Patent title: DEPOSITION PRODUCTS, COMPOSITE MATERIALS AND PROCESSES FOR THE PRODUCTION THEREOF
Abstract:
A composite material comprising a substrate and a deposition product and
the use of a deposition product for providing an antimicrobial effect.
The substrate of the composite material is a medical device. Further, in
each of the composite material and the use, the deposition product
consists essentially of at least one oxidized silver species and wherein
the deposition product is comprised of a compound having the formula
Ag.sub.7O.sub.8X, where X is an anion.Claims:
1. A composite material comprising a substrate and a deposition product,
wherein the substrate is a medical device, and wherein the deposition
product consists essentially of at least one oxidized silver species, and
wherein the deposition product is comprised of a compound having the
formula Ag.sub.7O.sub.8X, where X is an anion.
2. The composite material as claimed in claim 1 wherein the deposition
product is further comprised of Ag.sub.2SO.sub.4.
3. The composite material as claimed in claim 1 wherein the deposition
product is further comprised of at least one silver oxide selected from
the group of silver oxides consisting of monovalent silver oxide,
bivalent silver oxide, trivalent silver oxide and mixtures thereof.
4. The composite material as claimed in claim 1 wherein X is derived from
an acid.
5. The composite material as claimed in claim 1 wherein the deposition
product is comprised of a plurality of oxidized silver species having a
plurality of valent states of silver.
6. The composite material as claimed in claim 1 wherein X is selected from
the group of anions consisting of HCO.sub.3.sup.-, CO.sub.3.sup.2-,
NO.sub.3.sup.-, ClO.sub.4.sup.-, SO.sub.4.sup.2-, F.sup.-, and mixtures
thereof.
7. The composite material as claimed in claim 6 wherein X is comprised of
NO.sub.3.sup.-.
8. The composite material as claimed in claim 1 wherein the medical device
is comprised of a wound dressing.
9. The composite material as claimed in claim 8 wherein the medical device
is comprised of a high density polyethylene material.
10. The composite material as claimed in claim 8 wherein the medical
device is comprised of a cross-linked silicon gel.
11. The composite material as claimed in claim 8 wherein the medical
device is comprised of a skin adhesive layer, wherein the skin adhesive
layer is comprised of a cross-linked silicon gel, and wherein the
deposition product is deposited on the skin adhesive layer.
12. The composite material as claimed in claim 11 wherein the deposition
product is further comprised of Ag.sub.2SO.sub.4.
13. The composite material as claimed in claim 11 wherein the deposition
product is further comprised of at least one silver oxide selected from
the group of silver oxides consisting of monovalent silver oxide,
bivalent silver oxide, trivalent silver oxide and mixtures thereof.
14. The composite material as claimed in claim 11 wherein X is derived
from an acid.
15. The composite material as claimed in claim 11 wherein the deposition
product is comprised of a plurality of oxidized silver species having a
plurality of valent states of silver.
16. The composite material as claimed in claim 11 wherein X is selected
from the group of anions consisting of HCO.sub.3.sup.-, CO.sub.3.sup.2-,
NO.sub.3.sup.-, ClO.sub.4.sup.-, SO.sub.4.sup.2-, F.sup.-, and mixtures
thereof.
17. The composite material as claimed in claim 16 wherein X is comprised
of NO.sub.3.sup.-.
18. The composite material as claimed in claim 11 wherein the skin
adhesive layer has adhesive properties and wherein the deposition product
does not materially interfere with the adhesive properties of the skin
adhesive layer.
19. The use of a deposition product for providing an antimicrobial effect,
the deposition product consisting essentially of at least one oxidized
silver species, and wherein the deposition product is comprised of a
compound having the formula Ag.sub.7O.sub.8X, where X is an anion.
20. The use as claimed in claim 19 wherein the deposition product is
further comprised of Ag.sub.2SO.sub.4.
21. The use as claimed in claim 19 wherein the deposition product is
further comprised of at least one silver oxide selected from the group of
silver oxides consisting of monovalent silver oxide, bivalent silver
oxide, trivalent silver oxide and mixtures thereof.
22. The use as claimed in claim 19 wherein X is derived from an acid.
23. The use as claimed in claim 19 wherein the deposition product is
comprised of a plurality of oxidized silver species having a plurality of
valent states of silver.
24. The use as claimed in claim 19 wherein X is selected from the group of
anions consisting of HCO.sub.3.sup.-, CO.sub.3.sup.2-, NO.sub.3.sup.-,
ClO.sub.4.sup.-, SO.sub.4.sup.2-, F.sup.-, and mixtures thereof.
25. The use as claimed in claim 24 wherein X is comprised of
NO.sub.3.sup.-.Description:
FIELD OF INVENTION
[0001]Deposition products, composite materials including deposition
products, and methods for producing the deposition products and the
composite materials.
BACKGROUND ART
[0002]The germicidal properties of silver, even not known as such, have
been utilized since the early Mediterranean cultures. It has been known
since 1000 BC and possibly before that water kept in silver vessels and
then exposed to light and filtered could be rendered potable. Other forms
of silver have been used throughout centuries for various applications,
such as coatings for prevention of beverages from spoilage or silver
plates and foils in the surgical treatments of wounds and broken bones.
[0003]The lethal effects of metals towards bacteria and lower life forms
were first scientifically described by von Nageli in the late nineteenth
century, and this phenomenon has been defined as an "oligodynamic effect"
(N. R. Thompson, Silver, in Comprehensive Inorganic Chemistry, Vol. III
D, J. C. Bailer, H. J. Emeleus, R. Nyholm and A. F. Trutman-Dickenson,
Editors, Pergamon Press, Oxford (1973)). The term oligodynamic effect is
typically restricted to describing solutions in which the metal
concentration is several orders of magnitude lower than that which would
be lethal to higher organisms.
[0004]The investigation of the bacteriostatic properties of pure metals
such as Fe, Mo, Cu, V, Sn, W, Au, Al, Ta, Nb, Ti, Zr, Ni, Co, Ag and Cr,
has proved that Co was the only element which was inhibitory for the
bacterial growth under anaerobic conditions (K. J. Bundy, M. F. Butler
and R. F. Hochman, "An Investigation of the Bacteriostatic Properties of
Pure Metals", Journal of Biomedical Materials Research, Vol. 14 (1980)
653-663). Under aerobic conditions both Cu and Co consistently display
inhibitory effects. Some antimicrobial effects have been seen for Ni, Fe
and V. However, other metals such as Mo, W, Al, Nb, Zr, Cr and most
importantly for the present invention Ag and Sn never showed any tendency
to inhibit the growth of Streptococcus mutans.
[0005]In the case of silver metal, it was in 1920, when Acel who was the
first to attribute the antimicrobial properties of silver to the
liberation of Ag.sup.+ ions from the material (D. Acel, "Uber die
oligodynamische Wirkung der Metalle", Z. Biochem., 112 (1920) 23).
[0006]Gibbard reported in 1937 that pure metallic silver has no
antimicrobial activity (J. Gibbard, "Public Health Aspects of the
Treatment of Water and Beverages with Silver", Journal of American Public
Health, Vol. 27 (1937) 112-119). His experiments showed that if silver is
cleaned mechanically with an abrasive cloth or paper it becomes inactive.
Similarly, if molten silver is allowed to cool in a reduction atmosphere
(e.g. hydrogen), no antimicrobial activity is found. When cooling of
molten silver is carried out in air, and formation of surface oxide
occurred, an antimicrobial activity may be observed. Similar results were
found when silver metal was treated with nitric acid in an air atmosphere
(dissolution and formation of an oxide layer). Based on Gibbard's
results, pure silver was devoid of activity, but surface oxidized silver
was active. Silver oxide, silver nitrate and silver chloride were always
active. Also, Gibbard observed that the antimicrobial properties of
silver and its compounds were reduced in the presence of proteins or
glucose.
[0007]Djokie investigated the behavior of silver films, e.g. physical
vapor deposited, electrodeposited, electroless deposited and
metallurgical in physiological saline solutions (S. S. Djokie and R. E.
Burrell, "Behavior of Silver in Physiological Solutions", Journal of the
Electrochemical Society, Vol. 145 (5) (1998) 1426-1430). Djokie found
that an essential factor leading to an antimicrobial activity of metallic
silver is a presence of Ag oxide(s) at the surface of this material. It
was demonstrated that only silver films containing silver oxides (most
likely Ag.sub.2O) showed an antimicrobial activity. The behavior was
attributed to the dissolution of Ag.sub.2O from the "silver" material and
formation of Ag.sup.+ or other complexed ions which become
antimicrobially active. There was no evidence that pure metallic silver,
no matter which way it was produced i.e., physical vapor deposited,
electrodeposited or electroless deposited could be dissolved in
physiological media, or that these materials would exhibit antimicrobial
activity.
[0008]It should be noted that when the physical vapor deposition of silver
was carried out in an atmosphere containing oxygen the resulted product,
as found by the XRD analysis contained silver oxide. Consequently, these
samples exhibited antimicrobial activity. Conversely, when the physical
vapor deposition was carried out from an argon atmosphere (no presence of
oxygen) pure metallic, nanocrystalline silver film was deposited as
confirmed by the XRD analysis. However, these films did not dissolve in
physiological saline solutions, nor they exhibited antimicrobial activity
at all.
[0009]For an in depth understanding of structural properties of silver
films produced by reactive sputtering, see Djokie et al. (S. S. Djokie,
R. E. Burrell, N. Le and D. J. Field, "An Electrochemical Analysis of
Thin Silver Produced by Reactive Sputtering", Journal of the
Electrochemical Society, Vol. 148 (3) (2001) C191-C196.). To prove the
concept that only oxidized silver species are responsible for the
antimicrobial activity, Djokie further oxidized pure metallic silver
samples (i.e. those produced by the electrodeposition, electroless
deposition, physical vapor deposition in an argon atmosphere or
metallurgically). The oxidation of these samples was carried out
electrochemically in 1 M KOH solutions, using a process very well
established in the art. The electrochemically oxidized silver samples
were tested for the antimicrobial activity against Pseudomonas
Aeruginosa. Clear evidence was found that the electrochemically oxidized
silver samples exhibited antimicrobial activity.
[0010]The above referenced work shows that only oxidized silver species,
but not elemental silver will affect antimicrobial activity. The findings
to date show that the "nanocrystalline" or "macrocrystalline" elemental
silver does not have antimicrobial activity at all. Elemental silver,
either nanocrystalline or "macrocrystalline" may exhibit some
antimicrobial activity only if oxidized silver species are present at
these surfaces or within the silver metal. Only the formation of silver
oxide(s), carbonates or other silver salts (except silver sulfide, due to
its extremely low solubility) at the surface or within the material,
which may be influenced by an exposure of elemental silver to various
bases, acids or due to atmospheric corrosion may lead to an antimicrobial
activity of this material.
[0011]The use of silver on chronic wounds dates back in the 17.sup.th and
18.sup.th centuries. In the early 19.sup.th century, silver nitrate began
to be used on burns and in opthalmology. Concentrations of the solution
ranged from 0.20 to 2.5 wt. % with the weaker solutions being reserved
for children. Silver has been found to be active against a wide range of
bacterial, fungal and viral pathogens. Topical treatment of acute and
chronic wounds is a preferred and selective approach to the prevention of
infection and healing. In order to achieve these requirements products
that are used in the prevention of infections must have certain physical
and chemical properties.
[0012]When used for topical dressings, silver compounds must have
relatively low solubility. This is usually achieved by choosing compounds
with a relatively low solubility products (e.g. AgCl, Ag.sub.2SO.sub.4,
Ag.sub.2CO.sub.3, Ag.sub.3PO.sub.4, Ag-oxides). Kinetics of dissolution
of these compounds in neutral aqueous solutions is quite slow. This
property is very convenient for two reasons. First, a sustained release
of silver ions from the silver compounds is more likely to provide a
prolonged antimicrobial activity. Second, low amounts of the silver ions
released into wound exudates may not give rise to transient high tissue
blood and urine levels, thus avoiding systemic toxicity. The choice of a
particular silver compound will depend upon its reactivity with wound
exudates. This reactivity should preferably be minimized in order to
achieve the desired effect of the released silver ions (i.e.,
antimicrobial activity without systemic toxicity).
[0013]Besides silver nitrate, one of the most widely used topical
antimicrobial materials is silver sulfadiazine (C. L. Fox, "Topical
Therapy and the development of Silver Sulfadiazine", Surgery, Gynecology
& Obstetrics, 157 (1) (1983) 82-88). This compound is synthesized from
silver nitrate and sodium sulfadiazine. Silver sulfadiazine has been used
in treatments of burns, leg ulcers and also as a topical antimicrobial
agent in the management of infected wounds.
[0014]Products such as silver protein (argyrols) or mild silver protein
are mixtures of silver nitrate, sodium hydroxide and gelatin. These
products are recommended for internal use and are promoted as essential
mineral supplements. Although there is no theoretical or practical
justification for their use, this class of compounds has been recommended
for the treatment of diverse diseases such as cancer, diabetes, AIDS and
herpes (M. C. Fung, D. L. Bowen, "Silver Products for Medical
Indications: Risk--Benefit Assessment", Clinical Toxicology, Vol. 34 (1)
(1996) 119-126).
[0015]Silver-zinc-allantoinate has been formulated as a cream and
represents a combination of silver, zinc and allantoin (an agent that
stimulates debridement and tissue growth (H. W. Margaf, T. H. Covey, "A
Trial of Silver-Zinc-Allantoinate in the Treatment of Leg Ulcers", Arch.
Surg., Vol. 112 (1977) 699-704). This composition exhibited promising
effects in preliminary studies.
[0016]In the past few decades several topical dressings containing silver
have been developed for wound care. Such materials include Arglaes.TM.,
Silverlon.TM., Acticoat.TM., Actisorb.TM., and Silver 220.TM..
[0017]Antimicrobial coatings and methods of forming same are the subject
of U.S. Pat. No. 5,681,575 (Burrell et al) and U.S. Pat. No. 6,238,686
(Burrell et al). The coatings are formed by the physical vapour
deposition of biocompatible metal and the preferred biocompatible metal
is silver.
[0018]Burrell et al teach that atomic disorder may be created in metal
powders or foils by cold working and in metal coatings by depositing by
vapor deposition at low substrate temperatures and that such metal
coatings constitute a matrix containing atoms or molecules of a different
material. The presence of different atoms or molecules results in atomic
disorder in the metal matrix, for instance due to different sized atoms.
The different atoms or molecules may be one or more second metals, metal
alloys or metal compounds which are co- or sequentially deposited with
the first metal or metals to be released. Alternatively, the different
atoms or molecules may be adsorbed or trapped from the working gas
atmosphere during reactive vapor deposition.
[0019]In U.S. Pat. No. 6,238,686 Burrell et al claim a modified material
comprising one or more metals in a form characterized by sufficient
atomic disorder such that the material, in contact with a solvent for the
material, releases atoms, ions, molecules or clusters containing at least
one metal at an enhanced rate relative to its normal ordered crystalline
structure. In U.S. Pat. No. 5,681,575 Burrell et al claim a medical
device which includes a coating of one or more anti-microbial metals
having a "sufficient atomic disorder".
[0020]It is unclear from either U.S. Pat. No. 5,681,575 or U.S. Pat. No.
6,238,686 what would constitute a material characterized by "sufficient
atomic disorder". In nature, most materials would exhibit sufficient
atomic disorder if the true atomic disorder described (by drawings or
mapping) in ordinary Chemistry or Physics handbooks were insufficiently
ordered (with a regular geometric structure or like).
[0021]In any event, the teachings of Burrell et al appear to connect
"atomic disorder" with an "enhanced rate" of release of "atoms, ions,
molecules or clusters". If the term "release" further relates to a
dissolution (as defined in textbooks of General Chemistry and Physics),
then this dissolution should lead to the liberation of ions or molecules
in solvent. When released in the solvent, these ions or molecules are
usually solvated i.e. surrounded by the molecules of the solvent. It is
very unlikely that atoms of a metal will be released into a solution
comprising of water such as in the wound environment. If released into
solution in its elemental state, metals would rather represent a
relatively larger particles comprising of more than one or a few atoms.
[0022]As a result, the term "atom" as used in Burrell et al is not exactly
descriptive. It is not known yet scientifically whether atoms of metals
can be released into aqueous solutions at pH close to neutral (e.g., pH
range 6 to 8), except in the case of colloidal solutions which are
usually prepared by adequate chemical reactions in-situ.
[0023]U.S. Pat. No. 6,087,549 (Flick) discloses a multilayer laminate
wound dressing comprising a plurality of layers of a fibrous material,
with each layer comprising a unique ratio of metalized fibers to
nonmetalized fibers. In a preferred embodiment the wound dressing
consists of three layers and the metal is silver. The wound contact layer
has the highest ratio of metalized fibers to nonmetalized fibers, the
intermediate layer has a lower ratio of metalized fibers to nonmetalized
fibers, and the outer layer has the lowest ratio of metalized fibers to
nonmetalized fibers. The wound dressing described by Flick is
commercially available under the trade-mark Silverlon.TM..
[0024]U.S. Pat. No. 5,211,855 (Antelman), U.S. Pat. No. 5,676,977
(Antelman) and U.S. Pat. No. 6,436,420 (Antelman) teach that tetrasilver
tetroxide (Ag.sub.4O.sub.4) containing two monovalent and two trivalent
silver ions exhibits bactericidal, fungicidal and algicidal properties.
As a result, "tetrasilver tetroxide" is suggested for use for water
treatment in U.S. Pat. No. 5,211,855 and for use in destroying the AIDS
virus in U.S. Pat. No. 5,676,977.
[0025]In U.S. Pat. No. 6,436,420, Antelman describes a method of
deposition or interstitial precipitation of tetrasilver tetroxide
(Ag.sub.4O.sub.4) crystals within the interstices of fibers, yarns and/or
fabrics forming such articles in order to produce fibrous textile
articles possessing enhanced antimicrobial properties. The interstitial
precipitation of Ag.sub.4O.sub.4 is achieved by immersion of the article
to be treated (e.g., fiber, yarn or fabric) in an aqueous solution
containing a water soluble silver salt, most preferably silver nitrate.
After uniformly wetting the article, the article is removed into a second
heated aqueous solution (having a temperature of at least 85 degrees
Celsius or more preferably at least 90 degrees Celsius) containing strong
alkali (most preferably NaOH) and a water soluble oxidizing agent (most
preferably potassium persulfate) for 30 seconds to 5 minutes to
facilitate the precipitation of tetrasilver tetroxide.
[0026]After the reaction is completed, the article is removed and washed.
The article treated in this way is described as exhibiting outstanding
antimicrobial resistance towards pathogens such as bacteria, viruses,
yeast and algae. The article is also described as being resistant to
ultraviolet light and as maintaining its antimicrobial properties after a
number of launderings.
SUMMARY OF INVENTION
[0027]The present invention is directed at deposition products, composite
materials and at methods for the production of deposition products and
composite materials. The deposition products are comprised of at least
one oxidized species of a metal.
[0028]The methods of the invention are based upon chemical deposition
principles and techniques. The methods of the invention may be carried
out under either acidic or alkaline conditions. The methods of the
invention may comprise the step of exposing ions of the metal to an
oxidizing agent to produce the deposition product. The methods of the
invention may involve the production of the deposition product itself or
the production of a composite material which comprises a substrate and
the deposition product.
[0029]The methods of the invention are particularly suited for producing a
composite material which is comprised of a substrate and a very thin
coating or deposition layer of the deposition product. This thin coating
or layer may be in the order of one or several atoms in thickness, which
facilitates the production of a composite material which has a relatively
high surface area to volume ratio. The coating may also be deposited so
that it does not completely cover the substrate, thus leaving portions of
the surface of the substrate uncoated. Composite materials produced using
the methods of the invention may be useful for a variety of applications,
including but not limited to electronics, materials engineering and
medical applications.
[0030]The methods of the invention may be carried out at relatively low
temperatures. Preferably the methods of the invention are carried out at
temperatures of no greater than about 60 degrees Celsius. More preferably
the methods of the invention are carried out at room temperature (i.e.,
between about 10 degrees Celsius and about 25 degrees Celsius).
[0031]The metal and the oxidizing agent are selected so that they are
compatible with the production of the desired deposition product. As a
result, any suitable metal and any suitable oxidizing agent may be used
in the invention. The metal may also be comprised of more than one
element, with the result that the deposition product may be comprised of
at least one oxidized species of more than one metal element.
[0032]Preferably the metal is comprised of silver and the deposition
product is comprised of at least one oxidized species comprising silver.
The metal may, however, be further comprised of other metal elements such
as gold, copper, tin or zinc so that the deposition product is comprised
of at least one oxidized species comprising silver and one or more other
metals.
[0033]Where the metal is comprised of silver, the resulting deposition
product may exhibit significant antimicrobial properties. Without
intending to be limited by theory, it is believed that these
antimicrobial properties are due to the presence in the deposition
product of one or more oxidized silver species. The presence of other
metals in the deposition product may enhance these antimicrobial
properties or may provide other complementary properties to the
deposition product.
[0034]More particularly, it is believed that silver containing deposition
products produced using the methods of the invention may be comprised of
silver ions having valent states higher than one, such as for example Ag
(II) and Ag (III) valent states. It is also believed that silver
containing deposition products produced using the methods of the
invention may be comprised of silver ions having more than one valent
state so that the oxidized silver species may be comprised of a
multivalent substance. Finally, it is believed that silver containing
deposition products produced using the methods of the invention may be
comprised of a silver containing substance or a plurality of silver
containing substances which react over time to form other silver
containing substances which may exhibit differing antimicrobial
properties. It is believed that if this is the case, the deposition
products produced by the invention may be useful for providing a varied
antimicrobial response and for overcoming bacterial resistance.
[0035]In particular, in certain aspects, the methods of the invention may
be used to produce a deposition product which comprises a substance
having the general formula Ag.sub.7O.sub.8X, where X is an anion. The
deposition product may be further comprised of Ag.sub.2SO.sub.4. The
deposition product may also be comprised of other oxidized silver
compounds such as one or more silver oxides selected from the group of
silver oxides consisting of monovalent silver oxide, bivalent silver
oxide, trivalent silver oxide and mixtures thereof.
[0036]The anion X may be comprised of a single anion or may be comprised
of a plurality of different anions. The anion may therefore be comprised
of any anion or combination of ions. The anion may, for example, be
selected from the group of anions consisting of HCO.sub.3.sup.-,
CO.sub.3.sup.2-, NO.sub.3.sup.-, ClO.sub.4.sup.-, SO.sub.4.sup.2-,
F.sup.-, and mixtures thereof. The source of the anion may be a metal
compound which provides the ions of the metal. For example, where the
deposition solution is comprised of a silver salt such as silver nitrate,
the anion may be comprised of the nitrate ion (NO.sub.3.sup.-). An
alternative or secondary source of the anion X may optionally be provided
in order to provide sufficient quantities of the anion for production of
the deposition product. Where an alternative or secondary source of the
anion X is provided, the source of anions may be comprised of any source,
including but not limited to any organic or inorganic acid.
[0037]Where the metal is comprised of silver, the composite materials
produced by the methods may therefore be useful as medical devices or as
components of medical devices due to their specific antimicrobial
properties. These composite materials may also provide other advantages.
As one example, the ability to provide a very thin coating or layer of
the deposition product on the substrate makes it possible to minimize the
amount of silver which must be used in the composite material in order to
provide a desired antimicrobial response. As a second example, the
ability to provide a very thin coating or layer of the deposition product
on the substrate minimizes the extent to which the deposition product
will interfere with the properties and functions of the substrate,
particularly if the deposition product is deposited on the substrate so
that it does not completely cover the surface of the substrate. This
second example may be particularly significant where the substrate is
comprised of an adhesive material such as a skin adhesive layer.
[0038]In a first aspect, the invention is a method for producing a
composite material comprising a substrate and a deposition product,
wherein the deposition product is comprised of at least one oxidized
species of a metal, the method comprising the following steps:
[0039](a) first contacting the substrate with a first basic environment
comprising ions of the metal in order to expose the substrate to the ions
of the metal; and [0040](b) second contacting the substrate with a second
basic environment in order to produce the composite material.
[0041]The first basic environment may be comprised of any environment in
which metal ions are present under alkali conditions. The metal may be
comprised of any metal or combinations of metals but preferably the metal
is comprised of silver.
[0042]Preferably the first basic environment is comprised of a first basic
solution comprising an amount of a silver diamino complex. More
preferably, the first basic solution results from a mixture of a silver
compound and ammonium hydroxide in an aqueous medium. Preferably the
silver compound is selected from the group of silver compounds consisting
of silver salts, silver oxides and mixtures thereof. More preferably the
silver compound is comprised of silver nitrate.
[0043]The first basic solution may have any alkaline pH. Preferably the
first basic solution has a pH in the range from about 8 to about 14.
Within these parameters, the amount of ammonium hydroxide in the first
basic solution is preferably selected such that a concentration of
ammonium hydroxide in the first basic solution is between about 25
percent and about 35 percent by volume of the first basic solution.
Preferably the amount of silver compound in the first basic solution is
selected such that a concentration of the silver compound in the first
basic solution is between about 1 gram per liter and about 20 grams per
liter.
[0044]The second basic environment may be comprised of any environment
having alkali conditions. Preferably the second basic environment is a
strongly alkaline environment having a pH at least about 12. Preferably
the second basic environment is comprised of a second basic solution
containing an amount of a strong alkali compound. The strong alkali
compound may be comprised of any compound which can provide the strong
alkaline environment. For example, the strong alkali compound may be
comprised of one or more Group I elements, including lithium, sodium,
potassium, rubidium, cesium and francium. Preferably the strong alkali
compound is selected from the group of compounds consisting of sodium
hydroxide and potassium hydroxide and mixtures thereof and more
preferably the strong alkali compound is comprised of sodium hydroxide.
Preferably the amount of hydroxide compound in the second basic solution
is selected such that a concentration of the hydroxide compound in the
second basic solution is between about 15 grams per liter and about 35
grams per liter.
[0045]The first contacting step may be performed for any length of time
which is sufficient to expose the substrate to the ions of the metal.
Preferably the substrate is substantially completely exposed to the ions
of the metal. Preferably the first contacting step is performed for
between about 1 minute and about 10 minutes.
[0046]The second contacting step may be performed for any length of time
which is sufficient to cause the production of the deposition product.
Preferably the second contacting step is performed for a sufficient time
in order to maximize the yield of the deposition product. Preferably the
second contacting step is performed for between about 1 minute and about
60 minutes.
[0047]The first contacting step may be performed at any temperature. The
second contacting step may be performed at any temperature. Preferably,
however, the second contacting step is performed at a temperature of
between about 2 degrees Celsius and about 60 degrees Celsius.
[0048]The method according to the first aspect may be further comprised of
the step of washing the composite material following the second
contacting step.
[0049]The method according to the first aspect may be further comprised of
the step of adding an amount of an oxidizing agent to the second basic
environment during the second contacting step. The oxidizing agent may be
comprised of any oxidizing agent which is compatible with the metal, but
the oxidizing agent is preferably selected from the group of oxidizing
agents consisting of persulfates, permanganates, peroxides and mixtures
thereof. More preferably the oxidizing agent is comprised of a
persulfate. The persulfate may be comprised of any persulfate but
preferably the persulfate is selected from the group of persulfates
consisting of potassium persulfate, sodium persulfate, ammonium
persulfate and mixtures thereof. More preferably the persulfate is
comprised of ammonium persulfate, potassium persulfate or mixtures
thereof, and most preferably the persulfate is comprised of potassium
persulfate.
[0050]The amount of the oxidizing agent is preferably selected to be
compatible with the amount of the ions of the metal so that the
deposition product can be produced as efficiently as possible. In other
words, the amount of the oxidizing agent is preferably selected to be a
stoichiometrically appropriate amount relative to the amount of the ions
of the metal. Preferably the amount of persulfate oxidizing agent is
selected such that a concentration of the persulfate in the second basic
solution is between about 1 gram per liter and about 25 grams per liter.
[0051]The method according to the first aspect may be further comprised of
the step, prior to the first contacting step, of etching the substrate by
immersing the substrate in an etching solution in order to prepare the
substrate for the deposition product. The etching step may involve either
or both of a physical process or a chemical process. The etching step
preferably prepares the substrate for the deposition product by
increasing the roughness of the substrate surface and/or creating
attraction sites for adsorption and/or deposition of the deposition
product.
[0052]Any etching solution may be utilized which is suitable for a
particular substrate. For example, where the substrate is comprised of an
organic material or polymer such as polyethylene, the etching solution is
preferably comprised of a mixture of an alcohol and an aqueous solution
of a hydroxide compound. The hydroxide compound may be comprised of any
hydroxide compound but is preferably selected from the group of hydroxide
compounds consisting of sodium hydroxide, potassium hydroxide and
mixtures thereof. More preferably the hydroxide compound is comprised of
sodium hydroxide. The etching step may be performed for any length of
time sufficient to prepare the substrate, but preferably the etching step
is performed for less than about 20 minutes and preferably is performed
for at least 5 minutes.
[0053]The method according to the first aspect may be further comprised of
the step of adding a residual silver compound to the second basic
environment during the second contacting step. The residual silver
compound may be comprised of any suitable source of silver ions, but
preferably the residual silver compound is comprised of silver nitrate.
Preferably the amount of residual silver compound is selected such that a
concentration of the residual silver compound in the second basic
solution is between about 1 gram per liter and about 5 grams per liter.
[0054]The method according to the first aspect may be further comprised of
the step of agitating the second basic environment during at least a
portion of the second contacting step in order to enhance the production
of the deposition product and the composite material.
[0055]In a second aspect, the invention is a method for producing a
deposition product, wherein the deposition product is comprised of at
least one oxidized species of a metal, the method comprising the
following steps: [0056](a) providing a deposition solution comprising
an amount of ions of the metal and an amount of an oxidizing agent; and
[0057](b) producing the deposition product by facilitating a chemical
reaction in the deposition solution between the ions of the metal and the
oxidizing agent.
[0058]The metal may be comprised of any metal or combinations of metals
but preferably the metal is comprised of silver so that the ions of the
metal are comprised of silver ions. The deposition solution may be
comprised of silver ions from any source or in any form but preferably
the deposition solution is comprised of an aqueous solution of a silver
salt. More preferably the silver salt is comprised of silver nitrate.
[0059]The ions of the metal may be present in any concentration.
Preferably, where the ions of the metal are comprised of silver ions, the
amount of the silver ions is selected so that a concentration of the
silver salt in the deposition solution is between about 1 gram per liter
and about 20 grams per liter.
[0060]The oxidizing agent may be comprised of any oxidizing agent which is
compatible with the metal, but the oxidizing agent is preferably selected
from the group of oxidizing agents consisting of persulfates,
permanganates, peroxides and mixtures thereof. More preferably the
oxidizing agent is comprised of a persulfate. The persulfate may be
comprised of any persulfate but preferably the persulfate is selected
from the group of persulfates consisting of potassium persulfate, sodium
persulfate, ammonium persulfate and mixtures thereof. More preferably the
persulfate is comprised of ammonium persulfate, potassium persulfate or
mixtures thereof, and most preferably the persulfate is comprised of
potassium persulfate.
[0061]The amount of the oxidizing agent is preferably selected to be
compatible with the amount of the ions of the metal so that the
deposition product can be produced as efficiently as possible. In other
words, the amount of the oxidizing agent is preferably selected to be a
stoichiometrically appropriate amount relative to the amount of the ions
of the metal. For example, where the metal is comprised of silver nitrate
the amount of silver nitrate is preferably selected such that a
concentration of the silver nitrate in the deposition solution is between
about 1 gram per liter and about 20 grams per liter, in which case the
amount of the oxidizing agent is preferably selected so that a
concentration of the oxidizing agent in the deposition solution is
between about 1 gram per liter and about 50 grams per liter.
[0062]The method according to the second aspect may be used to produce a
deposition product which comprises a substance having the general formula
Ag.sub.7O.sub.8X, where X is an anion. The deposition product may be
further comprised of Ag.sub.2SO.sub.4. The deposition product may also be
comprised of other oxidized silver compounds such as one or more silver
oxides selected from the group of silver oxides consisting of monovalent
silver oxide, bivalent silver oxide, trivalent silver oxide and mixtures
thereof.
[0063]The anion X may be comprised of a single anion or may be comprised
of a plurality of different anions. The anion may therefore be comprised
of any anion or combination of ions. The anion may, for example, be
selected from the group of anions consisting of HCO.sub.3.sup.-,
CO.sub.3.sup.2-, NO.sub.3.sup.-, ClO.sub.4.sup.-, SO.sub.4.sup.2-,
F.sup.-, and mixtures thereof. The source of the anion may be a metal
compound which provides the ions of the metal. For example, where the
deposition solution is comprised of a silver salt such as silver nitrate,
the anion may be comprised of the nitrate ion (NO.sub.3.sup.-). An
alternative or secondary source of the anion X may optionally be provided
in order to provide sufficient quantities of the anion for production of
the deposition product.
[0064]As a result, in the method according to the second aspect, the
method may be further comprised of the step of adding a source of anions
to the deposition solution. The source of anions may be comprised of one
or more acids. The acid may be comprised of any organic or inorganic
acid. For example, the acid may be selected from the group of acids
consisting of carbonic acid, nitric acid, perchloric acid, sulfuric acid,
acetic acid, fluoroboric acid, phosphoric acid, phosphorous acid, citric
acid, acetylsalicylic acid and mixtures thereof. The amount of the source
of anions which is added to the deposition solution preferably is an
amount which is selected to be compatible with the amount of the ions of
the metal. In other words, the amount of the source of anions is
preferably selected to be a stoichiometrically appropriate amount
relative to the amount of the ions of the metal.
[0065]The deposition product producing step is preferably performed at a
relatively low temperature, since the deposition product may experience
increasing solubility with increasing temperature. The deposition product
producing step is preferably performed at a temperature of between about
2 degrees Celsius and about 60 degrees Celsius, more preferably at a
temperature of between about 2 degrees Celsius and about 40 degrees
Celsius, and even more preferably at a temperature of between about 10
degrees Celsius and about 25 degrees Celsius.
[0066]Preferably the deposition solution is agitated during at least a
portion of the deposition product producing step in order to enhance the
production of the deposition product.
[0067]The method according to the second aspect may be used to produce the
deposition product as a product, or may be used to produce a composite
material comprising a substrate and the deposition product. Where the
method is used to produce a composite material, the method may be further
comprised of the following steps: [0068](a) providing a substrate; and
[0069](b) contacting the substrate with the deposition solution during
the deposition product producing step, thereby producing a composite
material comprising the substrate and the deposition product.
[0070]The substrate contacting step may be performed for any length of
time which is sufficient to produce the composite material having a
desired composition. The substrate contacting step is preferably
performed for at least about 1 minute, more preferably for between about
1 minute and about 60 minutes, even more preferably for between about 1
minute and about 20 minutes, and even more preferably for between about 2
minutes and about 10 minutes.
[0071]The method in the second aspect may be further comprised of the
step, following the substrate contacting step, of washing the composite
material.
[0072]The method according to the second aspect may be further comprised
of the step, prior to the substrate contacting step, of etching the
substrate by immersing the substrate in an etching solution in order to
prepare the substrate for the deposition product. The etching step may
involve either or both of a physical process or a chemical process. The
etching step preferably prepares the substrate for the deposition product
by increasing the roughness of the substrate surface and/or creating
attraction sites for adsorption and/or deposition of the deposition
product.
[0073]Any etching solution may be utilized which is suitable for a
particular substrate. For example, where the substrate is comprised of an
organic material or polymer such as polyethylene, the etching solution is
preferably comprised of a mixture of an alcohol and an aqueous solution
of a hydroxide compound. The hydroxide compound may be comprised of any
hydroxide compound but is preferably selected from the group of hydroxide
compounds consisting of sodium hydroxide, potassium hydroxide and
mixtures thereof. More preferably the hydroxide compound is comprised of
sodium hydroxide. The etching step may be performed for any length of
time sufficient to prepare the substrate, but preferably the etching step
is performed for less than about 20 minutes and preferably is performed
for at least 5 minutes. Where the etching step is performed, the method
according to the second aspect preferably further comprises the step,
following the etching step, of washing the substrate to remove residual
alkali from the substrate.
[0074]The method according to the second aspect may be further comprised
of the step, following the substrate contacting step, of immersing the
composite material in boiling water. The immersing step may be useful for
converting the deposition product into other oxidized silver species
(such as silver oxides), thus potentially providing an opportunity
further to "engineer" the composite material to provide desired
properties of the deposition product. The immersing step may be performed
for any length of time, but preferably the immersing step is performed
for at least about 1 minute.
[0075]The composite material may be produced for many different
applications including for electronics, materials engineering and medical
purposes. The method according to the second aspect is particularly
suited for the production of medical devices in circumstances where the
metal is silver and the deposition product is comprised of an oxidized
silver species having the general formula Ag.sub.7O.sub.8X and optionally
Ag.sub.2SO.sub.4 and/or optionally one or more silver oxide compounds,
due to the antimicrobial properties exhibited by the deposition product
and to the capability to control the extent of the deposition of the
deposition product on the substrate.
[0076]The term "medical device" as used herein means any article which has
a medical application where antimicrobial properties may be desirable,
and includes all natural and synthetic materials and both fibrous and
non-fibrous materials. For example, the materials may be comprised of a
metal, plastic, paper, glass, ceramic, textile, rubber, polymer,
composite material or any other material or combination of materials.
Non-limiting examples of medical devices which are encompassed by the
invention include wound dressings, splints, sutures, catheters, implants,
tracheal tubes, orthopedic devices, drains, shunts, connectors,
prosthetic devices, needles, medical instruments, laboratory, clinic and
hospital equipment, furniture and furnishings, dental devices, as well as
health care products such as personal hygiene products, sterile
packaging, clothing, footwear etc.
[0077]Accordingly, the composite material may comprise a medical device or
a component of a medical device and the term "medical device" as used
herein extends to both medical devices and components of medical devices.
[0078]In a preferred embodiment, the substrate is comprised of a wound
dressing. The wound dressing may be comprised of any material or
combination of materials, including but not limited to metals, ceramics,
glass, polymers, plastics, composite materials, natural materials,
synthetic materials, synthetic textiles such as HDPE, rayon, nylon,
polyacetates, polyacrylics and glass and natural textiles such as
cellulose, wool, jute and cotton, whether in fibrous or non-fibrous form.
[0079]In a preferred embodiment of wound dressing, the wound dressing may
be comprised of a polymer material such as high density polyethylene and
may be further comprised of an adhesive material comprising a skin
adhesive layer. The skin adhesive layer may be comprised of a
cross-linked silicon gel material. The wound dressing and/or the
cross-linked silicon gel material may for example be comprised of a
product sold under the Mepitel.TM. trade-mark or the Safetac.TM.
trade-mark, both of which trade-marks are owned by Molnlycke Health Care
AB of Sweden.
[0080]In one application, the deposition product may be selectively
deposited on the skin adhesive layer and the production of the deposition
product is preferably controlled so that the deposition product does not
materially interfere with the adhesive properties of the skin adhesive
layer, yet still provides an acceptable antimicrobial effect without
significant undesirable toxic effects. This result may be achieved by
depositing the deposition product on the skin adhesive layer such that
the deposition product provides a desired antimicrobial effect but does
not completely cover the surface of the skin adhesive layer. In this
application, preferably the amount of the deposition product which is
deposited on the substrate is such that the amount of total silver on the
substrate is selected to be between about 0.1 mg/cm.sup.2 and about 1.0
mg/cm.sup.2, or more preferably between about 0.2 mg/cm.sup.2 and about
0.6 mg/cm.sup.2, in order to achieve the desired result.
[0081]In other applications in which the deposition product is not
deposited on an adhesive such as the skin adhesive layer, the amount of
the deposition product is preferably controlled to balance the desired
antimicrobial effect, undesirable toxic effects, and economic
considerations.
[0082]In a third aspect, the invention is a medical device comprising a
composite material, wherein the composite material is comprised of a
substrate and a deposition product and wherein the deposition product is
comprised of an antimicrobially active oxidized silver species comprising
a silver salt and a silver oxide.
[0083]The medical device according to the third aspect may be produced
using any of the methods of the invention. Preferably the medical device
is produced using a method according to the second aspect of the
invention.
[0084]In certain preferred embodiments the invention provides methods for
depositing a deposition product comprising at least one oxidized silver
species onto a substrate, thus producing a composite material. Since the
oxidized silver species of the invention exhibit an antimicrobial
activity, composite materials comprising the oxidized silver species can
be used in various medical devices for prevention or inhibition of
infections. These medical devices may include but are not limited to
wound dressings, adhesives, sutures, catheters and other articles where
antimicrobial properties are desirable.
[0085]The preferred embodiments of the invention may be used to produce
deposition products and composite materials from aqueous solutions under
a wide range of pH conditions, involving reactions in either acidic or
alkaline solutions. The methods can be performed at, but are not limited
to, temperatures between about 2 degrees Celsius and about 60 degrees
Celsius with about 10 degrees Celsius to about 40 degrees Celsius being
the most preferable.
[0086]The method steps for certain preferred embodiments of the invention
are as follows:
I. Under acidic conditions: [0087](a) immersing an article to be used as
a medical device in an aqueous/alcohol solution of NaOH for a sufficient
time to provide a reasonable etching and cleaning of the surface,
followed by washing of the article with distilled water until a pH of 7
is attained, in order to remove residual alkali; [0088](b) immersing the
article in an aqueous silver salt solution. The aqueous silver salt
solution may be prepared from any silver salt which is soluble in water
with the most preferred silver salt being silver nitrate; [0089](c)
adding a stoichiometrically suitable quantity of an oxidizing agent to
the mixed silver salt solution containing the article. The oxidizing
agent can be any oxidizing substance such as persulfates, permanganates,
hydrogen peroxide and the like, with potassium persulfate
(K.sub.2S.sub.2O.sub.8) being the most preferred oxidizing agent;
[0090](d) adding a stoichiometrically suitable quantity of an acid to the
mixed silver salt solution containing the immersed article in order to
provide a source of anions. The acids that can be used include any
inorganic or organic acids including, but not limited to carbonic acid,
nitric acid, perchloric acid, sulfuric acid, acetic acid, fluoroboric
acid, phosphoric acid, phosphorous acid, citric acid, acetylsalicylic
acid and mixtures thereof, but most preferably nitric acid, perchloric
acid, phosphoric acid, acetic acid or sulfuric acid; [0091](e) agitating
the article in the mixed silver salt solution comprising the soluble
silver salt (preferably AgNO.sub.3), the acid (preferably nitric acid,
perchloric acid, phosphoric acid, acetic acid or sulfuric acid), and the
oxidizing agent (preferably potassium persulfate) at temperatures between
2 degrees Celsius and 30 degrees Celsius with temperatures between 10
degrees Celsius and 25 degrees Celsius being the most preferred for
between about 2 and 40 minutes until the article is coated with a
grayish, gray or black color; [0092](f) removing the article from the
slurry and washing the article with distilled water until a pH of 7 is
achieved; and [0093](g) drying the article at room temperature.
[0094]Alternatively after step (e) the article may be immersed in boiling
water (about 90 degrees Celsius to about 100 degrees Celsius) for at
least 1 minute.
II. Under Alkaline Conditions:
[0095](a) immersing an article to be used as a medical device in an
aqueous/alcohol solution of NaOH for a sufficient time to provide a
reasonable etching and cleaning of the surface; [0096](b) removing the
article into a solution containing a silver diamino complex in a
concentration sufficient to adsorb the silver ions at the surface of the
article and for a duration of about 2 minutes to about 5 minutes. The
silver diamino complex may be prepared by dissolving any silver salt or
silver oxide in ammonium hydroxide, and may be achieved by adding a
stoichiometrically suitable quantity of ammonium hydroxide to an aqueous
solution or suspension of the silver salt or silver oxide until a clear
colorless solution containing [Ag(NH.sub.3).sub.2].sup.+ is obtained. The
pH of this solution is usually in the range from about 8 to about 12;
[0097](c) removing the article without washing or rinsing into another
solution containing a strong alkali, most preferably NaOH or KOH, and
agitating the article in this solution until a clear colorless solution
is obtained and the article is clearly dyed with a tan, gray, brown or
black color, depending on the desired amount of oxidized silver species.
The time of contact of the article with the alkaline solution may vary,
depending on temperature and silver ion concentration, but the most
preferable duration is about 1 minute to about 15 minutes at room
temperature or about 1 minute to about 10 minutes at a temperature of
between about 40 degrees Celsius and about 60 degrees Celsius; [0098](d)
removing the dyed article from the solution and washing with distilled
water until a pH of 7 is achieved; and [0099](e) drying the article at
room temperature.
[0100]Alternatively, in step (c), the method may involve, depending on the
amount of silver required at the surface of the article, further
additions to the strong alkali solution of the silver diamino complex
solution and/or additions to the strong alkali solution of an oxidizing
agent such as a persulfate, permanganate, peroxide or a mixture thereof,
with potassium persulfate being the most preferred oxidizing agent.
BRIEF DESCRIPTION OF DRAWINGS
[0101]Embodiments of the invention will now be described with reference to
the accompanying drawings, in which:
[0102]FIG. 1 is an XRD pattern generated from a deposition product
obtained from the reaction of AgNO.sub.3 and
(NH.sub.4).sub.2S.sub.2O.sub.8 according to Examples 15-16.
[0103]FIG. 2 is an SEM micrograph (magnification=2000.times.) generated
from a deposition product obtained from the reaction of AgNO.sub.3 and
(NH.sub.4).sub.2S.sub.2O.sub.8 according to Examples 15-16.
[0104]FIG. 3 is an XRD pattern generated from a deposition product
obtained from the reaction of AgNO.sub.3 and K.sub.2S.sub.2O.sub.8
according to Examples 15-16.
[0105]FIG. 4 is an SEM micrograph (magnification=2000.times.) generated
from a deposition product obtained from the reaction of AgNO.sub.3 and
K.sub.2S.sub.2O.sub.8 according to Examples 15-16.
[0106]FIG. 5(a) is an SEM micrograph (magnification=150.times.) generated
from a sample of uncoated HDPE mesh.
[0107]FIG. 5(b) is an SEM micrograph (magnification=1000.times.) generated
from a sample of HDPE mesh upon which a deposition product has been
deposited according to Examples 15-16.
[0108]FIG. 6(a) is a photograph depicting a controlled zone of inhibition
(CZOI) against Staphylococcus Aureus for a sample of HDPE mesh coated
with a deposition product according to Examples 15-16.
[0109]FIG. 6(b) is a photograph depicting a controlled zone of inhibition
(CZOI) against Pseudomonas Aeruginosa for a sample of HDPE mesh coated
with a deposition product according to Examples 15-16.
[0110]FIG. 6(c) is a photograph depicting a controlled zone of inhibition
(CZOI) against Candida Albicans for a sample of HDPE mesh coated with a
deposition product according to Examples 15-16.
[0111]FIG. 7 is an SEM micrograph (magnification=30.times.) generated from
a substrate consisting of an uncoated sample of a perforated plastic
carrier material with a skin adhesive layer comprised of a hydrophobic
cross-linked silicon gel (trade-mark Mepitel.TM.).
[0112]FIG. 8 is an SEM micrograph (magnification=40.times.) generated from
a composite material consisting of a coated sample of a perforated
plastic carrier material with a skin adhesive layer comprised of a
hydrophobic cross-linked silicon gel (trade-mark Mepitel.TM.), in which a
relatively small amount of deposition product has been deposited on the
substrate in accordance with the second and third aspects of the
invention.
[0113]FIG. 9 is an SEM micrograph (magnification=2000.times.) generated
from the composite material of FIG. 8, depicting the density and coverage
of the deposition product on the substrate.
[0114]FIG. 10 is an SEM micrograph (magnification=40.times.) generated
from a composite material consisting of a coated sample of a perforated
plastic carrier material with a skin adhesive layer comprised of a
hydrophobic cross-linked silicon gel (trade-mark Mepitel.TM.), in which a
relatively larger amount of deposition product (relative to FIG. 8 and
FIG. 9) has been deposited on the substrate in accordance with the second
and third aspects of the invention.
[0115]FIG. 11 is an SEM micrograph (magnification=2000.times.) generated
from the composite material of FIG. 10, depicting the density and
coverage of the deposition product on the substrate.
[0116]FIG. 12 is an XRD pattern generated from a substrate consisting of
an uncoated sample of a perforated plastic carrier material with a skin
adhesive layer comprised of a hydrophobic cross-linked silicon gel
(trade-mark Mepitel.TM.).
[0117]FIG. 13 is an XRD pattern generated from a composite material
consisting of a coated sample of a perforated plastic carrier material
with a skin adhesive layer comprised of a hydrophobic cross-linked
silicon gel (trade-mark Mepitel.TM.), in which a deposition product has
been deposited on the substrate in accordance with the second and third
aspects of the invention.
[0118]FIG. 14 is a superimposition of the XRD patterns depicted in FIG. 12
and FIG. 13.
DETAILED DESCRIPTION
[0119]In preferred embodiments of the invention, antimicrobial properties
of medical devices are achieved by the adsorption and deposition of a
deposition product comprising an antimicrobially active silver species
within or at the surface of the medical device. These active silver
species may include but are not limited at all oxidized silver species
such as silver salts, silver oxide (Ag.sub.2O), higher silver oxides i.e.
Ag(II) and Ag(III) (AgO, Ag.sub.2O.sub.3, Ag.sub.3O.sub.4 or like),
silver oxy-salts with a general formula Ag.sub.7O.sub.8X where X can
include one of acid anions such as sulfates, chlorides, phosphates,
carbonates, citrates, tartrates, oxalates and like. The deposition
product may also contain some elemental silver deposited during the
process.
[0120]The term "total silver" as used in herein is the total amount of
silver as determined by a chemical analysis, which may include elemental
(metallic) silver as well as silver originating from oxidized silver
species.
[0121]The term "oxidized silver species" as used herein may involve but is
not limited at all compounds of silver where said silver is in +I, +II or
+III valent states or any combinations thereof. These oxidized silver
species include, for example silver (I) oxide, silver (II) oxide, silver
(III) oxide or mixtures thereof, all silver salts having a solubility
product higher than 10.sup.-20 (such as for example Ag.sub.2SO.sub.4,
AgCl, Ag.sub.2S.sub.2O.sub.8, Ag.sub.2SO.sub.3, Ag.sub.2S.sub.2O.sub.3,
Ag.sub.3PO.sub.4, and the like), and silver oxy-salts such as
Ag.sub.7O.sub.8X were X can include but is not limited at NO.sub.3.sup.-,
ClO.sub.4.sup.-, SO.sub.4.sup.2-, F.sup.- etc.
[0122]The term "medical device materials" as used herein may include
materials such as metals, ceramics, glass, polymers, plastics, composite
materials, a variety of natural materials, fabrics, textile made of
either synthetic (HDPE, rayon, nylon, polyacetates, polyacrylics, glass
etc.) or natural (cellulose, wool, jute, cotton, etc.) fibers.
[0123]The term "bacteriostatic activity", as used herein relates to the
inhibition of bacterial growth, but not to actually killing the bacteria.
Successful treatment therefore requires the host's immune system to clear
the pathogen. Treatment is compromised when the antimicrobial materials
are stopped before the pathogen has been completely cleared.
[0124]The term "bactericidal activity" as used herein relates to killing
bacteria with or without lysis of the target cell. These types of
antimicrobial materials are particularly advantageous in immunosuppressed
individuals. A disadvantage to bactericidal activity is cell lysis, which
can release lipolysaccharides which are toxic to the host. However, if
the concentration of the said antimicrobial material is relatively low so
that toxic effects cannot occur, a combination of both bacteriostatic and
bactericidal activities may be ideal for antimicrobial materials.
[0125]In the preferred embodiments, the deposition of the deposition
product comprising the oxidized silver species is accomplished by first
providing an aqueous solution of monovalent silver salt or a silver
complex such as silver nitrate, perchlorate or silver diamino complex,
with silver nitrate being the most preferable if the reaction is carried
out under acidic conditions or at close to neutral conditions (i.e. at pH
below 7), and with silver diamino complex, (i.e.,
[Ag(NH.sub.3).sub.2].sup.+) being the most preferable if the reaction is
carried out under alkaline conditions (i.e. at pH above 7).
[0126]Prior to the production of the composite material comprising the
article as a substrate and the deposition product, the article is
preferably immersed in an alkaline solution containing 50 vol. % ethanol
and 50 vol. % of an aqueous solution containing 30 g/L NaOH. Other
cleaning and etching solutions can be used depending upon the material
from which the medical device is made, upon the toxicity of the said
cleaning or etching solutions, and upon the possibility that some toxic
substances may adsorb at the surface of the article. Of course any use of
toxic or carcinogenic substances during the etching step should be
avoided. If production of the deposition product is carried out under
acidic conditions, the article is preferably washed with distilled water
after the etching step until a pH of 7 is achieved in order to remove
residual alkali remaining after the etching step.
[0127]When the reaction is carried out in the pH range below 7 (i.e.,
under acidic conditions), the clean pretreated article to be used as a
medical device containing oxidized silver species at the surface of the
same is simply immersed into an agitated 1% AgNO.sub.3 aqueous solution
as a deposition solution. After exposure of the said article to the
deposition solution for a duration preferably of about 2 to about 10
minutes, a solution of an oxidizing agent is added. Alternatively, the
oxidizing agent may be added to the deposition solution before the
article is immersed into the deposition solution, but this may result in
some production of the deposition product before the article is present
in the deposition solution.
[0128]Although a wide range of oxidizing agents such as permanganates,
persulfates, hydrogen peroxide, hypochlorites etc., may be used under
specific conditions and with the proper concentrations, the preferred
oxidizing agent is a persulfate, more preferably either ammonium
persulfate or potassium persulfate., and most preferably potassium
persulfate The persulfate facilitates the precipitation and deposition of
the deposition product on or within the article.
[0129]The concentration of persulfate in the deposition solution may be in
a range from about 1 gram per liter to about 250 gram per liter with the
concentration of about 50 gram per liter being the most preferable. After
agitation for about 2 minutes to about 5 minutes, the solution of 1%
AgNO.sub.3 and persulfate may be acidified with an organic or inorganic
acid such as HNO.sub.3, HClO.sub.4, H.sub.2SO.sub.4 or CH.sub.3COOH such
that the concentration of the free acid preferably is about 9% HNO.sub.3,
9% HClO.sub.4 acid, 5% H.sub.2SO.sub.4, or 5% CH.sub.3COOH. Although
other acids may be used the most preferable acids are H.sub.2SO.sub.4,
HClO.sub.4 or HNO.sub.3.
[0130]The agitation of the deposition solution is not strictly required,
but in order to achieve a more uniform distribution of the deposition
product and an efficient reaction yield, the agitation of the solution is
recommended. Agitation can be realized by many different ways such as for
example mechanical stirring, magnetic stirring or ultrasonic agitation.
[0131]Following addition of the persulfate (preferably potassium
persulfate) to the deposition solution of 1% AgNO.sub.3 within the time
of about 1 minute to about 10 minutes, and depending on the concentration
of the persulfate as well as on the conditions of agitation, the
formation first of a yellow brown color of the solution and then a black
grayish precipitate will occur. This brown color of the solution is
attributed to the oxidation of Ag(I) to Ag(II).
[0132]The black grayish deposit at the article or in the bulk solution is
a consequence of the formation of silver oxy-salts such as
Ag.sub.7O.sub.8X, were X is an anion, depending on the acid used in the
method e.g. HNO.sub.3 (NO.sub.3--), H.sub.2SO.sub.4 (SO.sub.4 2), etc.
The decomposition of the silver oxy-salts may be presented as:
Ag(Ag.sub.3O.sub.4).sub.2X=AgX+AgO (1)
[0133]Persulfates are powerful oxidizing agents. They can therefore be
reduced in aqueous solutions according to the following reactions:
S.sub.2O.sub.8.sup.2-+2e.sup.-=2SO.sub.4.sup.2-, with E.degree.=1.96 V
(2)
S.sub.2O.sub.8.sup.2-+2H.sup.++2e.sup.-=2HSO.sub.4.sup.-, with
E.degree.=1.96 V (3)
and
S.sub.2O.sub.8.sup.2-+2H.sub.2O=2H.sup.++2SO.sub.4.sup.2-+H.sub.2O.sub.2,
with .DELTA.G.degree.=-36 kJ/mol (4)
[0134]A consequence of the reduction of persulfate is the oxidation of
Ag(I) to Ag(II) and Ag(III), probably according to the following
reactions:
Ag.sup.+=Ag.sup.2++e.sup.-, with E.degree.=1.98 V (5)
Ag.sup.++H.sub.2O=AgO.sup.++2H.sup.++e.sup.-, with E.degree.=1.998 V (6)
Ag.sup.2++H.sub.2O=AgO.sup.++2H.sup.++e.sup.-, with E.degree.=2.06 V (7)
Ag.sup.++H.sub.2O=AgO+2H.sup.++e.sup.-, with E.degree.=1.772 V (8)
[0135]In this way the composite material comprising the article to be used
as a medical device and the deposition product may include a combination
of oxidized silver species i.e. Ag(I)- and Ag(II)-oxides as well as
silver salts such as nitrates, persulfates, sulfates, phosphates,
perchlorates and like, silver salts of a general formula Ag.sub.7O.sub.8X
and perhaps traces of pure elemental silver. After production of the
composite material, the article is removed from the deposition solution
and then preferably washed with distilled water until a pH of 7 is
achieved. When the washing is completed, the medical device comprising
the composite material may be dried at room temperature and packaged.
[0136]When the reaction is carried out in the pH range above 7 (i.e.,
under alkaline conditions) the article to be used as a medical device is
first immersed in an etching solution comprising an alkaline solution
containing alcohol. The most preferable solution according to this
invention is either NaOH or KOH with concentrations 15 to 40 g/L. The
alcohol used in this solution may be ethyl alcohol, methyl alcohol or
mixtures therein in a concentration above 50 vol. %. The immersion of the
article into the etching solution is carried out in order to etch and
clean the surface of the article to provide a reasonable adhesion of the
deposition product comprising an oxidized silver species which is
deposited on or within the article thereafter. The immersion time of the
article is preferably in the range of between about 5 minutes and about
20 minutes, with about 10 minutes being the most preferable.
[0137]After the exposure to the alkali/alcohol solution for about 10
minutes, the article is then removed without washing or rinsing into a
first basic environment comprising a first basic solution containing
silver diamino complex i.e. [Ag(NH.sub.3).sub.2].sup.+ in a concentration
sufficient to adsorb silver ions at the surface of the article and for a
duration of about 2 minutes to about 5 minutes. The silver diamino
complex is preferably prepared from a silver salt or silver oxide
dissolved or suspended in water by a dissolution with NH.sub.4OH (28 vol.
%).
[0138]Consequently, the first basic solution is prepared in a way such
that a solution of any silver salt (such as for example AgNO.sub.3 or
AgClO.sub.4) or any silver oxide (such as Ag.sub.2O or Ag.sub.2O.sub.2 or
AgO) or any silver salt suspended in water (such as AgCl,
Ag.sub.2CO.sub.3, Ag.sub.2SO.sub.4 or the like), the ammonium hydroxide
is added in a stoichiometrically suitable concentration so that a clear
colorless solution is obtained. The concentration of silver ion in this
silver diamino complex solution, as calculated for Ag.sup.+ ion can vary
from 1 to 20 g/L with about 10 g/L being the most preferable. The pH of
the first basic solution is usually between about 8 and about 12 with the
most preferred pH being in the range of between about 10 and about 11.
[0139]After exposure of the article to the first basic solution for about
2 minutes to about 5 minutes, the article is removed without washing or
rinsing into a second basic environment comprising a second basic
solution containing a strong alkali, most preferably NaOH or KOH. The
article is kept in this solution under agitation until a clear colorless
solution is obtained and the article is dyed with a tan, gray, brown or
black color, depending on the desired amount of oxidized species to be
deposited at or within the surface of the article. The time of contact of
the article with the second basic solution may vary depending on
temperature and the silver ion concentration, but most preferable time is
about 1 minute to about 15 minutes at room temperature or about 1 minute
to about 10 minutes at a temperature of between about 40 degrees Celsius
and about 60 degrees Celsius.
[0140]Alternatively, the method may involve an addition of an oxidizing
agent to the second basic solution, preferably a persulfate, more
preferably either ammonium persulfate or potassium persulfate, and most
preferably potassium persulfate. The oxidizing agent may be added
directly to the second basic solution containing the article. In
addition, depending on the amount of silver desired to be deposited as
the deposition product, addition of a residual silver compound such as
the silver diamino complex [Ag(NH.sub.3).sub.2].sup.+ may also be
beneficial.
[0141]Upon immersion of the article, previously exposed to the first basic
solution, into the second basic solution, the following reaction at the
surface of the article may occur:
2Ag(NH.sub.3).sub.2NO.sub.3+2NaOH=Ag.sub.2O+4NH.sub.3+H.sub.2O+2NaNO.sub.3
(9)
[0142]In this way, at the surface of the article, Ag.sub.2O will deposit
as the result of the reaction (9). The addition of an oxidizing agent
such as ammonium persulfate (i.e., (NH.sub.4).sub.3S.sub.2O.sub.8) to the
second basic solution may result in the oxidation of silver ions and the
reduction of S.sub.2O.sub.8.sup.2- ions pursuant to the following
reactions:
Ag.sup.+=Ag.sup.2++e.sup.-, with E.degree.=1.96 V (10)
and
S.sub.2O.sub.8.sup.2-+2e=2SO.sub.4.sup.2-, with E.degree.=1.96 V (11)
[0143]The reactions of Ag(NH.sub.3).sub.2.sup.+ ion with ammonium
persulfate can be represented as follows:
Ag(NH.sub.3).sub.2NO.sub.3+(NH.sub.4).sub.2S.sub.2O.sub.8=Ag.sub.2S.sub.2O-
.sub.8+2NH.sub.4NO.sub.3+4NH.sub.3 (12)
Ag.sub.2S.sub.2O.sub.8+H.sub.2O=2AgO+2H.sub.2SO.sub.4 (13)
Ag(NH.sub.3).sub.2NO.sub.3+(NH.sub.4).sub.2S.sub.2O.sub.8+2H.sub.2O=2NH.su-
b.4NO.sub.3+2AgO+2H.sub.2SO.sub.4+4NH.sub.3 (14)
or
Ag(NH.sub.3).sub.2NO.sub.3+(NH.sub.4).sub.2S.sub.2O.sub.8+2H.sub.2O=2NH.su-
b.4NO.sub.3+2AgO+2(NH.sub.4).sub.2SO.sub.4 (15)
[0144]In this way, the deposition product may contain Ag.sub.2O, AgO or
other higher oxides of silver Ag(II), Ag(III) and mixtures therein. Also,
if alcohol is present in the reacting solution, due to transferring from
the etching solution some elemental silver may occur in the deposition
product. This is because in the presence of persulfates, alcohols can be
oxidized to aldehydes according to the reactions:
CH.sub.3OH.dbd.H.sub.2CO+2H.sup.++2e.sup.- (16)
C.sub.2H.sub.5OH.dbd.CH.sub.3CHO+2H.sup.++2e.sup.- (17)
[0145]Under the alkaline conditions, the aldehydes can reduce the silver
ions to the elemental silver according to the reaction:
2Ag(NH.sub.3).sub.2OH+HCHO=2Ag+4NH.sub.3+HCOOH+H.sub.2O (18)
[0146]After production of the composite material comprising the article
and the deposition product comprising the oxidized silver species is
completed, the article is removed, carefully washed with water until a pH
of 7 is achieved. The article may then be dried at room temperature and
packaged.
[0147]Following are examples which illustrate the present invention.
EXAMPLES
Example 1
[0148]Nine (9) pieces of high density polyethylene mesh (HDPE), with
dimensions 10.times.8 cm each, were immersed in 100 ml of an etching
solution containing 50 mL alcohol (95% C.sub.2H.sub.5OH and 5%
CH.sub.3OH) and 50 mL of 28 g/L NaOH solution for 5 minutes. After 5
minutes of etching the HDPE mesh was transferred without washing or
rinsing into 40 mL of an Ag.sup.+ solution, containing 15.3 g/L
AgNO.sub.3 and a stoichiometrically suitable volume of NH.sub.4OH (28
vol. %). The HDPE mesh was kept in this solution for 2 minutes. After 2
minutes of exposure to the ammoniacal Ag(NH.sub.3).sub.2.sup.+ solution,
the HDPE mesh was transferred without washing or rinsing into 150 mL of a
28 g/L NaOH solution stirred with a magnetic stirrer. As soon as the HDPE
mesh was immersed into NaOH solution, the formation of a precipitate
yellowish-brown in color occurred. Under agitation a residual silver
compound (about 38 mL of the Ag(I) solution) was added and after that 5
mL of a 250 g/L (NH.sub.4).sub.2S.sub.2O.sub.8 solution was added.
Agitation was continued for 10 minutes. During this time the
solution/precipitate became black. The HDPE mesh was uniformly coated and
was black and shiny in appearance. The coated HDPE mesh was then removed
from the solution and carefully washed with distilled water until pH
7.00, and dried at room temperature. After drying, the mesh was a black
and shiny in appearance.
[0149]Chemical analysis determined that the HDPE mesh coated with oxidized
silver species contained about 0.08 mg total silver per cm.sup.2 of mesh.
The coated mesh was further analyzed by XRD analysis. As found by the XRD
analysis the mesh included Ag.sub.2O, Ag(II) oxides,
Ag.sub.7O.sub.8NO.sub.3 and some traces of the elemental silver. Both
bacteriostatic and bactericidal activities of silver coated HDPE
substrates were tested against Pseudomonas Aeruginosa and Staphylococcus
Aureus. One hour bactericidal activity tests of coated HDPE mesh against
both Pseudomonas Aeruginosa and Staphylococcus Aureus were positive. The
bacteriostatic activity was also tested. The controlled zone of
inhibition surrounding the test sample, where no bacteria growth
occurred, was estimated at about 9 mm to about 10 mm.
Example 2
[0150]Samples of HDPE mesh with dimensions 10.times.8 cm were immersed in
100 mL of an etching solution containing 50 mL of 28 g/L NaOH and 50 mL
of denatured ethanol (95% C.sub.2H.sub.5OH and 5% CH.sub.3OH) for 5
minutes. After 5 minutes of etching the HDPE mesh was transferred without
washing or rinsing into 40 mL of an ammoniacal Ag(I) solution containing
15.3 g/L AgNO.sub.3 and a stoichiometrically suitable quantity of
NH.sub.4OH (28 vol. %). The HDPE mesh was kept in this solution for 2
minutes. The HDPE mesh was then transferred without washing or rinsing
into 150 mL of a solution containing 28 g/L NaOH. The NaOH solution
immediately became brown. Upon addition of a residual silver compound
(about 38 mL of the Ag(I) solution) the solution turned to a dark brown
color and with a continued agitation for about 5 minutes the solution
became black. When the agitation was stopped, the black precipitate
occurred in the bulk solution as a result of its separation from the HDPE
mesh material. After washing and rinsing with distilled water the mesh
appeared to be light tan or at the most slightly gray as a consequence of
the coating with silver compounds.
[0151]The amount of total silver deposited on the HDPE mesh as determined
by chemical analysis was estimated at about 0.04 mg/cm.sup.2.
Antimicrobial activities (bactericidal and bacteriostatic) were tested
against Pseudomonas Aeruginosa and Staphylococcus Aureus. One hour
bactericidal activity of the coated HDPE mesh was positive. The
bacteriostatic activity, as estimated according to the controlled zone of
inhibition (CZOI) for the bacterial growth was also positive. The CZOI
was estimated at about 4 mm.
Example 3
[0152]Samples of HDPE mesh were immersed in an etching solution containing
100 mL of 28 g/L NaOH solution for 5 minutes. The mesh was then
transferred without washing or rinsing into 40 mL of an ammoniacal Ag(I)
solution containing 15.3 g/L AgNO.sub.3 and a stoichiometrically suitable
volume of NH.sub.4OH (28%). After 2 minutes of immersion, the mesh was
transferred without washing or rinsing into 150 mL of a 28 g/L NaOH
solution stirred magnetically. The solution became immediately brown due
to formation of a precipitate. Addition of a residual silver compound
(about 38 mL of the Ag(I) solution) resulted in the formation of a dark
brown precipitate. The color of the solution did not change further even
after 30 minutes of mixing at room temperature. The HDPE mesh was then
washed and rinsed very carefully with distilled water. The color of the
HDPE mesh did not change significantly, but some change in color from
white to a light tan appeared.
[0153]The amount of total silver deposited on the HDPE mesh was estimated
at about 0.02 mg/cm.sup.2. The antimicrobial activities (both
bacteriostatic and bactericidal) of these samples were tested against
Pseudomonas Aeruginosa and Staphylococcus Aureus. The results showed a
positive bactericidal activity and the CZOI was estimated at about 3 mm.
Example 4
[0154]Samples of HDPE mesh were immersed in 100 mL of a solution
containing 1 g AgNO.sub.3 and 1 mL of 67% HNO.sub.3 as a source of
anions. After 5 minutes of immersion, 5 g of
(NH.sub.4).sub.2S.sub.2O.sub.8 dissolved in 20 mL of water was added. The
sample was left for 30 minutes at room temperature, during which the
solution was stirred occasionally with a glass rod. During this time the
solution changed color from colorless to a dark brown and a formation of
a light gray precipitate in the bulk solution appeared. After 30 minutes,
the HDPE mesh was removed from the solution and carefully washed with
distilled water. The washed HDPE mesh had a gray color. The coating was
uniformly distributed at the surface of this material.
[0155]The amount of total silver deposited on the HDPE mesh was estimated
at 0.09 mg/cm.sup.2. The bactericidal activity for these samples was
positive. The CZOI was estimated at about 8 mm.
Example 5
[0156]HDPE mesh was coated with silver oxidized compounds using a method
similar to that described in Example 4, with a few differences as
outlined in the description that follows.
[0157]Samples of HDPE mesh were immersed in 100 mL of a solution
containing 10 g/L AgNO.sub.3 and 15 mL/L HNO.sub.3 (67%) as a source of
anions. To this solution 10 mL of 500 g/L (NH.sub.4).sub.2S.sub.2O.sub.8
was added. The solution was magnetically stirred. After 7 minutes of
stirring the solution became yellow-brown and formation of a very small
amount of precipitate occurred. The stirring was continued for the next
30 minutes. After 30 minutes, the HDPE mesh was removed from the slurry
and carefully washed with distilled water. The washed HDPE mesh had a
gray color. The coating was uniformly distributed at the surface of the
HDPE mesh.
[0158]The amount of total silver deposited on the HDPE mesh was estimated
at 0.08 mg/cm.sup.2. The bactericidal activities against Pseudomonas
Aeruginosa and Staphylococcus Aureus were positive. The CZOI was
estimated at about 7 mm.
Example 6
[0159]HDPE mesh was coated with silver oxidized compounds using a method
similar to that described in Example 4 and Example 5, with a few
differences as outlined in the description that follows.
[0160]Samples of HDPE mesh were immersed in 100 mL of a solution
containing 10 g/L AgNO.sub.3 and 15 mL/L HNO.sub.3 (67%) as a source of
anions. To this solution 10 mL of 500 g/L (NH.sub.4).sub.2S.sub.2O.sub.8
was added. The solution was agitated ultrasonically. After 2 minutes of
stirring the solution became yellow-brown and formation of a very small
amount of precipitate occurred. The stirring was continued for the next
30 minutes. After 30 minutes, the HDPE mesh was removed from the solution
and carefully washed with distilled water. The washed HDPE mesh had a
gray color. The coating was uniformly distributed at the surface of the
HDPE mesh.
[0161]The amount of total silver deposited on the HDPE mesh was estimated
at 0.08 mg/cm.sup.2. The bactericidal activities against Pseudomonas
Aeruginosa and Staphylococcus Aureus were positive. The CZOI was
estimated at about 7 mm.
Examples 7-9
[0162]In these examples the effect of different acids (i.e., sources of
anions) is clearly shown for coating of HDPE mesh with oxidized silver
species under acidic conditions. In Example 4, HNO.sub.3 was used as a
source of anions to supplement the anions contained in the AgNO.sub.3,
while in Examples 7-9 perchloric acid (HClO.sub.4), sulfuric acid
(H.sub.2SO.sub.4) and acetic acid (CH.sub.3COOH) respectively were used
as a source of anions.
[0163]Samples of HDPE mesh were immersed in 100 mL of a solution
containing 1 g AgNO.sub.3. To this solution 1 mL of HClO.sub.4 (70%)
(Example 7), 0.5 mL of H.sub.2SO.sub.4 (98%) (Example 8) and 15 mL of
CH.sub.3COOH (5%) (Example 9) were added. After 2 minutes of the exposure
of HDPE mesh to these solutions, 20 mL of 250 g/L
(NH.sub.4).sub.2S.sub.2O.sub.8 was added. The mixing was continued for
the next 30 minutes. In the solutions containing HClO.sub.4 (Example 7)
and H.sub.2SO.sub.4 (Example 8) formation of a black grayish precipitate
occurred similar to Example 4. When the precipitate settled the solutions
were clear and yellow-brown in color. The yellow-brown color suggests the
presence of Ag(II) complexes in the solution. The coated HDPE mesh was
then removed from the slurry and carefully washed and rinsed with
distilled water and thereafter dried at room temperature. After drying
the HDPE mesh coated in the presence of 1 mL of HClO.sub.4 (70%) (Example
7), or in the presence of 0.5 mL of H.sub.2SO.sub.4 (98%) (Example 8)
appeared to be grayish in color. However, the HDPE mesh coated in the
presence of 15 mL of CH.sub.3COOH (5%) (Example 9) was white and it did
not change its color.
[0164]The coated HDPE mesh (Examples 7-9) were analyzed for the total
silver content, and the antimicrobial activity was also evaluated against
Pseudomonas Aeruginosa and Staphylococcus Aureus. The amount of total
silver deposited on the HDPE mesh was estimated at 0.08 mg/cm.sup.2 (for
samples coated in the presence of HClO.sub.4), 0.07 mg/cm.sup.2 (for
samples coated in the presence of H.sub.2SO.sub.4) and 0.01 mg/cm.sup.2
(for the samples coated in the presence of CH.sub.3COOH). The
bactericidal activities against Pseudomonas Aeruginosa and Staphylococcus
Aureus were positive. The CZOI was estimated at about 6 mm (for samples
coated in the presence of HClO.sub.4 or H.sub.2SO.sub.4) and about 1 to 2
mm (for samples coated in the presence of CH.sub.3COOH).
Example 10
[0165]Samples of HDPE mesh with dimensions 10.times.8 cm were immersed in
100 mL of an etching solution containing 50 mL of 28 g/L NaOH and 50 mL
of denatured ethanol (95% C.sub.2H.sub.5OH and 5% CH.sub.3OH) for 5
minutes. After 5 minutes of etching the HDPE mesh was transferred without
washing or rinsing into 40 mL of an ammoniacal Ag(I) solution containing
15.3 g/L AgNO.sub.3 and a stoichiometrically suitable quantity of
NH.sub.4OH (28 vol. %). The HDPE mesh was kept in this solution for 2
minutes. The HDPE mesh was then transferred without washing or rinsing
into 150 mL of a solution containing 28 g/L NaOH. The NaOH solution
immediately became brown. After mixing for 2 minutes, the solution became
clear and colorless and the mesh was tan in color. When the agitation was
stopped, the HDPE mesh was removed from solution and washed with
distilled water. After washing and rinsing the mesh appeared to be tan in
color as a consequence of the coating with silver compounds.
[0166]The coated HDPE mesh was analyzed for silver content and for
antimicrobial activity against Pseudomonas Aeruginosa and Staphylococcus
Aureus. These samples contained between 0.04 and 0.08 mg/cm.sup.2 total
silver. The bactericidal activities against Pseudomonas Aeruginosa and
Staphylococcus Aureus were positive. The CZOI was estimated at about 10
mm.
Example 11
[0167]A patterned wound dressing made of a perforated plastic carrier
material with a skin adhesive layer comprised of a hydrophobic
cross-linked silicon gel (trade-mark Mepitel.TM., product of Molnlycke
Health Care AB, Sweden), dimensions 8.times.15 cm was exposed to a
solution containing 15 g/L NaOH at room temperature for 5 minutes. Under
conditions of agitation 40 mL of a solution containing 15.3 g/L
AgNO.sub.3 and a proper volume of NH.sub.4OH (28 vol. %) was added. The
wound dressing was kept in this solution and agitated for the next 5
minutes. The wound dressing was then removed from the solution and
carefully washed with distilled water. Drops of water were removed with a
soft paper and the wound dressing was dried at room temperature.
[0168]The coated wound dressing was analyzed for antimicrobial activity
against Pseudomonas Aeruginosa and Staphylococcus Aureus. MH plates and
Tryptic Soy Broth were used for analysis. Pseudomonas Aeruginosa standard
was set to 0.5 McFarland standard. One hour of bactericidal activity of
the coated wound dressing against the bacteria where TSB broths were
incubated for 24 hours was positive. The controlled zones of inhibition
(CZOI), for the bacterial growth (bacteriostatic activity) were above 8
mm. The same samples of coated wound dressing were tested for seven days
for antimicrobial activity. The values of CZOI after 2 days were 20.5 mm,
after 3 days 19 mm, after 4 days 20.5 mm, after 5 days 19 mm and after 7
days 7 mm. These results show very good resistance towards bacteria for a
relatively long time (7 days).
Example 12
[0169]A patterned wound dressing made of a perforated plastic carrier
material with a skin adhesive layer comprised of a hydrophobic
cross-linked silicon gel (trade-mark Mepitel.TM., product of Molnlycke
Health Care AB, Sweden), dimensions 8.times.15 cm was exposed to 500 mL
of a 1% AgNO.sub.3 solution. To this solution was added 200 mL of a
solution containing 20 g K.sub.2S.sub.2O.sub.8 and mixing was continuous
for the next 20 minutes. The wound dressing was then removed from the
solution and carefully washed with distilled water. Drops of water were
removed with soft paper and the wound dressing was dried at room
temperature.
[0170]The coated wound dressing contained 0.25-0.55 mg/cm.sup.2 of total
silver. The coated wound dressing was then analyzed for antimicrobial
activity in the same manner as described in Example 11. The results
showed excellent antimicrobial activity for 7 days.
Example 13
[0171]A patterned wound dressing made of a perforated plastic carrier
material with a skin adhesive layer comprised of a hydrophobic
cross-linked silicon gel (trade-mark Mepitel.TM., product of Molnlycke
Health Care AB, Sweden), dimensions 8.times.15 cm was coated in a way as
described in Example 12, except that (NH.sub.4).sub.2 S.sub.2O.sub.8 was
used as an oxidizing agent instead of K.sub.2S.sub.2O.sub.8, in the same
amount and in the same manner as described in Example 12.
[0172]The coated wound dressing produced as described in this example was
analyzed for the antimicrobial activity. The results showed excellent
antimicrobial activity.
Example 14
[0173]A slurry was prepared by mixing 500 mL of a 1% AgNO.sub.3 solution
and 200 mL of an aqueous solution containing 20 g K.sub.2S.sub.2O.sub.8
for 10 minutes. To this slurry a patterned wound dressing made of a
perforated plastic carrier material with a skin adhesive layer comprised
of a hydrophobic cross-linked silicon gel (trade-mark Mepitel.TM.,
product of Molnlycke Health Care AB, Sweden), dimensions of 8.times.15 cm
was added and mixing was continued for the next 20 minutes. The coated
wound dressing was then removed from the slurry, carefully washed with
water then dried as described in the Example 12. The coated wound
dressing was black-greyish in appearance.
[0174]The antimicrobial activity of the coated wound dressing was tested
in a way described in Example 11. The results showed excellent
antimicrobial activity for seven days.
Examples 15-16
[0175]All method steps were performed at room temperature (22 degrees
Celsius .+-.2 degrees Celsius), unless otherwise specified.
[0176]Samples of HDPE mesh were coated with oxidized silver species as
follows. HDPE mesh with dimensions 10.times.10 cm were immersed into 100
mL of a 1% AgNO.sub.3 solution and thoroughly wetted. After the exposure
of the HDPE mesh to the solution for 10 minutes, 20 mL of a solution
containing either 250 g/L of (NH.sub.4).sub.2S.sub.2O.sub.8 or 250 g/L of
K.sub.2S.sub.2O.sub.8 was added under magnetic stirring. The mixing was
continued for the next 15 minutes. The coated HDPE mesh was then removed
from the slurry and was observed to be grayish-black in appearance. After
coating, the HDPE mesh was washed with water and then dried.
[0177]The bacteriostatic activity for the controlled zone of inhibition
(CZOI) of bacterial or fungal growth was tested against Pseudomonas
Aeruginosa, Staphylococcus Aureus or Candida Albicans, using standard
procedures as described in the literature.
Discussion of Examples 15-16
(a) Deposition of Silver Deposition Products Using
(NH.sub.--4).sub.2S.sub.2O.sub.8
[0178]Upon addition of ammonium persulfate to the AgNO.sub.3 solution, a
gradual color change from colorless through yellow, brown and finally to
a cloud solution containing grayish-black precipitate was observed. Time
for the appearance of the grayish-black precipitate at room temperature
was estimated at 5 to 10 minutes. It was noted that if the reaction takes
place at temperatures above 30 degrees Celsius, the precipitation and
color change do not occur.
[0179]Persulfates are powerful oxidizing agents. In aqueous solutions
persulfates can be reduced to sulfates (S. I. Zhdanov, Sulfur, Selenium,
Tellurium and Polonium, in Standard Potentials in Aqueous Solutions, A.
J. Bard, R. Parsons and J. Jordan Editors, Marcel Dekker Inc., New York
(1985)). A consequence of the reduction of persulfate is the oxidation of
Ag(I) to Ag(II) and Ag(II) to Ag(III). The grayish-black precipitate
deposited on the HDPE mesh was formed as a result of the reduction of
persulfate and a consequent oxidation of Ag(I) ions.
[0180]During precipitation of the deposition product, the pH of the
solution dropped from about 2 to below 1. The decrease in pH of the
solution was more significant when K.sub.2S.sub.2O.sub.8 is used as an
oxidizing agent instead of (NH.sub.4).sub.2S.sub.2O.sub.8, in that a
decrease in pH from about 7 to below 1 was observed.
(b) Properties of Deposition Products Produced Using
(NH.sub.4).sub.2S.sub.2O.sub.8
[0181]The grayish-black precipitate itself represents a mixture of silver
argentic nitrate Ag(Ag.sub.3O.sub.4).sub.2NO.sub.3Ag.sub.7NO.sub.1, and
Ag.sub.2SO.sub.4. Indeed, as found by XRD analysis, the peaks in the
patterns showed a reasonable match for Ag.sub.2SO.sub.4 and
Ag.sub.7O.sub.8NO.sub.3 (FIG. 1). It is apparent that the oxidation of
AgNO.sub.3 with (NH.sub.4).sub.2S.sub.2O.sub.8 leads to the precipitation
of silver oxy-salt Ag.sub.7NO.sub.11, and also Ag.sub.2SO.sub.4. The
precipitation of Ag.sub.2SO.sub.4 is usually not observed when
K.sub.2S.sub.2O.sub.8 is used as an oxidizing agent of Ag(I) ions (see
the discussion below relating to oxidation with K.sub.2S.sub.2O.sub.8).
[0182]FIG. 2 provides a SEM micrograph of the grayish black precipitate.
The smaller "cubical" particles represent Ag.sub.7O.sub.8NO.sub.3 and
their size, based on SEM is estimated at about 2.5 .mu.m. The shape of
these particles was found to be in very good agreement with the results
of Skanavi-Grigoreva (M. S. Skanavi-Grigoreva, I. L. Shimanovich, Zh.
Obsh., Khim., 24, 1490 (1954)). who produced this material by the
electrolysis of an aqueous AgNO.sub.3 solution. The larger, cylindrical
particles represent silver sulfate (Ag.sub.2SO.sub.4).
(c) Deposition of Silver Deposition Products Using K.sub.2S.sub.2O.sub.8
[0183]Some differences in the formation of the grayish-black precipitate
were observed when K.sub.2S.sub.2O.sub.8 was used instead of
(NH.sub.4).sub.2S.sub.2O.sub.8, as the oxidizing agent of Ag(I). The
precipitation of the grayish-black compound was significantly faster, and
occurred within 1 minute upon addition of K.sub.2S.sub.2O.sub.8 to the
AgNO.sub.3 solution. During this time, the pH of the solution changed
from the initial pH of about 7 to below 1 after the precipitation.
(d) Properties of Deposition Products Produced Using K.sub.2S.sub.2O.sub.8
[0184]As determined by XRD analysis in FIG. 3, all the peaks in the
pattern exactly match the compound of composition
Ag.sub.7O.sub.8NO.sub.3. No other compounds were identified in this XRD
pattern.
[0185]The theoretical amount of Ag in the compound Ag.sub.7O.sub.8NO.sub.3
is 79.90%. The chemical analysis determined that the grayish black
precipitate contained about 78.80% Ag. This result shows a good agreement
of the experiments with the theory.
[0186]The SEM micrographs of the powder produced by the chemical oxidation
of AgNO.sub.3 with K.sub.2S.sub.2O.sub.8 are presented in FIG. 4. It
appears that the particles are uniform and cubical in their shape. The
size of these particles is estimated at about 2.5 .mu.m.
(e) Antimicrobial Activity
[0187]The comparison of the SEM micrographs of uncoated and coated HDPE
mesh samples is presented in FIG. 5. As shown in FIG. 5, the surface of
the HDPE is partially covered with the Ag(Ag.sub.3O.sub.4).sub.2NO.sub.3
particulates.
[0188]These samples were tested for bioactivity against the bacteria
Pseudomonas Aeruginosa, Staphylococcus Aureus or fungi Candida Albicans.
As can be seen from the photographs presented in FIG. 6, clear zones
surrounding the test samples (where a growth of tested microorganisms did
not occur) were observed in all cases for Staphylococcus Aureus (a
gram-positive bacteria), Pseudomonas Aeuguginosa (a gram-negative
bacteria) and Candida Albicans (an example of fungi). The size of the
controlled zone of inhibition (CZOI), where the growth of tested
microorganisms was not observed, was estimated at 3 mm to 5 mm for all
tested samples. These results suggest that the deposition products have
antibacterial and antifungal properties. Furthermore these results are in
agreement with previously published results, where was suggested that
only oxidized silver species, but not metallic silver exhibit an
antimicrobial activity.
(f) Conclusions Relating to Examples 15-16
[0189]It has been demonstrated that deposition products, namely those of
composition Ag.sub.7NO.sub.11.times.3Ag.sub.2SO.sub.4 or
Ag.sub.7NO.sub.1, can successfully be deposited as powders or on a
substrate such as HDPE mesh, by a simple reaction between AgNO.sub.3 and
(NH.sub.4)S.sub.2O.sub.8 or K.sub.2S.sub.2O.sub.8. These compounds are
soluble in both concentrated HNO.sub.3 or NH.sub.4OH.
Example 17
[0190]Samples of a substrate consisting of a patterned wound dressing made
of a perforated plastic carrier material with a skin adhesive layer
comprised of a hydrophobic cross-linked silicon gel (trade-mark
Mepitel.TM., product of Molnlycke Health Care AB, Sweden) were subjected
to SEM micrography to observe the density and coverage on the substrate
of a deposition product deposited on the substrate in accordance with the
second and third aspects of the invention, and to XRD analysis to analyze
the composition of the deposition product deposited on the substrate.
[0191]FIG. 7 depicts an uncoated sample of the Mepitel.TM. wound dressing
at a magnification of 30.times.. FIGS. 8-11 depict samples of composite
materials which have been produced according to the second and third
aspects of the invention in the same manner as described in Example 14.
[0192]FIG. 8 depicts a composite material comprising a coated sample of
the Mepitel.TM. wound dressing at a magnification of 40.times., in which
a relatively low amount of deposition product has been deposited on the
substrate. FIG. 9 depicts the composite material of FIG. 8 at a
magnification of 2000.times., and clearly shows that the density and
coverage of the deposition product is such that the skin adhesive layer
of the Mepitel.TM. wound dressing is relatively unobstructed by the
deposition product.
[0193]FIG. 10 depicts a composite material comprising a coated sample of
the Mepitel.TM. wound dressing at a magnification of 40.times., in which
a higher amount of deposition product has been deposited on the substrate
in comparison with FIG. 8 and FIG. 9. FIG. 11 depicts the composite
material of FIG. 10 at a magnification of 2000.times., and clearly shows
that the skin adhesive layer remains relatively unobstructed by the
deposition product.
[0194]FIG. 12 depicts an XRD pattern for an uncoated sample of the
Mepitel.TM. wound dressing. FIG. 13 depicts an XRD pattern for a
composite material comprising a sample of the Mepitel.TM. wound dressing
which has been coated with a deposition product according to the second
and third aspects of the invention in the same manner as described in
Example 14. FIG. 14 superimposes the XRD patterns from FIG. 12 and FIG.
13.
[0195]Referring to FIG. 14, the peaks which are observed in the pattern
from FIG. 13 but which are not observed in the pattern from FIG. 12 may
be attributed to the deposition product. These peaks define the
deposition product as comprising at least some amount of
Ag.sub.7O.sub.8NO.sub.3.
Example 18
[0196]Samples of a substrate consisting of a patterned wound dressing made
of a perforated plastic carrier material with a skin adhesive layer
comprised of a hydrophobic cross-linked silicon gel (trade-mark
Mepitel.TM., product of Molnlycke Health Care AB, Sweden) coated with 0.6
mg/cm.sup.2 of total silver according to the second and third aspects of
the invention in the same manner as described in Example 14 were exposed
to a solution containing 10 g/L Na.sub.2S. After 10 minutes of exposure
to the Na.sub.2S solution the coated wound dressing samples were
carefully washed with water until pH 7.
[0197]After drying, the samples were tested for antimicrobial activity
against Pseudomonas Aeruginosa and Staphylococcus Aureus using standard
procedures. Clear zones of inhibition of bacterial growth surrounding
test samples were observed for both Pseudomonas Aeruginosa and
Staphylococcus Aureus, suggesting that a deposition product produced
according to the second and third aspects of the invention will exhibit
an antimicrobial activity even after exposure to a sulfide containing
environment.