be used to reduce atomic diffusion and thus stabilize disordered structures. It is preferred to use a thin film deposition apparatus with multiple targets to place the respective antimicrobial and inert metals. When the different layers are deposited sequentially, the layer(s) of inert metal(s) should be discontinuous, e.g., as islands in the antimicrobial metal matrix. The final ratio of antimicrobial metal(s) to inert metal(s) should be greater than about 0.2. Most preferred inert metals are Ti, Ta, Zn and Nb. The antimicrobial coating may also be formed from one or more antimicrobial metals and/or one or more oxides, carbides, nitrides, sulfides, borides, halides, or hydrides of an inert metal to achieve the desired atomic disorder.

Another composite material within the scope of the present invention is formed by reactive co-deposition or sequential deposition of reacted materials into the antimicrobial metal film(s) using physical vapor techniques. The reacted material is an oxide, nitride, carbide, boride, sulfide, hydride or halide of an antimicrobial and/or inert metal, which is formed in situ by injecting a suitable reactant, or a gas containing a reactant (e.g., air, oxygen, water, nitrogen, hydrogen, boron, sulfur, halogen), into the deposition chamber. Atoms or molecules of these gases may also be absorbed or trapped in the metal film, creating atomic disorder. For co-deposition, the reactants may be supplied continuously during deposition, and for sequential deposition, may be supplied in pulses. The final ratio of antimicrobial metal(s) to reaction product should be greater than about 0.2. Air, oxygen, nitrogen and hydrogen are particularly preferred reactants.

The deposition techniques described above for preparing composite coatings may or may not utilize the conditions discussed above for lower substrate temperatures, high working gas pressures, and low angles of incidence. One or more of these conditions are preferred to maintain and increase the amount of atomic disorder created in the coating.

It may be advantageous to form an adhesive layer on the substrate or medical device to be coated prior to depositing the antimicrobial metal according to the present invention, as is known in the art. For example, for latex appliances, a layer of Ti, Ta, or Nb may be deposited first to improve adhesion to subsequently deposited antimicrobial coatings. If Ta is used, it may be desirable to form a barrier layer, such as tantalum oxide, by anodization, as previously described.

2. Wound dressing

The wound dressing of the invention comprises at least two and preferably at least three layers laminated by ultrasonic welding. A three-layer wound dressing of the invention is shown generally at 10 in figure 2 and comprises a first layer 12 which, in use, faces the wound, a second layer 14 which preferably forms an absorbent core, and a third layer, optionally layer 16, which forms an outer layer. The layers 12, 14 (and optionally 16) are laminated together by ultrasonic welds 18 at the points of discontinuity throughout the dressing 10.

A) Wound facing layer

The first layer 12 of the wound dressing 10 is composed of a porous, preferably non-adhesive material that allows fluid to permeate or diffuse through it in one or both directions. The porous material may be formed from a woven or non-woven fabric, preferably a non-woven fabric, such as cotton, gauze, a polymeric film such as polyethylene, nylon, polypropylene or polyester, a high elastomer such as polyurethane or polybutadiene, or a foam such as an open-cell polyurethane foam. Examples of porous, non-adhesive materials that can be used in wound dressings include non-woven webs such as DELNETT^TMP530, which is a nonwoven wound facing formed from high density polyethylene using an Extrusion, embossing and orientation process, produced by Applied Extrusion Technologies, Middletown, tera, usa. The same product Exu-Dry ConFORMANT 2 is available from Frass Survival Systems, Inc, of Bronx, N.Y., USA^TMWound Veil, which is a component of the company Wound DressingDoll (Non-Adherent) product. Other useful nonwoven webs include CARELLE available from Carolina Formed Fabrics Corp, Richardson, Tex^TMOr NYLON 90^TMN-TERFACE available from Winfield Laboratories, Inc^TM. Examples of textile webs may be formed from fiberglass or acetate or cotton gauze. An example of a hydrophilic polyurethane foam is HYPOL^TMAvailable from new york city, new york, usa& Co.。

As will be given in more detail below in connection with ultrasonic welding techniques, at least one of the first and second layers 12, 14 is composed of a polymer material suitable for ultrasonic welding, i.e. it will melt upon local heating, after which the different layers will fuse together upon cooling.

B) Absorbing layer

The second absorbent layer is formed of an absorbent material for absorbing moisture from the wound or, in the case of burn dressings, for retaining moisture in the vicinity of the wound. Preferably, the absorbent material is an absorbent, needle-punched non-woven nylon/polyester core such as SONTARA^TM8411, an 70/30 rayon/polyester blend sold by Dupont Canada of Mississauga, Ontario, Canada. This product is sold by National Patent Medical as the American whiteflors sterile gauze pad. However, other suitable absorbent materials include woven or nonwoven fabrics made from rayon, polyester, rayon/polyester, polyester/cotton, and cellulosic fibers, preferably nonwoven fabrics. Examples are creped cellulose wadding, airfelt of airlaid pulp fibres, cotton, gauze, and other well-known absorbent materials suitable for wound dressings.

C) Outer layer

The third layer of the wound dressing 10 is optional, but is preferably included to regulate moisture loss, or to act as a barrier layer (e.g., to prevent moisture, oxygen infiltration), to carry an antimicrobial coating, or to otherwise act as an adhesive layer to secure the wound dressing around the wound. In the case of a burn dressing, the third layer 16 is preferably composed of a porous, non-adhesive material such as that used in the first layer 12. When disinfectant water or the like is added, it allows water to permeate.

D) Additional optional layers

Additional layers (not shown) may be included between or on the first, second and third layers 12, 24, 16, as is well known in wound dressings.

The terms first, second and third layer, as used herein and in the claims, are therefore meant to exclude such additional layers.

E) Ultrasonic welding

The first and second layers (and preferably the third layer, if present) are laminated together at intermittent sites throughout the dressing 10 by the ultrasonic welds 18. Ultrasonic welding is a technique known in the art and therefore need not be discussed in detail herein. In short, heat (ultrasound generated) and pressure are applied at localized points by the ultrasound head to either side of the dressing 10, which causes at least one of the plastic materials in the first and second layers to melt, and subsequently, upon cooling, bonds the different layers together. The weld points are local dots and preferably have a diameter of less than 0.5 cm. If the third layer 16 is present, ultrasonic welding may be performed on either side of the dressing and all three layers 12, 14 and 16 are bonded together.

Ultrasonically welding the layers at spaced points has the advantage of maintaining the absorbent and moisture permeable properties of the layers 12, 14, while at the same time maintaining the comfort properties of the dressing. Edge stitching, sewing and adhesion have the disadvantage of interfering with one or more of these desirable properties of the wound dressing. Furthermore, by separating the welds 18 at the sites of the discontinuities throughout the dressing, the wound dressing can be cut to smaller sizes as desired without causing delamination. The preferred spacing between the welds is about 2.5cm, allowing the dressing to be cut to a size of about 2.5cm while maintaining at least one weld to secure the stacked layers together.

F) Antimicrobial coatings on wound dressings

The wound dressing of the present invention preferably includes an antimicrobial coating formed from an antimicrobial metal. The coating is applied to one or more of the layers 12, 14, 16, but most preferably is applied to at least the first layer 12 facing the wound to provide a topical antimicrobial effect in proximity to the wound. The coating may also be applied to the outer layer 16 to provide additional antimicrobial effects.

The coating most preferably forms atomic disordered states according to the method described above and as in US5,454,886. Most preferably, the coating forms a multi-layer antimicrobial coating as described above, producing an interference color. In this way, the coating not only provides an antimicrobial effect to limit infection, but also acts as an indicator of dressing activation. Even a small dissolution of the antimicrobial metal results in a detectable color change when the top layer of the coating is activated by contact with electrolytes such as wound exudate, blood or added water, indicating that an antimicrobial effect is provided. If there is no color change, additional water can be provided to the coating by adding water until a color change can be detected. Wound exudate is generally sufficient to activate the coating when treating a burn with the dressing of the present invention. Once activated, the dressing should be maintained in a moist condition, and sterile water may be added if desired.

G) Wound dressing sterilization and packaging

Wound dressings with antimicrobial coatings of antimicrobial metals in atomic disordered states are preferably sterilized without the application of excessive heat, which can cause the disorder to disappear, thereby reducing or eliminating the useful antimicrobial effect. Such wound dressings are preferably sterilized using gamma radiation, as discussed in US5,454,886.

It will be appreciated that the lamination of multiple layers of a wound dressing with an antimicrobial coating formed from an antimicrobial metal in an atomic disordered state by ultrasonic welding is advantageous in that it achieves bonding at a localized site and avoids heating of any significant portion of the dressing, thus avoiding a significant reduction in antimicrobial effectiveness due to the disappearance of the atomic disorder.

The sterile wound dressing should be sealed in an air-impermeable package to exclude light penetration to avoid additional oxidation of the antimicrobial coating. Preferably a metallized polyester peelable pouch. The shelf life of such sealed antimicrobial wound dressings exceeds one year.

H) Burn wound treatment

Animal or human tests with the burn dressing of the invention showed excellent results in the prevention of infection. The burn dressing used was provided with a two-layer antimicrobial coating formed from atomic disordered silver, produced as described above and in more detail in example 3. In addition, the antimicrobial metal coating has been found to improve dressing feel, reduce static electricity and add weight to the dressing, thereby keeping it in place during handling and bandaging. In use, the dressing remains moist at 100% relative humidity. Wound exudate itself may be sufficient to maintain such moisture levels. Otherwise, it is sufficient to add sterile water, for example three times a day. The wound dressing is then bandaged in a known manner to keep the wound moist and clean. Dressing changes are required to observe the wound and clean, but do not require frequent changes for less than 24 hours, which can provide antimicrobial effects over a longer period of time.

I) Advantages of the invention

The advantages of these burn dressings over conventional burn treatment are described below.

i) Ag in solution adjacent to dressing⁺And amount of silver species from Ag in solution⁺Is controlled at a level of 60-100 micrograms/ml, which is sufficient to provide sustained antimicrobial effect over a relatively long period of time. The application of a 0.5% silver nitrate solution 12 times per day provided a cumulative exposure of 61,000 micrograms/square inch/day of silver ions (calculated assuming an absorptive capacity of 200 micrograms/square inch for each of the 8 layers of dressing). Comparable calculations were performed on the silver coated dressings of the present invention assuming a maximum of 8 ml/sq in/day of wound exudate and a cumulative exposure of 800 μ g/sq in/day.

ii) compared to silver nitrate treatment, the silver coated burn dressing of the present invention eliminates silver nitrate contamination, scares the patient and relatives from discoloration at the point of injury, and reduces hospital cleaning (e.g., bed washing, floor washing) costs.

iii) Ag treated when treated with silver nitrate⁺The ions complex with chloride ions at the wound dressing interface, forming a non-antimicrobial zone. The silver coated wound dressing of the present invention provides a sustained release of silver species at a controlled and not excessive equilibrium concentration, ensuring that the silver species can still reach the wound interface.

iv) the absorbent core of the wound dressing maintains a high relative humidity at the wound site, thereby maintaining the antimicrobial effect and reducing desiccation and dehydration of new cell growth. The absorbent core also provides an "antimicrobial zone" over the wound that extends through the thickness of the dressing, creating sufficient residence/exposure time for migrating microorganisms to ensure that the microorganisms are killed. This is different from the silver nitrate treatment, which has no silver ion replenishment at the wound interface after silver ions are consumed by chloride ions or proteins (excluding the possibility of diffusion).

v) the wound dressing is maximally non-wettable (no more than three times per day), limiting the hypothermia problems encountered with silver nitrate treatment, which requires wetting 12 times per day and rinsing when silver sulfadiazine cream is used.

vi) it has been found that the silver coating on the wound dressing is non-adhesive and therefore less prone to disrupting wound healing than adhesive dressings which are frequently used in silver nitrate treatment.

viii) the silver coated wound dressing of the invention, upon contact with electrolytes, produces an interference color and the top layer releases silver ions etc. providing a visible color change to confirm that the antimicrobial metal film has been activated and released silver species.

3. Examples of the embodiments

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

Example 1

This example is given to demonstrate the application of a top antimicrobial silver layer on various reflective substrates to produce multi-layer color coatings of primary and secondary interference colors. The two-layer metal coating was produced by magnetron sputtering Ag, Ta or Au on a glass cover substrate and applying a top layer of Ag under the sputtering conditions given in table 1. To experimentally illustrate the case of Al as the base layer, a top Ag layer was sputtered onto the Al foil under the Ag sputtering conditions given in table 1.

Table 1 spray conditions: 99.99% Ag, Ta, Au 99.99% Ag target, working gas 100 wt% Ar 99/1 wt% Ar/O with diameter of 20.3cm and diameter of 20.3cm₂Working air pressure 40 mTorr40 millitorr power 0.1kW 0.05kW substrate temperature 20 ℃ and 20 ℃ base pressure 2.0 x 10^-62.0X 10 torr^-6The sputtering time of 100mm with the distance between the anode and the cathode is Ta-16 min, 220nm 1-10 min, 10-100nm

Ag-8 min, 200nm

Au-9 min, 200nm voltage Ta-193V 295V

Ag-291V

Au-322V

The thickness of the top layer varied as shown in table 2 below. Ag. The thickness of the base layer of Ta and Au was 200 nm. The resulting two-layer coating had the appearance given in table 2.

TABLE 2

Thickness of the top layer:	base layer Ag 99/1% Ar/O2Color: bronze color	Base layer Ag 100% Ar color: silver color	Base layer Ta 100% Ar color: grey colour	Base layer Au 100% Ar color: golden color
					10nm	Bronze/red color	Light red	Light grey	Yellow/orange
20nm	Purple color	Pink/yellow	Silver color	Golden brown
					30nm	Blue/purple	Light purple	Silver color	Blue color
40nm	Light blue	Grey/blue colour	Gold to silver	Bluish green
					50nm	Light blue/yellow	Silver color	Purple to silver	Teal blue
60nm	Light yellow	Light yellow	Blue toSilver color	Light blue/green
					70nm	Bronze color	Light green/yellow	Blue to silver	Yellow colour
80nm	Purple color	Light pink colour	Olive to gray	Green/yellow
					90nm	Purple/pink	Pink colour	Olive to gray	Olive color
100nm	Blue green color	Blue-green/pink	Pink to grey	Light pink/yellow

Within about 10 minutes of sputtering, the coating formed on the Ta metal changed to a silver or gray color, indicating that a barrier layer was needed to prevent reduction of the Ag-based metal by the top layer.

When a top layer of silver was sprayed on the Al foil sample, the conditions given above were used, but at 96/4 wt% Ar/O₂Neutralization was carried out at 0.15kW and a blue interference color was observed.

The sputtering conditions for the Ag-based layer samples were changed, and the working gas was changed to 96/4 wt% Ar/O₂And a 900nm thick film was deposited followed by 96/4 wt% Ar/O₂The top layer was applied by sputtering Ag at 0.15kW, V346V for about 1, 1.5 and 2.25 minutes to obtain films of about 67, 100, 140nm thickness. All other conditions are given in table 1. The interference colors produced are purple, blue and yellow, respectively. Example 2

This example is given to demonstrate a bilayer antimicrobial silver coating on a wound dressing. High density polyethylene wound dressing- -CONFORMANT 2^TMCoated with a silver-based layer and a silver/oxide top layer, produces a colored antimicrobial coating having indicator value. The coatings were formed by magnetron sputtering under the conditions given in table 3.

TABLE 3

Spraying conditions: top layer of base layer

Target 99.99% Ag

The size diameter of the target body is 20.3cm, the diameter is 20.3cm

Working gas 96/4 wt% Ar/O₂ 96/4wt％Ar/O₂

Working pressure 40 mTorr

The power is 0.3kW and 0.15kW

The temperature of the substrate is 20 ℃ and 20 DEG C

Base pressure 3.0X 10^-6Tray 3.0X 10^-6Support

Anode/cathode distance 100mm

Spraying time/film thickness of 7.5-9 min and 1.5 min

Voltage 369-373V 346V

The resulting coating was blue in appearance. The fingertip touches enough to turn the color yellow. The base layer is approximately 900nm thick and the top layer is 100nm thick.

Zone of inhibition assays were performed. Mueller Hinton agar was distributed in petri dishes. The agar plate surfaces were allowed to dry before inoculation with a lawn of Staphylococcus Aureus (Staphylococcus Aureus) ATCC # 25923. The inoculum was prepared from Bactrol Discs (Difco, M.), which itself was reconstituted according to the instructions of each manufacturer. Immediately after inoculation, the coated material intended for testing is placed on the surface of the agar. The dishes were incubated at 37 ℃ for 24 hours. After this incubation period, the inhibition zone (the positive inhibition zone-the diameter of the test material in contact with agar) was calculated. The results show a more positive ZOI of about 10 mm.

The coating was analyzed by nitric acid dissolution and atomic absorption analysis to yield 0.24+/-0.04mg silver per high density polyethylene. According to secondary ion mass spectrometry, the coating is a binary alloy of silver (> 97%) and oxygen with negligible contamination. This coating, as observed with SEM, is very porous and consists of equiaxed nanocrystals forming a coarse columnar structure with an average grain size of 10 nm. Silver release studies confirmed that silver was released from the coating continuously until an equilibrium concentration of about 66mg/L (as measured by atomic absorption) was reached, which was 50 to 100 times higher than expected for bulk silver metal (solubility ≦ 1 mg/L).

By varying the application conditions of the top layer so as to extend the spray time to 2 minutes and 15 seconds, a yellow coating was produced. The thickness of this top layer was about 140nm and the color changed to purple when touched with a fingertip. Similarly, by reducing the plating time to 1 minute, a violet coating is produced, resulting in a top layer thickness of about 65 nm. Finger tip touch causes a color change to yellow. Example 3

This example is given for experimental illustration of a multilayer burn dressing according to the present invention. High-density polyethylene mesh dressing material CONFORMANT^TM2 the dressing was coated with a two-layer blue antimicrobial coating as described in example 2, using the spray conditions of table 3. The two layers of the coating dressing are placed on a rayon/polyester (SONTARA) perforated by needle punching^TM8411) The upper and lower surfaces of the formed absorption core material. The first layer of coated polyethylene facing the wound faces downwards with a blue coating, while in the third layer the outer layer of coated polyethylene faces towards the absorbent core with a blue coating. The three layers were laminated together by ultrasonic welding, forming welds spaced about 2.5cm apart between all three layers across the entire dressing. The wound dressing may be cut into pieces having a size of about 2.5cm for treating smaller wounds, while still providing at least one spot weld on the dressing piece.

The coated dressing was sterilized using gamma radiation at a dose of 25 kGy. The finished dressing is individually sealed packaged in metallized polyester peel-off pouches and in this form has a shelf life of over 1 year.

The absorbent capacity and moisture content of the finished dressing were tested to determine the ability of the dressing to remain absorbent after application. The packaged sterile dressing was tested and compared to an uncoated, untreated control dressing. The absorbent capacities of the tested dressings were 7.36g of distilled water and 7.32g of 1.23 g of sodium nitrate, while the absorbent capacities of the control dressings were 7.76g and 7.45g, respectively, indicating similar absorption of both materials. The applied dressings were tested for lotion penetration and were found to be indistinguishable from the control dressing. The moisture content of the coated dressing and the untreated control were 4.1% and 3.6%, respectively. From this result, it was concluded that the coating of the present invention did not alter the moisture-related properties of the dressing.

Clinical studies using the above-described coated dressing on 30 patients with varying degrees of burns have demonstrated a reduction in burn wounds "Ability to infect "(4 organs (org.)/50 biopsies of the dressing of the invention versus 16 organs treated with silver nitrate/50 biopsies), the dressing of the invention was changed every 24 hours with three additions of sterile water per day maintaining a relative humidity of 100%, whereas the control burn treatment was applied 12 times per day with a 0.5% silver nitrate solution, the dressing was changed every 24 hours. In the above, "infection" means more than 1X 10⁵Colony forming units per gram of tissue. Example 4

This example is given for the experimental illustration of an antimicrobial material with an in situ generated top layer upon contact with alcohol or electrolyte to cause a color change by generating an interference color. A single layer antimicrobial coating was produced by magnetron sputtering onto a high density polyethylene wound dressing using the substrate given in example 3, under conditions such as those given in table 3 of example 2. The resulting coating was approximately 900nm thick and bronze in appearance. The coating was spotted with wet fingertips (saliva) causing the color of the coating to change to blue.

Without being limited thereto, it is believed that the color change is a result of the in situ generation of a thin film that meets the description of the reflective and light transmissive top layers mentioned above, thus creating the conditions necessary to produce the interference color. The mechanism can be considered as follows. The water on the coating causes a change in both the thickness of the coating and the composition of the thin top layer of the coating, thus creating a thin top layer having a different refractive index than the underlying coating. The water from the fingertip is sufficient to displace air from the surface pores of the film (which is porous as can be seen by SEM), initiating both dissolution of the film and a change in the refractive index of the thin layer. The blue interference color is a result of incident light reflecting off the air/film interface and the thin layer/base layer interface and recombining to produce a changing blue color.

All publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The terms and expressions in the specification have been used as terms of description and not of limitation unless otherwise specifically stated herein. There is no intention, in the use of such terms and expressions, of excluding equivalents of the features shown and described, it being recognized that the scope of the invention is defined and limited only by the claims which follow.

Claims (46)

1. A multi-layered antimicrobial material comprising:

a base layer of partially reflective material capable of producing interference colors when covered with a partially reflective, partially light transmissive top layer;

a top layer formed on said base layer, said top layer being a partially reflective, partially light transmissive film containing at least one antimicrobial metal and having a thickness that produces an interference color, said top layer having a refractive index different from that of the base layer, and the antimicrobial metal being in a sufficiently atomic disorder such that, upon contact with the alcohol or water-based electrolyte, the top layer continuously releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte at a concentration sufficient to provide a localized antimicrobial effect.

2. The material of claim 1, wherein the material in the base layer is a partially reflective form of a metal selected from the group consisting of Ag, Au, Pt, Pd, Cu, Ta and Al or an alloy or compound of one or more of these metals.

3. The material of claim 2, wherein the antimicrobial metal in the top layer is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn and alloys or compounds of one or more of these metals.

4. The material of claim 3, wherein the material in the base layer and the antimicrobial metal in the top layer is a partially reflective form of a metal selected from the group consisting of Au, Ag, Pt, Pd, and Cu, and is formed by vapor deposition in a sufficiently atomic disordered state such that, upon contact with the alcohol or aqueous electrolyte, the top layer releases ions, atoms, molecules, or clusters of the antimicrobial metal into the alcohol or aqueous electrolyte continuously at a concentration sufficient to provide a localized antimicrobial effect.

5. The material of claim 4, wherein the metal in the base and top layers is Ag, Pt or Au.

6. The material of claim 4, wherein the top layer is a composite film formed by co-depositing, sequentially depositing or reaction depositing the antimicrobial metal by vapor deposition into a matrix with atoms or molecules of different materials selected from biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulfur or halogens, or oxides, nitrides, borides, halides, sulfides or hydrides of either or both of the antimicrobial metal or biocompatible metal, creating atomic disorder in the matrix.

7. The material of claim 6, wherein the biocompatible metal is selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al, and wherein the antimicrobial metal is selected from the group consisting of Ag, Au, Pt, Pd, and Cu.

8. The material of claim 6, wherein the antimicrobial metal is silver and the different material is silver oxide and one or both of atoms or oxygen-containing molecules trapped or absorbed in the matrix.

9. The material of claim 1, wherein the top layer is less than 400nm thick and the base layer is at least 25nm thick.

10. The material of claim 8, wherein the top layer is between 5 and 210nm thick and the base layer is at least 60nm thick.

11. The material of claim 8, wherein the top layer is about 40-160nm thick and the base layer is at least about 300nm thick.

12. The material of claim 1, wherein the base layer and the top layer are provided on a medical device.

13. The material of claim 10, wherein the base layer and the top layer are provided on a wound dressing.

14. A method of producing a multi-layer antimicrobial material capable of indicating exposure to an alcohol or aqueous electrolyte comprising

Providing a base layer of partially reflective material capable of producing interference colors when covered with a partially reflective, partially light transmissive top layer;

providing a top layer formed on said base layer, said top layer being a partially reflective, partially light transmissive film containing at least one antimicrobial metal and having a thickness that produces an interference color, said top layer having a refractive index different from that of the base layer, and the antimicrobial material being in a sufficiently atomic disorder such that, upon contact with the alcohol or water-based electrolyte, the top layer continuously releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte at a concentration sufficient to provide a localized antimicrobial effect.

15. The method of claim 14, wherein the material in the base layer is a partially reflective form of a metal selected from Ag, Au, Pt, Pd, Cu, Ta, Al or an alloy or compound of one or more of these metals.

16. The method of claim 15, wherein the material in the top layer is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn and alloys or compounds of one or more of these metals.

17. The method of claim 16, wherein the material in the base layer and the antimicrobial metal in the top layer is a partially reflective form of a metal selected from the group consisting of Au, Ag, Pt, Pd and Cu, and is formed by vapor deposition in a sufficiently atomic disordered state such that, upon contact with the alcohol or aqueous electrolyte, the top layer releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or aqueous electrolyte continuously at a concentration sufficient to provide a localized antimicrobial effect.

18. The method of claim 17, wherein the metal in the base layer and the top layer is Ag, Pt, or Au.

19. The method of claim 17, wherein the top layer is a composite film formed by co-depositing, sequentially depositing, or reaction depositing the antimicrobial metal by vapor deposition into a matrix with atoms or molecules of different materials selected from biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulfur, or halogens, or oxides, nitrides, carbides, borides, halides, sulfides, or hydrides of either or both of the antimicrobial metal or biocompatible metal, creating atomic disorder in the matrix.

20. The method of claim 19, wherein the biocompatible metal is selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si, and Al, and wherein the antimicrobial metal is selected from the group consisting of Ag, Au, Pt, Pd, and Cu.

21. The method of claim 19, wherein the antimicrobial metal is silver and the different material is silver oxide and one or both of atoms or oxygen-containing molecules trapped or absorbed in the matrix.

22. The method of claim 14, wherein the top layer is less than 400nm thick and the base layer is at least 25nm thick.

23. The method of claim 19, wherein the top layer is between 5 and 210nm thick and the base layer is at least 60nm thick.

24. The method of claim 21, wherein the top layer is about 40-160nm thick and the base layer is at least about 300nm thick.

25. The method of claim 14, wherein the base layer and the top layer are provided on a medical device.

26. The method of claim 23, wherein the base layer and the top layer are provided on a wound dressing.

27. A multilayer laminated wound dressing comprising

A wound-facing first layer formed of a porous, non-adhesive material;

a second layer laminated on the first layer and formed of an absorbent material;

an optional third layer laminated to one or both of the first and second layers;

at least one of the first, second and optional third layers is formed of plastic; and

the first, second and optional third layers are laminated together by ultrasonic welds spaced apart on the dressing so that the dressing can be cut to size without delamination.

28. The wound dressing of claim 27, wherein the first layer comprises a coating comprising an antimicrobial metal.

29. The wound dressing according to claim 27, wherein the first layer comprises a film comprising at least one antimicrobial metal, said antimicrobial metal being in a sufficiently disordered state such that, upon contact with the alcohol or water-based electrolyte, the film releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte continuously at a concentration sufficient to provide a topical antimicrobial effect.

30. The wound dressing of claim 27, wherein the first layer comprises a multi-layer antimicrobial coating comprising:

a base layer of partially reflective material capable of producing interference colors when covered with a partially reflective, partially light transmissive top layer;

a top layer formed on said base layer, said top layer being a partially reflective, partially light transmissive film containing at least one antimicrobial metal and having a thickness that produces an interference color, said top layer having a refractive index different from that of the base layer, and the antimicrobial metal being in a sufficiently atomic disorder such that, upon contact with the alcohol or water-based electrolyte, the top layer continuously releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte at a concentration sufficient to provide a localized antimicrobial effect.

31. A wound dressing as claimed in claim 30 wherein a multi-layer antimicrobial coating is provided on both the first and third layers such that a colour change is detectable on either side of the wound dressing.

32. The wound dressing of claim 30, wherein the material in the base layer is a partially reflective form of a metal selected from Ag, Au, Pt, Pd, Cu, Ta, Al or an alloy or compound of one or more of these metals.

33. The wound dressing according to claim 32, wherein the material in the top layer is selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn and alloys or compounds of one or more of these metals.

34. The wound dressing of claim 33, wherein the material in the base layer and the antimicrobial metal in the top layer is a partially reflective form of a metal selected from the group consisting of Au, Ag, Pt, Pd and Cu, and is formed by vapor deposition in a sufficiently atomic disordered state such that, upon contact with the alcohol or water-based electrolyte, the top layer continuously releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte at a concentration sufficient to provide a local antimicrobial effect.

35. The wound dressing of claim 34, wherein the metal in the base layer and the top layer is Ag, Pt or Au.

36. The wound dressing of claim 33, wherein the top layer is a composite film formed by co-depositing, sequentially depositing or reaction depositing the antimicrobial metal by vapor deposition into a matrix with atoms or molecules of different materials selected from biocompatible metals, oxygen, nitrogen, hydrogen, boron, sulfur or halogens, or oxides, nitrides, carbides, borides, halides, sulfides or hydrides of either or both of the antimicrobial metal or biocompatible metal, resulting in atomic disorder in the matrix.

37. The wound dressing of claim 36, wherein the biocompatible metal is selected from the group consisting of Ta, Ti, Nb, V, Hf, Zn, Mo, Si and Al, and wherein the antimicrobial metal is selected from the group consisting of Ag, Au, Pt, Pd and Cu.

38. The wound dressing of claim 36, wherein the antimicrobial metal is silver and the different material is silver oxide and one or both of atoms or oxygen-containing molecules trapped or absorbed in the matrix.

39. The wound dressing of claim 30, wherein the top layer is less than 400nm thick and the base layer is at least 25nm thick.

40. The wound dressing of claim 34, wherein the top layer is between 5 and 210nm thick and the base layer is at least 60nm thick.

41. The wound dressing of claim 38, wherein the top layer is about 40-160nm thick and the base layer is at least about 300nm thick.

42. The wound dressing of claim 30, wherein the base layer and the top layer are provided on a medical device.

43. The wound dressing of claim 40, wherein the base layer and the top layer are provided on the wound dressing.

44. The wound dressing of claim 38, wherein the material in the base layer is a metal selected from the group consisting of Au, Ag, Pt, Pd and Cu in a partially reflective form and is formed by vapor deposition in a sufficiently atomic disordered state such that, upon contact with the alcohol or water-based electrolyte, the top layer releases ions, atoms, molecules or clusters of the antimicrobial metal into the alcohol or water-based electrolyte continuously at a concentration sufficient to provide a localized antimicrobial effect.

45. The wound dressing of claim 43, wherein the first and optional third layers are formed from a non-woven, porous, non-adhesive high density polyethylene material.

46. The wound dressing of claim 45, wherein the second layer is formed of a non-woven, absorbent rayon/polyester material.