U.S. patent application number 15/526348 was filed with the patent office on 2017-11-02 for enhancement of antimicrobial silver, silver coatings, or silver platings.
The applicant listed for this patent is SILVER BULLET THERAPEUTICS, INC.. Invention is credited to Paul E. CHIRICO, Houdin DEHNAD, Thomas Lee GUTSHALL, Jason A. JEGGE, Julie LUCERO.
Application Number | 20170312399 15/526348 |
Document ID | / |
Family ID | 55955097 |
Filed Date | 2017-11-02 |
United States Patent
Application |
20170312399 |
Kind Code |
A1 |
DEHNAD; Houdin ; et
al. |
November 2, 2017 |
ENHANCEMENT OF ANTIMICROBIAL SILVER, SILVER COATINGS, OR SILVER
PLATINGS
Abstract
Antimicrobial metal ion coatings. In particular, described
herein are coatings including an anodic metal (e.g., silver and/or
zinc and/or copper) that is co-deposited with a cathodic metal
(e.g., palladium, platinum, gold, molybdenum, titanium, iridium,
osmium, niobium or rhenium) on a substrate (including, but not
limited to absorbable/resorbable substrates) so that the anodic
metal is galvanically released as antimicrobial ions when the
apparatus is exposed to a bodily fluid. The anodic metal may be at
least about 25 percent by volume of the coating, resulting in a
network of anodic metal with less than 20% of the anodic metal in
the coating fully encapsulated by cathodic metal.
Inventors: |
DEHNAD; Houdin; (El Granada,
CA) ; LUCERO; Julie; (San Jose, CA) ; CHIRICO;
Paul E.; (Campbell, CA) ; JEGGE; Jason A.;
(San Jose, CA) ; GUTSHALL; Thomas Lee; (Los Altos,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SILVER BULLET THERAPEUTICS, INC. |
San Jose |
CA |
US |
|
|
Family ID: |
55955097 |
Appl. No.: |
15/526348 |
Filed: |
November 13, 2015 |
PCT Filed: |
November 13, 2015 |
PCT NO: |
PCT/US2015/060541 |
371 Date: |
May 12, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14806554 |
Jul 22, 2015 |
9452242 |
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15526348 |
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62123339 |
Nov 14, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2300/80 20130101;
A61L 29/148 20130101; A61L 31/16 20130101; A61L 2300/606 20130101;
A61L 2420/02 20130101; B05D 3/0453 20130101; A61L 29/106 20130101;
A61L 29/16 20130101; A61L 31/148 20130101; A61L 2420/06 20130101;
A61L 31/06 20130101; A61L 31/088 20130101; A61L 27/58 20130101;
A61L 2300/404 20130101; A61L 27/306 20130101; A61L 27/54
20130101 |
International
Class: |
A61L 31/08 20060101
A61L031/08; A61L 31/14 20060101 A61L031/14; A61L 27/54 20060101
A61L027/54; A61L 27/58 20060101 A61L027/58; A61L 29/16 20060101
A61L029/16; A61L 29/14 20060101 A61L029/14; A61L 31/16 20060101
A61L031/16; A61L 27/30 20060101 A61L027/30; A61L 31/06 20060101
A61L031/06; B05D 3/04 20060101 B05D003/04; A61L 29/10 20060101
A61L029/10 |
Claims
1. A method of forming an enhanced antimicrobial surface, the
method comprising: co-depositing a coating of silver and a cathodic
metal onto a substrate surface, wherein the co-deposited coating
comprises a mixture of between about 25% and 75% by volume of
silver, and between about 25% to 75% by volume of the cathodic
metal; and applying ozone to the coated surface for at least 5
minutes.
2. The method of claim 1, further comprising blasting the substrate
surface with a noble gas or charged noble gas before applying the
silver material.
3. The method of claim 1, further comprising blasting the substrate
surface with argon before applying the silver metal.
4. The method of claim 1, wherein coating comprises coating the
substrate surface with a silver material comprising a mixture of
between about 25% and 75% by volume of silver, and between about
25% to 75% by volume of a cathodic metal co-deposited on the
substrate so that the coating comprises a plurality of microregions
or microdomains of the silver in a matrix of cathodic metal or a
plurality of microregions or microdomains of cathodic metal in a
matrix of silver, the microregions or microdomains forming a
continuous path of interconnected veins of silver through the
coating thickness, or a continuous path of interconnected veins of
cathodic metal through the coating thickness, wherein the
continuous path extends from an outer surface of the coating
through the coating to an opposite side of the coating.
5. The method of claim 1, wherein applying ozone to the coated
surface for at least 5 minutes comprises applying the ozone for at
least 10 minutes.
6. The method of claim 1, wherein applying the ozone comprises
spraying the surface with a jet comprising ozone.
7. A method of galvanically releasing antimicrobial ions to form an
antimicrobial zone around a surface of a substrate, the method
comprising: contacting the surface with a conductive fluid, wherein
the surface comprises a coating comprising a mixture of between
about 25% and 75% by volume of silver, and between about 25% to 75%
by volume of a cathodic metal co-deposited on the substrate,
further wherein the coating has been ozonized by the application of
ozone to the surface for at least 5 minutes; and galvanically
releasing antimicrobial ions of the anodic metal from the
coating.
8. The method of claim 7, wherein the coating comprises a plurality
of microregions or microdomains of the silver in a matrix of
cathodic metal or a plurality of microregions or microdomains of
cathodic metal in a matrix of silver, the microregions or
microdomains forming a continuous path of interconnected veins of
silver through the coating thickness, or a continuous path of
interconnected veins of cathodic metal through the coating
thickness, wherein the continuous path extends from an outer
surface of the coating through the coating to an opposite side of
the coating.
9. An apparatus that galvanically releases antimicrobial ions, the
apparatus comprising: a substrate surface; and an ozonated coating
on the outer substrate surface, the ozonated coating comprising a
mixture of between about 25% and 75% by volume of silver, and
between about 25% to 75% by volume of a cathodic metal co-deposited
on the substrate surface, so that there is a continuous path of
silver from the surface to the outer substrate surface.
10. The apparatus of claim 9, wherein the ozonated coating
comprises Ag.sub.4O.sub.4.
11. The apparatus of claim 9, wherein, in the ozonated coating,
less than 30% of the silver is fully encapsulated within the matrix
of cathodic metal and connects through a microregion or microdomain
of silver to the outer surface of the coating.
12. The apparatus of claim 9, wherein, in the ozonated coating,
less than 20% of the silver is fully encapsulated within the matrix
of cathodic metal and connects through a microregion or microdomain
of silver to the outer surface of the coating.
13. The apparatus of claim 9, wherein the cathodic metal comprises
one or more of: palladium, platinum, or gold.
14. The apparatus of claim 9, wherein the cathodic metal comprises
one or more of: palladium, platinum, gold, molybdenum, titanium,
iridium, osmium, niobium and rhenium.
15. The apparatus of claim 9, wherein the ozonated coating
comprises the silver and the cathodic metal that have been
vapor-deposited onto the length of a filament so that the silver is
not encapsulated by the cathodic metal.
16. The apparatus of claim 9, wherein the substrate surface is an
outer surface of one of: a pacemaker, defibrillator,
neurostimulator, or ophthalmic implant.
17. The apparatus of claim 9, wherein the substrate surface is an
outer surface of one of: an implantable shunt, an artificial joint,
a hip implant, a knee implant, a catheter, a stent, an implantable
coil, a pump, an intrauterine device (IUD), a heart valve, a
surgical fastener, a surgical staple, a surgical pin, a suture, a
surgical screw, an implantable electrical lead, or an implantable
plate.
18. The apparatus of claim 9, wherein the substrate surface is an
outer surface of one of: a retractor, a bariatric balloon, an
orthodontic brace, a breast implant, a surgical sponge, a gauze, a
mesh, a mesh pouch, or a wound packing material.
19. The apparatus of claim 9, wherein the ozonated coating is
fractured.
20. The apparatus of claim 9, wherein the ozonated coating is
fractured so that a surface area of the coating is increased by at
least 25% compared to the surface area of the coating in an
unfractured state.
21. The apparatus of claim 9, wherein the substrate is a
bioabsorbable filament.
22. The apparatus of claim 9, wherein the substrate is a
bioabsorbable filament comprise one or more of: polylactic acid
(PLA), poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),
polyglycoside-co-trimethylene carbonate (PGTMC),
poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), and
poly(caprolactone) (PCL).
23. An apparatus that galvanically releases antimicrobial ions, the
apparatus comprising: a substrate surface; and an ozonated coating
on the outer substrate surface, the ozonated coating comprising a
mixture of between about 25% and 75% by volume of silver, and
between about 25% to 75% by volume of a cathodic metal co-deposited
on the substrate surface, wherein the coating comprises a plurality
of microregions or microdomains of anodic metal in a matrix of
cathodic metal or a plurality of microregions or microdomains of
cathodic metal in a matrix of anodic metal, the microregions or
microdomains forming a continuous path of interconnected veins of
anodic metal through the coating thickness, or a continuous path of
interconnected veins of cathodic metal through the coating
thickness, wherein the continuous path extends from an outer
surface of the coating through the coating to an opposite side of
the coating.
24. The apparatus of claim 23, wherein the ozonated coating
comprises Ag.sub.4O.sub.4.
25. The apparatus of claim 23, wherein, in the ozonated coating,
less than 30% of the silver is fully encapsulated within the matrix
of cathodic metal and connects through a microregion or microdomain
of silver to the outer surface of the coating.
26. The apparatus of claim 23, wherein the cathodic metal comprises
one or more of: palladium, platinum, or gold.
27. The apparatus of claim 23, wherein the cathodic metal comprises
one or more of: palladium, platinum, gold, molybdenum, titanium,
iridium, osmium, niobium and rhenium.
28. The apparatus of claim 23, wherein the ozonated coating
comprises the silver and the cathodic metal that have been
vapor-deposited onto the length of a filament so that the silver is
not encapsulated by the cathodic metal.
29. The apparatus of claim 23, wherein the coating is
fractured.
30. The apparatus of claim 23, wherein the coating is fractured so
that a surface area of the coating is increased by at least 25%
compared to the surface area of the coating in an unfractured
state.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims priority to U.S. Provisional
Patent Application No. 62/123,339, filed Nov. 14, 2014, titled
"CREATION OF ANTIMICROBIAL AGENT ON SILVER, SILVER COATING, OR
PLATING VIA EXPOSURE OF THE SILVER TO OZONE" which is herein
incorporated by reference in its entirety.
[0002] This patent may also be related to U.S. patent application
Ser. No. 1/679,893, filed on Apr. 6, 2015, titled "COATINGS FOR THE
CONTROLLABLE RELEASE OF ANTIMICROBIAL METAL IONS," which claims
priority as a continuation-in-part to U.S. patent application Ser.
No. 14/569,545, filed on Dec. 12, 2014, now U.S. Pat. No.
8,999,367, and titled "BIOABSORBABLE SUBSTRATES AND SYSTEMS THAT
CONTROLLABLY RELEASE ANTIMICROBIAL METAL IONS," which is a
continuation of U.S. patent application Ser. No. 14/302,352, filed
on Jun. 11, 2014 and titled "BIOABSORBABLE SUBSTRATES AND SYSTEMS
THAT CONTROLLABLY RELEASE ANTIMICROBIAL METAL IONS," now U.S. Pat.
No. 8,927,004, and U.S. Provisional Patent Application No.
62/059,714, filed on Oct. 3, 2014 and titled "COATINGS FOR THE
CONTROLLABLE RELEASE OF ANTIMICROBIAL METAL IONS." Each of these
patents and patent applications is herein incorporated by reference
in its entirety.
INCORPORATION BY REFERENCE
[0003] All publications and patent applications mentioned in this
specification are herein incorporated by reference in their
entirety to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference.
FIELD
[0004] Described herein are substrates having antimicrobial metal
ion coatings that are treated with ozone to enhance their
antimicrobial properties. In particular, described herein are
substrates that are coated with an anodic metal such as silver that
is co-deposited with a cathodic metal (e.g., palladium, platinum,
gold, molybdenum, titanium, iridium, osmium, niobium or rhenium) on
the substrate to form a continuous path of interconnected veins of
(e.g., silver) metal within the matrix of cathodic metal or a
continuous path of interconnected veins of cathodic metal within
the matrix of anodic metal, wherein the continuous path extends
from an outer surface of the coating to the substrate; these
coatings may then be treated with ozone to remove biologic material
prior to sterilization and to greatly enhance the antimicrobial
properties of silver/cathodic coating. Other oxidizing agents
(e.g., peroxide, etc.) may be used in alternatively or in addition
to ozone. Thus, in addition to the galvanic released of
antimicrobial silver as antimicrobial ions (e.g., when the coated
substrates is contacted by a conductive fluid environment,
including when inserted into a subject's body), the ozonation may
further enhance the antimicrobial effects of just galvanically
released silver alone.
BACKGROUND
[0005] Antimicrobial or antibiotic agents are widely used to treat
as well as to prevent infection. In particular, silver is known to
be antimicrobial and has been used (primarily as a coating) in
various medical devices with limited success. Both active (e.g., by
application of electrical current) and passive (e.g., galvanic)
release of silver ions have been proposed for use in the treatment
and prevention of infection. However, the use of silver-releasing
implants have been limited because of the difficulty in controlling
and distributing the release of silver ions as well as the
difficulty in maintaining a therapeutically relevant concentration
of silver ions in an appropriate body region. Zinc shares many of
the same antimicrobial properties of silver, but has been less
commonly used, and thus even less is known about how to control the
amount and distribution of the release of silver ions to treat
and/or prevent infection.
[0006] In addition, ozone (O.sub.3) by itself has been known to act
as an antimicrobial agent. For example, ozonated water has been
used as a strong antimicrobial agent against foodborne pathogens.
Although combinations of ozone and antimicrobial ions such as
silver have been suggested (see., e.g., Kang S-N, et al., "Effect
of a Combination of Low Level Ozone and Metal Ions on Reducing
Escherichia coli O157:H7 and Listeria monocytogenes" Molecules
2013, 18, 4018-4025), such an approach has suggested only the
addition of ozone in a solution already containing silver ions.
Pre-treatment of "dry" sources of antimicrobial ions (including
silver coatings) has not previously been suggested, as the
proposed, and previous experiments have assumed that ozone must be
applied concurrently with silver ion treatment, which is
impractical in many instances where it would be useful to provide
for the release of antimicrobial ions.
[0007] For example, it would be highly beneficial to use an
antimicrobial agent such as silver and/or zinc as part of an
implant, including a bioabsorbable implant, in part because the
risk of acquiring infections from bioabsorbable materials in
medical devices is very high. Many medical applications exist for
bioabsorbable materials including: wound closure (e.g., sutures,
staples, adhesives), tissue repair (e.g., meshes, such as for
hernia repair), prosthetic devices (e.g., internal bone fixation
devices, etc.), tissue engineering (e.g., engineered blood vessels,
skin, bone, cartilage, liver, etc.) and controlled drug delivery
systems (such as microcapsules and ion-exchange resins). The use of
bioabsorbable materials in medical applications such as these may
reduce tissue or cellular irritation and the induction of an
inflammatory response.
[0008] Bioabsorbable materials for medical applications are well
known. For example, synthetic bioabsorbable polymers may include
polyesters/polylactones such as polymers of polyglycolic acid,
glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate
etc., polyanhydrides, polyesteramides, polyortheoesters,
polyphosphazenes, and copolymers of these and related polymers or
monomers, as well as naturally derived polymers such as albumin,
fibrin, collagen, elastin, chitosan, alginates, hyaluronic acid;
and biosynthetic polyesters (e.g., 3-hydroxybutyrate polymers).
However, like other biomaterials, bioabsorbable materials are also
subjected to bacterial contamination and can be a source of
infections which are difficult to control. Those infections quite
often require their removal and costly antimicrobial
treatments.
[0009] Efforts to render bioabsorbable materials more infection
resistant generally have focused on impregnating the materials with
antibiotics or salts such as silver salts, and have provided only
limited and instantaneous antimicrobial activity. It is desirable
to have an antimicrobial effect which is sustained over time, such
that the antimicrobial effect can be prolonged for the time that
the bioabsorbable material is in place. This can range from hours
or days, to weeks or even years.
[0010] Further, although antimicrobial/antibacterial metal coatings
on medical devices have been suggested, metal coatings (such as
silver or copper coatings) have not been characterized or
optimized. In such applications, it is important that the metal
coatings do not shed or leave behind large metal particulates in
the body, which may induce unwanted immune responses and/or toxic
effects. Further, it is essential that the release of the
antimicrobial agent (metal) be metered over the lifetime of the
implant.
[0011] For example, U.S. Pat. No. 8,309,216 describes substrates
including degradable polymers that include an electron donor layer
(such as silver, copper or zinc) onto which particles of palladium
and platinum, plus one other secondary metal (chosen from gold,
ruthenium, rhodium, osmium, iridium, or platinum) are deposited
onto. Although such materials are described for anti-microbial
implants (e.g., pacemakers, etc.), the separate layers formed by
this method would be problematic for antimicrobial coatings in
which the undercoating of silver, copper or zinc were being
released, potentially undermining the platinum and secondary
metal.
[0012] Similarly, U.S. Pat. No. 6,719,987 describes bioabsorbable
materials having an antimicrobial metal (e.g., silver) coating that
can be used for an implant. The silver coating is for release of
particles (including ions) and must be in a crystalline form
characterized by sufficient atomic disorder. In this example, the
silver is also deposited in one or more layers. U.S. Pat. No.
6,080,490 also describes medical devices with antimicrobial
surfaces that are formed by layers of metals (e.g., silver and
platinum) to release ions; layers are etched to expose regions for
release. The outer layer is always Palladium (and one other metal),
beneath which is the silver.
[0013] Thus, it would be highly desirable to provide devices,
systems and methods for the controlled release (particularly the
controlled galvanic release) of a high level of silver, zinc or
silver and zinc ions from a bioabsorbable material into the tissue
for a sufficient period of time to treat or prevent infection.
[0014] Known systems and devices, including those described above,
that have attempted to use ions (e.g., silver and/or zinc) on
bioabsorbable materials to treat infection have suffered from
problems such as: insufficient amounts of ions released (e.g., ion
concentration was too low to be effective); insufficient time for
treatment (e.g., the levels of ions in the body or body region were
not sustained for a long enough period of time); and insufficient
region or volume of tissue in which the ion concentration was
elevated (e.g., the therapeutic region was too small or limited,
such as just on the surface of a device). Further, the use of
galvanic release has generally been avoided or limited because it
may effectively corrode the metals involved, and such corrosion is
generally considered an undesirable process, particularly in a
medical device.
[0015] There is a need for antimicrobial coatings for substrates
generally, and more specifically, there is a need for highly
effective ("enhanced") coatings that provide a high level of
antimicrobial activity. Antimicrobial coatings (and particularly
the ozone-enhanced coatings described herein) may be useful for any
surface that will be exposed to a conductive fluid, including
blood, sweat, lymph, etc., whether implanted or not. For example,
there is a particular need for antimicrobial coatings for
bioabsorbable materials, which can create an effective and
sustainable antimicrobial effect, which do not interfere with the
bioabsorption of the bioabsorbable material, and which do not shed
or leave behind large metal particulates in the body as the
bioabsorbable material disappears.
[0016] Therapeutically, the level of silver and/or zinc ions
released into a body is important, because it may determine how
effective the antimicrobial ions are for treating or preventing
infection. As described in greater detail below, the amount or ions
released galvanically may depend on a number of factors which have
not previously been well controlled. For example, galvanic release
may be related to the ratio of the anode to the cathode (and thus,
the driving force) as well as the level of oxygen available; given
the galvanic reaction, the level of oxygen may be particularly
important for at the cathode. Insufficient oxygen at the cathode
may be rate-limiting for galvanic release.
[0017] For example, with respect to silver, it has been reported
that a concentration of 1 mg/liter of silver ions can kill common
bacteria in a solution. Silver ions may be generated a galvanic
system with silver as the anode and platinum or other noble metal
as the cathode. However one of the challenges in designing a
galvanic system for creation of silver ion in the body that has not
been adequately addressed is the appropriate ratios of the areas of
the electrodes (e.g., anode to cathode areas) in order to create
the germicidal level of free silver ions.
[0018] Thus, to address the problems and deficiencies in the prior
art mentioned above, described herein are systems, methods and
devices (and in particular coatings, methods of coatings) for
substrates that controllably release antimicrobial metal ions,
including apparatuses (e.g., devices and/or systems) and methods
for prevent infection and for eliminating existing infections, in
which the antimicrobial coating has be treated with ozone
(resulting in an ozone-treated or enhanced coating) having superior
antimicrobial activity. The enhanced coatings described herein may
be used as part of any appropriate substrate, including medical
devices (both implanted, inserted, and non-implanted/inserted
medical devices), and non-medical devices including hand-held
articles. In some particular examples, described below are implants
including bioabsorbable substrates, and methods for using them.
SUMMARY OF THE DISCLOSURE
[0019] In general, described herein are ozone-enhanced
antimicrobial coatings and methods of forming and using such
ozone-enhanced coatings for any substrate that will come into
contact with a bodily fluid and/or secretion, in which the coating
may galvanically release antimicrobial ions. These enhanced
coatings are configured so that the release of the antimicrobial
ions is sustained over a predetermined time period of continuous or
intermittent exposure to the bodily fluid, and further so that the
amount and/or concentration of the antimicrobial ions released is
above a predetermined threshold for effective antimicrobial effect
either locally or within a region exposed to the coating.
[0020] Treatment of antimicrobial metals (e.g., anionic metals such
silver, nickel, etc.) and in particular the silver/cathodic metal
co-coatings described herein, with ozone will result in an ozonated
metal (e.g., ozonated silver, ozonated silver ion) surface. An
ozonated metal (e.g., ozonated silver) surface may be any metal
surface that has been treated by the application of ozone gas, as
described herein, resulting in a modification of the anodic metal
(e.g., silver). The modification may be detectable both chemically
and empirically, based on the enhancement of the antimicrobial
effect (e.g., a greater than 30%, 40%, 50%, 60%, 70%, 80%, 100%,
etc., increase in the region of antimicrobial activity compared to
non-enhanced anodic metal. Without being bound by a particular
theory of effect or operation, these enhanced anodic (and
particularly co-deposited silver/cathodic coatings) surfaces have a
much larger observable antimicrobial effect, which is sustained
over many hours, days, weeks and months, compared to untreated
surfaces. For example, ozone treatment of silver and/or
silver/cathodic co-deposited surfaces may result in the formation
of Ag.sub.4O.sub.4. The Ag.sub.4O.sub.4 maybe on the outer surface
and/or may penetrate somewhat into the coating (e.g., may be more
concentrated towards the outer surface). Although the exact nature
of the modification of the ozone-treated antimicrobial surfaces
described herein may be more complicated, the effects are striking.
Pre-treatment of even a simple silver surface (e.g., compared to
surfaces including the co-deposited silver/cathodic metals
described herein) may result in a greater than 50% (or in most
cases more, e.g., 2.times., 3.times., 4.times., etc.) enhancement
of the antimicrobial activity when assayed as described herein.
However, pre-treatment (e.g., for greater than 5 min, greater than
10 min, greater than 15 min) of a coating comprising co-depositions
of an anodic metal (e.g., one or more of zinc, silver, and/or
copper) and a cathodic metal (e.g., one or more of: palladium,
platinum, gold, molybdenum, titanium, iridium, osmium, niobium and
rhenium) as described herein may enhance the already high
antimicrobial effects seen with these coatings.
[0021] Although particular attention and examples of types of
substrates, such as medical devices, and in particular implantable
medical device including bioabsorbable substrates, it should be
readily understood that the coatings described herein may be used
on any substrate surface that will come into contact with bodily
fluids which would benefit from an antimicrobial effect, including
devices that are not inserted or implanted into a body. Bodily
fluids are generally electrically conductive, and may include any
of: blood, blood serum, amniotic fluid, aqueous humor, vitreous
humor, bile, breast milk, cerebrospinal fluid, cerumen, chyle,
chyme, endolymph, perilymph, exudates, feces (diarrhea), female
ejaculate, gastric acid, gastric juice, lymph, mucus (including
nasal drainage and phlegm), pericardial fluid, peritoneal fluid,
pleural fluid, pus, rheum, saliva, sebum, semen, sputum, synovial
fluid, sweat, tears, urine, vaginal secretion, vomit, etc.
[0022] As used herein, a substrate may be any surface onto which
the coating may be applied, which may be any appropriate material,
including, but not limited to metals (e.g., alloys, etc.),
ceramics, stone, polymers, wood, glass, etc., including
combinations of materials. In some variations the surface of the
substrate may be prepared before the coating is applied, as
described herein. The substrate may be rigid or flexible. In
particular, the coatings described herein may be applied to
flexible and/or fiber-like materials such as strings, sutures,
woven materials, thin electrical leads, and the like. As described
in greater detail herein, the coating typically does not inhibit
the flexibility, pliability, bendability, etc. of the substrate
material.
[0023] For example, described herein are methods of forming an
enhanced antimicrobial surface comprising: coating a substrate
surface with a silver material; and applying ozone to the coated
surface for at least 1 minute, at least 2 minutes, at least 3
minutes, at least 4 minutes, at least 5 minutes, etc., including
preferably at least 5 minutes.
[0024] Any silver material may be used, including pure silver
(metallic silver), or in particular, silver coatings including
co-depositions of silver and a cathodic metal to drive galvanic
release of the silver. This coating may be any of the coatings
described herein.
[0025] For example a method of forming an enhanced antimicrobial
surface may include: co-depositing a coating of silver and a
cathodic metal onto a substrate surface, wherein the co-deposited
coating comprises a mixture of between about 25% and 75% by volume
of silver, and between about 25% to 75% by volume of the cathodic
metal; and applying ozone to the coated surface for at least 1
minute, at least 2 minutes, at least 3 minutes, at least 4 minutes,
at least 5 minutes, etc., including preferably at least 5
minutes.
[0026] Any of the methods of applying a coating described herein
may include preparing the surface. In particular, the method may
include preparing the surface by treating it with a noble gas (such
as argon) to remove any impurities, oxides, or the like. In some
variations, this may involve applying the noble gas (which may
include a charged noble gas) under pressure (e.g., blasting)
against the surface. In some variations the method may include
blasting the substrate surface with a noble gas before applying the
silver material. The method of preparing by forcing a noble gas
such as argon (e.g., charged argon) against the surface may be used
in place of applying an additional adhesive layer. Surprisingly,
the applicants have found that cleaning and preparing the surface
with argon may alleviate the need for the application of an
additional adhesion layer when the surface is made, for example, of
a nickel titanium material. For example, any of these methods may
include a step of preparing the surface by forcing a jet of argon
(e.g., blasting the substrate surface with argon and/or charged
argon, plasma, etc.) before applying the silver metal.
[0027] As mentioned, the silver coating may be a layer or coating
of silver that is co-deposited with a cathodic metal. For example,
coating may include coating the substrate surface with a coating
comprising a mixture of between about 25% and 75% by volume of
silver, and between about 25% to 75% by volume of a cathodic metal
co-deposited on the substrate, e.g., so that the coating comprises
a plurality of microregions or microdomains of the silver in a
matrix of cathodic metal or a plurality of microregions or
microdomains of cathodic metal in a matrix of silver, the
microregions or microdomains forming a continuous path of
interconnected veins of silver through the coating thickness, or a
continuous path of interconnected veins of cathodic metal through
the coating thickness, wherein the continuous path extends from an
outer surface of the coating through the coating to an opposite
side of the coating.
[0028] Ozonation, or the application of ozone on the surface for a
predetermined time to modify the surface, may be generally
performed by, e.g., directing a jet of ozone against the surface
for the predefined time. For example, ozonation may include
applying ozone to the coated surface for at least 5 minutes, at
least 10 minutes, at least 15 min, at least 20 min, at least 25
min, etc. The longer the application of ozone to/against the
surface, the greater the resulting ozonation, which may in turn
more effectively enhance the antimicrobial effects, as illustrated
herein. For example, applying the ozone may comprise spraying the
surface with a jet comprising ozone.
[0029] Also described herein are methods of galvanically releasing
antimicrobial ions to form an antimicrobial zone around a surface
of a substrate, the method comprising: contacting the surface with
a conductive fluid, wherein the surface comprises a coating
comprising a mixture of between about 25% and 75% by volume of
silver, and between about 25% to 75% by volume of a cathodic metal
co-deposited on the substrate, further wherein the coating has been
ozonized by the application of ozone to the surface for at least 5
minutes; and galvanically releasing antimicrobial ions of the
anodic metal from the coating. As mentioned above, the coating may
comprise a plurality of microregions or microdomains of the silver
in a matrix of cathodic metal or a plurality of microregions or
microdomains of cathodic metal in a matrix of silver, the
microregions or microdomains forming a continuous path of
interconnected veins of silver through the coating thickness, or a
continuous path of interconnected veins of cathodic metal through
the coating thickness, wherein the continuous path extends from an
outer surface of the coating through the coating to an opposite
side of the coating.
[0030] Also described herein are apparatuses that include ozonated
silver coatings (or outer surfaces) that have enhanced
antimicrobial activity. For example, an apparatus that galvanically
releases antimicrobial ions may include: a substrate surface; and
an ozonated coating on the outer substrate surface, the ozonated
coating comprising a mixture of between about 25% and 75% by volume
of silver, and between about 25% to 75% by volume of a cathodic
metal co-deposited on the substrate surface, so that there is a
continuous path of silver from the surface to the outer substrate
surface.
[0031] An apparatus that galvanically releases antimicrobial ions
having an enhanced antimicrobial surface may include: a substrate
surface; and an ozonated coating on the outer substrate surface,
the ozonated coating comprising a mixture of between about 25% and
75% by volume of silver, and between about 25% to 75% by volume of
a cathodic metal co-deposited on the substrate surface, wherein the
coating comprises a plurality of microregions or microdomains of
anodic metal in a matrix of cathodic metal or a plurality of
microregions or microdomains of cathodic metal in a matrix of
anodic metal, the microregions or microdomains forming a continuous
path of interconnected veins of anodic metal through the coating
thickness, or a continuous path of interconnected veins of cathodic
metal through the coating thickness, wherein the continuous path
extends from an outer surface of the coating through the coating to
an opposite side of the coating. The ozonated coating may comprise
oxides of silver (e.g., Ag.sub.4O.sub.4).
[0032] In any of the ozonated coating described herein, less than
30% of the silver may be fully encapsulated within the matrix of
cathodic metal and connects through a microregion or microdomain of
silver to the outer surface of the coating. For example, less than
20% of the silver may be fully encapsulated within the matrix of
cathodic metal and connects through a microregion or microdomain of
silver to the outer surface of the coating.
[0033] In any of the methods and apparatuses described herein the
cathodic metal may comprises one or more of: palladium, platinum,
or gold. In any of these methods and apparatuses, the cathodic
metal may be one or more of: palladium, platinum, gold, molybdenum,
titanium, iridium, osmium, niobium and rhenium.
[0034] Any substrate may be used. For example, the coating may
comprise the silver and the cathodic metal that have been
vapor-deposited onto the length of a filament so that the silver is
not encapsulated by the cathodic metal. The substrate surface may
be an outer surface of one of: a pacemaker, defibrillator,
neurostimulator, or ophthalmic implant. The substrate surface may
be an outer surface of one of: an implantable shunt, an artificial
joint, a hip implant, a knee implant, a catheter, a stent, an
implantable coil, a pump, an intrauterine device (IUD), a heart
valve, a surgical fastener, a surgical staple, a surgical pin, a
surgical screw, a suture (e.g., surgical suture material, or other
suture), an implantable electrical lead, or an implantable plate.
The substrate surface may be an outer surface of one of: a
retractor, a bariatric balloon, an orthodontic brace, a breast
implant, a surgical sponge, a gauze, a mesh pouch (e.g., mesh
envelope) or a wound packing material. For example, the substrate
may be a bioabsorbable filament, such as one or more of: polylactic
acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyglycolide
(PGA), polyglycolide-co-trimethylene carbonate (PGTMC),
poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), and
poly(caprolactone) (PCL).
[0035] In any of the methods and apparatuses described herein, the
coating may be fractured (e.g., to increase the surface area), as
described herein. The coating may be fractured so that a surface
area of the coating is increased by at least 25% compared to the
surface area of the coating in an unfractured state.
[0036] In general, any of the galvanic release coatings or surfaces
described herein may be ozonated (e.g., treated with ozone), which
may enhance their antimicrobial effects. Further any of the methods
of forming a coating described herein may include a step of
enhancing the antimicrobial effect of the coating by treating with
ozone, as discussed above. Finally, any of the methods of
galvanically releasing ozone may include treating or using an
ozone-treated layer.
[0037] The coatings described herein typically include
co-depositions of an anodic metal (e.g., one or more of zinc,
silver, and/or copper) and a cathodic metal (e.g., one or more of:
palladium, platinum, gold, molybdenum, titanium, iridium, osmium,
niobium and rhenium). In some cases, the anodic metal is silver, or
silver and an additional anodic metal. In particular, the
ozone-treated surfaces described herein may include silver as the
anodic metal. The anodic and cathodic material in the coating are
non-uniformly dispersed within the coating, so that there are veins
(e.g., microdomains or microregions, such as clusters, clumps,
etc.) of anodic metal within a matrix of cathodic metal and/or
veins of cathodic metal within a matrix of anodic metal. The
relative amounts of anodic metal in the coating may be between 20%
and 80% by volume, or more preferably between 25% and 75% by
volume, or more preferably still, between 30% and 70% by volume
(e.g., greater than 20%, greater than 25%, greater than 30%,
etc.).
[0038] The anodic metal within the coating typically forms a
continuous path through the coating (extending from the outer
surface of the coating all the way to the base of the coating,
which may be the portion against the substrate), so that all or
most all (e.g., greater than 80%, greater than 85%, greater than
90%, greater than 95%, greater than 96%, greater than 97%, greater
than 98%, greater than 99%, etc.) of the anodic metal in the
coating is interconnected, preventing entrapment of a substantial
portion of the anodic metal within the coating. Similarly, the
cathodic metal within the coating may be in continuous contact
throughout the coating layer (extending from the outer surface of
the coating all the way to the base of the coating, which may be
the portion against the substrate) so that all or most all (e.g.,
greater than 80%, greater than 85%, greater than 90%, greater than
95%, greater than 96%, greater than 97%, greater than 98%, greater
than 99%, etc.) of the cathodic metal in the coating is
interconnected.
[0039] As mentioned, the coatings described herein may be applied
to any appropriate substrate. For example, an apparatus that
galvanically releases antimicrobial ions may include: a substrate;
and a coating on the substrate comprising an anodic metal (that has
been co-deposited with a cathodic metal on the substrate) to form a
non-uniform mixture of the anodic and cathodic metals, wherein the
coating comprises a plurality of microregions or microdomains of
anodic metal in a matrix of cathodic metal or a plurality of
microregions or microdomains of cathodic metal in a matrix of
anodic metal, the microregions or microdomains forming a continuous
path of interconnected veins of anodic metal within the matrix of
cathodic metal or a continuous path of interconnected veins of
cathodic metal within the matrix of anodic metal, wherein the
continuous path extends from an outer surface of the coating to the
substrate; further wherein the anodic metal is galvanically
released as antimicrobial ions when the apparatus is inserted into
a subject's body.
[0040] The substrate may be an implant configured to be inserted
into a human body, including a medical device. The substrate may be
device configured to be temporarily or permanently inserted into
the body (e.g., surgical tools, implants, etc.). In some variations
the substrate may be a device configured to be worn on a human body
(e.g., jewelry, clothing, surgical gowns, masks, gloves, etc.). The
substrate may be a structure configured to hold, support and/or
house a subject (e.g., gurney, chair, bed, etc.). The coating may
be applied to all or a portion of the substrate, particularly those
surfaces of the substrate that may be placed in contact with a
bodily fluid (e.g., a handle, supporting surface, etc.). The
substrate may be a household item, such as a cutlery (e.g., spoons,
baby spoons, forks, etc.), food handling items (e.g., platters,
plates, straws, cups, etc.), handles (e.g., doorknobs, pushes,
etc.), faucets, drains, tubs, toilets, toilet knobs, light
switches, etc.
[0041] The anodic metal may be any combination of the anodic metals
described herein (e.g., zinc, silver, copper, both zinc and silver,
etc.). The anodic metal may be least about 30 percent by volume (or
in some variations, by weight, e.g., when the densities of anodic
and cathodic materials are similar) of the coating.
[0042] The cathodic metal may generally have a higher galvanic
potential than the anodic metal. This may drive the galvanic (e.g.,
"corrosion") of the anodic metal when the coating is exposed to a
bodily fluid. For example, the cathodic metal may comprise one or
more of: palladium, platinum, gold, molybdenum, titanium, iridium,
osmium, niobium and rhenium.
[0043] The coating may be formed by vapor deposition. For example,
the anodic metal and the cathodic metal may have been
vapor-deposited onto the substrate so that the anodic metal is not
encapsulated by the cathodic metal, e.g., so that the anodic metal
(and/or in some variations the cathodic metal) include veins that
extend continuously through the coating from the outer surface to
the base (e.g., the "bottom" of the coating adjacent to the
substrate) of the coating. Thus, the continuous path of
interconnected veins may be interconnected so that less than 15% of
the anodic metal is completely encapsulated within the matrix of
cathodic metal, or less than 15% of the cathodic metal is
completely encapsulated within the matrix of anodic metal. The
continuous path of interconnected veins may be interconnected so
that less than 10% of the anodic metal is completely encapsulated
within the matrix of cathodic metal, or less than 10% of the
cathodic metal is completely encapsulated within the matrix of
anodic metal.
[0044] An apparatus that galvanically releases antimicrobial ions
may include: a substrate; and an ozonated coating on the substrate
comprising zinc and silver and a cathodic metal that are all
co-deposited onto the substrate, wherein the zinc and silver are at
least about 25 percent by volume (or in some variations by weight)
of the coating and form a non-uniform mixture of the zinc and the
cathodic metal and a non-uniform mixture of the silver and the
cathodic metal, wherein the coating comprises a plurality of
microregions or microdomains of zinc and silver in a matrix of
cathodic metal or a plurality of microregions or microdomains of
cathodic metal in a matrix of zinc and a matrix of silver, the
microregions or microdomains forming a continuous path of
interconnected veins of zinc and silver within the matrix of
cathodic metal or a continuous path of interconnected veins of
cathodic metal within the matrix of zinc and the matrix of silver,
wherein the continuous paths extend from an outer surface of the
substrate; further wherein the zinc and silver are galvanically
released as antimicrobial ions when the apparatus is inserted into
a subject's body.
[0045] In some variations, the substrate may be bio-absorbable. For
example, in some variations, the substrate is configured to degrade
within the body to form a degradation product including an anion
that complexes with ions of the anodic metal and diffuses into the
subject's body to form an antimicrobial zone. For example, a
bioabsorbable apparatus that galvanically releases antimicrobial
ions may include: an implant having an outer surface comprising a
substrate; and an ozonated coating on the substrate comprising an
anodic metal that is co-deposited with a cathodic metal on the
substrate to form a non-uniform mixture of the anodic and cathodic
metals, wherein the coating comprises a plurality of microregions
or microdomains of anodic metal in a matrix of cathodic metal or a
plurality of microregions or microdomains of cathodic metal in a
matrix of anodic metal, the microregions or microdomains forming
continuous paths of interconnected veins of anodic metal within the
matrix of cathodic metal or continuous paths of interconnected
veins of cathodic metal within the matrix of anodic metal, wherein
the continuous paths extend from an outer surface of the coating to
the substrate; further wherein the anodic metal is galvanically
released as antimicrobial ions when the apparatus is inserted into
a subject's body.
[0046] Thus, also described herein are bioabsorbable substrates,
and particularly bioabsorbable filaments, that galvanically release
antimicrobial ions. The bioabsorbable filament is coated with an
anodic metal (such as silver, copper and/or zinc) that has been
co-deposited with a cathodic metal (such as platinum, gold,
palladium) along at least a portion of the length of the filament.
The filament retains its flexibility. After insertion into the
body, the anodic metal corrodes as the filament is bioabsorbed. The
degradation of the filament may create a local pH that enhances the
release of the silver and/or copper and/or zinc ions.
[0047] In general, the coated filaments may be arranged into
structures (e.g., sutures, mesh, slings, yarns, etc.) that can be
implanted into the body.
[0048] As mentioned, the anodic and cathodic metals forming the
coatings described herein are typically co-deposited together, and
not coated in layers (e.g., atop each other). For example, the
metals may be jointly vapor deposited. Examples of jointly
deposited anodic and cathodic materials include silver-platinum,
copper-platinum, zinc-platinum, silver-gold, copper-gold,
zinc-gold, etc. Different types of jointly deposited anodic and
cathodic metals may be arranged on the bioabsorble substrate. For
example, silver-platinum may be coated near (either not touching or
touching) a region of zinc-platinum; different co-deposited
anodic/cathodic metals may be a spacer region on the substrate.
[0049] In some variations, described herein are devices and methods
for preventing an infection in an implantable device such as a
pacemaker or a defibrillator when inserting it into a body by
incorporating bioabsorbable materials that galvanically release
antimicrobial/antibacterial metals such as silver and/or zinc
and/or copper. For example, an implant may be inserted into a woven
mesh made of a bioabsorbable material that is coated (or
impregnated) with an anti-microbial anodic metal ions such as
silver or zinc co-deposited with a catalytic cathodic metal such as
platinum, gold, or palladium.
[0050] In general, as mentioned above, the anodic metal may be
silver, zinc, or any other metal with germicidal activity, and the
cathode metal may be platinum, gold, palladium, or any other metal
with catalytic action, including molybdenum, titanium, iridium,
osmium, niobium and rhenium. The biodegradable substrate may be a
biodegradable filament, such as polylactic acid (PLA),
poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),
polyglycoside-co-trimethylene carbonate (PGTMC),
poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), and
poly(caprolactone) (PCL). As used herein the terms biodegradable
and bioabsorbable may be used interchangeably.
[0051] For example, described herein are biodegradable filaments
that may be formed into an envelope, pouch, pocket, etc.
(generically, a co-implantable structure) made of a biodegradable
polymer (such as PLGA, PGA, PLA, polycaprolactone, etc.). The
implant may be co-implanted with the co-implantable structure, for
example, by placing the mesh onto the implant before, during or
after insertion into the body. The co-deposited metal coating of
the co-implantable structure creates a galvanic system resulting in
release of germicidal ions protecting the device from getting
infected in the body once the device is implanted with the
structure into a body. In the semi-aqueous environment of the body,
the metal will corrode over time by releasing the ions (e.g.,
silver ions, copper ions, zinc ions, etc.). A coated bioabsorbable
polymer could also or alternatively be used as an insert inside the
lumen of the device such as a cannula, cannulated screw, or as an
ozonated coating on a device. In another configuration the metal
ions could be coupled with a poly-anionic (negatively charged)
polymer and mixed with the polymer.
[0052] For example, described herein are bioabsorbable apparatuses
that galvanically release antimicrobial ions. The apparatus may
comprise: a flexible length of bioabsorbable filament; and an
ozonated coating on the length of filament comprising an anodic
metal that is co-deposited with a cathodic metal on the length of
filament; wherein the coated filament is flexible; further wherein
the anodic metal is galvanically released as antimicrobial ions
when the apparatus is inserted into a subject's body.
[0053] In general, in apparatuses (systems and devices) in which
the anodic metal and the cathodic metal are co-deposited (e.g., by
vapor deposition) the anodic metal may be at least about 25 percent
(e.g., at least about 30 percent, at least about 35 percent, etc.)
by volume of the coating. This may prevent complete encapsulation
of the anodic material (e.g., zinc, silver, etc.) by the cathodic
material (e.g., palladium, platinum, gold, molybdenum, titanium,
iridium, osmium, niobium and rhenium). As described in greater
detail below, the ozonated coatings applied may be configured to
result in microregions or microdomains of anodic material in a
matrix of cathodic material. The microdomains may be interconnected
or networked, or they may be isolated from each other. In general,
however, the concentrations of anodic material and cathodic
material may be chosen (e.g., greater than 25% by volume of the
anodic material, between about 20% and about 80%, between about 25%
and about 75%, between about 30% and about 70%, etc.) so that the
majority of the anodic material in the ozonated coating thickness
is connected to an outer surface of the coating, allowing eventual
corrosion of most, if not all of the anodic metal as anti-bacterial
metal ions, while providing sufficient cathodic material to provide
adequate driving force for the corrosion of the anodic material.
Thus, the ozonated coating may comprise the anodic metal and the
cathodic metal that have been vapor-deposited onto the length of
filament so that the anodic metal is not encapsulated by the
cathodic metal.
[0054] As mentioned, the anodic metal may comprise zinc, copper or
silver, or in some variations both zinc and silver. In general, the
cathodic metal has a higher galvanic potential than the anode. For
example, the cathodic metal may be one or more of: palladium,
platinum, gold, molybdenum, titanium, iridium, osmium, niobium and
rhenium.
[0055] As mentioned, in general the bioabsorbable substrate (e.g.,
filament) may comprise one or more of: polylactic acid (PLA),
poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),
polyglycoside-co-trimethylene carbonate (PGTMC),
poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), and
poly(caprolactone) (PCL).
[0056] In general, the bioabsorbable substrate (including a length
of bioabsorbable filament) is configured to degrade within the body
to form a degradation product, including an anion that complexes
with ions of the anodic metal and diffuses into the subject's body
to form an antimicrobial zone.
[0057] The bioabsorbable substrate (e.g., bioabsorbable filament)
may be configured as a mesh, bag, envelope, pouch, net, or the
like, that may be configured to hold an implant. For example, the
flexible structure may be configured to at least partially house a
pacemaker, defibrillator, neurostimulator, or ophthalmic
implant.
[0058] Also described herein are bioabsorbable apparatuses that
galvanically release antimicrobial ions and comprise: a plurality
of lengths of bioabsorbable filament arranged in a woven structure;
and an ozonated coating on the lengths of filament comprising zinc
and silver and a cathodic metal that are all co-deposited onto the
lengths of filament, wherein the zinc and silver are at least about
25 percent by volume of the coating; further wherein the zinc and
silver are galvanically released as antimicrobial ions when the
apparatus is inserted into a subject's body. As mentioned, the
woven structure may form a mesh, bag, envelope, pouch, net, or
other structure that is configured to at least partially enclose an
implant within the subject's body.
[0059] Also described herein are bioabsorbable apparatuses that
galvanically releases antimicrobial ions and include: a plurality
of lengths of bioabsorbable filament; and an ozonated coating on
the lengths of filament comprising an anodic metal that is
co-deposited with a cathodic metal on the lengths of filament;
wherein the lengths of filament are arranged into a flexible
structure; further wherein the anodic metal is galvanically
released as antimicrobial ions when the apparatus is inserted into
a subject's body.
[0060] Methods of forming any of these apparatuses are also
described, including methods of forming a coated bioabsorbable
substrate, for example, by co-depositing (vapor depositing) an
anodic material and a cathodic material onto the substrate. The
substrate may be a fiber or the structure formed of the fiber. In
some variations the method may also include forming different
regions of co-deposited anodic and cathodic materials, wherein the
different regions include different combinations of anodic and
cathodic materials. The different regions may be non-contacting. In
general, co-deposing anodic and cathodic materials are typically
performed so that the anodic material forms greater than 25% by
volume of the ozonated coating, preventing encapsulation of the
anodic material by cathodic material within the coating.
[0061] Also described are methods of treating a subject using the
bioabsorbable materials that are co-deposited with one or more
ozonated coating of anodic and cathodic metals (e.g., materials).
For example, described herein are methods of galvanically releasing
antimicrobial ions to form an antimicrobial zone around an implant
that is inserted into a subject's tissue. The method may include
step of: inserting into the subject's tissue an apparatus
comprising a plurality of lengths of bioabsorbable filament having
an ozonated coating comprising an anodic metal and a cathodic metal
that are co-deposited onto the lengths of filament, wherein the
implant is at least partially housed within the apparatus;
galvanically releasing antimicrobial ions from the coating (e.g.,
galvanically releasing ions of silver and zinc); allowing the
lengths of filament to degrade into a degradation product including
anions, wherein the anions complex with antimicrobial ions of the
anodic metal and diffuse into the tissue to form an antimicrobial
zone around the implant. The method may also include inserting an
implant into the apparatus before the apparatus is inserted into
the subject's body. For example, inserting the apparatus into the
body may comprise inserting a flexible apparatus comprising the
plurality of length of bioabsorbable filaments forming a bag,
envelope, pouch, net or other structure (woven or otherwise) formed
to hold the implant. For example, the method may also include
inserting a pacemaker, a defibrillator or a neurostimulator into
the apparatus.
[0062] Inserting the apparatus may comprise inserting the apparatus
having a plurality of lengths of bioabsorbable filaments coated
with the anodic metal that comprises silver and zinc that are
co-deposited onto the lengths of filament with the cathodic
metal.
[0063] Allowing the lengths of filament to degrade may comprise
degrading the lengths of filament into anions that bind to silver
ions from the coating. For example, inserting the apparatus
comprises inserting the apparatus having a plurality of lengths of
bioabsorbable filaments coated with the anodic metal that is
co-deposited onto the lengths of filament with the cathodic metal,
wherein the anodic metal is at least about 25 percent by volume of
the coating (e.g., at least about 30%, at least about 35%,
etc.).
[0064] Inserting the apparatus comprising the plurality of lengths
of bioabsorbable filament may comprise inserting the apparatus
having a plurality of lengths of one or more of: polylactic acid
(PLA), poly(lactic-co-glycolic acid) (PLGA), and polyglycolide
(PGA).
[0065] In general, the antimicrobial zone around the implant may be
sustained for at least seven days.
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] The novel features of the invention are set forth with
particularity in the claims that follow. A better understanding of
the features and advantages of the present invention will be
obtained by reference to the following detailed description that
sets forth illustrative embodiments, in which the principles of the
invention are utilized, and the accompanying drawings of which:
[0067] FIGS. 1A-1F illustrate the general concept of galvanic
release of silver ions.
[0068] FIG. 2A shows a cross-sectional view through one example of
a substrate having a combined coating, comprising an anodic metal
that is co-deposited with a cathodic metal. These coatings (and
indeed any of the coating and/or substrates described herein) may
be ozonated, e.g., treated with ozone to enhance the antimicrobial
properties as described herein.
[0069] FIG. 2B is a schematic representation of an enlarged view of
a portion of the coated substrate of FIG. 2A, schematically
illustrating micro-domains or veins of anodic metal (not to scale)
within a cathodic matrix.
[0070] FIG. 2C is another schematic representation of an enlarged
view of a portion of the coated substrate of FIG. 2A.
[0071] FIG. 2D is an example of the galvanic release (and
corrosion) of a coating on a substrate such as the one shown in
FIG. 2A.
[0072] FIGS. 3A-3C illustrate top views of alternative variations
of coating patterns for different combined coatings, such as
silver/platinum and zinc/platinum.
[0073] FIG. 4 is an example of a bioabsorbable pouch woven from one
or more strands, wherein the strands of the pouch are coated with
the combined coatings described herein for release of antimicrobial
ions.
[0074] FIG. 5A illustrates a fiber or filament (e.g., suture fiber)
coated with a striped pattern of a combined coating for galvanic
release of metal ions.
[0075] FIG. 5B illustrates a portion of a barbed suture fiber
coated as described herein.
[0076] FIG. 5C is a portion of a suture fiber that is coated as
described herein.
[0077] FIG. 5D is an example of a needle and suture (shown as a
combined needle preloaded with suture) in which both needle and
suture are coated as described herein.
[0078] FIG. 6 is an example of a length of suture formed from a
bioabsorbable substrate onto which a combined coating has been
regionally applied (e.g., near the distal end).
[0079] FIG. 7 illustrates one example of a medical device
configured as a transvaginal mesh having a combined coating for
release of metal ions after insertion into the body.
[0080] FIG. 8A is a side perspective view of one example of a plug
or patch that may be used, e.g., to repair a hernia. The device is
coated with multiple types of combined coatings for galvanic
release of metal ions.
[0081] FIG. 8B shows an enlarged view of one region of the
plug.
[0082] FIG. 9 is a perspective view of one variation of a bandage
or patch including a combined coating, shown on a patient's
knee.
[0083] FIG. 10 illustrates one variation of an artificial dura
(mesh) including a combined coating for galvanic release of metal
ions.
[0084] FIG. 11 shows an example of a material that may be used as
within a wound or surgical site to prevent or treat infection. The
material may be a porous and/or bioabsorbable mesh that is
configured to galvanically release metal ions.
[0085] FIGS. 12A and 12B show side perspective and end views,
respectively of one variation of a cannula including a pattern of a
combined coating for the release of antimicrobial metal ions.
[0086] FIGS. 13A and 13B illustrate one example of a medical device
(an implantable pacemaker) that may be used with the co-deposited
galvanic coatings described herein.
[0087] FIG. 13C is a schematic depiction of a conventional cardiac
stimulation and defibrillation arrangement.
[0088] FIGS. 14A and 14B illustrate another example of a medical
device (a venous catheter) that may be coated with the co-deposited
galvanic coatings described herein.
[0089] FIGS. 15A and 15B show an example of a catheter (including a
cuff) that may include a galvanically released antimicrobial
coating that is co-deposited as described herein. FIG. 15A is an
example of a triple lumen device and FIG. 15B is an example of a
dual lumen device.
[0090] FIG. 16 shows one example of a catheter that has been coated
by co-deposition of the galvanic coating described herein.
[0091] FIG. 17A shows a cannulated bone screw that may be used with
a coated insert as shown in FIG. 17B. The coated insert may be a
bioabsorbable mesh, coated as described herein.
[0092] FIGS. 17C shows the bone screw of FIG. 17A with the mesh of
FIG. 17B inserted.
[0093] FIG. 18A shows a bone screw coated as described herein.
[0094] FIG. 18B shows a bone screw similar to that shown in FIG.
18A, but which has been coated in a striped pattern (e.g., having
regions that are either uncoated, or coated with different anionic
materials/combinations of materials, as described in FIGS. 3A-3C,
above.
[0095] FIG. 19A is another example of bone screw implant having
openings or channels from which members (shown extending in FIG.
19B) may extend. Either or both the bone screw and the extending
members may be coated as described herein.
[0096] FIG. 20 shows an example of an animal cage coated as
described herein.
[0097] FIG. 21 shows an example of a doorknob coated as described
herein.
[0098] FIG. 22A shows an example of cutlery (a fork and spoon)
coated as described herein.
[0099] FIG. 22B shows another example of spoon coated as described
herein.
[0100] FIG. 23A show a cross-sectional view through an example of a
substrate surface having a coating comprising an anodic metal
co-deposited with a cathodic metal, in which the coating has been
cracked, enhancing available surface area, as described herein.
[0101] FIG. 23B is a schematic representation of an enlarged view
of a portion of the coated substrate of FIG. 23A, schematically
showing (not to scale) micro-domains or veins of anodic metal
within a cathodic matrix, showing cracks in the coating.
[0102] FIG. 24 is a schematic outline of one method of forming an
ozone coating as described herein.
[0103] FIG. 25 is one example of piece of silver wire that were and
were not ozonated (e.g., treated with ozone), showing that
treatment with ozone results in a greatly enhanced antimicrobial
effect. In FIG. 25, pieces of silver wire both treated (top) and
untreated (bottom) with ozone are show in a bacterial culture dish;
bacteria did not grow around the treated wire.
[0104] FIG. 26 is an example of four galvanic silver ion releasing
implants in a culture dish in which bacteria have been cultured. In
this example, the two treated (ozonated, left and right) devices
formed substantially larger `clearing` regions of antibacterial
activity than the unozonated devices (top and bottom).
[0105] FIG. 27 shows an example of a mesh coated with co-deposited
silver and a cathodic metal as discussed herein, in which the
left-hand side coated meshes where treated with ozone, resulting in
substantially large clearing regions where antimicrobial activity
prevented bacterial growth, and the right-hand side including a
mesh that was uncoated and untreated with ozone, showing bacterial
growth.
[0106] FIGS. 28A and 28B illustrate alternative variations of
microbial cultures in the presence of treated (ozonated) mesh
materials including a coating of a co-deposited sliver and cathodic
metal as described herein.
DETAILED DESCRIPTION
[0107] In general, described herein are apparatuses (e.g., systems
and devices) that include a an anionic metal material (e.g.,
silver) that has been treated with ozone to enhance the
antimicrobial properties of the anionic metal. For example,
described herein are ozonated coatings or layers that galvanically
releases antimicrobial ions over an extended period of time. The
coating may be applied to a substrate, e.g., a bioabsorbable and/or
biodegradable substrate that may degrade during the same period
that the antimicrobial ions are being released, e.g., days, months,
years. In some variations the substrate may be coated with an
adhesion layer on the substrate. The substrate may be pre-treated
(e.g., to remove oxides, such as the titanium oxide layer on a
nickel titanium substrate). In general, the coating may include a
combination of anodic metal (and particularly silver alone or in
combination with one or more of zinc and/or copper), and a cathodic
metal, such as palladium, platinum, gold, molybdenum, titanium,
iridium, osmium, niobium and rhenium, where the anodic metal and
cathodic metals are co-deposited (e.g., by vapor deposition) so
that the anodic metal is exposed to an outer surface of the coating
and not fully encapsulated in the cathodic metal, and there is
sufficient cathodic metal to drive the galvanic release of anodic
ions when exposed to bodily fluids such as blood, lymph, etc.
(e.g., when implanted into the body). Finally, the coating may be
treated with ozone to supercharge the antimicrobial effects present
in normal galvanically released silver ions.
[0108] For example, described herein are apparatuses including
substrates onto which anodic metal and cathodic metals are
co-deposited to form a coating that is ozonated, allowing the
anodic metal to be galvanically released as ions (e.g.,
antimicrobial silver, copper and/or zinc ions) when the apparatus
is exposed to a conductive fluid (e.g., a bodily fluid). The
substrate may include an adhesive coating (such as a tantalum or
titanium layer that is applied before the galvanic coating of
co-deposited antic and cathodic metal).
Galvanically Releasable Coating
[0109] In general, the antimicrobial metal ion coatings described
herein are galvanically releasable within a tissue, and include one
or more anodic metal (typically silver and/or zinc and/or copper)
that is co-deposited with a cathodic metal (typically platinum
and/or palladium). Any of the coatings mentioned herein may be
ozonated as described below. The anodic metal and the cathodic
metal are co-deposited, e.g., by sputtering or other appropriate
methods described herein, so that the resulting coating is
non-homogenous, with a percentage of anodic metal (e.g., silver)
that is greater than about 30% co-distributed (typically in
clusters, veins or clumps as illustrated and described below) with
the cathodic metal (e.g., platinum), where the cathodic metal is
greater than about 30% (e.g. w/w) of the coating. The antimicrobial
metal ion coatings described herein may be generally referred to as
non-homogenous mixtures where the anode is distributed in connected
clusters (veins) within the cathodic metal (or vice-versa).
Generally, both the anodic metal and the cathodic metal are exposed
in microdomains across the outer surface of the coatings, allowing
galvanic release; as the anodic metal is released, it may form
channels (e.g., tunnels, mines, etc.) through the coating, e.g.,
within the cathodic material. In some variations the cathodic
material remains behind. In some variations some of the cathodic
material may also be released.
[0110] Thus, in any of these variations, the coating may comprise a
non-uniform mixture of the anodic and cathodic metals, with a
plurality of microregions or microdomains of anodic metal in a
matrix of cathodic metal, and/or a plurality of microregions or
microdomains of cathodic metal in a matrix of anodic metal. These
microregions or microdomains may be formed by co-deposition as
described herein.
[0111] Any of the coatings described herein may include
co-deposited multiple anodic and/or multiple cathodic metals
forming the coating. In some variations, it may be preferable to
separate regions having a first anodic metal (e.g., silver) from
regions having a second anodic metal (e.g., zinc), so that they are
separated (e.g., in some variations electrically separated) and/or
non-contacting, allowing preferential release of one metal ion
(e.g., zinc) compared to silver. This may allow control of the
release profile, and may extend the length of effective release
time for as coating.
[0112] In general, these coatings may be any appropriate thickness.
For example, the thickness could be a few microns thick or more
(e.g., greater than 2 microns, greater than 5 microns, greater than
10 microns, greater than 15 microns), etc. For example, the
thickness of the coating may be between about 10 microinches
(approximately 2500 Angstroms or approximately 0.25 microns) and
about 25 microinches (approximately 6350 Angstroms or about 0.64
microns). The thickness of the coating may be uniform or
non-uniform. Only some regions of the substrate may be coated,
while other regions may be masked to prevent coating. For example,
in an electrical stimulation apparatus (e.g., cardiac stimulator,
neurostimulator, etc.) the body and/or connectors of the device may
be insulated while the electrical leads (electrical contacts) to
deliver energy to the tissue may be uncoated. Alternatively in some
variations the electrical contacts are coated as described
herein.
[0113] FIGS. 1A-1F conceptually describe a simple galvanic cell
setup such as for use in a body. The setup is shown treating an
infection, but the same process could be applied to healthy tissue
to prevent an infection (prophylactically). The components
including a first metal 2 (e.g., silver), second metal 4 (e.g.,
platinum), and electrolytic fluid 6 (e.g., blood) are shown
individually in FIGS. 1A-1C and arranged in a tissue in FIGS.
1D-1F. Electrolytic body fluid 6 is shown bathing or contacting
healthy tissue 10 as well as infected tissue 8. When silver metal 2
contacts platinum metal 4 in body fluid 6, it forms a galvanic cell
with a silver anode and platinum cathode. As shown in FIG. 1E,
ionic silver 12 is generated and spreads through the body fluid,
killing microorganisms and creating an infection-free zone 14 in
body fluid 16 in the vicinity of the anode. After treatment is
complete, the silver anode 2 may be completely corroded 20 leaving
an infection-free body fluid 18. Any metal with a higher redox
potential than silver may be used as the cathode. The metal may be
a noble metal, such as gold, palladium or platinum. Although the
example shown in FIGS. 1A-1F describes using a silver metal anode
that is placed adjacent to a platinum metal cathode, described
herein are coatings in which the anodic metal (e.g., silver, zinc,
copper) is co-deposited onto a biodegradable substrate.
[0114] In general, a coating of anodic metal and cathodic metal may
be configured so that the anodic metal and cathodic metal are
within the same coating layer. The microregions of anodic metal may
be embedded within the cathodic metal, including being embedded
within a matrix of cathodic metal (or vice versa). As illustrated
below, the microdomains or microregions of anodic metal are within
a cathodic matrix, allowing a large spatial release pattern of
anodic metal ions by galvanic action triggered by the contact of
the anodic metal and the cathodic metal within the electrolytic
bodily fluid. The coatings described herein, in which the anodic
metal and the cathodic metal are combined as part of the same layer
may be referred to as "combined" coatings, in which an anionic
metal and a cationic metal are both jointly coated, and/or
non-homogenous (non-uniform) mixtures of anodic and cathodic
metal.
[0115] The combined coatings described herein may be non-uniform
mixtures of anodic and cathodic metals. For example, the anionic
metal may form microregions or microdomains within the cationic
metal (or vice versa). In general, the cathodic metal microdomains
may form one or more (typically a plurality) of continuous paths
through the cathodic metal. For example, the microdomains described
herein may be veins, clusters, threads, clumps, particles, etc.
(including interconnected veins, clusters, threads, clumps,
particles, etc.) of anodic metal, e.g., silver, copper, and/or
zinc, etc., that are connected to an outer surface of the coating,
so that they are exposed to the electrolytic bodily fluid (e.g.,
blood). The microdomains of anodic metal may form a network within
the matrix of the cathodic metal. Thus, the anodic metals may be
present in one or more networks that are electrically connected
within the cathodic matrix. The individual sizes of particles,
threads, branches, veins, etc. forming the microdomains may be
small (typically having a length and/or diameter, e.g., less than a
1 mm, less than 0.1 mm, less than 0.05, less than 0.01 mm, less
than 0.001 mm, less than 0.0001 mm, less than 0.00001 mm, etc.).
Similarly, in some variations the matrix may be the anodic metal
and the cathodic metal may be referred to as forming microdomains
(e.g., where the percentage of cathodic metal in the coating is
less than 50%, less than 45%, less than 40%, less than 30%, etc. by
volume of the coating).
[0116] A combined anodic metal and cathodic metal forming a
combined coating (or a portion of a coating) may be formed of a
single anodic metal (e.g., silver) with a single cathodic metal
(e.g., platinum), which may be referred to by the combined anodic
metal and cathodic metals forming the coating or portion of a
coating (e.g., as a combined silver/platinum coating, a combined
silver/palladium coating, a combined zinc/platinum coating, a
combined zinc/palladium coating, etc.). In some variations a
combined coating may include multiple anodic and/or cathodic
metals. For example, the combined coating may include zinc and
silver co-deposited with platinum.
[0117] As mentioned, the anodic metal in the combined coating may
include a continuous path connecting the anodic metal to an exposed
outer surface of the coating so that they can be galvanically
released from the coating. Deeper regions (veins, clusters, etc.)
of the anodic metal may be connected to more superficial regions so
that as the more superficial regions are corroded away by the
release of the anodic ions, the deeper regions are exposed,
allowing further release. This may also expose additional cathodic
metal. Thus, in general, anodic metal microdomains are not
completely encapsulated within the catholic metal. In some
variations, the majority of the anodic metal is not completely
encapsulated within the cathodic metal, but is connected to an
exposed site on the surface of the coating via connection through a
more superficial region of anodic metal; although some of the
anodic metal may be completely encapsulated. For example, the
coating may include an anodic metal in which less than 50 percent
of the total anodic metal is completely encapsulated within the
cathodic metal (e.g., less than 40%, less than 35%, less than 30%,
less than 25%, less than 20%, less than 15%, less than 10%,
etc.).
[0118] The co-deposited anodic and cathodic combined coatings
described herein for the galvanic release of anodic ions may be
formed by co-depositing the anodic metal and the cathodic metal so
as to minimize the amount of encapsulation by the cathodic
material. For example, the percentage of the anodic material may be
chosen so that there is both an optimal amount of cathodic metal to
drive reasonable galvanic release in the presence of an
electrolyte, and so that there is sufficient continuity of anodic
metal with the combined coating to form a continuous path to an
exposed surface of the coating, making it available for galvanic
release. For example, a coating may be formed by co-depositing the
anodic metal and the cathodic metal (e.g., sputtering, vapor
deposition, electroplating, etc.) where the concentration of the
anodic metal is high enough to allow the formation of a sufficient
number of continuous paths through the thickness of the coating. We
have found that a combined coating in which more than 25% by volume
(or more preferably more than 30%) of the coating is formed of the
anodic metal is sufficient to form a combined coating with a
cathodic metal in which more than half (e.g., >50%) of the
anodic metal is connected by a continuous path to the surface of
the coating, permitting galvanic release. For example, a coating
having between about 33-67% of anodic metal and between about
67-33% of cathodic metal may be preferred. At these percentages,
less than half of the anodic metal is fully encapsulated by the
non-corroding cathodic metal and trapped within the coating. Thus,
in general, the combined coatings (also referred to as co-deposited
coatings) may include more than 25% (e.g., 30% or greater, 35% or
greater) by volume of anodic metal that is co-deposited with the
cathodic metal. In some variations, the remainder of the coating
(e.g., between 5% and 75%,) may be cathodic metal. Thus, the
percent of anodic metal co-deposited with cathodic metal may be
between 25%-95% (e.g., between about 30% and about 95%, between
about 30% and about 90%, between about 30% and about 80%, between
about 30% and about 70%, between about 25% and 75%, between about
25% and 80%, between about 25% and 85%, between about 25% and 90%,
between about 35% and 95%, between about 35% and 90%, between about
35% and 85%, between about 35% and 80%, between about 35% and 75%,
between about 35% and 70%, between about 35% and 65%, etc.), with
the remainder of the coating being cathodic metal. Further, the
coating (or at least the outer layer of the coating) may be
primarily (e.g., >95%) formed of anodic and cathodic metals
distributed in the micro-domains as described herein. In some
variations the coating may also include one or more additional
materials (e.g., a metal, polymer, or the like). The additional
material(s) may be inert (e.g., not participating in the galvanic
reaction between the anodic metal and the cathodic metal), or it
may be electrically conductive. For example, the additional
material may be co-deposited with the anodic and cathodic metals,
and may also be distributed in a non-homogenous manner.
[0119] For example, a mixed coating may be formed using a
PVD-system. Vaporization of metal components may be performed on a
substrate (with or without an adhesive layer), e.g., using an arc
and/or a magnetron sputter from metallic targets. Mixed coatings
may be produced by simultaneous vaporization of both metals while
the substrate is held fixed, or is moved (e.g., rotated). After
coating, the coated materials may be cleaned, e.g., using an argon
plasma and/or other methods.
[0120] As mentioned, any of the coatings described herein may be of
any appropriate thickness. For example, the coatings may be between
about 500 microinches and about 0.01 microinches thick, or less
than about 200 microinches (e.g., between about 10 microinches and
about 500 microinches), less than about 150 microinches, less than
about 100 microinches, less than about 50 microinches, etc. The
thickness may be selected based on the amount and duration (and/or
timing) of the release of anodic metal. In addition, the coatings
may be patterned, e.g., so that they are applied onto a substrate
in a desired pattern, or over the entire substrate. As mentioned
and described further below, different combined coatings may be
applied to the same substrate. For example, a combined coating of
silver/platinum may be applied adjacent to a combined coating of
zinc/platinum, etc. The different combined coatings may have
different properties (e.g., different anodic metal, different
anodic/cathodic metal percentages, different thicknesses, etc.) and
therefore different release profiles. Combinations in which
different combined coatings are in (electrical) contact with each
other may also have a different release profile than combinations
in which the different coatings are not in electrical contact. For
example, a material may include a first combined coating of zinc
and a cathodic metal (e.g., zinc/platinum) and a second combined
coating of silver and a cathodic metal (e.g., silver/platinum). If
the first and second combined coatings are in electrical contact,
the zinc will be galvanically released first. If the first and
second combined coatings are not in electrical contact, then both
zinc and silver will be concurrently released (though zinc may be
released more quickly and my diffuse further).
[0121] For example, FIG. 2A illustrates one example of a substrate
120 onto which a combined coating of anodic and cathodic metals
have been co-deposited 100. The substrate may be, for example, a
bioabsorbable material. In some variations the substrate may be an
adhesive layer, e.g., when applying the coating to some medical
devices. For example, an adhesive layer may be a metal layer such
as an undercoating of titanium or tantalum. The undercoating may be
of any appropriate thickness (e.g., the same thickness or smaller
than the thickness of the galvanically releasing coating). In some
variations the undercoating is thicker than the coating of the
non-homogeneous mixture of anodic and cathodic metals that are
galvanically released. Although an undercoating may be used in some
variations, the coatings of anodic and cathodic metals described
herein may be coated directly onto a medical device (e.g., implant)
without the need for an undercoating.
[0122] Although the combined coatings described herein may be used
with any substrate (even non-bioabsorbable substrates), any of the
examples described herein may be used with bioabsorbable
substrates. In the example of FIG. 2A the dimensions (thicknesses
of the substrate and coating) are not to scale. For example, the
coating may be less than 100 microinches thick. The substrate may
be any thickness. In FIG. 2A, region B shows a portion of the
coating and substrate, which is illustrated in the enlarged view of
FIG. 2B.
[0123] In FIG. 2B, a portion of the substrate 120 (e.g. a
bioabsorbable substrate) is shown coated with a combined coating
100. The anodic metal, e.g., silver, 110 is shown forming veins or
microregions within the cathodic metal 130. In this example, the
silver is schematically illustrated as forming veins through a
matrix of cathodic metal, e.g., platinum, not shown to scale. The
actual microdomains may be much smaller, and filamentous; for
example, the microdomains may be on the order of 10-1000 Angstroms
(or more) across. FIG. 2C is another schematic illustration of a
section through a portion of a combined coating on a substrate,
showing microdomains of anodic metal (e.g. silver) 110, within a
matrix of cathodic metal (e.g., platinum) 130. In FIGS. 2B and 2C
the majority of the microdomains of anodic metal are connected in
continuous paths to the outer surface of the coating 100, allowing
galvanic release of the anodic material.
[0124] FIG. 2D illustrates an example of the coating of FIG. 2C
during the galvanic release process, in which the implant including
the substrate and the combined coating is place into the body, so
that the coating is exposed to blood. As shown in FIG. 2D, the
anodic metal (silver) in the coating is progressively corroded as
ions of silver are released into the body to locally diffuse and
provide regional antimicrobial treatment. In this example the
anodic metal (e.g., silver) 120 exposed to the surface is release,
leaving a negative impression in the cathodic metal 130. Regions of
the cathodic metal that are left behind may remain coated (though
the substrate may also be biodegrading simultaneous with the
release of anodic metal, not shown). Typically, when the substrate
is part of an implanted apparatus, the coating layer is thin enough
that any remaining cathodic metal (e.g., platinum) is small enough
to be ignored or easily cleared by the body.
[0125] The combined layers are generally formed by co-depositing
the anodic metal and the cathodic metal onto the substrate. For
example, a combined layer may be formed by simultaneously
sputtering the two metals onto the substrate to the desired
thickness. For example, both silver and platinum may be placed into
a sputtering machine and applied to the substrate. The amount of
cathodic material and anodic material may be controlled, e.g.,
controlling the percentage of the coating that if anodic metal and
the percentage that is cathodic (e.g., 30%-70% anodic/70-30%
cathodic, such as 40% silver/60% platinum, etc.). This sputtering
process results in a non-uniform pattern, as discussed above, and
schematically illustrated in FIGS. 2B-2C, which may be observed.
Alternatively, combined layers may be formed by vacuum deposition,
or any other technique that can co-deposit the two (or more) metals
onto the substrate. Formation of the coating(s) may include
masking, for example, locating coatings in particular regions of
the substrate.
[0126] In general, any of the substrates (e.g., bioabsorbable
substrates) described herein may be applied in a pattern, including
patterns of multiple different combined coatings. Further, coatings
may be applied over only apportion of the substrate, which may
allow more localized release of the antimicrobial ions and may
prevent the coating from interfering with the properties of the
substrate and/or the device that the substrate is part of (e.g.,
flexibility, surface characteristics, etc.). For example, FIGS.
3A-3C show a top view of a substrate coated with various combined
coatings (co-deposited anodic and cathodic metals).
[0127] For example, in FIG. 3A, the surface of the substrate 210 of
an implant 200 that includes alternating patterns of a first
combined coating 212 of silver/platinum that have been co-deposited
onto the substrate and a second combined coating 214 of
zinc/platinum co-deposited onto the substrate. In this example the
first and second coating regions are formed into strips extending
along the width of the substrate; the first and second coating
regions do not overlap and are not in electrical contact with each
other. Thus, the silver ions in the first coating region(s) 212
will be galvanically released concurrently with the zinc ions
galvanically released from the second coating region(s) 214 when
exposed to an electrolytic bodily fluid (e.g., blood), corroding
the two layers. FIG. 3B shows another example of a pattern of a
first combined coating 212 (e.g., silver/platinum) and a second
combined coating 214 (zinc/palladium) that are arranged with
alternating stripes on the surface of the substrate 210, where the
stripes are end-to-end with each other.
[0128] FIG. 3C shows another variation of a surface 210 of an
implant 200 that includes a pattern, shown as a checkerboard
pattern, of first and second combined coatings. In FIG. 3C, the
edges of the different coating regions may contact each other or
may be separated by a channel so that they are not in electrical
contact for the galvanic reaction. For example, if the first and
second regions do contact each other so that they are in electrical
contact, then the galvanic reaction may drive the release of the
zinc ions before the release of the silver ions; once the zinc has
corroded, the silver ions may be released.
[0129] In general, there may be some benefit to including multiple
coatings, and in particular coatings having multiple anodic metals.
The antimicrobial region around the coated implant may be made
larger and the ions may be released over a longer time period, than
with a single type of anodic coating alone.
[0130] As mentioned, the combined coatings of co-deposited anodic
and cathodic metals could be formed in any pattern. As mentioned
above, all or a portion of these coatings/surfaces may be ozonated
by treatment with ozone to enhance the effects seen.
Bioabsorbable Substrates
[0131] In some variations, the substrate is bioabsorbable and/or
biodegradable. For example, the substrate may be formed as a
flexible filament, and the coating of anodic and cathodic metals
that may corrode to release anodic ions may allow the flexible
filament to remain flexible. Galvanic release results in
degradation (e.g., corrosion) of the coating.
[0132] The substrate onto which the combined coatings may be
applied may be any appropriate substrate, and in particular, may be
a bioabsorbable substrate. Examples of bioabsorbable materials that
may be used includes polymeric materials such as: polylactic acid
(PLA), poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),
polyglycoside-co-trimethylene carbonate (PGTMC),
poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), and
poly(caprolactone) (PCL), and combinations of these.
[0133] In general, bioabsorbable materials for medical applications
are well known, and include bioabsorbable polymers made from a
variety of bioabsorbable resins; for example, U.S. Pat. No.
5,423,859 to Koyfman et al., lists exemplary bioabsorbable or
biodegradable resins from which bioabsorbable materials for medical
devices may be made. Bioabsorbable materials extend to synthetic
bioabsorbable or naturally derived polymers.
[0134] For example, bioabsorbable substrates may include polyester
or polylactone selected from the group comprising polymers of
polyglycolic acid, glycolide, lactic acid, lactide, dioxanone,
trimethylene carbonate, polyanhydrides, polyesteramides,
polyortheoesters, polyphosphazenes, and copolymers of these and
related polymers or monomers. Other bioabsorbable substrates may
include substrates formed of proteins (e.g., selected from the
group comprising albumin, fibrin, collagen, or elastin), as well as
polysaccharides (e.g., selected from the group comprising chitosan,
alginates, or hyaluronic acid), and biosynthetic polymers, such as
3-hydroxybutyrate polymers.
[0135] The bioabsorbable substrate may be absorbed over a
predetermined time period after insertion into a body. For example,
the bioabsorbable substrate may be absorbed over hours, days,
weeks, months, or years. The substrate may be bioabsorbed before,
during or after release of the anodic metal ions from the combined
coating. In some variations the release of the antimicrobial ions
is timed to match the degradation/absorption of the substrate.
Further, the absorption of the substrate may facilitate the release
of the anodic metal ions. For example, some of the bioabsorbable
substrates described herein may result in a local pH change as the
substrate is bioabsorbed; the release of the metal ions may be
facilitated by the altered pH.
[0136] FIG. 4 shows an example of a pouch device formed from woven
lengths of bioabsorbable filament that is flexible. The filament is
formed of a bioabsorbable polymer, PGLA, and this bioabsorbable
substrate has been coated with the combined anodic metal/cathodic
metal coating described above. In FIG. 4A, the pouch of PGLA fibers
coated with (e.g., by vapor deposition) co-deposited silver and
platinum galvanically releases silver ions after insertion into the
body. The release of anodic metal ions (e.g., silver ions) is
enhanced as the bioabsorbable substrate (e.g., PGLA) is hydrolyzed.
Hydrolysis lowers the local pH and this may increase solubility of
silver and bio-absorption.
[0137] The pouch of FIG. 4 may be used similarly to those described
in U.S. Pat. No. 8,591,531, herein incorporated by reference in its
entirety.
[0138] In general, the bioabsorbable substrate may be formed into
any appropriate shape or structure. For example, a bioabsorbable
substrate may be a filament that is coated, completely or
partially, by one or more of any of the combined coatings of anodic
and cathodic metals co-deposited onto the bioabsorbable substrate.
Coated strands (e.g., filaments, strings, wires, etc.) of
bioabsorbable substrate may be used by themselves, e.g., as suture,
ties, etc. within a body, or they may be used to form 2D or 3D
implants, for example, by weaving them. The combined coatings
described herein may be coated onto these structures either before
or after they have been formed. For example, a coated filament may
be woven into a net (or into a pouch for holding an implantable
device, as shown in FIG. 4), or the filament may be woven into a
net and then coated.
[0139] FIG. 5A shows an example of a filament that may be formed of
a bioabsorbable substrate that is coated with a combined
anodic/cathodic metal coating for galvanic release of anodic metal
ions. In FIG. 5A, the fiber 500 may include uncoated regions 505
alternating with coated regions 503. The coated region(s) may be a
spiral shape around the fiber, a ring around the fiber (as shown in
FIG. 5) or any other pattern. Multiple coatings may be used (see,
e.g., FIGS. 3A-3C). The coated fiber may retain its flexibility. In
some variations the fiber may be used, e.g., as a suture.
[0140] FIGS. 5B-5D and 6 illustrate different variations of sutures
that may be coated as described herein. Note that although some of
these substrates forming the suture are bioabsorbable, they do not
need to be. In some variations, the suture material (the substrate
onto which the galvanically releasable coating is applied) is not
biodegradable or bioabsorbable. Any variation of suture material
may be used. For example, the suture material may be a barbed
suture, as shown in FIG. 5B. The barbed suture 560 may be coated
565 or otherwise treated to include the co-deposited coating of
anodic metal (e.g., 40% by volume of silver) and cathodic metal
(e.g., 50% by volume of platinum) arranged with continuous
microdomains of the anodic (and/or cathodic) metal extending from
the outer side of the outer surface of the coating through the
thickness of the coating. An entire length of suture 580 may be
coated 585, as shown schematically in FIG. 5C, or just a portion of
the suture. The thickness of the coating may be below a threshold,
which may help maintain the flexibility of the suture material. For
example, the thickness may be between 10 microinches and 50
microinches. FIG. 5D illustrates a suture kit including a length of
suture 580 and a needle 591; either or both the suture 580 and
needle 591 may be coated. The same or different anodic metal and/or
cathodic metal may be used on the needle as the thread. For
example, the needle may include the more quickly releasing nickel
as the anode, while the thread, which resides longer in the body,
may use and anodic metal of silver.
[0141] FIG. 6 shows another example of a suture 600 that is coated
620 over the distal portion of the suture, which may be used in the
body. The suture may be pre-loaded on a device (including an
implant, needle, etc.). The suture may be formed of a bioabsorbable
substrate 610 onto which the coating is applied.
[0142] In any of the devices described herein, the coating may be
made directly onto the substrate. In some variations the coating
may be made on top of another coating (e.g., a primer coating)
which may be made to prepare the substrate for the coating.
Examples of primer coatings are adhesion coatings. An example of a
primer coating may include titanium and/or tantalum undercoatings,
as described above.
[0143] Additional examples of woven structures are shown in FIGS.
7-11. In FIG. 7, the device 700 is formed of filaments 710 woven or
arranged into a mesh (shown in the enlarged view 720) that are
coated with a combined coating (or multiple types of combined
coatings) as described herein. In this example, the mesh formed is
configured as a transvaginal mesh (intravaginal mesh) that may be
used for the treatment of vaginal prolapse, for example. Slings or
other anatomical support structures, either durable or
biodegradable, could also be formed. These devices may galvanically
release one or more type of anionic metal ion having antimicrobial
effect. For example the mesh may be coated with a coating of
silver/platinum that is co-deposited onto the mesh or the fibers
forming the mesh for galvanic release of silver from the
coating.
[0144] FIGS. 8A and 8B illustrate another example of a structure,
shown as a woven structure, that may also be configured as a
non-woven (e.g., solid) structure. In FIG. 8A the device 400 is a
patch or plug that may be used for treating a hernia. In this
example, the patch is a woven mesh that includes two types of
combined coatings: silver/platinum and zinc/platinum in different
regions over the surface of the patch. Darker regions 803 may
indicate the silver/platinum co-deposited coating regions, while
the lighter regions 805 represent co-deposited zinc/platinum
regions. The entire patch outer surface or only a portion of the
outer surface may be coated; in FIG. 8A, only discrete regions are
shown as coated, for the sake of simplicity. FIG. 8B shows an
enlarged view illustrating the fibers forming the weave of the
patch. As shown in FIG. 8B, only some of the fibers are coated
(e.g., every other fiber of the warp); in some variations,
alternating fibers in one direction (warp) are coated with
different anodic/cathodic metals, while fibers in the opposite
direction (weft) are uncoated.
[0145] FIG. 9 illustrates another example of a woven material,
formed of a bioabsorbable fiber, coated with the combined coatings
described herein for galvanic release of antimicrobial metal ions.
In FIG. 9, the device is a patch that could be used, e.g., within
the knee after surgery, to reduce the chance of infection. In this
example, as in FIGS. 8A and 8B above, the patch may include
filaments/fibers having different coatings (e.g., silver/platinum,
zinc platinum, silver palladium, zinc palladium, etc.) and/or
different regions on the patch, as shown by the light and darker
regions in FIG. 9. In some variations the patch may be worn outside
of the body, e.g., it is "implanted" by placing it over a wound,
rather than entirely within the body. Blood in the wound region may
act as the electrolytic fluid, allowing galvanic release of the
metal ions.
[0146] Similarly, FIG. 10 illustrates a dural replacement mesh 810
that may be implanted into a subject's head 812 to replace dural
matter following trauma and/or surgery. The mesh may be formed of a
non-bioabsorbable material (or a bioabsorbable material) that is
coated as described above so as to galvanically release
antimicrobial metal ions.
[0147] FIG. 11 illustrates another example of a fabric or mesh that
may be implanted into a patient as part of a surgical procedure. In
FIG. 11, the mesh is a woven fabric that has been coated with one
or more combined coatings of anodic and cathodic metals
co-deposited on the substrate (e.g., bioabsorbable substrate) for
galvanic release of metal ions. The material may be used, for
example, as part of a large joint procedure such as knee
replacement, or spinal surgery (e.g., fixation using rods, screws,
etc.) in place of currently used antibiotic powers. For example the
coated bioabsorbable mesh could be in, around, or over the surgical
site and used to galvanically release antimicrobial ions following
surgery. The implant (material) would break down over time, and be
absorbed following implantation (e.g., within 30 days following the
procedure), allowing sufficient time for the patient to recover and
avoid infection potentially introduced by the procedure and/or the
resulting wound.
[0148] Although the devices described herein include flexible,
e.g., filament or mesh, structures, the devices may also be
configured as rigid or more traditional surgical implants,
including screws, rods, staples, cannulas, etc. The substrate may
be bioabsorbable.
[0149] For example, FIGS. 12A-12B shows one variation of a cannula
that may be used within a body and galvanically release
antimicrobial metal ions. In FIG. 12A, the cannula 300 includes a
substrate 320 onto which a combined coating 330 is applied in a
spiral pattern. The combined coating galvanically releases anodic
metal ions (e.g., silver, zinc, copper), is includes the anodic
metal that has been co-deposited with cathodic metal (e.g.,
platinum, palladium, etc.). In this example, the inner surface 310
of the cannula 300 may also be separately coated with a combined
coating (the same or a different coating). FIG. 12B shows a side
view of the catheter of FIG. 12A.
[0150] Any of the devices described herein may be used as part of a
surgical procedure within a body (e.g., human, animal, etc.). In
general, the combined coatings described herein may be implanted
into the body and may galvanically release metal ions over an
extended period of time (e.g., days, weeks, months). For example,
in some variations the coating and/or apparatus (e.g., device) may
be configured to galvanically release metal ions for 30 days, 60
days, 90 days, or more.
[0151] The anti-microbial coatings, devices and systems described
herein may use two or more types of metal ions with anti-microbial
properties, such as silver and zinc. The zone of inhibition of
microbial activity/growth formed around the coated devices due to
the released metal ions may be enhanced where two different types
(e.g., silver and zinc) are released. The combination of zinc and
silver has been observed to have a synergistic effect compared to
either metal alone.
[0152] Further, when the combined coatings described herein are
used in combination with a bioabsorbable (e.g., biodegradable)
substrates or material, the metal ions may form complexes with the
byproducts of degradation of the substrate (e.g., polymeric
substrates including PLA, PLGA, PGA) such as lactate, galactate, or
glucoate. These substrates may increase the anti-microbial
activity. For example, the range of diffusion of the anionic metal
ions (e.g., zinc, silver, etc.) may be increased by the creation of
a complex between the metal ions and the polymeric degradation
byproduct. Further, as mentioned above, degradation of the polymers
may create acidic byproducts such as lactic acid, galactic acid,
and/or glycolic acid. The drop in pH and formation of the anionic
byproducts may further enhance the rate of the galvanic
reaction.
[0153] Thus, the apparatuses and methods above may, in some
variations, generally take advantage of the use of bioabsorbable
substrates that are coated through a co-deposition process of a
cathodic metal (e.g., platinum, palladium, gold, etc.) and an
anodic metal (e.g., silver, zinc, copper) to form a galvanic
circuit in a fluid (e.g., electrolytic) medium to create an
antimicrobial zone. The degradation of the bioabsorbable substrate
may further enhance this antimicrobial zone, e.g., by forming
complexes with the released metal ions to further diffuse the ions
as well as to alter the local pH to enhance the galvanic reaction.
In general, as described above, the combined coatings described
herein can be quite thin and do not compromise the flexibility,
chemic structure, strength (e.g., tensile strength) or chemical
properties of the underlying substrate(s).
EXAMPLES
[0154] Any of the coatings described herein may be ozonated and may
be included on all or a portion of a medical device. For example,
any of the following devices may be wholly or partially coated with
a mixture of an anodic metal and a cathodic metal as described
herein: shunts (e.g., drainage shunts, dialysis shunts, etc.),
catheters (e.g., urinary catheters, intravascular catheters, etc.),
ports (e.g., portacath, etc.), artificial joints (e.g., total hip,
knee, etc.), pacemakers, defibrillators (ICD), pain management
implants, neuro-stimulators, neuro-pacemakers, stents, bariatric
balloons, artificial heart valves, orthodontic braces, pumps (drug
pumps, e.g., insulin pumps, etc.), implantable birth control
devices, IUDs, etc.
[0155] Any of the coatings described herein may be included on all
or a portion of a medical tool. For example, any of the following
materials for use in operating on a subject may be wholly or
partially coated with a mixture of an anodic metal and a cathodic
metal as described herein: surgical gauze, surgical sponges, wound
packing materials, augmentation and/or cosmetic implants (e.g.,
breast/chin/facial implants), surgical retractors, needles, clamps,
forceps, and the like.
[0156] For example, FIG. 13B illustrates one example of an implant
that may be coated on an outer surface with any of the
antimicrobial coatings comprising a non-homogeneous mixture of
anodic and cathodic metals for galvanic release of anti-microbial
ions, as described herein, and implant as illustrated in FIG. 13A.
In this example all or just a portion of a pacemaker 1301 may be
coated on an outer surface with the mixture of between about 30%
and 70% by volume of an anodic metal, and between about 30% to 70%
by volume of a cathodic metal. The anodic and cathodic metals may
be co-deposited on the outer substrate surface to form a
non-uniform mixture of the anodic and cathodic metals, wherein the
coating comprises a plurality of microregions or microdomains of
anodic metal in a matrix of cathodic metal or a plurality of
microregions or microdomains of cathodic metal in a matrix of
anodic metal. In some variations different regions may be coated
with different anodic metals (e.g., forming a pattern of silver,
nickel, etc. releasing regions). In some variations the electrical
leads (e.g., an outer surface of the leads that are tunneled
through the body, as illustrated in FIG. 13A) may be coated as
described herein. Similarly, electrical leads for other devices
(e.g., neurostimulators) may be coated as described herein. In
general, these coatings may terminate before the electrically
active regions of the lead.
[0157] For example, FIG. 13C shows a schematic depiction of an
implantable pacemaker (defibrillator) system 1300 including
electrodes implanted in the heart H of a subject (patient). A
cardiac stimulation and defibrillation device 1310 is connected to
the heart H via an electrode lead 1320 which comprises three lead
branches or electrode supply leads 1330, 1340 and 1350. Each lead
branch comprises sensing or stimulation electrodes (which are not
depicted individually) on or near the distal end thereof, and lead
branch 1350 also comprises an elongated defibrillation electrode
1360. In the arrangement shown, lead branch 1330 is placed in the
right atrium, lead branch 1340 is placed in the left atrium of the
heart H, and lead branch 1350 on which defibrillation electrode
1360 is installed is placed in the right ventricle (RV). As
mentioned above, any of the leads described herein may be coated
with the mixture of between about 25% to 75% (e.g., 30% and 70%) by
volume of an anodic metal, and a cathodic metal that are
co-deposited on the outer substrate surface to form a non-uniform
mixture of the anodic and cathodic metals. The coatings may include
the electrical contacts (not shown) or the contacts may not be
coated. Different coatings may be used (e.g., different anodic
and/or cathodic metals, different patterns of coating, etc.) may be
used. In general, the coating comprises a plurality of microregions
or microdomains of anodic metal in a matrix of cathodic metal or a
plurality of microregions or microdomains of cathodic metal in a
matrix of anodic metal. This coating may be made on the leads
without detrimentally affecting the flexibility of the leads. For
example, the coating may be applied thin enough to allow the lead
to bend easily, while still providing sufficient elution of
antimicrobial metal ions (e.g., silver ions) over a long time
period (of weeks and months).
[0158] FIGS. 14A and 14B, as well as FIGS. 15A and 15B illustrate
another variation of a type of device, a catheter such as a Venus
catheter that may be partially or completely coated as described
herein. The coatings described herein may benefit virtually any
type of catheter; a Venus catheter is generally a tube inserted
into a vein in the neck (as shown in FIG. 14A), chest, or leg,
e.g., near the groin, usually only for short-term hemodialysis. In
FIG. 14A, the tube splits in two after the tube exits the body. The
two tubes have caps designed to connect to the line that carries
blood to the dialyzer and the line that carries blood from the
dialyzer back to the body. A person must close the clamps on each
line when connecting and disconnecting the catheter from the tubes.
Any portion (or the entire device) may be coated as described
herein. For example, in FIGS. 14A and 14B, the outer surface of the
catheter 1405 and/or the Venus and arterial lines may be coated as
described herein.
[0159] In some devices, it may be helpful to provide a cuff or
cuffs on the device that are specifically configured for the
galvanic release of antimicrobial ions. For example, FIGS. 15A and
15B illustrate catheters 1500, 1501 for long-term vascular access
that includes a cuff that may be at least partially coated as
described herein for the release of antimicrobial ions. Adjacent to
the ion-releasing cuff 1505 is a tissue-ingrowth cuff 1507.
[0160] In general, the wide use of invasive medical devices,
including intravascular catheters has led to an increase in
infections related to the use of the medical device. However,
intravascular catheters are often associated with serious
infectious complications, such as catheter-related bloodstream
infection (CRBSI). In fact, CRBSI is considered to be the most
common type of nosocomial bloodstream infection, a finding that has
been attributed to the wide use of intravascular catheters in
hospitalized patients. It is estimated that 7 million central
venous catheters (CVCs) will be inserted annually in the United
States. Even with the best available aseptic techniques being used
during insertion and maintenance of the catheter, 1 of every 20
CVCs inserted will be associated with at least 1 episode of
bloodstream infection.
[0161] In the early 2000's, an estimated 300,000 cases of
catheter-related bloodstream infection (CRBSI) occurred in the
United States each year. Existing interventions to control CRBSI
include anticoagulant/antimicrobial lock, use of ionic silver at
the insertion site, employment of an aseptic hub model, and
antimicrobial impregnation of catheters. However, these solutions
have not proven ideal.
[0162] Several factors pertaining to the pathogenesis of CRBSI have
been identified during the last decade. The skin and the hub are
the most common sources of colonization of percutaneous vascular
catheters. For short-term, nontunneled, noncuffed catheters, the
organisms migrate from the skin insertion site along the
intercutaneous segment, eventually reaching the intravascular
segment or the tip. Thus, it may be beneficial to include the
galvanic release coating(s) described herein along any (or all)
portions of the catheters that are inserted into the patient, to
allow galvanic release of the antimicrobial ions (e.g., silver,
nickel, etc.) as described above. For example, FIG. 16 illustrates
one variation of a catheter 1601 (shown as an intravascular
catheter in this example) that has been coated along its length (or
over a region) with a layer of the mixture of between about 25% to
about 75% (e.g., 30% and 70%) by volume of an anodic metal, and
between about 25% to about 75% (e.g., 30% to 70%) by volume of a
cathodic metal co-deposited on an outer substrate surface to form a
non-uniform mixture of the anodic and cathodic metals. The coating
may comprise a plurality of microregions or microdomains of anodic
metal in a matrix of cathodic metal or a plurality of microregions
or microdomains of cathodic metal in a matrix of anodic metal. The
anodic metal is galvanically released as antimicrobial ions when
the apparatus is inserted into a subject's body.
[0163] Generally, long-term catheters (particularly those that are
cuffed or surgically implanted, such as those illustrated in FIGS.
15A-15B), the hub is a major source of colonization of the catheter
lumen, which ultimately leads to bloodstream infections through
luminal colonization of the intravascular segment. Thus, in some
variations the hub region may be coated as described herein.
[0164] In addition to the examples described above, other
insertable or implantable device that may be coated as described
herein may include implantable devices such as drug delivery
devices (e.g., pumps), cardiac management devices (e.g.,
pacemakers), cochlear implants, analyte sensing devices, catheters,
cannulas or the like. Essentially any medical device which
experiences microbial colonization and/or biofilm formation and/or
encrustation is appropriate for the practice of the present
invention, including analyte sensing devices such as
electrochemical glucose sensors, drug delivery devices such as
insulin pumps, devices which augment hearing such as cochlear
implants, urine contacting devices (for example, urethral stents,
urinary catheters), blood contacting devices (including needles,
blood bags, cardiovascular stents, venous access devices, valves,
vascular grafts, hemodialysis and biliary stents), and body tissue
and tissue fluid contacting devices (including biosensors, implants
and artificial organs). Medical devices include but are not limited
to permanent catheters, (e.g., central venous catheters, dialysis
catheters, long-term tunneled central venous catheters, short-term
central venous catheters, peripherally inserted central catheters,
peripheral venous catheters, pulmonary artery Swan-Ganz catheters,
urinary catheters, and peritoneal catheters), long-term urinary
devices, tissue bonding urinary devices, vascular grafts, vascular
catheter ports, wound drain tubes, ventricular catheters,
hydrocephalus shunts, cerebral and spinal shunts, heart valves,
heart assist devices (e.g., left ventricular assist devices),
pacemaker capsules, incontinence devices, penile implants, small or
temporary joint replacements, urinary dilator, cannulae,
elastomers, hydrogels, surgical instruments, dental instruments,
tubings, such as intravenous tubes, breathing tubes, dental water
lines, dental drain tubes, and feeding tubes, fabrics, paper,
indicator strips (e.g., paper indicator strips or plastic indicator
strips), adhesives (e.g., hydrogel adhesives, hot-melt adhesives,
or solvent-based adhesives), bandages, orthopedic implants, and any
other device used in the medical field. Medical devices also
include any device which may be inserted or implanted into a human
being or other animal, or placed at the insertion or implantation
site such as the skin near the insertion or implantation site, and
which include at least one surface which is susceptible to
colonization by biofilm embedded microorganisms. Medical devices
also include any other surface which may be desired or necessary to
prevent biofilm embedded microorganisms from growing or
proliferating on at least one surface of the medical device, or to
remove or clean biofilm embedded microorganisms from the at least
one surface of the medical device, such as the surfaces of
equipment in operating rooms, emergency rooms, hospital rooms,
clinics, and bathrooms. Non-implanted devices for use in a medical
procedure that may be coated as described herein include surgical
tools, e.g., suturing devices, forceps, retractors, sponges,
etc.
[0165] Orthopedic devices may in particular benefit from the
coatings described herein. An implant as described herein may be
used to treat bone and/or soft tissue. In some variations the
implants are bone implants specifically, and may be configured to
support as well as treat the bone. For example, the implant may be
used to secure (as a screw, nail, bolt, clamp, etc.) another member
such as a plate, rod, or the like, or the implant may itself
include a support member such as a rod, plate, etc. In some
variations, the implant is a soft tissue implant that is configured
to be secured within non-bone body structures.
[0166] For example, FIGS. 17A-17C illustrate one variation of an
apparatus for use in delivering an antimicrobial ion (e.g., silver
ions) to a repair site to prevent or treat infection. In this
example, apparatus includes a replaceable/removable insert that is
coated. The insert maybe a mesh or other material having a
relatively large surface to volume ratio (e.g., large surface
area). For example, FIG. 17A shows a cannulated bone screw 1701,
e.g., a bone screw having a central cannula region (not visible in
FIG. 17A) into which another device or element may be inserted,
such as the bioabsorbable material 1703 (mesh) shown in FIG. 17B.
In FIG. 17A, the bone screw includes a distal threaded region 1705
and a more proximal head 1707. In FIG. 17B the bioabsorbable mesh
1703 is coated with the antimicrobial ion releasing coating such as
described herein (e.g., 30% silver/70% platinum) to a thickness of
100 microinches. The cannulated bone screw 1701 may also be coated,
or may not be coated. Either before or after inserting the bone
screw into the body, the bioabsorbable insert 1703 may be inserted
into the cannula of the bone screw 1701. This is illustrated in
FIG. 17C. In practice, multiple inserts 1703 may be added to the
bone screw device.
[0167] In some variations, the bone screw may itself be coated,
without the use of an additional element (e.g., a bioabsorbable
insert). FIGS. 18A and 18B illustrate different variations of
implants (e.g., bone screw) that include antimicrobial ion
releasing coatings as described herein. In FIG. 18A, the entire
bone screw 1801 is coated with an antimicrobial ion releasing
coating comprising a mixture of between about 25% to 75% (e.g., 30%
and 70%) by volume of an anodic metal, and between about 25% to 75%
(e.g., 30% to 70%) by volume of a cathodic metal co-deposited on
the outer substrate surface to form a non-uniform mixture of the
anodic and cathodic metals, wherein the coating comprises a
plurality of microregions or microdomains of anodic metal in a
matrix of cathodic metal or a plurality of microregions or
microdomains of cathodic metal in a matrix of anodic metal, the
microregions or microdomains forming a continuous path of
interconnected veins of anodic metal through the coating thickness,
or a continuous path of interconnected veins of cathodic metal
through the coating thickness, wherein the continuous path extends
from an outer surface of the coating to the substrate to the
opposite side of the coating (which may be adjacent to the
substrate). In FIG. 18B, the bone screw apparatus is a screw that
has not been completely coated, but includes differently coated
regions, or regions that are both coated and uncoated. In this
example the substrate is the surface of a bone screw having a
striated pattern of regions of coatings alternating with uncoated
regions.
[0168] FIGS. 19A-19B illustrate another variation in which the
implant is configured as an orthopedic device (e.g., bone screw)
having extendable members that can be extended out of the body of
the bone screw to project into the tissue and allow release of
antimicrobial ions into the surrounding tissue. In this variation,
the implant 1901 is configured as a bone screw that is hollow or
contains a hollow inner body region (not visible in FIG. 19A) into
which a replaceable/rechargeable treatment cartridge may be
inserted and/or removed. The cartridge may be itself screwed into
the body, or it may be otherwise secured within the body. The
cartridge may include one or more (e.g., a plurality) of ion
release members 1909 extending or extendable from the cartridge and
therefore the implant. The ion release member(s) may be configured
to release silver, zinc or silver and zinc and may be coated with
any of the coatings described herein. In general, an ion release
member may be configured as an elongate member such as an arm,
wire, branch, or the like. The ion release member may be a coated
member such as a Nitinol or other shape-memory member coated with
an antimicrobial ion releasing coating comprising a mixture of
between about 25% to about 75% (e.g., 30% and 70%) by volume of an
anodic metal (e.g., silver), and between about 25% to about 75%
(e.g., 30% to 70%) by volume of a cathodic metal (e.g., platinum)
co-deposited on the outer substrate surface to form a non-uniform
mixture of the anodic and cathodic metals, wherein the coating
comprises a plurality of microregions or microdomains of anodic
metal in a matrix of cathodic metal or a plurality of microregions
or microdomains of cathodic metal in a matrix of anodic metal, the
microregions or microdomains forming a continuous path of
interconnected veins of anodic metal through the coating thickness,
or a continuous path of interconnected veins of cathodic metal
through the coating thickness, wherein the continuous path extends
from an outer surface of the coating to the substrate to the
opposite side of the coating (which may be adjacent to the
substrate). As mentioned, the implant (or the treatment cartridge
portion) may include a plurality of ion release members.
[0169] These implants may have one or more exit channels 1905. In
general the exit channels may be openings from the inner hollow
region (e.g. cannulated body) of the implant through a side wall of
the implant and out, possibly in the threaded region 1907. Thus, in
FIGS. 19A and 19B, the exit channel is configured to deflect the
one or more ion release members away from a long axis of the
implant. For example, the exit channel may be configured to deflect
the one or more ion release members against a thread of the outer
threaded region so that it deflects away from the implant. In some
variations a plurality of exit channels extending through the
cannulated body 1903.
[0170] An implant such as the one shown in FIGS. 19A-19B may also
include a guide (or guide element, including a rail, keying, etc.)
within the channel configured to guide or direct the one or more
ion release member out of the cannulated body 1903 from the at
least one exit channel 1905. The exit channels may be configured to
allow tissue (e.g., bone) ingrowth, which may help with stability
of the device once implanted. For example, the exit channels may be
slightly oversized compared to the ion release members, permitting
or encouraging in-growth. In some variations the exit channels may
be doped or otherwise include a tissue-growth enhancing or
encouraging factor (such as a growth factor), or may be otherwise
modified to encourage tissue growth.
[0171] A treatment cartridge may be replaceable. For example, a
treatment cartridge may be configured to be removable from the
cannulated body of the implant in situ, without removing the body
of the implant from the device. Thus, the body of the implant may
be structurally supportive (e.g., supporting the bone) while the
silver-releasing cartridge arms may be re-charged by inserting
another (replacement) cartridge after the previous cartridge has
corroded. For example, an elongate cannulated body 1903 may be
configured as bone screw (e.g., an intramedullary bone screw).
[0172] In addition, the antimicrobial coatings described herein may
also be effective for use in non-implantable and/or insertable
devices. As mentioned above, any apparatus that may come into
contact with a conductive (e.g., electrolytic) fluid, such as
bodily fluids, may benefited from the antimicrobial coatings
described herein; such apparatuses are not limited to medical
devices and systems.
[0173] For example, also descried herein are garments (e.g.,
gloves, masks, scrubs), including facial masks (surgical masks,
filters, or the like), sporting equipment (e.g., facemasks,
mouthpieces, helmets, etc.), shoes (sole/shoe inserts, etc.),
jewelry (necklaces, bracelets, rings, etc.) and the like, that may
be coated or may include a coated region, wherein the coating
comprises any of the antimicrobial ion releasing coatings described
herein, such as a coating comprising a mixture of between about 25%
to about 75% (e.g., 30% and 70%) by volume of an anodic metal
(e.g., silver), and between about 25% to about 75% (e.g., 30% to
70%) by volume of a cathodic metal (e.g., platinum) co-deposited on
the outer substrate surface to form a non-uniform mixture of the
anodic and cathodic metals, wherein the coating comprises a
plurality of microregions or microdomains of anodic metal in a
matrix of cathodic metal or a plurality of microregions or
microdomains of cathodic metal in a matrix of anodic metal, the
microregions or microdomains forming a continuous path of
interconnected veins of anodic metal through the coating thickness,
or a continuous path of interconnected veins of cathodic metal
through the coating thickness, wherein the continuous path extends
from an outer surface of the coating to the substrate to the
opposite side of the coating (which may be adjacent to the
substrate).
[0174] FIG. 20 is one example of a non-medical application of a
coating as described herein. For example, an animal cage 2005 may
be coated (particularly on the bottom region) with any of the
antimicrobial coatings described herein. In this example, the cage
may include an antimicrobial ion releasing coatings as described
herein, such as a coating comprising a mixture of between about 25%
to about 75% (e.g., 30% and 70%) by volume of an anodic metal
(e.g., silver), and between about 25% to about 75% (e.g., 30% to
70%) by volume of a cathodic metal (e.g., platinum) co-deposited on
the outer substrate surface to form a non-uniform mixture of the
anodic and cathodic metals, wherein the coating comprises a
plurality of microregions or microdomains of anodic metal in a
matrix of cathodic metal or a plurality of microregions or
microdomains of cathodic metal in a matrix of anodic metal, the
microregions or microdomains forming a continuous path of
interconnected veins of anodic metal through the coating thickness,
or a continuous path of interconnected veins of cathodic metal
through the coating thickness, wherein the continuous path extends
from an outer surface of the coating to the substrate to the
opposite side of the coating (which may be adjacent to the
substrate).
[0175] Similarly, any household apparatus that may be exposed to a
bodily fluid (including sweat and/or mucus, as from sneezing or
coughing) may be coated with any of the coatings described herein,
to act as an effective antimicrobial barrier. For example, FIG. 21
illustrates a doorknob 2101 that may be partially or completely
coated with any of the antimicrobial ion releasing coatings
described herein on a portion that will be held by an operator's
hand 2109. Thus, this region may be coated with a coating
comprising an antimicrobial ion releasing coating such as a coating
comprising a mixture of between about 25% to about 75% (e.g., 30%
and 70%) by volume of an anodic metal (e.g., silver), and between
about 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic
metal (e.g., platinum) co-deposited on the outer substrate surface
to form a non-uniform mixture of the anodic and cathodic metals,
wherein the coating comprises a plurality of microregions or
microdomains of anodic metal in a matrix of cathodic metal or a
plurality of microregions or microdomains of cathodic metal in a
matrix of anodic metal, the microregions or microdomains forming a
continuous path of interconnected veins of anodic metal through the
coating thickness, or a continuous path of interconnected veins of
cathodic metal through the coating thickness, wherein the
continuous path extends from an outer surface of the coating to the
substrate to the opposite side of the coating (which may be
adjacent to the substrate). Other household fixtures that may be
readily coated include light switches, door handles/pulls, kitchen
appliances (and particularly handles/controls for kitchen
appliances), tabletop and/or countertop surfaces, and bathroom
surfaces. For example, a toilet handle, toilet (including toilet
seat and/or bowl), sink, and/or faucet may be coated as described
herein.
[0176] In addition, cookware, dining wear, and/or cutlery may be
coated. Such coatings are safe, and non-toxic, though still
antimicrobial, and may be extremely long lasting (e.g., extending
over months or years, depending on coating thicknesses and use).
Further, these coatings do not degrade or lose their antimicrobial
activity, which is dependent primarily or exclusively on the
galvanic release of ions (e.g., silver ions). For example, as shown
in FIGS. 22A-22B, cutlery (e.g., spoons 2205, forks 2207, etc.) may
be coated as described herein, particularly on the portions to be
placed in a user's mouth. FIG. 22B shows an example of an infant
spoon 2205' having an elongate handle and end region 2230 forming
the spoon that is to be placed in an infant's mouth; this end
region 2230 may be coated specifically, e.g., with an antimicrobial
ion releasing coating as described herein, such as a coating
comprising a mixture of between about 25% to about 75% (e.g., 30%
and 70%) by volume of an anodic metal (e.g., silver), and between
about 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic
metal (e.g., platinum) co-deposited on the outer substrate surface
to form a non-uniform mixture of the anodic and cathodic metals,
wherein the coating comprises a plurality of microregions or
microdomains of anodic metal in a matrix of cathodic metal or a
plurality of microregions or microdomains of cathodic metal in a
matrix of anodic metal, the microregions or microdomains forming a
continuous path of interconnected veins of anodic metal through the
coating thickness, or a continuous path of interconnected veins of
cathodic metal through the coating thickness, wherein the
continuous path extends from an outer surface of the coating to the
substrate to the opposite side of the coating (which may be
adjacent to the substrate). The substrate may be stainless steel,
polymer, or any other appropriate material. The coating is both
washable and sterilizable without losing efficacy.
[0177] In some variations, the substrate is a particle, such as a
micro (or nano) particle that is coated as described herein, to
form a powder or other material that may be added to a device or
system to provide antimicrobial activity. For example, polymeric
particles may be coated (or a polymeric material may be coated and
ground/broken up into smaller particles) with any of the
antimicrobial ion releasing coatings described herein, such as a
coating comprising a mixture of between about 25% to about 75%
(e.g., 30% and 70%) by volume of an anodic metal (e.g., silver),
and between about 25% to about 75% (e.g., 30% to 70%) by volume of
a cathodic metal (e.g., platinum) co-deposited on the outer
substrate surface to form a non-uniform mixture of the anodic and
cathodic metals, wherein the coating comprises a plurality of
microregions or microdomains of anodic metal in a matrix of
cathodic metal or a plurality of microregions or microdomains of
cathodic metal in a matrix of anodic metal, the microregions or
microdomains forming a continuous path of interconnected veins of
anodic metal through the coating thickness, or a continuous path of
interconnected veins of cathodic metal through the coating
thickness, wherein the continuous path extends from an outer
surface of the coating to the substrate to the opposite side of the
coating (which may be adjacent to the substrate). The resulting
particles (which may be referred to as an antimicrobial powder) may
be added, e.g., into structures or onto surfaces that will come
into contact with bodily fluids.
Surface Treatments
[0178] As mentioned above, the antimicrobial coatings described
herein may be applied directly to any appropriate substrate; the
substrate may, in some variations, form a part of another device or
system that comes into contact with a bodily fluid and therefore
benefits from the use of these antimicrobial coatings. For example,
a coating may be made directly onto the substrate, or it may be
made onto another coating (e.g., a primer coating) which may be
made to prepare the substrate for the coating. Examples of primer
coatings are adhesion coatings, which may include a titanium and/or
tantalum undercoating, as described above.
[0179] In some variations, the material is pretreated to prepare
the surface to receive the coating. For example, in some metals
(e.g., nickel titanium, stainless steel, etc.) the surface may
oxidize naturally, and it may be beneficial to remove this oxide
layer prior to applying the antimicrobial coatings described
herein. For example, a substrate may be prepared by removing an
oxide layer (or for other reasons) by vacuum blast cleaning with a
noble gas such as argon (e.g., argon blasting or argon blast
cleaning under a vacuum). Removing the thin outer oxide layer may
enhance adhesion of the coating. In general, vacuum cleaning may be
helpful, and may be performed immediately before applying the
coating (e.g., co-sputtering the anodic and cathodic
materials).
[0180] Other useful pre-treatments may include applying an
undercoating layer (e.g., of platinum, parylene, etc.). Such
undercoatings may be applied first (e.g., by sputter deposition,
etc.).
[0181] One additional benefit of the coatings described herein is
that they may be applied in a relatively cool application process,
e.g., in which the temperature at which the co-deposition of the
anodic material and cathodic material is applies is relatively cool
(e.g., less than 150.degree. C., less than 120.degree. C., less
than 100.degree. C., less than 90.degree. C., less than 80.degree.
C., less than 70.degree. C., less than 60.degree. C., less than
50.degree. C., etc.). The temperature of application may be
adjusted along with the time to form the coating (e.g., cooler
application may generally take longer). Cooler application may be
particularly beneficial when the substrates to which it is being
applied is temperature sensitive, or when it is being applied to a
device (including devices having active/electronic parts) that are
rate below a predetermined temperature.
Post-Coating Treatments
[0182] Any of the apparatuses described herein (e.g., any of the
coatings described herein) maybe treated to enhance the galvanic
release of antimicrobial ions (e.g., silver). Such treatments may
be referred to as post-coating treatments because they may be
performed after the coating has been applied. For example, any of
the apparatuses described herein may include coatings that are
treated to enhance the surface area by cracking, fracturing, or
otherwise roughening the coating, which may increase the exposed
surface area of the coating. Another post-coating treatment is the
application of ozone (ozonation) as described in more detail and
illustrated below.
[0183] Post-coating treatments may include thermal treatments
(e.g., exposing the surface to a cooler temperature to crack or
fracture the coating), and/or energy (e.g., ultrasound, RF, etc.)
to fracture the surface. For example, in some variations the
coating may be connected to an oscillating high voltage source that
makes cracks in the coating. For example, FIG. 23A and 23B
illustrates a variation of a substrate 2320 (similar to the example
shown in FIGS. 2A-2D) has been coated with an antimicrobial ion
releasing coating 2300 as described above. In this example, after
co-depositing the anodic and cathodic metals, the coated apparatus
has been treated to fracture the coating, forming breaks/fractures
2350 (shown schematically in FIG. 23B from the enlarged region B in
FIG. 23A). In this example, the fractures 2350 are formed
vertically into the coating to expose more of the anodic metal and
cathodic metal, potentially allowing for greater (and/or faster)
release of anodic antimicrobial ions.
[0184] Thus, in any of the apparatuses described herein, the
coatings may be fractured (cracked, etc.) to enlarge the surface
area. Cracks or fractures may be formed of a predetermined density
and/or depth. For example, the coating may be fractured or may
include cleavage regions into the thickness of the coating at a
density of between 0.01% and 80% of the surface (e.g., greater than
0.1%, greater than 1%, greater than 5%, greater than 10%, greater
than 15%, etc.). The percentage of fracturing typically results in
an increase the in the surface area, and may therefore be referred
to as a percentage increase in the surface area. For example the
percent increase in the surface area due to fracturing the surface
may result in an increase of greater than 0.25 times the
un-fractured surface area (e.g., a 25% or greater surface area
following fracturing). In some variations the surface area may be
increased greater than 0.3 times (e.g., 0.35.times. or greater,
0.40.times. or greater, 0.45.times. or greater, 0.5.times. or
greater, 0.6.times. or greater, 0.75.times. or greater, 0.8.times.
or greater, 0.9.times. or greater, 1.times. or greater, 2.times. or
greater, 3.times. or greater, etc.).
Ozone
[0185] As mentioned above, any of the coatings (or solid
substrates, e.g., solid silver substrates) described herein may be
treated with ozone, which will generally greatly enhance the
antimicrobial effects.
[0186] For example, FIG. 24 illustrates one method of forming an
apparatus including an ozonated surface coating. In FIG. 24, an
optional step of pretreating/preparing a substrate surface (e.g.,
by cleaning it with argon gas preparation and/or applying an
adhesion layer, as described above) may be used 2401. Thereafter
the substrate surface may be coated with silver or a coating of
co-deposited silver/cathodic material (e.g., 25%-75% anodic
silver), where the remainder is mostly the cathodic metal) 2403.
Optionally, the surface may be further treated by, e.g., cracking
2405, as described above. Finally, the surface may be treated with
ozone 2407. For example, the surface may be treated by applying a
jet of gas including ozone (e.g., oxygen gas) to/against the
surface.
[0187] FIGS. 25-28B illustrate by comparison some of the effects of
ozonation on substrates including examples of the substrates
described herein, although the same results (showing robust
enhancement of the antimicrobial effect of the anion, e.g., silver,
following ozonation).
[0188] For example, FIG. 25 illustrates the enhancement of
antimicrobial acitivty in a silver wire (pieces of solid silver
wire) with 2505 and without 2509 ozonation. In this example, even
with pure silver an antimicrobial effect is seen, as made apparent
by the clearing regions 2507 around the ozonated silver wire pieces
in the top of the figure, in contrast to the non-ozonated silver
wire pieces 2509 in the bottom. In this example, the elemental
silver (wire) is exposed to ozone, which may create complexes that
allow for formation of the clearings; zones of inhibition where the
silver wire is exposed to a liquid (such as a growth media in this
example). For implantable devices, the surface(s) of the devices
may be coated or plated with silver (or any of the coatings
described herein), e.g., via vapor deposition or plating, and
subsequently the coating may be exposed to ozone for a period of
time to create silver complexes having antimicrobial activity.
Thus, although the majority of these example shown herein are
silver-containing coatings, with respect to FIG. 24, any of these
methods (e.g., enhancement of antimicrobial activity due to
ozonation of the silver) may be used.
[0189] FIGS. 26-28B illustrate the use of ozonation to enhance
antimicrobial effects. For example, in FIG. 26, two pairs of
otherwise-identical implants (silver-ion releasing implants) coated
with a layer of co-deposited silver and platinum (cathodic metal)
are cultured with bacteria to determine the effect of ozonation. In
this figure, the implants on the left and right 2605 are treated by
blowing in a stream of ozone for greater than 5 minutes, in
contrast to the coated implants on the top and bottom 2609. After
culturing with bacterial for 24 hrs (or more) there are distinct
clearing regions 2607 (antibacterial regions) around the ozonated
implants that are substantially larger (greater than 20%, 30%, 40%,
50%, 60%, 70%, 80%,90%, 100%, 2.times., 3.times., 4.times.,
5.times., 6.times., etc.) than the non-ozonated implants that are
otherwise identical. The size of the clearing region may be
dependent upon the length of the application of ozone, although
this relationship may be limited (e.g., may reach a plateau, e.g.,
beyond a certain time period).
[0190] Similarly, FIGS. 27 and 28A-28B also illustrate the general
principles described above, e.g., enhancement of antimicrobial
activity by pre-treatment with ozone for greater than 5 minutes. In
FIG. 27, sample of bioabsorbable mesh 2705 has been coated with a
co-deposited silver and cathodic material as described herein, and
treated by exposure of ozone for greater than 15 minutes (e.g.,
greater than 5 min), resulting in clearing regions 2707. In
contrast a similar piece of mesh without any coating 2709 shows
overgrowth of the bacterial in the culture dish. Similarly, FIGS.
28A and 28B illustrate the use of ozonation to increase the
antibacterial effects; in FIGS. 27, and 28A-28B, similar meshes,
coated by a co-deposition of silver and platinum are exposed to
ozone for different times, and shown approximately increasing
enhancement of the antibacterial effects (as measurable by the size
of the bacterial clearing in the test). For example, in FIG. 28A,
similar pieces of mesh are used to example different exposure times
to the ozone (in general, the shortest exposure time of the ozone
2804 has a smaller clearing relative to the increasing exposures to
ozone 2805, 2806, 2807).
[0191] Another example (not shown) of ozone treatment was used to
confirm that the mesh (such as the mesh shown in FIGS. 28A-28B)
when coated with silver/platinum matrix as described above could
result in enhanced antimicrobial activity. In this example, a
double sided mesh substrate was coated with a co-deposition of
Ag/Pt matrix (as described above) and ozone-treated. The mesh is a
bioabsorbable knitted mesh. A 40.times.10 mm piece of coated and
ozone-treated knitted mesh was placed into a microcentrifuge tube
containing 300 .mu.L Tryptic Soy Broth (TSB). The tube and a
control tube containing 300 .mu.L TSB was inoculated with
Staphylococcus aureus at a concentration of 2.97.times.10.sup.5
CFU/mL. After 24 hours, a count for viable bacteria in the
ozone-treated tube and a control tube (in which the mesh was coated
but not ozonated) was performed and counted. The results showed
zero (0) Colony Forming Units/mL of S. aureus for the ozone-treated
coated mesh, and 1.85.times.10.sup.9 Colony Forming Units/mL of S.
aureus for the non-ozone treated coated mesh (where the limit of
detection for this example is 100 CFU/mL and reported data is
<100 CFU/mL when 0 colonies are observed).
[0192] When a feature or element is herein referred to as being
"on" another feature or element, it can be directly on the other
feature or element or intervening features and/or elements may also
be present. In contrast, when a feature or element is referred to
as being "directly on" another feature or element, there are no
intervening features or elements present. It will also be
understood that, when a feature or element is referred to as being
"connected", "attached" or "coupled" to another feature or element,
it can be directly connected, attached or coupled to the other
feature or element or intervening features or elements may be
present. In contrast, when a feature or element is referred to as
being "directly connected", "directly attached" or "directly
coupled" to another feature or element, there are no intervening
features or elements present. Although described or shown with
respect to one embodiment, the features and elements so described
or shown can apply to other embodiments. It will also be
appreciated by those of skill in the art that references to a
structure or feature that is disposed "adjacent" another feature
may have portions that overlap or underlie the adjacent
feature.
[0193] Terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
the invention. For example, as used herein, the singular forms "a",
"an" and "the" are intended to include the plural forms as well,
unless the context clearly indicates otherwise. It will be further
understood that the terms "comprises" and/or "comprising," when
used in this specification, specify the presence of stated
features, steps, operations, elements, and/or components, but do
not preclude the presence or addition of one or more other
features, steps, operations, elements, components, and/or groups
thereof. As used herein, the term "and/or" includes any and all
combinations of one or more of the associated listed items and may
be abbreviated as "/".
[0194] Spatially relative terms, such as "under", "below", "lower",
"over", "upper" and the like, may be used herein for ease of
description to describe one element or feature's relationship to
another element(s) or feature(s) as illustrated in the figures. It
will be understood that the spatially relative terms are intended
to encompass different orientations of the device in use or
operation in addition to the orientation depicted in the figures.
For example, if a device in the figures is inverted, elements
described as "under" or "beneath" other elements or features would
then be oriented "over" the other elements or features. Thus, the
exemplary term "under" can encompass both an orientation of over
and under. The device may be otherwise oriented (rotated 90 degrees
or at other orientations) and the spatially relative descriptors
used herein interpreted accordingly. Similarly, the terms
"upwardly", "downwardly", "vertical", "horizontal" and the like are
used herein for the purpose of explanation only unless specifically
indicated otherwise.
[0195] Although the terms "first" and "second" may be used herein
to describe various features/elements, these features/elements
should not be limited by these terms, unless the context indicates
otherwise. These terms may be used to distinguish one
feature/element from another feature/element. Thus, a first
feature/element discussed below could be termed a second
feature/element, and similarly, a second feature/element discussed
below could be termed a first feature/element without departing
from the teachings of the present invention.
[0196] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising" means various
components can be co-jointly employed in the methods and articles
(e.g., compositions and apparatuses including device and methods).
For example, the term "comprising" will be understood to imply the
inclusion of any stated elements or steps but not the exclusion of
any other elements or steps.
[0197] As used herein in the specification and claims, including as
used in the examples and unless otherwise expressly specified, all
numbers may be read as if prefaced by the word "about" or
"approximately," even if the term does not expressly appear. The
phrase "about" or "approximately" may be used when describing
magnitude and/or position to indicate that the value and/or
position described is within a reasonable expected range of values
and/or positions. For example, a numeric value may have a value
that is +/-0.1% of the stated value (or range of values), +/-1% of
the stated value (or range of values), +/-2% of the stated value
(or range of values), +/-5% of the stated value (or range of
values), +/-10% of the stated value (or range of values), etc. Any
numerical range recited herein is intended to include all
sub-ranges subsumed therein.
[0198] Although various illustrative embodiments are described
above, any of a number of changes may be made to various
embodiments without departing from the scope of the invention as
described by the claims. For example, the order in which various
described method steps are performed may often be changed in
alternative embodiments, and in other alternative embodiments one
or more method steps may be skipped altogether. Optional features
of various device and system embodiments may be included in some
embodiments and not in others. Therefore, the foregoing description
is provided primarily for exemplary purposes and should not be
interpreted to limit the scope of the invention as it is set forth
in the claims.
[0199] The examples and illustrations included herein show, by way
of illustration and not of limitation, specific embodiments in
which the subject matter may be practiced. As mentioned, other
embodiments may be utilized and derived there from, such that
structural and logical substitutions and changes may be made
without departing from the scope of this disclosure. Such
embodiments of the inventive subject matter may be referred to
herein individually or collectively by the term "invention" merely
for convenience and without intending to voluntarily limit the
scope of this application to any single invention or inventive
concept, if more than one is, in fact, disclosed. Thus, although
specific embodiments have been illustrated and described herein,
any arrangement calculated to achieve the same purpose may be
substituted for the specific embodiments shown. This disclosure is
intended to cover any and all adaptations or variations of various
embodiments. Combinations of the above embodiments, and other
embodiments not specifically described herein, will be apparent to
those of skill in the art upon reviewing the above description.
* * * * *