U.S. patent application number 16/923486 was filed with the patent office on 2020-10-29 for post-charging of zeolite doped plastics with antimicrobial metal ions.
The applicant listed for this patent is DiFusion, Inc.. Invention is credited to Joseph J. Crudden, Derrick Johns.
Application Number | 20200338237 16/923486 |
Document ID | / |
Family ID | 1000004954121 |
Filed Date | 2020-10-29 |
United States Patent
Application |
20200338237 |
Kind Code |
A1 |
Crudden; Joseph J. ; et
al. |
October 29, 2020 |
Post-Charging Of Zeolite Doped Plastics With Antimicrobial Metal
Ions
Abstract
Methods of post-loading ceramic particles with antimicrobial
metal cations are disclosed. In certain embodiments, the
post-loaded particles are zeolites, wherein the zeolites have been
incorporated into a resin and the combination is used as an
implantable device. In certain embodiments, the polymer is a
thermoplastic polymer such as polyaryletheretherketone (PEEK). In
certain embodiments, the source of antimicrobial activity includes
ion-exchangeable cations contained in a zeolite. In certain
embodiments, disclosed are methods of imparting antimicrobial
activity to devices by controlling the delivery of certain cations
through ion-exchange via a zeolite incorporated in the device.
Inventors: |
Crudden; Joseph J.; (Hudson,
NH) ; Johns; Derrick; (Austin, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DiFusion, Inc. |
Austin |
TX |
US |
|
|
Family ID: |
1000004954121 |
Appl. No.: |
16/923486 |
Filed: |
July 8, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15287845 |
Oct 7, 2016 |
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16923486 |
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13511176 |
Aug 30, 2012 |
9492584 |
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PCT/US2010/058009 |
Nov 24, 2010 |
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15287845 |
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61264289 |
Nov 25, 2009 |
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61300631 |
Feb 2, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 27/18 20130101;
A61L 2202/21 20130101; A61L 27/54 20130101; A61L 27/10 20130101;
A61L 2300/104 20130101; A61L 27/443 20130101; A61L 2300/404
20130101; A61L 27/56 20130101; A61L 27/446 20130101 |
International
Class: |
A61L 27/54 20060101
A61L027/54; A61L 27/44 20060101 A61L027/44; A61L 27/10 20060101
A61L027/10; A61L 27/18 20060101 A61L027/18; A61L 27/56 20060101
A61L027/56 |
Claims
1. A surgical implant configured for implantation at an implant
site of a host, said device having an exposed surface and
comprising a thermoplastic resin and zeolite incorporated in said
resin, and one or more non-oxidized ion-exchangeable metal ions
incorporated in said zeolite, said surgical implant upon
implantation and exposure to bodily fluids of said host being
capable of releasing from said exposed surface said one or more
non-oxidized ion-exchangeable metal ions in an antimicrobially
effective amount.
2. The surgical implant of claim 1, wherein said thermoplastic
resin comprises PEEK.
3. The surgical implant of claim 1, wherein said one or more
non-oxidized ion-exchangeable metal ions are selected from the
group consisting of silver, copper, zinc, mercury, tin, lead, gold,
bismuth, cadmium, chromium and thallium.
4. The surgical implant of claim 1, wherein said one or more
non-oxidized ion-exchangeable metal ions are silver ions.
5. The surgical implant of claim 1, wherein said zeolite comprises
an A-type zeolite.
6. The surgical implant of claim 1, wherein said non-oxidized
ion-exchangeable metal ions are incorporated in said zeolite only
at said exposed surface.
7. The surgical implant of claim 1, wherein said thermoplastic
resin has a porosity between 50% and 85% by volume.
8. The surgical implant of claim 2, wherein said one or more
non-oxidized ion-exchangeable metal ions are selected from the
group consisting of silver, copper, zinc, mercury, tin, lead, gold,
bismuth, cadmium, chromium and thallium.
9. The surgical implant of claim 2, wherein said one or more
non-oxidized ion-exchangeable metal ions are silver ions.
10. The surgical implant of claim 2, wherein said zeolite comprises
an A-type zeolite.
11. The surgical implant of claim 2, wherein said non-oxidized
ion-exchangeable metal ions are incorporated in said zeolite only
at said exposed surface.
12. The surgical implant of claim 2, wherein said PEEK has a
porosity between 50% and 85% by volume.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/287,845 filed Oct. 7, 2016, which is a
continuation of U.S. patent application Ser. No. 13/511,176 filed
Aug. 30, 2012 (now U.S. Pat. No. 9,492,584 Issued Nov. 15, 2016),
which is a 371 of PCT/US2010/058009 filed Nov. 24, 2010, which
claims priority of U.S. Provisional Application Ser. No. 61/264,289
filed Nov. 25, 2009 and U.S. Provisional Application Ser. No.
61/300,631 filed Feb. 2, 2010, the disclosures of which are
incorporated herein by reference.
BACKGROUND
[0002] Implantable medical devices are implanted into the body for
various reasons, including orthopedics (e.g., hip replacement,
spinal procedures, knee replacement, bone fracture repair, etc. In
view of the structural integrity requirements of such devices,
materials of fabrication are limited, and conventionally include
metal, plastic and composites.
[0003] The benefits derived from these devices are often offset by
infection, which can lead to sepsis and death. The most common
organisms causing infections are Staphylococcus epidermidis and
Staphylococcus aureus. Other gram-positive bacteria, gram-negative
bacteria and fungal organisms also are problematic. Of particular
concern is Methicillin-resistant Staphylococcus aureus (MRSA), a
type of staphylococcus bacteria that are resistant to many
antibiotics. As a result, MRSA infections are more difficult to
treat than ordinary staph infections, and have become a serious
problem.
[0004] Many pathogenic bacteria can form multicellular coatings,
called biofilms on bioengineered implants. Biofilms can facilitate
the proliferation and transmission of microorganisms by providing a
stable protective environment. These biofilms, when well developed,
can disseminate bacterial planktonic showers which can result in
broad systemic infection.
[0005] Bioengineered materials act as excellent hosts for the
formation of bacterial biofilms. Occasionally, (the implant itself
carries the infecting organism) implants develop very tenacious
biofilms seeded by infecting organisms. When this occurs, usually
the implant must be removed, the patient must be treated with a
prolonged course of one or more antibiotics in an effort to cure
the infection, and a new implant is then re-implanted. This
obviously subjects the patient to additional trauma and pain, and
is extremely expensive.
[0006] Accordingly, much research has been devoted toward
preventing colonization of bacterial and fungal organisms on the
surfaces of orthopedic implants by the use of antimicrobial agents,
such as antibiotics, bound to the surface of the materials employed
in such devices. For example, silver is a powerful, natural
antibiotic and preventative against infections. Acting as a
catalyst, it disables the enzyme that one-cell bacteria, viruses
and fungi need for their oxygen metabolism. They suffocate without
corresponding harm occurring to human enzymes or parts of the human
body chemistry. The result is the destruction of disease-causing
organisms in the body. Silver disrupts bacteria membranes,
inter-membrane enzymes, and DNA transcription.
[0007] Ceramics such as zeolite function as a cation cage, being
able to be loaded with silver and other cations having
antimicrobial properties. Metal zeolites can be used as an
antimicrobial agent, such as by being mixed with the resins used as
thermoplastic materials to make the implantable devices, or as
coatings to be applied to the devices; see, for example, U.S. Pat.
No. 6,582,715, the disclosure of which is hereby incorporated by
reference. The antimicrobial metal zeolites can be prepared by
replacing all or part of the ion-exchangeable ions in zeolite with
ammonium ions and antimicrobial metal ions. Preferably, not all of
the ion-exchangeable ions are replaced.
[0008] One particular thermoplastic resin that has been found to be
useful in an implant is polyetheretherketone (PEEK). PEEK is
suitable because its modulus closely matches that of bone. It is
possible, under conditions of high temperature and high shear, to
incorporate antimicrobial zeolite, such as silver zeolite, into
PEEK, such as by mixing doped metal zeolites into molten PEEK
(melting point between 300 and 400.degree. C.), followed by molding
and processing of the composite blend. Pure PEEK is very light tan
and silver zeolite is white. However, the heated melt after
processing becomes a dark brown color. The reasons for color
development may include oxidation of some of the silver to silver
oxides, which may be less soluble and less effective than pure
silver cation attached to the zeolite cage. Silver metal can have
catalytic properties and may cause breakdown and partial
decomposition of the PEEK polymer. Grades of PEEK approved for
implantation are very pure and inert and need to pass stringent
cytotoxicity testing before being allowed to be implanted into
mammals.
[0009] The ISO 10993 set entails a series of standards for
evaluating the biocompatibility of a medical device prior to a
clinical study. These documents were preceded by the Tripartite
agreement and are a part of the harmonization of the safe use
evaluation of medical devices. Those standards include: [0010] ISO
10993-1:2003 Biological evaluation of medical devices Part 1:
Evaluation and testing [0011] ISO 10993-2:2006 Biological
evaluation of medical devices Part 2: Animal welfare requirements
[0012] ISO 10993-3:2003 Biological evaluation of medical devices
Part 3: Tests for genotoxicity, carcinogenicity and reproductive
toxicity [0013] ISO 10993-4:2002/Amd 1:2006 Biological evaluation
of medical devices Part 4: Selection of tests for interactions with
blood [0014] ISO 10993-5:2009 Biological evaluation of medical
devices Part 5: Tests for in vitro cytotoxicity [0015] ISO
10993-6:2007 Biological evaluation of medical devices Part 6: Tests
for local effects after implantation [0016] ISO 10993-7:1995
Biological evaluation of medical devices Part 7: Ethylene oxide
sterilization residuals [0017] ISO 10993-8:2001 Biological
evaluation of medical devices Part 8: Selection of reference
materials [0018] ISO 10993-9:1999 Biological evaluation of medical
devices Part 9: Framework for identification and quantification of
potential degradation products [0019] ISO 10993-10:2002/Amd 1:2006
Biological evaluation of medical devices Part 10: Tests for
irritation and delayed-type hypersensitivity [0020] ISO
10993-11:2006 Biological evaluation of medical devices Part 11:
Tests for systemic toxicity [0021] ISO 10993-12:2007 Biological
evaluation of medical devices Part 12: Sample preparation and
reference materials (available in English only) [0022] ISO
10993-13:1998 Biological evaluation of medical devices Part 13:
Identification and quantification of degradation products from
polymeric medical devices [0023] ISO 10993-14:2001 Biological
evaluation of medical devices Part 14: Identification and
quantification of degradation products from ceramics [0024] ISO
10993-15:2000 Biological evaluation of medical devices Part 15:
Identification and quantification of degradation products from
metals and alloys [0025] ISO 10993-16:1997 Biological evaluation of
medical devices Part 16: Toxicokinetic study design for degradation
products and leachables [0026] ISO 10993-17:2002 Biological
evaluation of medical devices Part 17: Establishment of allowable
limits for leachable substances [0027] ISO 10993-18:2005 Biological
evaluation of medical devices Part 18: Chemical characterization of
materials [0028] ISO/TS 10993-19:2006 Biological evaluation of
medical devices Part 19: Physio-chemical, morphological and
topographical characterization of materials [0029] ISO/TS
10993-20:2006 Biological evaluation of medical devices Part 20:
Principles and methods for immunotoxicology testing of medical
devices
[0030] There is a possibility that reactions catalyzed by silver
while silver zeolite is being incorporated into PEEK, at high
temperature, could generate toxic materials which could cause the
product to fail these tests. Further still, at these high
processing temperatures, metal zeolite can release moisture if it
is not extremely dry. This moisture can cause the formation of
voids in the polymer melt and can contribute to the decomposition
of the PEEK polymer and to oxidation of metals, such as silver,
copper and/or zinc, incorporated into the zeolite antimicrobial.
Although the presence of voids may not be critical for certain
non-load bearing applications, the absence of voids is critical for
load-bearing applications such as spinal repair.
[0031] If the process of incorporating metal zeolites is carried
out in air, severe oxidation can occur as the temperature is
raised, and moisture and oxygen come into contact with the metal
ions. Silver will rapidly darken to a dark brown or black color.
Also, the incorporation of significant quantities of metal zeolites
into the PEEK polymer can affect the viscosity and rheology of the
composition.
[0032] Accordingly, it would be desirable to provide medical
devices with effective antimicrobial activity in order to reduce
the growth of bacteria and risk of infection that do not suffer
from the aforementioned drawbacks.
SUMMARY
[0033] The shortcomings of the prior art have been overcome by the
embodiments disclosed herein, which relate to devices, such as
surgical implants, having antimicrobial properties produced by an
inorganic antimicrobial agent, and methods of post-loading ceramic
particles with antimicrobial metal cations after the ceramic has
been incorporated into the plastic, and is preferably allowed to
cool and set in its final shape, which can be achieved by injection
molding or by cutting and machining. In certain embodiments, the
devices are orthopedic implants. In certain embodiments, the
antimicrobial agent is a ceramic species, preferably a metal
zeolite. In certain embodiments, the device includes a polymer. In
certain embodiments, the polymer is polyaryletheretherketone
(PEEK). In certain embodiments, the source of antimicrobial
activity includes ion-exchangeable cations contained in a zeolite.
In certain embodiments, disclosed are methods of imparting
antimicrobial activity to devices by controlling the delivery of
certain cations through ion-exchange via a zeolite incorporated in
the device introduced in a patient. In certain embodiments, the
metal cation is present at a level below the ion-exchange capacity
in at least a portion of the zeolite particles.
[0034] In certain embodiments, the zeolite is incorporated into the
device and surface exposed zeolite is charged with metal ions from
one or more aqueous solutions as a source of one or more metal
ions. The device is introduced into the body surgically. The rate
of release is governed by the extent of loading of the PEEK with
zeolite and the extent to which the exposed zeolite is charged with
metal ions. The electrolyte concentration in blood and body fluids
is relatively constant and will cause ion exchange with ions such
as silver, copper and zinc, etc. from the surface of the implant,
which deactivate or kill gram positive and gram negative organisms,
including E. coli and Staphylococcus aureus. Effective
antimicrobial control (e.g., a six log reduction of microorganisms)
is achieved even at low metal ion concentrations of 40 ppb. Radio
opacity when viewed under X-ray was retained.
DETAILED DESCRIPTION
[0035] Embodiments disclosed herein relate to the use of ceramics,
preferably zeolites, as a cation cage in combination with medical
implants to deliver and dose one or more antimicrobial cations.
Suitable cations include silver, copper, zinc, mercury, tin, lead,
gold, bismuth, cadmium, chromium and thallium ions, with silver,
zinc and/or copper being preferred, and silver being especially
preferred.
[0036] Either natural zeolites or synthetic zeolites can be used to
make the zeolites used in the embodiments disclosed herein.
"Zeolite" is an aluminosilicate having a three dimensional skeletal
structure that is represented by the formula:
XM.sub.2/nO.Al.sub.2O.sub.3.YsiO.sub.2.ZH.sub.2O, wherein M
represents an ion-exchangeable ion, generally a monovalent or
divalent metal ion, n represents the atomic valency of the (metal)
ion, X and Y represent coefficients of metal oxide and silica
respectively, and Z represents the number of water of
crystallization. Examples of such zeolites include A-type zeolites,
X-type zeolites, Y-type zeolites, T-type zeolites, high-silica
zeolites, sodalite, mordenite, analcite, clinoptilolite, chabazite
and erionite.
[0037] Zeolites can be incorporated into masterbatches of a range
of polymers. For final incorporation into PEEK, a masterbatch
should be produced by incorporating typically about 20% zeolite.
When provided in this form, the pellets of masterbatch PEEK
containing the zeolite particles can be further reduced by mixing
with more virgin PEEK at high temperature and under high shear. If
metal were present in the zeolite, this would result in yet a
second exposure to conditions which could cause deterioration of
the product.
[0038] Other suitable resins include low density polyethylene,
polypropylene, ultra high molecular weight polyethylene or
polystyrene, polyvinyl chloride, ABS resins, silicones, rubber, and
mixtures thereof, and reinforced resins, such as ceramic or carbon
fiber-reinforced resins, particularly carbon fiber-reinforced PEEK.
The latter can be produced by dispersing the reinforcing material
or materials (e.g., carbon fibers) in the polymer matrix, such as
by twin screw compounding of implantable PEEK polymer with carbon
fibers. The resulting carbon fiber-reinforced product can be used
to direct injection mold final devices and near net shapes, or it
can be extruded into stock shapes for machining. The incorporation
of fibers or other suitable reinforcing material(s) provides high
wear resistance, a Young's modulus of 12 GPa (matching the modulus
of cortical bone) and providing sufficient strength to permit its
use in very thin implant designs which distribute the stress more
efficiently to the bone. The amount of reinforcing material such as
carbon fiber incorporated into the resin such as PEEK can be
varied, such as to modify the Young's modulus and flexural
strength. One suitable amount is 30 wt % carbon fiber. The resins
also can be made porous, such as porous PEEK, PAEK and PEKK, with
suitable porosities including porosities between 50% and 85% by
volume. Average pore size is generally greater than 180 microns in
diameter, suitably between about 300 and about 700 microns.
Porosity can be imparted using a pore forming agent such as sodium
chloride, to create a porous polymer comprising a plurality of
interconnected pores, by processes known in the art. Each of the
foregoing can be formulated to contain suitable amounts of zeolite
particles, usually about 20 wt %. An UHMWPE is preferred for the
implant devices.
[0039] Typical amounts of zeolite particles incorporated in an
implant resin range from 0.01 to 50 wt. %, more preferably 0.01 to
8.0 wt. %, most preferably 0.1 to 5.0 wt. %. If an implant is
coated with a coating or resin which is loaded with zeolite, the
coating needs to be applied and dried or cured before the infusion
is carried out. The method used to coat an implant is not
particularly limited, and can include spraying, painting or
dipping. When compounded into a PEEK masterbatch, for example, the
PEEK should be protected from sources of moisture and contamination
prior to reduction with virgin resin. The compounding can be
carried out by blending the molten masterbatch and let down resin
under conditions of high temperature and high shear.
[0040] The masterbatch is a concentrated mixture of pigments and/or
additives (e.g., zeolite powder) encapsulated during a heat process
into a carrier resin which is then cooled and cut into a granular
shape. Using a masterbatch allows the processor to introduce
additives to raw polymer (let down resin) economically and simply
during the plastics manufacturing process.
[0041] In accordance with certain embodiments, a purer more stable
product can be produced by charging the polymer with pure zeolite
(e.g., one that is not yet loaded with antimicrobial metal ions, or
one that is only partially loaded), such as type X zeolite,
available from W.R. Grace & Co.-Conn., which is capable of
carrying a cationic metal ion cargo such as Ag+, Cu++, Cu+, or Zn+,
and subsequently charging the cooled (e.g. cooled to a temperature
between about 0 and 100.degree. C., preferably about room
temperature) zeolite-containing PEEK surface with metal ions from a
metal ion source such as an aqueous metal ion solution, such as
silver nitrate, copper nitrate and zinc nitrate, alone or in
combination. Cooling to lower temperatures gives lower loading
rates but higher stability. Loading at even higher temperatures can
be carried out at a faster rate by maintaining the system under
pressure, such as in a pressure cooker or autoclave. The content of
the ions can be controlled by adjusting the concentration of each
ion species (or salt) in the solution.
[0042] By incorporating the metal cation into the zeolite after the
zeolite has been incorporated into the polymer resin, oxidation of
the metal ions is reduced or eliminated. Those skilled in the art
will appreciate that other metal ion salt solutions, such as
acetates, benzoates, carbonates, oxides, etc., can be used instead
of or in addition to nitrates. Addition of nitric acid to the
infusion solution also may be advantageous in that it can etch the
surface of the implant, providing additional surface area for ion
exchange.
[0043] Since PEEK is susceptible to dissolution by strong oxidizing
acids, care should be taken to not use too high an acid
concentration that may lead to metal zeolite particles being
released from the surface. PEEK is very stable and impermeable to
water and bodily fluids. As a result, it is expected that metal
ions that are incorporated in a zeolite cage dispersed in PEEK will
only elute when the cage is exposed at the surface of the polymer.
For this reason, it is possible to post incorporate at least as
much available metal ions by post treatment from solution as would
be available from metal zeolite incorporated into the hot mix. In
fact, the availability of metal ions from the post incorporated
system is expected to be significantly higher since the metal ions
will be pure and will have experienced no thermal oxidation or hot
reactions with the polymer.
[0044] The amount of metal ions in the zeolite should be sufficient
such that they are present in an antimicrobial effective amount.
For example, suitable amounts can range from about 0.1 to about 20
or 30% of the exposed zeolite (w/w %). These levels can be
determined by complete extraction and determination of metal ion
concentration in the extraction solution by atomic absorption.
[0045] Preferably the ion-exchanged antimicrobial metal cations are
present at a level less than the ion-exchange capacity of the
ceramic particles. The amount of ammonium ions is preferably
limited to from about 0.5 to about 15 wt. %, more preferably 1.5 to
5 wt. %. For applications where strength is not of the utmost
importance the loading of zeolite can be taken as high as 50%. At
such loadings the permeation of metal ions can permeate well below
the surface layer due to interparticle contact, and much greater
loadings of metal ions are possible.
[0046] The amount of zeolite incorporated into the resin should
also be an amount effective for promoting antimicrobial activity;
e.g., a sufficient amount so as to prevent or inhibit the growth of
bacterial and/or fungal organisms or preferably to kill the same.
Suitable amounts of zeolite in the resin range from about 0.01 to
50.0 wt. %, more preferably from about 0.01 to 8.0 wt. %, most
preferably from about 0.1 to about 5.0 wt. %.
[0047] The absorption of metal ions into synthetic zeolites, or
natural Zeolites, in an aqueous dispersion, or loaded in a polymer
can be carried out from solutions of the metal salts. The rates of
absorption will be proportional to the area of zeolite surface
available, the concentration of metal ions in solution and the
temperature. As the concentration of metal absorbed by the zeolite
increases, the rate will be reduced. When the rate of absorption
reaches the rate of release, equilibrium is reached at that
solution concentration. A higher concentration in solution could
drive the loading higher. Loaded zeolite can be rinsed with
deionized water to completely remove adherent metal ion solution.
The objective is to have only ion exchanged metal cations attached
to the cage and these will only be removed by ion exchange, not by
deionized water.
[0048] The most useful ions to incorporate, for the purposes of
release into orthopedic implants, are silver, copper and zinc ions.
All three have antimicrobial properties, silver being the most
active. There also may be synergies between the metals, in terms of
antimicrobial activity. For instance, if a microorganism is
developing resistance to one metal species, it may still be readily
killed by one of the others. Copper and zinc ions also exert
further functions in healing and wound repair and bone growth.
[0049] For example, the PEEK zeolite composite can be loaded by
bringing the material into contact with an aqueous mixed solution
containing ammonium ions and antimicrobial metal ions such as
silver copper, zinc etc. The most suitable temperatures at which
the infusion can be carried out range from 5.degree. C. to
75.degree. C., but higher temperatures may also be used even above
100.degree. C. if the reaction vessel is held under pressure.
Higher temperatures will show increased infusion rates but lower
temperatures may eventually produce more uniform and higher
loadings. The pH of the infusion solution can range from about 2 to
about 11 but is preferably from about 4 to about 7.
[0050] Suitable sources of ammonium ions include ammonium nitrate,
ammonium sulfate and ammonium acetate. Suitable sources of the
antimicrobial metal ions include: a silver ion source such as
silver nitrate, silver sulfate, silver perchlorate, silver acetate,
diamine silver nitrate and diamine silver nitrate; a copper ion
source such as copper(II) nitrate, copper sulfate, copper
perchlorate, copper acetate, tetracyan copper potassium; a zinc ion
source such as zinc(II) nitrate, zinc sulfate, zinc perchlorate,
zinc acetate and zinc thiocyanate.
[0051] The following are illustrative examples of infusion
solutions but a wide range of concentrations and ratios are
effective.
TABLE-US-00001 Infusion solution A Component Composition (W/W)%
Ammonium hydroxide 2.0 Silver Nitrate 1.2 Purified water 96.8 pH
can be adjusted with acid such as citric acid or nitric acid Total
100
TABLE-US-00002 Infusion Solution B Component Composition (W/W)%
Ammonium hydroxide 2.0 Copper Nitrate 5.0 Purified water 93.0 pH
can be adjusted with acid such as citric acid or nitric acid Total
100.0
TABLE-US-00003 Infusion Solution C Component Composition (W/W)%
Ammonium hydroxide 2.0 Zinc Nitrate 7.0 Purified water 91.0 pH can
be adjusted with acid such as citric acid or nitric acid Total
100.0
TABLE-US-00004 Infusion Solution D Component Composition (W/W)%
Ammonium hydroxide 2.0 Silver Nitrate 0.5 Copper Nitrate 2.0 Zinc
Nitrate 2.5 Purified water 93.0 pH can be adjusted with acid such
as citric acid or nitric acid Total 100
[0052] Since there is a delicate balance between the concentrations
of silver, zinc and copper in metabolism for optimum healing, an
advantage of the current method is that it will provide and easy
method for accurately controlling the relative concentrations of
the individual metal ions. The optimum ratios can be achieved by
varying the concentrations of the various metal ion salts to load
at the appropriate ratios and subsequently release at the
appropriate ratios and rates.
[0053] The rates of release of the metal ions into phosphate
buffered saline or for example 0.8% sodium nitrate solution, can be
quantified by Inductively Coupled Plasma spectroscopy ICP, or
Graphite Furnace Atomic Absorption spectroscopy.
[0054] With a ladder study these results can be used to optimize
the elution rates. Because the metal ions are never exposed to high
temperature, the ions attached and eluting from the zeolite will be
pure metal cations.
[0055] Another advantage of the current method is that the amount
of metal being incorporated into the implant will be limited to
just what is incorporated in the surface layer. In terms of cost
and safety it is a superior solution.
[0056] The process will be effective whether the implants are
injection molded or machined to achieve the final dimensions of the
implant.
[0057] Whereas the process is most applicable to polymers with a
high melting point such as PEEK, it could also be used effectively
with polymers of lower melting points which are used in a wide
range of orthopedic applications. HDPE, for instance, is used in
certain elements of hip and knee transplants.
[0058] The post loading process is also appropriate for thermoset
resins such as polyesters epoxies and urethanes, etc.
[0059] This approach will avoid contact of the silver ion with the
reactants, reactive intermediates and catalysts which form the
finished polymer.
[0060] The embodiments disclosed herein are applicable to
generating self sterilizing plastic fibers and film. Such materials
can be used to produce wound dressings and in a wide array of
applications.
[0061] Facemasks which elute silver copper and zinc are used to
provide long term control of microorganisms which might be inhaled
in a medical setting or increasingly in the case of a possible
pandemic. Suitable substrates for such devices include polyethylene
(PE), polypropylene (PP), polyethylene terephthalate (PET), PCT,
PETG (PET, type G), Co-PET and co-polyesters generally, Styrene,
polytrimethylene terephalate (PTT).sub.m 3GT, Halar.RTM., polyamide
6 or 6,6, etc., See U.S. Pat. Nos. 6,946,196 and 6,723,428 to Foss
manufacturing, the disclosures of which are incorporated by
reference.
[0062] Other applications where self sterilizing fabrics or plastic
sheeting find application are within the scope of the embodiments
disclosed herein. [0063] Where material is exposed or can be
immersed, the depleted zeolite can be recharged with antimicrobial
metal ions.
[0064] It is possible to load a polymer with pure zeolite, extrude
the polymer into filaments, and post load the material with the
antimicrobial metal ions in the manner described for surgical
implants.
[0065] Although the focus of the embodiments disclosed herein is on
orthopedic implants, those skilled in the art will appreciate that
apply to a much wider array of applications, such as toothbrushes,
door handles, computer mice and keyboard components, knife handles,
and cutting boards, surgical instruments, telephone surface
components, water drinking vessels, food storage containers and
polymers for producing self sterilizing clothing and self
sterilizing face masks.
EXAMPLE 1
[0066] An ion exchange zeolite, natural, or synthetic such as
zeolite type A or type X commercially available from W.R. Grace
& Co.-Conn., or equivalent, is incorporated into PEEK. Typical
amounts of zeolite particles incorporated in an implant resin range
from 0.01 to 10 wt. %, more preferably 0.01 to 8.0 wt. %, most
preferably 0.1 to 5.0 wt. %. The method used to coat an implant is
not particularly limited, and can include spraying, painting or
dipping. When compounded into PEEK, for example, the PEEK composite
should be protected from sources of moisture and contamination. The
compounding can be carried out by blending.
[0067] About 5% by weight of the zeolite powder is mixed thoroughly
with the powdered or prilled PEEK. The mixture is brought up to
temperature and processed at 400.degree. C. using high shear. The
zeolite and PEEK must be dry before processing in order to minimize
decomposition and void formation in the product.
[0068] This system containing Zeolite without added silver ions
does not show the progressive color development and darkening which
is seen with systems containing silver.
[0069] The dark color development in silver zeolite containing
systems is thought to be due to silver oxide formation and polymer
decomposition.
[0070] The material is processed as before and can be formed into
prills for further processing, cast into blocks, extruded into rods
or injection molded into the final desired shapes.
[0071] The block and rod materials can be machined into shapes
which are suitable for use as orthopedic implants or other designs
where antimicrobial PEEK finds application. Implants can be
designed to provide enhanced surface area by having grooves cut in
the surfaces or by producing products with holes in the body of the
pieces. Surface area can be further enhanced by sanding or abrasive
blasting of the surfaces.
EXAMPLE 2
Loading the Finished Pieces with Antimicrobial Metal Ions
[0072] Finished pieces produced as described in Example 1 are
immersed in an infusion solution to charge the pieces with
antimicrobial metal ions.
[0073] A typical solution for infusion is produced by adding 2%
silver nitrate, 5% copper nitrate trihydrate and 1% nitric acid to
purified water.
TABLE-US-00005 Component Composition (W/W)% Silver Nitrate 2 Copper
nitrate trihydrate 5 Nitric acid 1 Purified water 92 Total 100
[0074] The finished pieces are supported or allowed to move freely
in the infusion solution. The solution should be agitated to
enhance diffusion of ions to and from the surface of the composite.
It is advisable to carry out the infusion process in the dark to
minimize photo oxidation of the silver in solution. This can be
affected on a lab scare by placing an opaque cover such as a tin
can over the beaker in which the pieces are being infused.
[0075] The rate of infusion depends on several variables. At normal
temperatures, 90 minutes is sufficient time to effectively charge
the surfaces with metal ions. The infusion process can be allowed
to run for 24 hours or more to maximize the antimicrobial metal
loading. [0076] The rate and extent of loading depends on several
variables, including solution concentration, solution composition,
(metal ion ratios), solution temperature, and agitation rate.
[0077] It should be possible to load the exposed zeolite to as much
as 40% by weight with metal ions.
[0078] When infusion is complete or carried out to the desired
levels, the pieces are removed from the infusion solution and
triply rinsed with purified water. They may then be dried in a
stream of hot air or in an oven or desiccator, etc.
[0079] A measure of the antimicrobial activity of an article is the
antimicrobial metal (e.g., silver) release from the exterior
surface of the article. Metal release can be measured as the amount
of antimicrobial metal released from the exterior surface of a 2
inch by 2 inch sample (0.05 meter by 0.05 meter, or 5 cm by 5 cm).
The exterior surface of the sample to be tested is contacted in a
sodium nitrate solution (40 mL of 0.8% sodium nitrate) for 24 hours
at room temperature (i.e., 25 C) to form a test solution. The test
solution is then analyzed to measure the amount of antimicrobial
metal in the test solution in parts per billion, and thus the
exposure of the inorganic antimicrobial agent at the surface of the
article. The amount of antimicrobial metal in the test solution may
then be measured using a graphite furnace atomic absorption
spectrophotometer or ICP. For an article comprising 2.0 percent by
weight (wt. %) of an inorganic antimicrobial agent based on the
weight of the article or a layer of a multi-layer article, and
wherein the inorganic antimicrobial comprises 2.0 wt % of a
antimicrobial metal based on the total weight of the inorganic
antimicrobial agent, the exterior surface has a antimicrobial metal
release of greater than or equal to about 10 parts per billion
(ppb), preferably greater than or equal to about 20 ppb, more
preferably greater than or equal to about 30 ppb, and most
preferably greater than or equal to about 40 ppb.
* * * * *