U.S. patent application number 11/220328 was filed with the patent office on 2006-03-09 for metallic structures incorporating bioactive materials and methods for creating the same.
This patent application is currently assigned to Medlogics Device Corporation. Invention is credited to Richard L. Klein, Nathan C. Maier.
Application Number | 20060051397 11/220328 |
Document ID | / |
Family ID | 34551388 |
Filed Date | 2006-03-09 |
United States Patent
Application |
20060051397 |
Kind Code |
A1 |
Maier; Nathan C. ; et
al. |
March 9, 2006 |
Metallic structures incorporating bioactive materials and methods
for creating the same
Abstract
Disclosed herein are methods to create medical devices and
medical devices including bioactive composite structures. The
methods include using electroless and electrophoretic deposition
and codeposition methods for providing implantable medical devices
coated with bioactive composite structures. In one use, the
implantable medical devices of the present invention include stents
with bioactive composite structures.
Inventors: |
Maier; Nathan C.;
(Forestville, CA) ; Klein; Richard L.; (Santa
Rosa, CA) |
Correspondence
Address: |
PRESTON GATES & ELLIS LLP;ATTN: C. RACHAL WINGER
925 FOURTH AVE
SUITE 9200
SEATTLE
WA
98104-1158
US
|
Assignee: |
Medlogics Device
Corporation
Santa Rosa
CA
|
Family ID: |
34551388 |
Appl. No.: |
11/220328 |
Filed: |
September 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10701262 |
Nov 3, 2003 |
|
|
|
11220328 |
Sep 6, 2005 |
|
|
|
Current U.S.
Class: |
424/423 ;
205/263 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61L 31/088 20130101; A61L 2300/42 20130101; A61L 2300/104
20130101; A61L 2300/102 20130101; A61L 2300/608 20130101; A61L
2300/414 20130101; A61L 31/16 20130101; A61L 2300/41 20130101 |
Class at
Publication: |
424/423 ;
205/263 |
International
Class: |
A61F 2/00 20060101
A61F002/00; C25D 3/46 20060101 C25D003/46 |
Claims
1. A method comprising: providing a first bath comprising metal
ions and at least one bioactive material wherein said metal ions
and said at least one bioactive material in said first bath are
provided at a first ratio; contacting a substrate with said first
bath; forming a bioactive composite structure with a first
concentration of metal ions and said at least one bioactive
material on said substrate using an electrochemical process;
altering said first ratio between said metal ions and said at least
one bioactive material to form a second ratio; continuing to form
said bioactive composite structure on said substrate using an
electrochemical process but with a second concentration of metal
ions and said at least one bioactive material.
2. The method according to claim 1, wherein said electrochemical
process is an electroless process or an electrophoretic
process.
3. The method according to claim 1, wherein said altering of said
first ratio to form said second ratio occurs in said first
bath.
4. The method according to claim 1, wherein said altering of said
first ratio to form said second ratio occurs in a second bath.
5. A method comprising: providing a first bath comprising metal
ions and at least one bioactive material at a first ratio wherein
said metal ions and said at least one bioactive material comprise a
positive charge; contacting a substrate with said first bath;
applying a negative charge to said substrate; forming a bioactive
composite structure on said substrate using an electrochemical
process.
6. The method according to claim 5, wherein said applying of said
negative charge is continuous and said electrochemical process is
an electrophoretic process.
7. The method according to claim 5, wherein said method further
comprises removing said negative charge from said substrate and
continuing to form said bioactive composite structure through an
electroless process.
8. The method according to claim 5, wherein said applying of said
negative charge is intermittent and wherein when said charge is
applied to said substrate said electrochemical process is an
electrophoretic process and wherein when said charge is not applied
to said substrate said electrochemical process is an electroless
process.
9. The method according to claim 5, wherein said at least one
bioactive material comprises a positive charge due to the coupling
of a surfactant to said at least one bioactive material.
10. The method according to claim 5, wherein after said forming of
a portion of said bioactive composite structure, said first ratio
in said first bath is altered to form a second ratio and wherein
thereafter, said forming of said bioactive composite structure is
continued.
11. The method according to claim 5, wherein after said forming of
a portion of said bioactive composite structure, a second ratio in
a second bath is created and wherein said substrate is contacted
with said second bath, thus continuing the formation of said
bioactive composite structure.
12. A medical device formed by a method comprising: providing a
first bath comprising metal ions and at least one bioactive
material wherein said metal ions and said at least one bioactive
material in said first bath are provided at a first ratio;
contacting a substrate with said first bath; forming a portion of a
bioactive composite structure with a first concentration of metal
ions and said at least one bioactive material on said substrate
using an electrochemical process; altering said first ratio between
said metal ions and said at least one bioactive material to form a
second ratio; and continuing to form said bioactive composite
structure on said substrate using an electrochemical process but
with a second concentration of metal ions and said at least one
bioactive material.
13. The medical device according to claim 12, wherein said
electrochemical process is an electroless process or an
electrophoretic process.
14. The medical device according to claim 12, wherein said altering
of said first ratio to form said second ratio occurs in said first
bath.
15. The medical device according to claim 12, wherein said altering
of said first ratio to form said second ratio occurs in a second
bath.
16. A medical device formed by a method comprising: providing a
first bath comprising metal ions and at least one bioactive
material at a first ratio wherein said metal ions and said at least
one bioactive material comprise a positive charge; contacting a
substrate with said first bath; applying a negative charge to said
substrate; forming a bioactive composite structure on said
substrate using an electrochemical process.
17. The medical device according to claim 16, wherein said applying
of said negative charge is continuous and said electrochemical
process is an electrophoretic process.
18. The medical device according to claim 16, wherein said applying
of said negative charge is intermittent and wherein when said
charge is applied to said substrate said electrochemical process is
an electrophoretic process and when said charge is not applied to
said substrate said electrochemical process is an electroless
process.
19. The medical device according to claim 16, wherein said at least
one bioactive material comprises a positive charge due to the
coupling of a surfactant to said at least one bioactive
material.
20. The medical device according to claim 16, wherein after said
forming of a portion of said bioactive composite structure, said
first ratio in said first bath is altered to form a second ratio
and wherein thereafter, said forming of said bioactive composite
structure is continued.
21. The medical device according to claim 16, wherein after said
forming of a portion of said bioactive composite structure, a
second ratio in said second bath is created and wherein said
substrate is contacted with said second bath, thus continuing the
formation of said bioactive composite structure.
22. The medical device according to claim 16, wherein said
substrate is a stent.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/701,262, filed on Nov. 3, 2003, which is
herein incorporated by reference in its entirety for all
purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to electroless and
electrophoretic deposition and codeposition methods for providing
implantable medical devices coated with bioactive composite
structures. The present invention also provides methods for
creating different concentrations of bioactive materials in
different portions or layers of the bioactive composite structure
through the use of electroless and/or electrophoretic codeposition
processes.
BACKGROUND OF THE INVENTION
[0003] In many circumstances, it is beneficial for an implanted
medical device to release a bioactive material into the body once
the device has been implanted. Such released bioactive materials
can enhance the treatment offered by the implantable medical
device, facilitate recovery in the implanted area and lessen the
local physiological trauma associated with the implant. Vascular
stents are a type of device that has benefited from the inclusion
of bioactive materials. Stents are ridged, or semi-ridged, tubular
scaffoldings that are deployed within the lumen (inner tubular
space) of a vessel or duct during angioplasty or related procedures
intended to restore patency (openness) to vessel or duct lumens.
Stents generally are left within the lumen of a vessel or duct
after angioplasty or a related procedure to reduce the risks of
restenosis, abrupt reclosure or re-occlusion. Including bioactive
materials such as, for example and without limitation, rapamycin or
paclitaxel on the surface of the implanted stent further helps to
treat, prevent or inhibit restenosis, abrupt reclosure or
re-occlusion (hereinafter "reclosure").
[0004] One challenge in the field of implantable medical devices
has been adhering bioactive materials to the surface of implantable
devices such that the bioactive materials will be released once the
device is implanted. One approach has been to include the bioactive
materials in polymeric coatings. Polymeric coatings can hold
bioactive materials onto the surface of implantable medical devices
and release the bioactive materials via degradation of the polymer
or diffusion into liquid or tissue (in this case the polymer is
non-degradable). Degradable and non-degradable polymers such as
polylactic acid, polyglycolic acid, and polymethylmethacrylate have
been used in drug-eluting stents.
[0005] While polymeric coatings can be used to adhere bioactive
materials to implanted medical devices, there are a number of
problems associated with their use. First, it is difficult to
predict the degradation kinetics of polymers. Consequently, it is
difficult to predict how quickly a bioactive material in a
polymeric coating will be released. If a drug releases from the
polymeric coating too quickly or too slowly, the intended
therapeutic effect may not be achieved. Second, in some cases,
polymeric coatings produce pro-thrombotic and pro-inflammatory
responses. These pro-thrombotic and pro-inflammatory effects lead
to the necessity of prolonged antiplatelet therapies. Further, in
the case of stents, these effects can exacerbate restenosis and
resulting reclosure, negative effects stents are designed to
prevent. Third, adherence of a polymeric coating to a substantially
different substrate, such as a stent's metallic substrate, is
difficult due to differing characteristics of the materials (such
as differing thermal expansion properties). The difficulty in
adhering the two different material types often leads to inadequate
bonding between the medical device and the overlying polymeric
coating which can result in the separation of the materials over
time. Such separation is an exceptionally undesirable property in
an implanted medical device. Fourth, it is difficult to evenly coat
a medical device with a polymeric coating. The uneven coating of a
medical device can lead to unequal drug delivery across different
portions of the device. This drawback is especially apparent in
relation to small implantable medical devices, such as stents. Due
to the viscosity of polymers during coating, it is difficult to
evenly coat a medical device to faithfully replicate its form.
Fifth, polymeric coatings are large and bulky relative to their
bioactive material storage capacity. Sixth, when delivering a
bioactive material to a patient over a longer period of time, the
bioactive material needs to be stabilized. Some polymeric coatings
cannot provide a stable storage environment for the bioactive
material, in particular when liquid, such as blood, is able to seep
into the polymeric coating. Seventh, polymeric coatings, which by
their nature have large pores, can protect microorganisms in the
interstices of the polymeric coating, thus increasing the risk of
infection. Finally, polymeric coatings remain on the medical device
once the bioactive materials they contained have fully-eluted.
Thus, the negative effects of the polymeric coating remain even
when the bioactive materials are no longer providing continued
treatment.
[0006] Sintered metallic structures can be used as an alternative
to polymeric coatings. In a typical sintering process, small
particles of metal are joined by an epoxy and then treated with
heat and/or pressure to weld them together and to the substrate.
After this process, a porous metallic structure has then been
created. While effective in some instances, sintered metallic
structures have relatively large pores. When a bioactive material
is loaded into the pores of a sintered metallic structure, the
larger pore size can cause the biologically active material to be
released too quickly. As noted above, it would be desirable to have
the ability to increase the bioactive material storage capacity in
a bioactive composite material so that, for example, the bioactive
material can be released to a patient over a long period of
time.
[0007] While several alternative methods for coating stents and
other implantable medical devices with bioactive materials have
also been proposed, these methods also suffer from drawbacks
including those resulting from processing limitations in relation
to the underlying substrate or bioactive agent to be coated;
inability to obtain even distribution of coatings or bioactive
materials; problems with adhesion; biocompatibility issues (e.g.
toxicity, or other adverse biological response); complexity of
processing; size; density (and thus volume of drug that can be held
and released); timing of drug release; high electrical impedance;
low radiopacity; or an impact of the coating on the underlying
substrate's intended function (e.g. mechanical properties,
expansion characteristics, electrical surface conduction, etc.).
Thus, notwithstanding certain benefits that may be provided by
polymeric coatings, sintering or other alternative methods for
coating implantable medical devices with bioactive materials, there
is still room for improvement. Specifically, it would be beneficial
if a coating process and matrix could be provided that overcomes
one or more of the above-mentioned limitations.
SUMMARY OF THE INVENTION
[0008] The present invention addresses many of the drawbacks
associated with previously-available methods of loading bioactive
materials onto implantable medical devices by loading bioactive
materials directly into a metallic layer formed on the surface of
the implantable medical device. Loading bioactive materials
directly into a metallic layer is advantageous for many reasons.
First, the deposited metallic layer or layers, unlike polymers, are
not pro-thrombotic or pro-inflammatory. Because polymers are not
used to carry the bioactive materials, once the bioactive materials
have eluted from the implantable medical device, only bare metal,
which is not pro-thrombotic or pro-inflammatory, is left behind.
Thus, no negative effects of including the bioactive materials are
left behind once the bioactive materials have fully eluted. Second,
when a metallic layer is deposited onto an implantable medical
device that is also made from a metal, the metallic layer and
underlying device do not have substantially different
characteristics, so the risk of separation is diminished
significantly. Third, deposition of a metallic layer in accordance
with the methods of the present invention allows for an even
coating of implantable medical devices regardless of their size or
geometry. Fourth, harsh processing conditions that may damage
bioactive materials during the coating or loading process are not
required and the ability to control the percentage of bioactive
materials present within or around the metallic layer can be easily
controlled. Finally, the methods according to embodiments of the
present invention are economical and scaleable, and are more
cost-effective than other methods of forming bioactive composite
structures.
[0009] Specifically, the methods of the present invention provide
electroless and/or electrophoretic deposition and codeposition
processes. These processes, which will be described fully below,
can provide methods for varying concentrations of bioactive
materials within different portions or layers of a metallic layer
formed through the particular electroless and/or electrophoretic
deposition or codeposition process.
[0010] In one embodiment of the methods of the present invention,
the method comprises providing a first bath comprising metal ions
and at least one bioactive material wherein the metal ions and
bioactive material in the first bath are provided in a first ratio;
contacting a substrate with the first bath, forming a portion of a
bioactive composite structure with a first concentration of metal
ions and bioactive material on the substrate using an
electrochemical process, altering the first ratio between the metal
ions and the at least one bioactive material to form a second
ratio, and continuing to form the bioactive composite structure on
the substrate using an electrochemical process but with a second
concentration of metal ions and the at least one bioactive
material.
[0011] In one embodiment of the methods of the present invention,
the electrochemical process is an electroless process. In another
embodiment of the methods of the present invention, the
electrochemical process is an electrophoretic process. In yet
another embodiment of the methods of the present invention, an
electrophoretic process is followed by an electroless process.
[0012] In another embodiment of the methods of the present
invention, the altering of the first ratio to form a second ratio
occurs in the first bath. In another embodiment of the methods of
the present invention, the altering of the first ratio to form a
second ratio occurs in a second bath.
[0013] In another embodiment of the methods of the present
invention, the at least one bioactive material is selected from the
group described in the detailed description definition of
"bioactive materials." In another embodiment of the methods of the
present invention, the at least one bioactive material is selected
from the group consisting of rapamycin, paclitaxel and HMG-COA
reductase inhibitors.
[0014] Another embodiment of the methods of the present invention
comprises providing a first bath comprising metal ions and at least
one bioactive material at a first ratio wherein both the metal ions
and the at least one bioactive material comprise a positive charge,
contacting a substrate with the first bath, applying a negative
charge to the substrate, and forming a bioactive composite
structure on the substrate using an electrochemical process.
[0015] In an embodiment of the methods of the present invention,
the applying of the negative charge is continuous and the
electrochemical process is an electrophoretic process. In another
embodiment of the methods of the present invention, the negative
charge is removed from the substrate and when the negative charge
is removed from the substrate the electrochemical process changes
from an electrophoretic process to an electroless process. In yet
another embodiment of the methods of the present invention, the
applying of the negative charge is intermittent (i.e. pulsed) and
when the charge is applied to the substrate the electrochemical
process is an electrophoretic process and when the charge is not
applied to the substrate the electrochemical process is an
electroless process.
[0016] In another embodiment of the methods of the present
invention, the at least one bioactive material comprises a positive
charge due to the coupling of a surfactant to the at least one
bioactive material.
[0017] In an embodiment of the methods of the present invention,
after the forming of a portion of the bioactive composite
structure, the first ratio in the first bath is altered to form a
second ratio and wherein thereafter, the forming of the bioactive
composite structure is continued. In another embodiment of the
methods of the present invention, after the forming of a portion of
the bioactive composite structure, a second ratio in a second bath
is created and the substrate is contacted with the second bath,
thus continuing the formation of the bioactive composite
structure.
[0018] In another embodiment of the methods of the present
invention, the at least one bioactive material is selected from the
group described in the detailed description definition of
"bioactive materials." In another embodiment of the methods of the
present invention, the at least one bioactive material is selected
from the group consisting of rapamycin, paclitaxel and HMG-COA
reductase inhibitors.
[0019] The present invention also includes medical devices. In one
embodiment of the medical devices of the present invention, the
medical device is formed by providing a first bath comprising metal
ions and at least one bioactive material wherein the metal ions and
the at least one bioactive material in the first bath are provided
at a first ratio, contacting a substrate with the first bath,
forming a portion of the bioactive composite structure with a first
concentration of metal ions and the at least one bioactive material
on the substrate using an electrochemical process, altering the
first ratio between the metal ions and the at least one bioactive
material to form a second ratio, and continuing to form the
bioactive composite structure on the substrate using an
electrochemical process but with a second concentration of metal
ions and the at least one bioactive material.
[0020] In one embodiment of the medical devices of the present
invention, the electrochemical process is an electroless process.
In another embodiment of the medical devices of the present
invention, the electrochemical process is an electrophoretic
process.
[0021] In an embodiment of the medical devices of the present
invention, the altering of the first ratio to form a second ratio
occurs in the first bath. In another embodiment of the medical
devices of the present invention, the altering of the first ratio
to form a second ratio occurs in a second bath.
[0022] In another embodiment of the medical devices of the present
invention, the at least one bioactive material is selected from the
group described in the detailed description definition of
"bioactive materials." In another embodiment of the medical devices
of the present invention, the at least one bioactive material is
selected from the group consisting of rapamycin, paclitaxel and
HMG-CoA reductase inhibitors.
[0023] In an embodiment of the medical devices of the present
invention, the medical device is formed by providing a first bath
comprising metal ions and at least one bioactive material at a
first ratio wherein the metal ions and the at least one bioactive
material comprise a positive charge, contacting a substrate with
the first bath, applying a negative charge to the substrate, and
forming a bioactive composite structure on the substrate using an
electrochemical process.
[0024] In another embodiment of the medical devices of the present
invention, the applying of the negative charge is continuous and
the electrochemical process is an electrophoretic process. In yet
another embodiment of the medical devices of the present invention,
the applying of the negative charge is intermittent (i.e. pulsed),
and when the charge is applied to the substrate the electrochemical
process is an electrophoretic process and when the charge is not
applied to the substrate the electrochemical process is an
electroless process.
[0025] In another embodiment of the medical devices of the present
invention, the at least one bioactive material comprises a positive
charge due to the coupling of a surfactant to the at least one
bioactive material.
[0026] In an embodiment of the medical devices of the present
invention, after a portion of the bioactive composite structure is
formed, the first ratio in the first bath is altered to form a
second ratio and wherein thereafter, the forming of the bioactive
composite structure is continued. In another embodiment of the
medical devices of the present invention, after a portion of the
bioactive composite structure is formed, a second ratio in a second
bath is created and the substrate is contacted with the second
bath, thus continuing the formation of the bioactive composite
structure.
[0027] In another embodiment of the medical devices of the present
invention, the at least one bioactive material is selected from the
group described in the detailed description definition of
"bioactive materials." In another embodiment of the medical devices
of the present invention, the at least one bioactive material is
selected from the group consisting of rapamycin, paclitaxel and
HMG-COA reductase inhibitors.
[0028] In another embodiment of the medical devices of the present
invention, the substrate is a stent.
DETAILED DESCRIPTION
I. DEFINITIONS
[0029] Some terms that are used herein are described as
follows.
[0030] The term "bioactive material(s)" as used herein refers to
any organic, inorganic, or living agent that is biologically active
or relevant. For example, a bioactive material can be a protein, a
polypeptide, a polysaccharide (e.g. heparin), an oligosaccharide, a
mono- or disaccharide, an organic compound, an organometallic
compound, or an inorganic compound. It can include a living or
senescent cell, bacterium, virus, or part thereof. It can include a
biologically active molecule such as a hormone, a growth factor, a
growth factor-producing virus, a growth factor inhibitor, a growth
factor receptor, an anti-inflammatory agent, an antimetabolite, an
integrin blocker, or a complete or partial functional insense or
antisense gene. It can also include a man-made particle or
material, which carries a biologically relevant or active material.
An example is a nanoparticle comprising a core with a drug and a
coating on the core. Such nanoparticles can be post-loaded into
pores or co-deposited with metal ions.
[0031] Bioactive materials also can include drugs such as chemical
or biological compounds that can have a therapeutic effect on a
biological organism. Bioactive materials include those that are
especially useful for long-term therapy such as hormonal treatment.
Examples include drugs for contraception and hormone replacement
therapy, and for the treatment of diseases such as osteoporosis,
cancer, epilepsy, Parkinson's disease and pain. Suitable biological
materials can include, without limitation, anti-inflammatory
agents, anti-infective agents (e.g., antibiotics and antiviral
agents), analgesics and analgesic combinations, antiasthmatic
agents, anticonvulsants, antidepressants, antidiabetic agents,
antineoplastics, anticancer agents, antipsychotics, and agents used
for cardiovascular diseases such as anti-restenosis and
anti-coagulant compounds. Exemplary drugs include, but are not
limited to, antiproliferatives such as paclitaxel and rampamycin
and HMG-COA reductase inhibitors such as atorvastatin,
cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin
and simvastatin, etc.
[0032] Bioactive materials also can include precursor materials
that exhibit the relevant biological activity after being
metabolized, broken-down (e.g. cleaving molecular components), or
otherwise processed and modified within the body. These can include
such precursor materials that might otherwise be considered
relatively biologically inert or otherwise not effective for a
particular result related to the medical condition to be treated
prior to such modification.
[0033] Combinations, blends, or other preparations of any of the
foregoing examples can be made and still be considered bioactive
materials within the intended meaning herein. Aspects of the
present invention directed toward bioactive materials can include
any or all of the foregoing examples.
[0034] The term "medical device" as used herein refers to an entity
not produced in nature, which performs a function inside or on the
surface of the human body. Medical devices include, but are not
limited to, biomaterials, drug delivery apparatuses, vascular
conduits, stents, catheters, plates, screws, spinal cages, dental
implants, dental fillings, braces, artificial joints, embolic
devices, ventricular assist devices, artificial hearts, heart
valves, venous filters, staples, clips, sutures, prosthetic meshes,
pacemakers, pacemaker leads, defibrillators, neurostimulators,
neurostimulator leads, and implantable or external sensors. Medical
devices are not limited by size and include micromechanical systems
and nanomechanical systems which perform a function in or on the
surface of the human body. Embodiments of the invention include
such medical devices.
[0035] The term "substrate" as used herein refers to any physical
object that can be submerged in a bath and subjected to an
electroless or electrophoretic deposition or codeposition
process.
[0036] The terms "implants" or "implantable" as used herein refer
to a category of medical devices, which are implanted in a patient
for some period of time. They can be diagnostic or therapeutic in
nature, and long- or short-term.
[0037] The term "self-assembly" as used herein refers to a
nanofabrication process of forming a material or coating, which
proceeds spontaneously from a set of ingredients. The processes of
electroless deposition or codeposition, which continues
spontaneously and auto-catalytically from a set of ingredients, can
also be considered a self-assembly process.
[0038] The term "stents" as used herein refers to devices that are
used to maintain patency of a body lumen or interstitial tract.
There are two categories of stents; those which are balloon
expandable (e.g., stainless steel) and those which are
self-expanding (e.g., nitinol). Stents are currently used in
peripheral, coronary, and cerebrovascular vessels, the alimentary,
hepatobiliary, and urologic systems, the liver parenchyma (e.g.,
porto-systemic shunts), and the spine (e.g., fusion cages). In the
future, stents will be used in smaller vessels (currently minimum
stent diameters are limited to about 2 millimeters). For example,
they will be used in the interstitium to create conduits between
the ventricles of the heart and coronary arteries, or between
coronary arteries and coronary veins. In the eye, stents are being
developed for the Canal of Schlem to treat glaucoma.
[0039] The phrase "bioactive composite structure" as used herein
refers to the material overlying a substrate that results from the
processes herein disclosed and includes a bioactive material. A
material that results from the processes herein disclosed that does
not contain a bioactive material at a particular time can be
referred to as a "metallic layer" or a "composite structure."
II. METHODS OF MANUFACTURE
[0040] Embodiments of the invention include methods of coating
substrates including implantable medical devices with bioactive
materials to form bioactive composite structures. In one embodiment
of the methods of the present invention, an electroless
codeposition process is provided. In this embodiment, the
concentration of bioactive materials found in one or more
electroless baths is changed during the electroless codeposition
process so that different amounts of bioactive materials codeposit
onto the forming metallic layer at different times. In another
embodiment of the present invention, an electrophoretic
codeposition process is provided. In this embodiment, a negative
charge is placed onto the implantable medical device during
submersion in a bath so that migration of positively-charged metal
ions and positively-charged bioactive materials is enhanced. In
another embodiment of the methods of the present invention, the
negative charge applied to the implantable medical device during
submersion in a bath is pulsed (i.e. applied intermittently) so
that the electrochemical process changes along with the pulsing
from an electroless to an electrophoretic process or vice versa. In
another embodiment of the methods of the present invention, the
concentration of bioactive materials can be changed in one or more
baths during the continuous or pulsed electrophoretic or
electroless/electrophoretic methods of the present invention.
[0041] A. Substrate (i.e. Implantable Medical Device) and Substrate
Preparation
[0042] The substrates of the present invention can be prepared in
any suitable manner prior to forming a bioactive composite
structure on its surface. For example, the substrate surface can be
sensitized and/or catalyzed prior to performing an electroless
and/or electrophoretic deposition or codeposition process of the
present invention (if the surface of the substrate is not itself
autocatalytic). Metals such as tin (Sn) can be used as sensitizing
agents. Many metals (e.g., nickel (Ni), cobalt (Co), copper (Cu),
silver (Ag), gold (Au), palladium (Pd), platinum (Pt)) are good
auto catalysts. Palladium, Pt, and Cu are examples of "universal"
nucleation center-forming catalysts. In addition, many non-metals
are good catalysts as well.
[0043] Before creating a composite or bioactive composite structure
on the surface of a substrate of the present invention, the
substrate also can be rinsed and/or pre-cleaned if desired. Any
suitable rinsing or pre-cleaning liquid or gas could be used to
remove impurities from the surface of the substrate before creating
a composite or bioactive composite structure. Also, in some
embodiments, distilled water can be used to rinse the substrate
after sensitizing and/or catalyzing, but before performing the
electroless and/or electrophoretic deposition or codeposition
process in order to remove loosely attached molecules of the
sensitizer and/or catalyst.
[0044] Prior to creating a composite or bioactive composite
structure, the substrates of the present invention also can undergo
an anodic process. In this process, the substrate is submerged in a
hydrochloric acid bath. Current is passed through the hydrochloric
acid bath, creating small pits in the substrate. Such pits promote
adhesion. Also, a sensitizing agent and/or catalyst can be
deposited on the substrate to assist in the creation of nucleation
centers leading to the formation of the composite or bioactive
composite structure. Loosely adhered nucleation centers can also be
removed from the surface of the substrate using, for example, a
rinsing process.
[0045] A substrate also can be immersed in a "striking" bath as
described in co-pending U.S. patent application Ser. No. 10/701,262
filed on Nov. 3, 2003, which incorporated by reference herein for
all it contains regarding striking baths. Specifically, in a
striking bath, a current is applied across the substrate causing
metal ions to move to the device and plate the surface. This step
causes an intermediate or "strike" layer to be formed on the
surface of the substrate. Metal ions for this first striking bath
are chosen to be compatible with the material making up the
substrate itself. For example, if the underlying substrate is made
of cobalt chrome, cobalt ions are used. It has been found that this
strike layer improves overall adherence of the coating to the
substrate as well as increasing the rate of deposition or
codeposition during subsequent electroless and/or electrophoretic
deposition or codeposition processes. In one embodiment, when
striking is performed, the substrate is rinsed with water prior to
subsequent electroless and/or electrophoretic deposition or
codeposition.
[0046] Substrates of the present invention also can be immersed in
a bath to form a seed layer (also disclosed in co-pending U.S.
patent application Ser. No. 10/701,262 filed on Nov. 3, 2003, which
is incorporated by reference herein for all it contains regarding
seed layers). A seed layer is an electrolessly deposited metallic
layer that is deposited before bioactive material deposition. In
one embodiment, a seed layer can be formed directly onto the
surface of a substate. In another embodiment, a seed layer can be
formed on the surface of a strike layer. Metals for this seed layer
also are chosen to be compatible with the material making up the
substrate itself and/or the strike layer. A seed layer can be
beneficial because it also can enhance the deposition and adhesion
of a subsequently deposited biocomposite structure. In one
embodiment, when a seed layer is formed, the substrate is rinsed
with water prior to subsequent electroless and/or electrophoretic
deposition or codeposition.
[0047] B. Electrochemical Processes
[0048] After a substrate has been prepared according to any of the
treatments described above, the substrate undergoes an electroless
and/or electrophoretic deposition or codeposition process to create
a metallic layer or metallic layer with bioactive materials on the
surface of the substrate. For purposes of the following discussion,
deposition refers to deposition of metal alone (although, as will
be understood by one of skill in the art, an electroless or
electrophoretic deposition process also involves ions of a reducing
agent). Codeposition refers to deposition of metal and bioactive
materials through an electroless or electrophoretic process. While
the majority of methods herein disclosed include codeposition
methods, deposition methods are mentioned as well because some
codeposition methods of the present invention begin (or end in the
case of topcoat formation (see infra)) with a stage of
deposition.
[0049] In conventional electrodeposition (i.e. electroplating), an
anode and cathode are electrically coupled through an electrolyte.
As current passes between the electrodes, metal is deposited on the
cathode while it is either dissolved from the anode or originates
from the electrolyte solution. These electrodeposition processes
are well known in, for example, the metal plating industry and in
the electronics industry.
[0050] An exemplary reaction sequence for the reduction of metal in
an electrodeposition process is as follows:
M.sup.Z+.sub.solution+z.sup.e.fwdarw.M.sub.lattice(electrode) In
this equation, M is a metal atom, M.sup.Z+ is a metal ion with z
charge units and e is an electron (carrying a unit charge). The
reaction at the cathode is a reduction reaction and is the location
where electrodeposition occurs. There is also an anode where
oxidation takes place. To complete the circuit, an electrolyte
solution is provided. The oxidation and reduction reactions occur
in separate locations in the solution. In an electrodeposition
process, the substrate is a conductor as it serves as the cathode
in the process. Specific electrodeposition conditions such as the
current density and metal ion concentration can be determined by
those of ordinary skill in the art.
[0051] As contrasted to electrodeposition, in an electroless
deposition process, current does not pass through a solution.
Rather, the oxidation and reduction processes both occur at the
same "electrode" (i.e., on the substrate). It is for this reason
that electroless deposition results in the deposition of a metal
and an anodic product (e.g., nickel and nickel-phosphorus).
[0052] In an electroless deposition process, the fundamental
reaction is: M.sup.Z+.sub.solution+R.sub.ed
solution.fwdarw.M.sub.lattice(catalytic surface)+Ox.sub.solution In
this equation, R is a reducing agent, which passes electrons to the
substrate and the metal ions. Ox is the oxidized byproduct of the
reaction. In an electroless process, electron transfer occurs at
substrate reaction sites (initially the nucleation sites on the
substrate; these then form into sites that are tens of nanometers
in size). The reaction is first catalyzed by the substrate and is
subsequently auto-catalyzed by the reduced metal as a metal matrix
forms.
[0053] The electroless deposition bath comprises at least a
reducing agent and metal ions alone or a reducing agent, metal ions
and a bioactive material. The solvent that is used in the
electroless deposition bath can include water so that the
deposition bath is aqueous. Deposition conditions such as the pH,
deposition time, bath constituents, and deposition temperature can
be chosen by those of ordinary skill in the art.
[0054] During the electroless deposition processes of the present
invention, metal ions deposit over the surface of the substrate.
When bioactive materials are included in the solution or bath
during electroless codeposition processes, without being bound by
theory, it is believed that tens of nanometers of metal first
deposit onto the surface of the stent. Following this deposition of
tens of nanometers of metal, metal ions and bioactive materials
codeposit onto the already deposited metal. Thus, the bioactive
material and the metal atoms can deposit substantially
simultaneously. When codepositing metal atoms and bioactive
materials, the bioactive material is incorporated into the metal
matrix. These crystallites confine the bioactive material in the
formed bioactive composite structure.
[0055] By codepositing the bioactive material along with the metal,
the concentration of the bioactive material in the bioactive
composite structure can be high. Moreover, the problems associated
with impregnating porous structures with bioactive materials are
not present in the electroless or electrophoretic codeposition
methods of the present invention.
[0056] As an example of an electroless codeposition method of the
present invention, in one embodiment, a nickel-phosphorous alloy
matrix can be electrolessly codeposited on a substrate along with a
bioactive material such as a drug. In one embodiment, the substrate
can be activated and/or catalyzed (using, e.g., Sn and/or Pd) prior
to metallizing. To produce the alloy matrix, the electroless
deposition bath can contain NiSO.sub.4 (26 g/L), NaH.sub.2PO.sub.2
(26 g/L), Na-acetate (34 g/L) and malic acid (21 g/L). The bath can
contain ions derived from the previously mentioned salts. A
bioactive material is also in the bath. Non-limiting examples of
bioactive materials that can be included in the presently-described
bath include 1 mg paclitaxel, 1 mg rapamycin, and/or 1 mg
cervistatin. In this embodiment, sodium hypophosphite is the
reducing agent and nickel ions are reduced by the sodium
hypophosphite. The temperature of the bath is from about room
temperature to about 95.degree. C. depending on desired
codeposition time. The pH is generally from about 5 to about 7
(these processing conditions could be used in other embodiments).
The substrate to be coated is then immersed in the bath and a
bioactive composite structure is formed on the surface of the
substrate after a predetermined amount of time. The Ni ions in
solution deposit onto the surface of the substrate as pure nickel
(reduction reaction) along with nickel-phosphorous alloy (oxidation
reaction); the bioactive material codeposits along the crystallite
and grain boundaries of the deposited metal matrix to form a
bioactive composite structure. Typically, the amount of phosphorous
ranges from about greater than 1% to about less than 25%. (mole %)
and can be varied by techniques known to those skilled in the
art.
[0057] In one embodiment of the electroless codeposition processes
of the present invention, the concentration of bioactive materials
in the electroless bath can be altered to vary the amount of
bioactive materials codepositing, and thus found, in different
portion or layers of the bioactive composite structure. In one
embodiment, the concentration of bioactive materials can be changed
in the same bath in which an electroless codeposition process is
occurring. In another embodiment, the changed concentration of
bioactive materials can occur in a second (or third, etc.) bath. In
this embodiment, the substrate is removed from one bath and placed
into another. These methods of varying the concentration of
bioactive materials in one or more baths provide avenues to
increase or decrease the amount of bioactive materials found in
different portions or layers of the bioactive composite structure
formed on the substrates of the present invention.
[0058] The present invention also provides electrophoretic
deposition and codeposition methods. In electrophoretic deposition
or codeposition methods, a slight charge is placed onto the
substrate to be coated in order to attract positively-charged metal
ions and positively-charged bioactive materials. The amount of
charge placed onto the substrate is not, however, sufficient to
change the balance of the process into an electrodeposition (or
electrocodeposition) only process as described above. Thus, the
reactions occurring in the bath resemble electroless processes but
with a migration of positively-charged metal ions and
positively-charged bioactive materials toward the slightly-charged
substrate.
[0059] In one embodiment of the electrophoretic codeposition
methods of the present invention, the substrate can be sensitized
in 37% hydrogen chloride (HCl) for approximately 3 to 10 minutes,
and in one embodiment, for approximately 5 minutes. The substrate
can then be activated with an electrolytic Ni-strike. The Ni-strike
can occur in, for example and without limitation, a Woods strike
bath (comprising approximately 240 g/L nickel chloride and
approximately 320 ml/L HCl) or a Sulfamate strike bath (comprising
approximately 320 g/L nickel sulfamate; approximately 30 g/L boric
acid; approximately 12 g/L HCl; and approximately 20 g/L sulfamic
acid). Appropriate submersion times in these strike baths can be
approximately 1-4 minutes and in one embodiment 2.5 minutes.
Activation also can include application of an approximately 50-200
mAmp current, and in one embodiment, a 100 mAmp current.
[0060] After activation in a strike bath, the substrate can have a
small nickel-phosphorous (Ni--P) layer created on its surface by
submerging the substrate in an electroless Ni--P bath comprising
approximately 35.6 g/L nickel sulfamate; approximately 17 g/L
sodium hypophosphate; approximately 15 g/L sodium succinate;
approximately 1.3 g/L succinic acid for approximately 2 to 10
minutes (in one embodiment 5 minutes) at approximately
30-70.degree. C. Following the creation of this Ni--P layer, the
substrate can be mounted on a masking electrode and immersed in, in
a non-limiting example, an electrophoretic
Ni--P-surfactant-paclitaxel solution. Submersion in this bath can
occur for approximately 20 to 60 minutes (in one embodiment for 30
minutes) at approximately 30-50.degree. C. (in one embodiment
50.degree. C.) with a current of approximately 0.1-20 mAmp (in one
embodiment 5 mAmp).
[0061] In the electrophoretic codeposition methods of the present
invention, bioactive materials can be given a positive charge by
coupling a surfactant to the bioactive material. Non-limiting
examples of surfactants that can be used in accordance with the
present invention include hexadecyl trimethyl ammonium bromide
(HTAB), benzethonium chloride (BZTC) and cationic cyclodextrin
complexes such as, without limitation,
N,N-diethylaminoethyl-.beta.-cyclodextrin and
2,3-Di-(N,N-diethylaminoethyl)-N-amino-2,3-deoxy-8-cyclodextrin. A
suitable example of a zwitterionic surfactant that can be used in
accordance with the present invention includes, without limitation
3-[(3-cholamido-propyl)-dimethyl-ammonio]-1-propanesulfonate
"CHAPS".
[0062] Dispersing agents also can be used in accordance with the
present invention. Dispersing agents can prevent bioactive
materials, such as, without limitation, taxol, from aggregating
within a solution or bath. Anionic dispersing agents that can be
used in accordance with the present invention include sodium
lignosulfonate, sodium naphthalene sulfonate-formaldehyde
condensate ("Lomar D"), sodium polystyrene sulfonate (Flexan 130),
polyacrylic acid (Acumer 9400'' and Good-Rite k-732) and organic
phosphate ester (Emphos CS-1361). Nonionic dispersing agents that
can be used in accordance with the present invention include,
without limitation, aliphatic alcohol ethoxylate (Atlas G5000),
ethylene oxide-propylene oxide block copolymer (HLB=17.0; Pluronic
P65) and polyoxyethylene (20) monolaurate (HLB=16.7; Tween 20.TM.).
Cationic dispersing agents that can be used in accordance with the
present invention include, without limitation, dimethyl dicoco
ammonium chloride (Arquad.RTM. 2C-75, Akzona Inc., Enka, N.C.) and
N-alkyl(soya)trimethyl ammonium chloride (Arquad.RTM. S-50, Akzona
Inc., Enka, N.C.). A zwitterionic dispersing agent that can be used
in accordance with the present invention includes, without
limitation, palmitamidopropylbetaine (Scheercotaine PAB).
[0063] Wetting agents also can be used in accordance with the
present invention. Wetting agents can lower the interfacial tension
between bioactive materials, such as and without limitation, taxol
and water. Anionic wetting agents that can be used in accordance
with the present invention include, without limitation, sodium
lauryl sulfate, sodium dioctyl sulfosuccinate ("aerosol otb"),
sodiumdodecyl benzene sulfonate ("witconate 90") and sodium
isopropyl naphthalene sulfonate ("aerosol OS"). Nonionic wetting
agents that can be used in accordance with the present invention
include, without limitation, secondary alcohol ethoxylate
(tergitolo 15-5-5; Union Carbide Chemicals & Plastics
Technology Corp., Danbury, Conn.) and Pluronic L-62 (a block
copolymer of propylene oxide and ethylene oxide).
[0064] In one embodiment of the methods of the present invention,
after a portion of a biocomposite structure has formed, the
negative charge applied to the substrate can be removed to change
the process from an electrophoretic process to an electroless
process. Changing the electrochemical process from an
electrophoretic process to an electroless process can be desirable
to alter the concentration of bioactive materials found in
different layers of the biocomposite structure. For example, an
electrophoretic process generally results in a higher concentration
of bioactive material deposition than an electroless process.
Performing an electrophoretic process first results in a higher
concentration of bioactive materials closer to the surface of the
substrate. These bioactive materials can release through a second
electroless layer. This codeposition and release procedure results
in an extended and sustained release of bioactive materials from
the electrophoretic layer through the second electroless layer. A
lower concentration of bioactive materials found in the second
electroless layer can be released more quickly for short term
release needs.
[0065] In another embodiment of the methods of the present
invention, the current applied to the substrate during the
electrophoretic processes can be pulsed on and off, changing the
process in an on-going manner from an electrophoretic to an
electroless deposition or codeposition process. In one embodiment
of the "pulsing" embodiments of the present invention, the current
can be pulsed on and off in approximately 1 to 10 second intervals
for approximately 10 to 60 seconds at a time. In another embodiment
of the present invention, phosphorous content is manipulated
through pulsing so that, within a particular bioactive composite
structure formed, phosphorous content is high only at the surface
of the structure, providing enhanced resistance to corrosion
without increasing the overall brittleness of the bioactive
composite structure.
[0066] Any suitable source of metal ions can be used in embodiments
of the invention. The metal ions in a particular bath can be
derived from soluble metal salts before they are in the bath. In
solution, the ions forming the metal salts can dissociate from each
other. Non-limiting examples of suitable metal salts for nickel
ions include nickel sulfate, nickel chloride, and nickel sulfamate.
Non-limiting examples of suitable metal salts for cobalt ions
include cobalt sulfate, cobalt chloride, and cobalt sulfamate.
Non-limiting examples of suitable metal salts for copper ions
include cupric and cuprous salts such as cuprous chloride or
sulfate. Non-limiting examples of suitable metal salts for tin
cations can include stannous chloride or stannous fluoroborate.
Other suitable salts useful for depositing other metals are known
in the electroless deposition art. Different types of salts can be
used if a metal alloy matrix is to be formed.
[0067] The bath also can include a reducing agent, complexing
agents, stabilizers, and buffers. The reducing agent reduces the
oxidation state of the metal ions in solution so that the metal
ions deposit on the surface of the substrate as metal. Non-limiting
examples of reducing compounds include boron compounds such as
amine borane and phosphites such as sodium hypophosphite.
Complexing agents are used to hold the metal in solution. Buffers
and stabilizers are used to increase bath life and improve the
stability of the bath. Buffers are used to control the pH of the
bath. Stabilizers can be used to keep the solution homogeneous.
Non-limiting examples of stabilizers include lead, cadmium, copper
ions, etc. Reducers, complexing agents, stabilizers and buffers are
well known in the electroless deposition art and can be chosen by
those of ordinary skill in the art.
[0068] The metallic matrix of the bioactive composite structure
formed during the electroless or electrophoretic deposition or
codeposition methods of the present invention can include any
suitable metal. The metal in the metallic matrix can be the same as
or different from the substrate metal (if the substrate is
metallic). The metallic matrix can include, for example, noble
metals or transition metals. Suitable metals include, but are not
limited to, nickel, copper, cobalt, palladium, platinum, chromium,
iron, gold, and silver and alloys thereof. Examples of suitable
nickel-based alloys include, without limitation, Ni--P,
nickel-boron (Ni--B) and nickel chromium (Ni--Cr). Any of these or
other metallic materials can be deposited using a suitable
electroless or electrophoretic deposition or codeposition process.
Appropriate metal salts can be selected to provide appropriate
metal ions in the bath for the metal matrix that is to be
formed.
[0069] After a substrate has contacted the baths of the present
invention and undergone an electroless or electrophoretic
codeposition process, a bioactive composite structure has been
formed on the substrate's surface. After this bioactive composite
structure has been formed, the structure/substrate combination can
be subjected to subsequent processing as desired.
[0070] C. Subsequent Processing
[0071] After electroless or electrophoretic codeposition onto the
surface of the substrate, the device can be processed further to
alter its clinical features. In one embodiment, this processing can
include formation of a top coat. This topcoat can include any
suitable material and can be in any suitable form. It can be
amorphous or crystalline, and can include a metal, ceramic, etc.
The topcoat can also be porous or solid (continuous).
[0072] The topcoat can be deposited using any suitable process. For
example, the above-described processes (e.g., electrodeposition or
codeposition or electroless or electrophoretic deposition or
codeposition) could be used to form the topcoat or another process
can be used to form the topcoat. Alternatively, the topcoat could
be formed by processes such as, but not limited to, dip coating,
spray coating, vapor deposition, etc.
[0073] In some embodiments, the topcoat can improve the properties
of the bioactive composite structure. For example, the topcoat can
include a membrane (e.g., collagen type 4) that is covalently bound
to the bioactive composite structure. The topcoat's function can be
to induce endothelial attachment to the surface of a bioactive
composite structure, while the bioactive material in the bioactive
composite structure diffuses from below the topcoat. In another
embodiment, a growth factor such as endothelial growth factor (EGF)
or vascular endothelial growth factor (VEGF) is present in a
topcoat that is on a bioactive composite structure. The growth
factor is released from the topcoat to induce endothelial growth
while the bioactive composite structure releases an inhibitor of
smooth muscle cell growth.
[0074] In yet another embodiment of the present invention, the
topcoat can improve the radioopacity of a medical device which
includes the bioactive composite structure, while the underlying
bioactive composite structure releases molecules to perform another
function. For example, drugs can be released from the bioactive
composite structure to prevent smooth muscle cell overgrowth, while
a topcoat on the bioactive composite structure improves the
radioopacity of the formed medical device. Illustratively, a
topcoat comprising, for example and without limitation, nickel,
cobalt, Ni--Cr and/or gold can be deposited on top of a bioactive
composite structure comprising Ni--P to enhance the radioopacity of
a device incorporating the bioactive composite structure.
Underneath the topcoat, a smooth muscle cell inhibitor such as
sirolimus can be released over a 30-60 day time period from the
bioactive composite structure.
[0075] The topcoat can also be used to alter the release kinetics
of the bioactive material in the underlying bioactive composite
structure. For example, an electroless nickel-phosphorous or
cobalt-phosphorous coating without bioactive material can serve as
a topcoat. This would require the bioactive material to travel
through an additional layer of material before entering the
surrounding environment, thereby delaying the release of the
bioactive material. The release kinetics of the formed medical
device can be adjusted in this manner.
[0076] Although medical devices such as stents are discussed in
detail, it is understood that embodiments of the invention are not
limited to stents or for that matter, to macroscopic devices. For
example, embodiments of the invention could be used in any device
or material, regardless of size and includes artificial hearts,
plates, screws, mems (microelectromechanical systems), and
nanoparticle based materials and systems, etc. Further, the
substrate can be porous or solid, flexible or rigid, and can have a
planar or non-planar surface (e.g., curved).
[0077] The terms and expressions which have been employed herein
are used as terms of description and not of limitation, and there
is no intention in the use of such terms and expressions of
excluding equivalents of the features shown and described, or
portions thereof, it being recognized that various modifications
are possible within the scope of the invention claimed. Moreover,
any one or more features of any embodiment of the invention can be
combined with any one or more other features of any other
embodiment of the invention, without departing from the scope of
the invention.
[0078] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the following specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained by the present
invention. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the
claims, each numerical parameter should at least be construed in
light of the number of reported significant digits and by applying
ordinary rounding techniques. Notwithstanding that the numerical
ranges and parameters setting forth the broad scope of the
invention are approximations, the numerical values set forth in the
specific examples are reported as precisely as possible. Any
numerical value, however, inherently contains certain errors
necessarily resulting from the standard deviation found in their
respective testing measurements.
[0079] The terms "a" and "an" and "the" and similar referents used
in the context of describing the invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0080] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is herein deemed to contain the
group as modified thus fulfilling the written description of all
Markush groups used in the appended claims.
[0081] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Of course, variations on those preferred
embodiments will become apparent to those of ordinary skill in the
art upon reading the foregoing description. The inventor expects
skilled artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0082] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above cited references and printed publications are herein
individually incorporated by reference in their entirety.
[0083] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *