U.S. patent application number 14/030461 was filed with the patent office on 2014-01-16 for medical devices having polymer brushes.
This patent application is currently assigned to Boston Scientific Scimed, Inc.. The applicant listed for this patent is Boston Scientific Scimed, Inc.. Invention is credited to Mark Boden.
Application Number | 20140018440 14/030461 |
Document ID | / |
Family ID | 38533724 |
Filed Date | 2014-01-16 |
United States Patent
Application |
20140018440 |
Kind Code |
A1 |
Boden; Mark |
January 16, 2014 |
MEDICAL DEVICES HAVING POLYMER BRUSHES
Abstract
According to an aspect of the present invention, internal
medical devices are provided, which contain at least one surface
region that comprises a polymer brush. The polymer brush, in turn,
contains one or more types of hydrophobic polymer chains and one or
more types of hydrophilic polymer chains.
Inventors: |
Boden; Mark; (Harrisville,
RI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boston Scientific Scimed, Inc. |
Maple Grove |
MN |
US |
|
|
Assignee: |
Boston Scientific Scimed,
Inc.
Maple Grove
MN
|
Family ID: |
38533724 |
Appl. No.: |
14/030461 |
Filed: |
September 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11388652 |
Mar 24, 2006 |
8545865 |
|
|
14030461 |
|
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Current U.S.
Class: |
514/772.1 ;
525/92C; 525/92F; 525/92G; 525/94 |
Current CPC
Class: |
A61L 29/085 20130101;
A61L 27/34 20130101; A61L 31/10 20130101; A61L 29/16 20130101; A61K
47/32 20130101; A61K 47/34 20130101; A61L 27/34 20130101; A61L
31/16 20130101; A61L 27/54 20130101; A61L 2300/00 20130101; A61L
29/085 20130101; C08L 101/005 20130101; A61L 31/10 20130101; C08L
101/005 20130101; C08L 101/005 20130101 |
Class at
Publication: |
514/772.1 ;
525/92.C; 525/92.F; 525/92.G; 525/94 |
International
Class: |
A61K 47/32 20060101
A61K047/32; A61K 47/34 20060101 A61K047/34 |
Claims
1. An internal medical device comprising a surface region that
comprises a polymer brush, said polymer brush comprising
hydrophobic polymer chains and hydrophilic polymer chains.
2-3. (canceled)
4. The internal medical device of claim 1, wherein said hydrophobic
polymer chains and said hydrophilic polymer chains are
independently attached to said surface region.
5. The internal medical device of claim 1, wherein said polymer
brush comprises a block copolymer that comprises said hydrophobic
polymer chains and said hydrophilic polymer chains.
6. The internal medical device of claim 5, wherein said block
copolymer is selected from the following: a diblock copolymer, a
triblock copolymer, a pentablock copolymer, a star-shaped block
copolymer, and a hyperbranched block copolymer.
7-8. (canceled)
9. The internal medical device of claim 1, wherein said medical
device is a stent.
10-11. (canceled)
12. The internal medical device of claim 1, wherein the hydrophobic
polymer chains are preferentially oriented at the surface by
contacting said polymer brush with a hydrophobic solvent.
13. The internal medical device of claim 1, wherein said
hydrophobic polymer chains are high glass transition temperature
chains and wherein said hydrophilic polymer chains are low glass
transition temperature chains.
14. The internal medical device of claim 1, wherein said
hydrophobic polymer chains and said hydrophilic polymer chains are
high glass transition temperature chains.
15. The internal medical device of claim 1, wherein said
hydrophobic polymer chains are selected from poly(vinyl aromatic)
chains, polyacrylate chains, polymethacrylate chains, polyamide
chains, polyester chains, and polycarbonate chains.
16. The internal medical device of claim 1, wherein said
hydrophilic polymer chains are low glass transition temperature
chains comprising monomers selected from alkylene oxide monomers
and amino acids.
17. The internal medical device of claim 1, further comprising a
therapeutic agent disposed within or beneath said polymer
brush.
18-19. (canceled)
20. The internal medical device of claim 1, wherein said surface
region is a metallic surface region.
21. The internal medical device of claim 1, wherein said surface
region is a polymeric surface region.
22. The internal medical device of claim 17, wherein said
therapeutic agent is selected from an anti-restenotic agent, an
anti-thrombotic agent, an endothelial growth promoting agent and
combinations thereof.
23. The internal medical device of claim 1, further comprising a
plurality of therapeutic agents disposed within or beneath said
polymer brush.
24. The internal medical device of claim 1, wherein said
hydrophobic polymer chains are selected from bioactive polymer
chains, biomimetic polymer chains, and biodegradable chains.
25. The internal medical device of claim 1, wherein said
hydrophilic polymer chains are selected from bioactive polymer
chains, biomimetic polymer chains, and biodegradable chains.
26. A treatment method comprising implanting or inserting the
internal medical device of claim 1 into a patient, wherein the
hydrophobic polymer chains are preferentially oriented at the
surface of said device at the time of implantation or insertions,
and wherein after implantation or insertion of said device into a
patient the polymer brush reorganizes such that the hydrophilic
polymer chains become preferentially oriented at the surface.
27. The internal medical device of claim 17, wherein said
therapeutic agent is compatible with said hydrophobic polymer
chains and said hydrophilic polymer chains.
28. The internal medical device of claim 17, wherein said
therapeutic agent is incompatible with said hydrophobic polymer
chains and said hydrophilic polymer chains.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of U.S. patent
application Ser. No. 11/388,652, filed Mar. 24, 2006, titled
MEDICAL DEVICES HAVING POLYMER BRUSHES, the disclosure of which is
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to medical devices and more
particularly to medical devices having polymer brushes that change
properties upon implantation or insertion of the devices into
patients.
BACKGROUND OF THE INVENTION
[0003] Surface properties of medical devices touch upon a whole
host of issues, including mechanical performance and
biocompatibility, among many others. For example, during a typical
balloon angioplasty procedure, a stent is crimped upon a balloon
and advanced into the vasculature of a patient. The stent is
subsequently expanded upon balloon inflation to engage the walls of
a blood vessel, thereby providing patency to the vessel. In
general, the lower the surface energy of the stent, the greater the
ease of balloon withdrawal after the stent is expanded. Because
they are hydrophobic, however, devices having low surface energies
are not necessarily desirable from a biocompatibility
standpoint.
[0004] The in vivo delivery of a biologically active agent within
the body of a patient is common in the practice of modern medicine.
In vivo delivery of biologically active agents is often implemented
using medical devices that may be temporarily or permanently placed
at a target site within the body. These medical devices can be
maintained, as required, at their target sites for short or
prolonged periods of time, delivering biologically active agents at
the target site. For example, drug delivery from stents for the
treatment of restenosis is widely accepted. Commercially available
drug eluting coronary stents include those available from Boston
Scientific Corp. (TAXUS), Johnson & Johnson (CYPHER), and
others. Unfortunately, only a few products have been successful to
date, in part, due to the inability to create products with
effective and safe dose and release kinetics. For coronary stents
with polymeric drug-eluting coatings, dose and release kinetics may
be affected, for example, by the physiochemical properties of the
drug and the polymeric carrier, by the interactions between the
drug and carrier, and by the geometry of the system.
SUMMARY OF THE INVENTION
[0005] According to an aspect of the present invention, internal
medical devices are provided, which contain at least one surface
region that comprises a polymer brush. The polymer brush, in turn,
contains one or more types of hydrophobic polymer chains and one or
more types of hydrophilic polymer chains.
[0006] An advantage of the present invention is that internal
medical devices are provided, which change properties upon
introduction into a patient.
[0007] These and other aspects, embodiments and advantages of the
present invention will become immediately apparent to those of
ordinary skill in the art upon review of the Detailed Description
and Claims to follow.
DETAILED DESCRIPTION OF THE INVENTION
[0008] As is well known, "polymers" are molecules that contain
multiple copies of the same or differing constitutional units,
commonly referred to as monomers. The number of constitutional
units within a given polymer may vary widely, ranging, for example,
from 5 to 10 to 25 to 50 to 100 to 1000 to 10,000 or more
constitutional units. Polymers for use in the present invention may
have a variety of architectures, including cyclic, linear and
branched architectures. Branched architectures include star-shaped
architectures (e.g., architectures in which three or more chains
emanate from a single branch point), comb architectures (e.g.,
architectures having a main chain and a plurality of side chains)
and dendritic architectures (e.g., arborescent and hyperbranched
polymers), among others. The polymers may contain, for example,
homopolymer chains, which contain multiple copies of a single
constitutional unit, and/or copolymer chains, which contain
multiple copies of at least two dissimilar constitutional units,
which units may be present in any of a variety of distributions
including random, statistical, gradient, and periodic (e.g.,
alternating) distributions. As defined herein, "block copolymers"
are polymers containing two or more differing polymer chains with
covalent linkages, for example, selected from homopolymer chains
and copolymer chains (e.g., random, statistical, gradient, and
periodic copolymer chains).
[0009] According to an aspect of the invention, internal medical
devices (i.e., medical devices that are adapted for implantation or
insertion into a patient) are provided, which comprise polymer
brushes at their surfaces. In some embodiments of the present
invention, therapeutic agents are disposed within or beneath the
polymer brushes. Typical subjects (or "patients") are vertebrate
subjects, more typically mammalian subjects, and even more
typically human subjects.
[0010] "Polymer brushes," as the name suggests, contain polymer
chains, one end of which is directly or indirectly tethered to a
surface and another end of which is free to extend from the
surface, somewhat analogous to the bristles of a brush. In the
devices of the present invention, polymer brushes are employed,
which have one or more types of hydrophobic polymer chains and one
or more types of hydrophilic polymer chains. These incompatible
polymer chains are capable of phase separating into distinct phase
domains, one type of which preferentially orients at the surface,
depending on nature of the surrounding environment. This process is
sometimes called perpendicular segregation. For example, upon
exposure to a hydrophobic environment (e.g., exposure to a
relatively nonpolar organic solvent such as toluene), the surface
becomes more hydrophobic due to the migration of the hydrophobic
chains to the surface and the formation of a hydrophobic phase
domain (e.g., a continuous or discontinuous phase domain) there,
whereas upon exposure to a hydrophilic environment (e.g., exposure
to an aqueous environment or exposure to a relatively polar organic
solvent such as methanol or ethanol), the surface becomes more
hydrophobic because the hydrophobic chains migrate to the surface
forming a surface a hydrophilic phase domain. As a result of this
ability to change properties, such polymer brushes are sometimes
referred to a stimulus responsive, "switchable" or "smart".
[0011] As used herein, "polymer brush regions" are surface regions
having polymer brushes.
[0012] Typically, stimulus responsive polymer brushes fall into one
of two categories. In the first category, one or more types of
hydrophobic chains and one or more types of hydrophilic chains
extend separately from the surface. In the second category, one or
more hydrophobic chains and one or more hydrophilic chains are
provided within a single block copolymer that extends from the
surface.
[0013] A variety of internal medical devices and portions thereof
may be provided with polymer brush regions including, for example,
catheters (e.g., renal or vascular catheters), balloons, catheter
shafts, guide wires, filters (e.g., vena cava filters), stents
(including coronary vascular stents, cerebral, urethral, ureteral,
biliary, tracheal, gastrointestinal and esophageal stents), stent
grafts, cerebral aneurysm filler coils (including Guglilmi
detachable coils and metal coils), vascular grafts, myocardial
plugs, patches, pacemakers and pacemaker leads, heart valves,
vascular valves, tissue engineering scaffolds for cartilage, bone,
skin and other in vivo tissue regeneration, and so forth.
[0014] The polymer brushes may be provided over the entire surface
of the medical device or over only a portion of the medical device
surface. For example, with tubular devices such as stents (which
can comprise, for example, a laser or mechanically cut tube, or one
or more braided, woven, or knitted filaments, etc.), polymer
brushes may be provided over the entire surface of the stent, or
they may be provided on the inner luminal surface of the stent, on
the outer abluminal surface of the stent, and/or on the lateral
surfaces between the luminal and abluminal surfaces (including the
ends). The polymer brushes may be provided in desired patterns, for
instance, using appropriate masking techniques. As another example,
polymer brushes may be provided over some device components but not
others (e.g., over the balloon of a balloon catheter, but not over
the catheter shaft).
[0015] A few exemplary uses for medical devices in accordance with
the invention will now be discussed. As a first example, it is
known that adhesion between a balloon and surrounding stent can
lead to an increase in the force that is needed for balloon
withdrawal. It is also known that materials having low surface
energy, including a wide variety of homopolymer and copolymer
chains, are hydrophobic and that they typically exhibit low
frictional forces when moved along the surface of another material.
By providing a medical device with a polymer brush region in
accordance with the invention and by ensuring that the coated
device is exposed to a hydrophobic environment prior to delivery to
a patient, the hydrophobic polymer component is segregated at the
surface, thereby giving the overall device a low surface energy.
For example, by soaking the device in a solvent which is selective
for the hydrophobic chains and flash drying to remove the solvent,
a coating may be provided whose surface is primarily composed of
hydrophobic polymer chains. Where the device is a stent, the
resulting hydrophobic surface may facilitate withdrawal of the
balloon, after which the surface becomes hydrophilic in the aqueous
environment of the body.
[0016] The wide range of choices for the hydrophobic chains will
enable tailoring the surface properties of the device, including
surface energy and hardness, among others. In the case of a stent,
this may allow the frictional forces to the varied, for example,
allowing the optimization of both the securement and withdrawal of
the stent.
[0017] An advantage of a brush polymer surface having both
hydrophilic and hydrophobic polymer chains is that the surface will
reorient once it is exposed to an aqueous environment, resulting in
a surface that is primarily composed of hydrophilic chains such
that a hydrophilic surface is presented to the surrounding
environment. Therefore, the device biocompatibility will actually
change after the device is deployed. Selection of the proper
hydrophilic polymer chains will allow control of the compatibility.
As discussed further below, rigidity is related to the glass
transition temperature of the polymer chains, with high glass
transition temperature chains being more rigid and low glass
transition temperature chains being more flexible.
[0018] In this manner, two polymer chains may be selected--one that
is optimized for balloon adhesion and release, and another that is
optimized for biocompatibility. Examples of hydrophobic polymer
chains include those that are glassy or partially crystalline at
the application temperature, for instance, polystyrene and its
derivatives, polyacrylates having alkyl side chains, and so forth.
Examples of hydrophobic polymer chains also include those that are
soft at the application temperature, for instance, polyalkylene
chains, poly(halogenated alkylene) chains and polysiloxane chains.
Examples of hydrophilic polymer chains include materials such as
peptides or their synthetic derivatives, polyalkylene oxides (e.g.,
PEO), ionic polymers including polyelectrolytes, and so forth. For
example, use of poly(methyl methacrylate) chains will result in a
relatively rigid surface that may adsorb biopolymers, whereas use
of glycol ether chains will result in a softer segment that may
prevent biofouling and impart completely different properties to
the device surface. In addition, the hydrophilic polymer chain may
be formed from a bioactive polymer, thereby promoting healing,
preventing thrombolytic reactions, or serving as a binding site for
antibodies, cells, and so forth. Further hydrophobic and
hydrophilic chains may be selected from those set forth below.
[0019] Polymer brush regions may be provided over a number of
medical device substrates. Materials for use as underlying medical
device substrates include (a) organic materials (e.g., materials
containing 50 wt % or more organic species) such as polymeric
materials and (b) inorganic materials (e.g., materials containing
50 wt % or more inorganic species), such as metallic materials
(e.g., metals and metal alloys) and non-metallic materials (e.g.,
including carbon, semiconductors, glasses and ceramics, which may
contain various metal- and non-metal-oxides, various metal- and
non-metal-nitrides, various metal- and non-metal-carbides, various
metal- and non-metal-borides, various metal- and
non-metal-phosphates, and various metal- and non-metal-sulfides,
among others).
[0020] Specific examples of non-metallic inorganic materials may be
selected, for example, from materials containing one or more of the
following: metal oxides, including aluminum oxides and transition
metal oxides (e.g., oxides of titanium, zirconium, hafnium,
tantalum, molybdenum, tungsten, rhenium, and iridium); silicon;
silicon-based ceramics, such as those containing silicon nitrides,
silicon carbides and silicon oxides (sometimes referred to as glass
ceramics); calcium phosphate ceramics (e.g., hydroxyapatite);
carbon; and carbon-based, ceramic-like materials such as carbon
nitrides.
[0021] Specific examples of metallic inorganic materials may be
selected, for example, from metals (e.g., biostable metals such as
gold, platinum, palladium, iridium, osmium, rhodium, titanium,
tantalum, tungsten, and ruthenium, and bioresorbable metals such as
magnesium) and metal alloys, including metal alloys comprising iron
and chromium (e.g., stainless steels, including platinum-enriched
radiopaque stainless steel), alloys comprising nickel and titanium
(e.g., Nitinol), alloys comprising cobalt and chromium, including
alloys that comprise cobalt, chromium and iron (e.g., elgiloy
alloys), alloys comprising nickel, cobalt and chromium (e.g., MP
35N), alloys comprising cobalt, chromium, tungsten and nickel
(e.g., L605), and alloys comprising nickel and chromium (e.g.,
inconel alloys).
[0022] Specific examples of organic materials may be selected, for
example, from the following: polycarboxylic acid polymers and
copolymers including polyacrylic acids; acetal polymers and
copolymers; acrylate and methacrylate polymers and copolymers
(e.g., n-butyl methacrylate); cellulosic polymers and copolymers,
including cellulose acetates, cellulose nitrates, cellulose
propionates, cellulose acetate butyrates, cellophanes, rayons,
rayon triacetates, and cellulose ethers such as carboxymethyl
celluloses and hydroxyalkyl celluloses; polyoxymethylene polymers
and copolymers; polyimide polymers and copolymers such as polyether
block imides and polyether block amides, polyamidimides,
polyesterimides, and polyetherimides; polysulfone polymers and
copolymers including polyarylsulfones and polyethersulfones;
polyamide polymers and copolymers including nylon 6,6, nylon 12,
polycaprolactams and polyacrylamides; resins including alkyd
resins, phenolic resins, urea resins, melamine resins, epoxy
resins, allyl resins and epoxide resins; polycarbonates;
polyacrylonitriles; polyvinylpyrrolidones (cross-linked and
otherwise); polymers and copolymers of vinyl monomers including
polyvinyl alcohols, polyvinyl halides such as polyvinyl chlorides,
ethylene-vinyl acetate copolymers (EVA), polyvinylidene chlorides,
polyvinyl ethers such as polyvinyl methyl ethers, polystyrenes,
styrene-maleic anhydride copolymers, vinyl-aromatic-alkylene
copolymers, including styrene-butadiene copolymers,
styrene-ethylene-butylene copolymers (e.g., a
polystyrene-polyethylene/butylene-polystyrene (SEBS) copolymer,
available as Kraton.RTM. G series polymers), styrene-isoprene
copolymers (e.g., polystyrene-polyisoprene-polystyrene),
acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrene
copolymers, styrene-butadiene copolymers and styrene-isobutylene
copolymers (e.g., polyisobutylene-polystyrene and
polystyrene-polyisobutylene-polystyrene block copolymers such as
those disclosed in U.S. Pat. No. 6,545,097 to Pinchuk), polyvinyl
ketones, polyvinylcarbazoles, and polyvinyl esters such as
polyvinyl acetates; polybenzimidazoles; ethylene-methacrylic acid
copolymers and ethylene-acrylic acid copolymers, where some of the
acid groups can be neutralized with either zinc or sodium ions
(commonly known as ionomers); polyalkyl oxide polymers and
copolymers including polyethylene oxides (PEO); polyesters
including polyethylene terephthalates and aliphatic polyesters such
as polymers and copolymers of lactide (which includes lactic acid
as well as d-, l- and meso lactide), epsilon-caprolactone,
glycolide (including glycolic acid), hydroxybutyrate,
hydroxyvalerate, para-dioxanone, trimethylene carbonate (and its
alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and
6,6-dimethyl-1,4-dioxan-2-one (a copolymer of poly(lactic acid) and
poly(caprolactone) is one specific example); polyether polymers and
copolymers including polyarylethers such as polyphenylene ethers,
polyether ketones, polyether ether ketones; polyphenylene sulfides;
polyisocyanates; polyolefin polymers and copolymers, including
polyalkylenes such as polypropylenes, polyethylenes (low and high
density, low and high molecular weight), polybutylenes (such as
polybut-1-ene and polyisobutylene), polyolefin elastomers (e.g.,
santoprene), ethylene propylene diene monomer (EPDM) rubbers,
poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers,
ethylene-methyl methacrylate copolymers and ethylene-vinyl acetate
copolymers; fluorinated polymers and copolymers, including
polytetrafluoroethylenes (PTFE),
poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modified
ethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidene
fluorides (PVDF); silicone polymers and copolymers; thermoplastic
polyurethanes (TPU); elastomers such as elastomeric polyurethanes
and polyurethane copolymers (including block and random copolymers
that are polyether based, polyester based, polycarbonate based,
aliphatic based, aromatic based and mixtures thereof; examples of
commercially available polyurethane copolymers include
Bionate.RTM., Carbothane.RTM., Tecoflex.RTM., Tecothane.RTM.,
Tecophilic.RTM., Tecoplast.RTM., Pellethane.RTM., Chronothane.RTM.
and Chronoflex.RTM.); p-xylylene polymers; polyiminocarbonates;
copoly(ether-esters) such as polyethylene oxide-polylactic acid
copolymers; polyphosphazines; polyalkylene oxalates; polyoxaamides
and polyoxaesters (including those containing amines and/or amido
groups); polyorthoesters; biopolymers, such as polypeptides,
proteins, polysaccharides and fatty acids (and esters thereof),
including fibrin, fibrinogen, collagen, elastin, chitosan, gelatin,
starch, glycosaminoglycans such as hyaluronic acid; as well as
further copolymers and blends of the above.
[0023] Where implantable or insertable medical devices are provided
which contain polymer brush regions that regulate the release of
therapeutic agents, the release profile associated with such
devices may be modified, for example, by changing the chemical
composition, size, and/or number of the polymer brush regions on
the device, among other parameters. For example, the release
profile may be affected by the concentration of therapeutic
agent(s) within the polymer brush region(s), by the polymer
composition of the polymer brush region(s), by the surface area of
the polymer brush region(s), and so forth. Multiple polymer brush
region(s), having either the same content or different content
(e.g., different polymer and/or therapeutic agent content), may be
provided on the medical device surfaces. Hence, polymer brush
region(s) may be adapted to release the same or different
therapeutic agents, at the same or different rates, from different
locations on the medical device. For instance, a tubular medical
device (e.g., a vascular stent) may be provided which has a polymer
brush region that contains or is disposed over an antithrombotic
agent at its inner, luminal surface and a second polymer brush
region which contains or is disposed over therapeutic agents at its
outer, abluminal surface (as well as on the ends, if desired).
[0024] As indicated above, delivery of a therapeutic agent may be
modified by varying the brush materials that are utilized. For
instance, a drug may be added that is preferentially associated
with either of the hydrophilic or the hydrophobic phase domains
(e.g., because it is soluble in or otherwise compatible with either
of the phase domains). If the drug is associated with the more
hydrophobic phase domain that is initially oriented at the surface,
the drug may be relatively rapidly released, for example, in a
burst process. If the drug is instead associated with the more
hydrophilic domain phase domain, it may elute primarily after the
surface has reoriented at the site of use.
[0025] More specifically, a hydrophobic drug that is associated
with the hydrophobic domain is initially exposed at the surface of
the device, and is subsequently internalized as the brushes
reoriented to present a hydrophilic surface. The overall result may
be an initial burst of drug, followed by a slow release over time,
as the drug diffuses through the hydrophilic surface to elute.
Conversely, if the drug is associated with the hydrophilic domain,
there may be little or no initial release. However, as the surface
reorients itself, the release drug may increase. The overall result
in this case may be an initial period of little or no drug release,
followed by fairly rapid, diffusion controlled release.
[0026] The polymer brush region may also serve to regulate delivery
of a drug primarily residing in the substrate on which the polymer
brush is prepared (e.g., within a polymer coating that the brush is
prepared upon). In this case, the rate of release of the drug may
depend, for example, on the relative amounts of each phase domain
and the relative solubility of the drug within each phase domain.
For instance, in the event that the hydrophobic phase domain
oriented at the surface is incompatible with the drug, it
essentially forms a barrier layer initially. As the two polymers
phases start to reorient such that the hydrophilic polymer phase is
preferentially at the surface, conduit for drug release may be
formed allowing the release rate to increase. Conversely, if the
hydrophobic phase initially oriented at the surface is compatible
with the drug, release should be rapid, followed by a decrease in
release rate as the two polymer chains/phase reorient and the
non-solvent polymer eventually forms a barrier layer at the
surface.
[0027] A wide range of polymers is available for forming the
polymer chains of polymer brushes, specific examples of which may
be selected, for example, from the polymers listed above for use in
substrates.
[0028] The hydrophobic and hydrophilic polymer chains within the
polymer brushes may be, for example, either high T.sub.g or low
T.sub.g polymer chains. In general, low T.sub.g polymer chains are
soft and elastomeric at room (and body) temperature, whereas high
T.sub.g polymer chains are hard. In certain advantageous
embodiments of the invention, the hydrophobic polymer chains within
the polymer brush are high T.sub.g polymer chains (e.g., to reduce
surface tack), whereas the hydrophilic polymer chains may be high
T.sub.g polymer chains or low T.sub.g polymer chains. Where the
hydrophobic and hydrophilic polymer chains are both high T.sub.g
polymer chains, the switching time for the polymers may be
increase, due to the rigidity of the polymer chains.
[0029] As used herein, "low T.sub.g polymer chains" are those that
display a T.sub.g that is below body temperature, more typically
37.degree. C. to 20.degree. C. to 0.degree. C. to -25.degree. C. to
-50.degree. C. or below. Conversely, elevated or "high T.sub.g
polymer chains" are those that display a glass transition
temperature that is above body temperature, more typically
37.degree. C. to 50.degree. C. to 75.degree. C. to 100.degree. C.
or above. T.sub.g can be measured by any of a number of techniques
including differential scanning calorimetry (DSC), dynamic
mechanical analysis (DMA), or dielectric analysis (DEA). It may be
possible to measure T.sub.g for polymer brushes directly, for
example, using selective surface probe microscope or atomic force
microscope techniques. Alternatively, T.sub.g may be determined for
the polymer chains when in free form (i.e., when not tethered to
the surface).
[0030] In cases where the hydrophilic and hydrophobic polymer
chains are present within a single block copolymer, configurations
may vary widely. Examples include the following:
CB.sub.HL.sub.H, CL.sub.HB.sub.H, B.sub.HCL.sub.H, L.sub.HCB.sub.H,
CB.sub.HL.sub.L, CL.sub.LB.sub.H, B.sub.HCL.sub.L, L.sub.LCB.sub.H,
CB.sub.LL.sub.H, CL.sub.HB.sub.L, B.sub.LCL.sub.H, L.sub.HCB.sub.L,
CB.sub.HL.sub.L, CL.sub.LB.sub.L, B.sub.LCL.sub.L, L.sub.LCB.sub.L,
where C is a covalent linking entity for linkage to the substrate
surface, B.sub.H is a hydrophobic high T.sub.g chain, B.sub.L is a
hydrophobic low T.sub.g chain, L.sub.H is a hydrophilic, high
T.sub.g chain, and L.sub.L is a hydrophilic, low T.sub.g chain.
[0031] Of course other block copolymer configurations may be
employed, for example, copolymers which contain a main chain (which
may be, for example, hydrophobic, hydrophilic or amphiphilic, low
or high T.sub.g) from which extends a mixture of hydrophilic (low
or high T.sub.g) and hydrophobic (low or high T.sub.g) side chains,
among many other possibilities.
[0032] Alternatively, the block copolymer may be linked to the
substrate by non-covalent interactions. Examples include the
following PB.sub.HL.sub.H, PB.sub.HL.sub.L, PL.sub.HB.sub.H,
PL.sub.LB.sub.H, B.sub.HPL.sub.H, B.sub.HPL.sub.L, L.sub.HPB.sub.H,
L.sub.LPB.sub.H, PB.sub.LL.sub.H, PB.sub.LL.sub.L, PL.sub.HB.sub.L,
PL.sub.LB.sub.L, B.sub.LPL.sub.H, B.sub.LPL.sub.L, L.sub.HPB.sub.L,
and L.sub.LPB.sub.L where P is a polymeric chain which is capable
of adsorption on the substrate. Note that the hydrophilic (low or
high T.sub.g) and hydrophobic (low or high T.sub.g) may be
provided, for example, at opposite ends of the polymer chain P,
along the backbone of the polymer chain P, and so forth.
[0033] Examples of low T.sub.g chains include low T.sub.g
polyalkylene chains, low T.sub.g polysiloxane chains, low T.sub.g
poly(halogenated alkylene) chains, low T.sub.g polyacrylate chains,
low T.sub.g polymethacrylate chains, low T.sub.g poly(vinyl ether)
chains, and low T.sub.g poly(cyclic ether) chains, among
others.
[0034] Examples of high T.sub.g chains include vinyl aromatic
chains, such as those made from styrenic monomers, high T.sub.g
polyacrylate chains, high T.sub.g polymethacrylate chains,
poly(vinyl alcohol) chains, high T.sub.g poly(vinyl ester) chains,
high T.sub.g poly(vinyl amine) chains, high T.sub.g poly(vinyl
halide) chains, high T.sub.g poly(alkyl vinyl ethers), and high
T.sub.g polyamide chains, among others.
[0035] Specific examples of low T.sub.g polymer chains include
those that consist of or contain one or more monomers selected from
the following (listed along with published T.sub.g's for
homopolymers of the same): (1) acrylic monomers including: (a)
alkyl acrylates such as methyl acrylate (T.sub.g 10.degree. C.),
ethyl acrylate (T.sub.g -24.degree. C.), propyl acrylate, isopropyl
acrylate (T.sub.g -11.degree. C., isotactic), butyl acrylate
(T.sub.g -54.degree. C.), sec-butyl acrylate (T.sub.g -26.degree.
C.), isobutyl acrylate (T.sub.g -24.degree. C.), cyclohexyl
acrylate (T.sub.g 19.degree. C.), 2-ethylhexyl acrylate (T.sub.g
-50.degree. C.), dodecyl acrylate (T.sub.g -3.degree. C.) and
hexadecyl acrylate (T.sub.g 35.degree. C.), (b) arylalkyl acrylates
such as benzyl acrylate (T.sub.g 6.degree. C.), (c) alkoxyalkyl
acrylates such as 2-ethoxyethyl acrylate (T.sub.g -50.degree. C.)
and 2-methoxyethyl acrylate (T.sub.g -50.degree. C.), (d)
halo-alkyl acrylates such as 2,2,2-trifluoroethyl acrylate (T.sub.g
-10.degree. C.) and (e) cyano-alkyl acrylates such as 2-cyanoethyl
acrylate (T.sub.g 4.degree. C.); (2) methacrylic monomers including
(a) alkyl methacrylates such as butyl methacrylate (T.sub.g
20.degree. C.), hexyl methacrylate (T.sub.g -5.degree. C.),
2-ethylhexyl methacrylate (T.sub.g -10.degree. C.), octyl
methacrylate (T.sub.g -20.degree. C.), dodecyl methacrylate
(T.sub.g -65.degree. C.), hexadecyl methacrylate (T.sub.g
15.degree. C.) and octadecyl methacrylate (T.sub.g -100.degree. C.)
and (b) aminoalkyl methacrylates such as diethylaminoethyl
methacrylate (T.sub.g 20.degree. C.) and 2-tert-butyl-aminoethyl
methacrylate (T.sub.g 33.degree. C.); (3) vinyl ether monomers
including (a) alkyl vinyl ethers such as ethyl vinyl ether (T.sub.g
-43.degree. C.), propyl vinyl ether (T.sub.g -49.degree. C.), butyl
vinyl ether (T.sub.g -55.degree. C.), isobutyl vinyl ether (T.sub.g
-19.degree. C.), 2-ethylhexyl vinyl ether (T.sub.g -66.degree. C.)
and dodecyl vinyl ether (T.sub.g -62.degree. C.); (4) cyclic ether
monomers include tetrahydrofuran (T.sub.g -84.degree. C.),
trimethylene oxide (T.sub.g -78.degree. C.), ethylene oxide
(T.sub.g -66.degree. C.), propylene oxide (T.sub.g -75.degree. C.),
methyl glycidyl ether (T.sub.g -62.degree. C.), butyl glycidyl
ether (T.sub.g -79.degree. C.), allyl glycidyl ether (T.sub.g
-78.degree. C.), epibromohydrin (T.sub.g -14.degree. C.),
epichlorohydrin (T.sub.g -22.degree. C.), 1,2-epoxybutane (T.sub.g
-70.degree. C.), 1,2-epoxyoctane (T.sub.g -67.degree. C.) and
1,2-epoxydecane (T.sub.g -70.degree. C.); (5) ester monomers (other
than acrylates and methacrylates) including ethylene malonate
(T.sub.g -29.degree. C.), vinyl acetate (T.sub.g 30.degree. C.),
and vinyl propionate (T.sub.g 10.degree. C.); (6) alkene monomers
including ethylene, propylene (T.sub.g -8 to -13.degree. C.),
isobutylene (T.sub.g -73.degree. C.), 1-butene (T.sub.g -24.degree.
C.), trans-butadiene (T.sub.g -58.degree. C.), 4-methyl pentene
(T.sub.g 29.degree. C.), 1-octene (T.sub.g -63.degree. C.) and
other .alpha.-olefins, cis-isoprene (T.sub.g -63.degree. C.), and
trans-isoprene (T.sub.g -66.degree. C.); (7) halogenated alkene
monomers including vinylidene chloride (T.sub.g -18.degree. C.),
vinylidene fluoride (T.sub.g -40.degree. C.), cis-chlorobutadiene
(T.sub.g -20.degree. C.), and trans-chlorobutadiene (T.sub.g
-40.degree. C.); and (8) siloxane monomers including
dimethylsiloxane (T.sub.g -127.degree. C.), diethylsiloxane,
methylethylsiloxane, methylphenylsiloxane (T.sub.g -86.degree. C.),
and diphenylsiloxane.
[0036] Specific examples of high T.sub.g polymer chains further
include those that consist of or contain one or more monomers
selected from the following: (1) vinyl aromatic monomers including
(a) unsubstituted vinyl aromatics, such as styrene (T.sub.g
100.degree. C.) and 2-vinyl naphthalene (T.sub.g 151.degree. C.),
(b) vinyl substituted aromatics such as a-methyl styrene, and (c)
ring-substituted vinyl aromatics including ring-alkylated vinyl
aromatics such as 3-methylstyrene (T.sub.g 97.degree. C.),
4-methylstyrene (T.sub.g 97.degree. C.), 2,4-dimethylstyrene
(T.sub.g 112.degree. C.), 2,5-dimethylstyrene (T.sub.g 143.degree.
C.), 3,5-dimethylstyrene (T.sub.g 104.degree. C.),
2,4,6-trimethylstyrene (T.sub.g 162.degree. C.), and
4-tert-butylstyrene (T.sub.g 127.degree. C.), ring-alkoxylated
vinyl aromatics, such as 4-methoxystyrene (T.sub.g 113.degree. C.)
and 4-ethoxystyrene (T.sub.g 86.degree. C.), ring-halogenated vinyl
aromatics such as 2-chlorostyrene (T.sub.g 119.degree. C.),
3-chlorostyrene (T.sub.g 90.degree. C.), 4-chlorostyrene (T.sub.g
110.degree. C.), 2,6-dichlorostyrene (T.sub.g 167.degree. C.),
4-bromostyrene (T.sub.g 118.degree. C.) and 4-fluorostyrene
(T.sub.g 95.degree. C.) and ring-ester-substituted vinyl aromatics
such as 4-acetoxystyrene (T.sub.g 116.degree. C.); (2) other vinyl
monomers including (a) vinyl esters such as vinyl benzoate (T.sub.g
71.degree. C.), vinyl 4-tert-butyl benzoate (T.sub.g 101.degree.
C.), vinyl cyclohexanoate (T.sub.g 76.degree. C.), vinyl pivalate
(T.sub.g 86.degree. C.), vinyl trifluoroacetate (T.sub.g 46.degree.
C.), vinyl butyral (T.sub.g 49.degree. C.), (b) vinyl amines such
as 2-vinyl pyridine (T.sub.g 104.degree. C.), 4-vinyl pyridine
(T.sub.g 142.degree. C.), and vinyl carbazole (T.sub.g 227.degree.
C.), (c) vinyl halides such as vinyl chloride (T.sub.g 81.degree.
C.) and vinyl fluoride (T.sub.g 40.degree. C.); (d) alkyl vinyl
ethers such as tert-butyl vinyl ether (T.sub.g 88.degree. C.) and
cyclohexyl vinyl ether (T.sub.g 81.degree. C.), and (e) other vinyl
compounds such as vinyl ferrocene (T.sub.g 189.degree. C.); (3)
other aromatic monomers including acenaphthalene (T.sub.g
214.degree. C.) and indene (T.sub.g 85.degree. C.); (4) methacrylic
monomers including (a) methacrylic acid anhydride (T.sub.g
159.degree. C.), (b) methacrylic acid esters (methacrylates)
including (i) alkyl methacrylates such as atactic methyl
methacrylate (T.sub.g 105-120.degree. C.), syndiotactic methyl
methacrylate (T.sub.g 115.degree. C.), ethyl methacrylate (T.sub.g
65.degree. C.), isopropyl methacrylate (T.sub.g 81.degree. C.),
isobutyl methacrylate (T.sub.g 53.degree. C.), t-butyl methacrylate
(T.sub.g 118.degree. C.) and cyclohexyl methacrylate (T.sub.g
92.degree. C.), (ii) aromatic methacrylates such as phenyl
methacrylate (T.sub.g 110.degree. C.) and including aromatic alkyl
methacrylates such as benzyl methacrylate (T.sub.g 54.degree. C.),
(iii) hydroxyalkyl methacrylates such as 2-hydroxyethyl
methacrylate (T.sub.g 57.degree. C.) and 2-hydroxypropyl
methacrylate (T.sub.g 76.degree. C.), (iv) additional methacrylates
including isobornyl methacrylate (T.sub.g 110.degree. C.) and
trimethylsilyl methacrylate (T.sub.g 68.degree. C.), and (c) other
methacrylic-acid derivatives including methacrylonitrile (T.sub.g
120.degree. C.); (5) acrylic monomers including (a) certain acrylic
acid esters such as tert-butyl acrylate (T.sub.g 43-107.degree.
C.), hexyl acrylate (T.sub.g 57.degree. C.) and isobornyl acrylate
(T.sub.g 94.degree. C.); and (b) other acrylic-acid derivatives
including acrylonitrile (T.sub.g 125.degree. C.). Further specific
examples of high T.sub.g polymer chains include polyamide chains
selected from nylon homopolymer and copolymer chains such as nylon
6, nylon 4/6, nylon 6/6, nylon 6/10, nylon 6/12, nylon 11 and nylon
12 chains.
[0037] Further specific examples of high and low T.sub.g polymer
chains include polymer chains that consist of or contain one or
more monomers selected from the following: (a) polyester-forming
monomers such as naphthalate and terephthalate esters (the T.sub.g
is 70-80.degree. C. for polyethylene terephthalate), d-lactide,
1-lactide (T.sub.g 60-65.degree. C.), glycolic acid (T.sub.g
35-40.degree. C.), epsilon-caprolactone (T.sub.g -65 to -60.degree.
C.), hydroxybutyrate, and hydroxyvalerate, (b) monomers that form
polyether-esters such as p-dioxanone (T.sub.g -10 to 0.degree. C.),
and (c) monomers that form polycarbonates such as ethylene
carbonate (1,3-dioxolan-2-one) (T.sub.g 10 to 30.degree. C.),
propylene carbonate (4-methyl-1,3-dioxolan-2-one), trimethylene
carbonate (1,3-dioxan-2-one), tetramethylene carbonate
(1,3-dioxepan-2-one), as well as 1,4-dioxepan-2-one,
1,5-dioxepan-2-one and 6,6-dimethyl-1,4-dioxan-2-one.
[0038] Further examples of hydrophobic and hydrophilic polymer
chains (which may be high or low T.sub.g polymer chains), include
hydrophobic and hydrophilic biodegradable chains such as those
listed in the prior paragraph as well as hydrophobic and
hydrophilic bioactive polymer chains and hydrophobic and
hydrophilic biomimetic polymer chains.
[0039] For example, hydrophobic and hydrophilic polymer chains may
be selected from one or more of the following (predominantly
hydrophilic) chains: the subunit chains found in collagen, laminin
or fibronectin, elastin chains, polymer chains containing cell
adhesion peptides such as RGD tripeptide (i.e., ArgGlyAsp), REDV
tetrapeptide (i.e., Arg-Glu-Asp-Val), and YIGSR pentapeptide (i.e.,
TyrlleGlySerArg), glycoprotein chains, polyanhydride chains,
polyorthoester chains, polyphosphazene chains, and sulfated and
non-sulfated polysaccharide chains, such as chitin, chitosan,
sulfated and non-sulfated glycosaminoglycans as well as species
containing the same such as proteoglycans, for instance, selected
from heparin, heparin sulfate, chondroitin sulfates including
chondroitin-4-sulfate and chondroitin-6-sulfate, hyaluronic acid,
keratan sulfate, dermatan sulfate, hyaluronan, bamacan, perlecan,
biglycan, fibromodulin, aggrecan, decorin, mucin, carrageenan,
polymers and copolymers of uronic acids such as mannuronic acid,
galatcuronic acid and guluronic acid, for example, alginic acid (a
copolymer of beta-D-mannuronic acid and alpha-L-guluronic acid),
which charged polysaccharide species may be attached to a cell
adhesion peptide, a protein, a protein fragment and/or a
biocompatible polymer, as described in U.S. Pat. App. No.
2005/0187146 to Helmus et al.
[0040] As noted above, the medical devices of the present invention
optionally contain one or more therapeutic agents. "Therapeutic
agents," "drugs," "pharmaceutically active agents,"
"pharmaceutically active materials," and other related terms may be
used interchangeably herein. These terms include genetic
therapeutic agents, non-genetic therapeutic agents and cells.
[0041] Therapeutic agents include, for example, adrenergic agents,
adrenocortical steroids, adrenocortical suppressants, alcohol
deterrents, aldosterone antagonists, amino acids and proteins,
ammonia detoxicants, anabolic agents, analeptic agents, analgesic
agents, androgenic agents, anesthetic agents, anorectic compounds,
anorexic agents, antagonists, anterior pituitary activators and
suppressants, anthelmintic agents, anti-adrenergic agents,
anti-allergic agents, anti-amebic agents, anti-androgen agents,
anti-anemic agents, anti-anginal agents, anti-anxiety agents,
anti-arthritic agents, anti-asthmatic agents, anti-atherosclerotic
agents, antibacterial agents, anticholelithic agents,
anticholelithogenic agents, anticholinergic agents, anticoagulants,
anticoccidal agents, anticonvulsants, antidepressants, antidiabetic
agents, antidiuretics, antidotes, antidyskinetics agents,
anti-emetic agents, anti-epileptic agents, anti-estrogen agents,
antifibrinolytic agents, antifungal agents, antiglaucoma agents,
antihemophilic agents, antihemophilic Factor, antihemorrhagic
agents, antihistaminic agents, antihyperlipidemic agents,
antihyperlipoproteinemic agents, antihypertensives,
antihypotensives, anti-infective agents, anti-inflammatory agents,
antikeratinizing agents, antimicrobial agents, antimigraine agents,
antimitotic agents, antimycotic agents, antineoplastic agents,
anti-cancer supplementary potentiating agents, antineutropenic
agents, antiobsessional agents, antiparasitic agents,
antiparkinsonian drugs, antipneumocystic agents, antiproliferative
agents, antiprostatic hypertrophy drugs, antiprotozoal agents,
antipruritics, antipsoriatic agents, antipsychotics, antirheumatic
agents, antischistosomal agents, antiseborrheic agents,
antispasmodic agents, antithrombotic agents, antitussive agents,
anti-ulcerative agents, anti-urolithic agents, antiviral agents,
benign prostatic hyperplasia therapy agents, blood glucose
regulators, bone resorption inhibitors, bronchodilators, carbonic
anhydrase inhibitors, cardiac depressants, cardioprotectants,
cardiotonic agents, cardiovascular agents, choleretic agents,
cholinergic agents, cholinergic agonists, cholinesterase
deactivators, coccidiostat agents, cognition adjuvants and
cognition enhancers, depressants, diagnostic aids, diuretics,
dopaminergic agents, ectoparasiticides, emetic agents, enzyme
inhibitors, estrogens, fibrinolytic agents, free oxygen radical
scavengers, gastrointestinal motility agents, glucocorticoids,
gonad-stimulating principles, hemostatic agents, histamine H2
receptor antagonists, hormones, hypocholesterolemic agents,
hypoglycemic agents, hypolipidemic agents, hypotensive agents,
HMGCoA reductase inhibitors, immunizing agents, immunomodulators,
immunoregulators, immunostimulants, immunosuppressants, impotence
therapy adjuncts, keratolytic agents, LHRH agonists, luteolysin
agents, mucolytics, mucosal protective agents, mydriatic agents,
nasal decongestants, neuroleptic agents, neuromuscular blocking
agents, neuroprotective agents, NMDA antagonists, non-hormonal
sterol derivatives, oxytocic agents, plasminogen activators,
platelet activating factor antagonists, platelet aggregation
inhibitors, post-stroke and post-head trauma treatments,
progestins, prostaglandins, prostate growth inhibitors,
prothyrotropin agents, psychotropic agents, radioactive agents,
repartitioning agents, scabicides, sclerosing agents, sedatives,
sedative-hypnotic agents, selective adenosine Al antagonists,
serotonin antagonists, serotonin inhibitors, serotonin receptor
antagonists, steroids, stimulants, thyroid hormones, thyroid
inhibitors, thyromimetic agents, tranquilizers, unstable angina
agents, uricosuric agents, vasoconstrictors, vasodilators,
vulnerary agents, wound healing agents, xanthine oxidase
inhibitors, and the like.
[0042] Further examples of therapeutic agents useful for the
practice of the present invention may be selected, for example,
from those described in paragraphs [0040] to of commonly assigned
U.S. Patent Application Pub. No. 2003/0236514, the disclosure of
which is hereby incorporated by reference.
[0043] Additional specific examples may be selected, for example,
from paclitaxel (including particulate forms thereof, for instance,
protein-bound paclitaxel particles such as albumin-bound paclitaxel
nanoparticles, e.g., ABRAXANE), sirolimus, everolimus, tacrolimus,
Epo D, dexamethasone, estradiol, halofuginone, cilostazole,
geldanamycin, ABT-578 (Abbott Laboratories), trapidil, liprostin,
Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel,
beta-blockers, bARKct inhibitors, phospholamban inhibitors, Serca 2
gene/protein, imiquimod, human apolioproteins (e.g., AI-AV), growth
factors (e.g., VEGF-2), heparin, as well a derivatives of the
forgoing, among others.
[0044] Polymer brush regions may be created by various methods,
including covalent and non-covalent (e.g., physical adsorption)
attachment. In one example of non-covalent attachment, a block
copolymer is adsorbed onto a substrate, with one chain of the
copolymer interacting strongly with the surface and the other
chains forming the brushes. For example, a first polymer chain of
the copolymer may be compatible with the device surface (e.g., a
polymer surface formed from the same polymer or a compatible
polymer) such that it becomes adsorbed to the surface. A second
polymer chain of the copolymer may be selected to provide
biocompatibility, whereas a third chain of the copolymer may be
selected to provide reduced adhesion. For example, if the second
chain is hydrophilic and biocompatible, the third chain may be
hydrophobic and have reduced adhesion to other surfaces, and vice
versa.
[0045] While physical adsorption is relatively simple to carry out,
covalent techniques may be preferred in some embodiments, due to
the stability and enhanced control over the polymer chain density
which may be afforded by such techniques. Covalent attachment of
polymers to form polymer brushes is commonly achieved by "grafting
to" and "grafting from" techniques. "Grafting to" techniques
involve tethering pre-formed end-functionalized polymer chains to a
suitable substrate under appropriate conditions. "Grafting from"
techniques, on the other hand, involve covalently immobilizing
initiators on the substrate surface, followed by surface initiated
polymerization to generate the polymer brushes.
[0046] Each of these techniques involves the attachment of a
species (e.g., a polymer or an initiator) to a surface, which may
be carried out using a number of techniques that are known in the
art.
[0047] For instance, covalent coupling of species to a substrate
surface, each having reactive functional groups, may be carried out
by direct reaction between the functional groups, or through the
use of linking/coupling agents that contain reactive moieties
capable of reaction with such functional groups. Specific examples
of known linking agents include glutaraldehyde, diisocyanates,
diiosothiocyanates, bis(hydroxysuccinimide)esters,
maleimidehydroxysuccinimide esters, carbodiimides,
N,N'-carbonyldiimidazole imidoesters, and difluorobenzene
derivatives, among others. One ordinarily skilled in the art will
recognize that any number of other coupling agents may be used
depending on the functional groups present. Further information on
covalent coupling may be found, for example, in U.S. Pub. No.
2005/0002865, which is incorporated by reference.
[0048] For many substrates, including polymer substrates, surface
functional groups may be introduced by treating the substrate with
a reactive plasma. For example, gas discharge techniques, in which
surface modification is achieved by exposing the surface to a
partially ionized gas (i.e., to a plasma). Because the plasma phase
consists of a wide spectrum of reactive species (electrons, ions,
etc.) these techniques have been used widely for functionalization
of polymer surfaces. Two types of processes are frequently
described, depending on the operating pressure: corona discharge
techniques (which are conducted at atmospheric pressure) and glow
discharge techniques (which are conducted at reduced pressure).
Glow discharge techniques may be preferred over corona discharge
techniques in certain embodiments, because the shape of the object
to be treated is of minor importance during glow discharge
processes. Moreover, glow discharge techniques are usually either
operated in an etching or in a depositing mode, depending on the
gas used, whereas corona discharge techniques are usually operated
in an etching mode. A commonly employed glow discharge technique is
radio-frequency glow discharge (RFGD).
[0049] Plasma treatment processes may be used to etch, crosslink
and/or functionalize polymer surfaces, with these processes
typically occurring simultaneously at a polymer surface that is
exposed to a discharge of a non-polymerizable gas. The gas that is
used primarily determines which of these processes is dominant As
seen from the table below (adapted from "Functionalization of
Polymer Surfaces," Europlasma Technical Paper, May 8, 2004),
depending on the gas that is used, a variety of various functional
groups may be generated on a given polymer.
TABLE-US-00001 Plasma treatment gas Substrate* Functional groups Ar
SR C.dbd.O O.sub.2, Ar PP, PS C--O, C.dbd.O O.sub.2 PE C--O
(C--O--C), C.dbd.O, C(O)--O CO, CO.sub.2 PE --OH, C.dbd.O, C(O)OH
CO.sub.2 PP C.dbd.O, C(O)--O, C.dbd.C CO.sub.2 SR C.dbd.O, C.dbd.C
SO.sub.2 PU --SO.sub.2, --SO.sub.3 H.sub.2O PE, PP, PS, PET, --OH
PMMA N.sub.2 PE C--N, C.dbd.N NH.sub.3 SR --C(O)--NH-- NH.sub.3
Kevlar C--NH.sub.2 N.sub.2O/Ar PET C.dbd.O (aldehyde) *where SR is
silicone rubber or poly(dimethyl siloxane), PS is polystyrene, PE
is polyethylene, PP is polypropylene, PU is polyurethane, PET is
poly(ethylene terepthalate), and PMMA is poly(methyl
methacrylate).
[0050] Functional-group-containing surfaces may also be obtained
for polymeric and non-polymeric substrates using plasma
polymerization processes in which so-called "monomers" are employed
that contain functional groups. By using a second feed gas
(commonly a non-polymerizable gas) in combination with the
unsaturated monomer, it is possible to incorporate this second
species in the plasma deposited layer as well. Examples of gases
that may be used include, allylamine, pyridine, nitroethane,
ethylene oxide, allylalcohol, ethylene glycol monomethyl ether,
acrylic acid, n-vinyl pyrrolidone, acetylene/H.sub.2O,
acetylene/CO, acetylene/N.sub.2, acetylene/CO/H.sub.2O,
acetylene/N.sub.2/H.sub.2O, ethylene/N.sub.2, allylamine/NH.sub.3,
acetylene/SO.sub.2, ethylene/SO.sub.2, and acrylic acid/CO.sub.2,
among others. Examples of functional groups that have been
reportedly formed using these methods include amine, hydroxyl and
carboxylate groups, among numerous others.
[0051] Further information concerning plasma functionalization may
be found, for example, in "Functionalization of Polymer Surfaces,"
Europlasma Technical Paper, May 8, 2004 and in U.S. Patent
Application Publication No. 2003/0236323.
[0052] For conductive substrates, electrochemical processes may be
employed for attachment of polymers or initiators. In this regard,
technology for linking an initiator to an electrically conductive
surface, including metallic substrate materials such as those
discussed above (e.g., stainless steel, nitinol, etc.), is
disclosed by Claes et al., "Polymer Coating of Steel by a
Combination of Electrografting and Atom-Transfer Radical
Polymerization," Macromolecules, Web release No. 0217130, published
Jul. 19, 2003 and in Ser. No. 10/894,391, filed Jul. 19, 2004 and
entitled "Medical Devices Having Conductive Substrate And
Covalently Bonded Coating Layer," the contents of which are hereby
incorporated by reference in their entirety. In general, the
initiator will have at least one functionality that is conducive to
electrografting and at least one functionality that is able to
initiate free radical polymerization (e.g., an activated halide
functionality, which is able to initiate ATRP polymerization of,
for example, vinyl monomers). One specific example of such a
species is 2-chloropropionate ethyl acrylate (cPEA).
[0053] As noted above, in the "grafting from" process once an
initiator is attached to the surface, a polymerization reaction is
then conducted to create a surface bound polymer. Various
polymerization reactions may be employed, including various
condensation, anionic, cationic and radical polymerization methods.
These and other methods may be used to polymerize a host of
monomers and monomer combinations.
[0054] Specific examples of radical polymerization processes are
controlled/"living" radical polymerizations such as metal-catalyzed
atom transfer radical polymerization (ATRP), stable free-radical
polymerization (SFRP), nitroxide-mediated processes (NMP), and
degenerative transfer (e.g., reversible addition-fragmentation
chain transfer (RAFT)) processes, among others. The advantages of
using a "living" free radical system for polymer brush creation
include control over the brush thickness via control of molecular
weight and narrow polydispersities, and the ability to prepare
block copolymers by the sequential activation of a dormant chain
end in the presence of different monomers. These methods are
well-detailed in the literature and are described, for example, in
an article by Pyun and Matyjaszewski, "Synthesis of Nanocomposite
Organic/Inorganic Hybrid Materials Using Controlled/"Living"
Radical Polymerization," Chem. Mater., 13:3436-3448 (2001), the
contents of which are incorporated by reference in its
entirety.
[0055] A few specific examples of techniques which have been used
to produce brush polymers are described below.
[0056] One example of a "grafting to" techniques is described in D.
Usov et al., "Mixed Polymer Brushes with Thermal Response Amplified
by Roughness," Polymeric Materials Science & Engineering 2004,
90, 622-623, in which .mu.m-scale surface roughness was created on
a semicrystalline PTFE substrate via etching with oxygen plasma.
Both etched and non-etched PTFE were then activated with ammonia
plasma. The following polymers were covalently attached to the
aminogroups on the PTFE substrates, via their end carboxylic
groups: .alpha.,.omega.-dicarboxy-terminated
poly(styrene-co-2,3,4,5,6-pentafluorostyrene) (PSF),
.alpha.,.omega.-dicarboxy-terminated
poly(methylacrylate-co-1,1,1,3,3,3-hexafluoroisopropyl
methacrylate) (PHFA), and carboxy terminated poly(N-isopropyl
acrylamide) (PNiPAAm). The polymer films were cast onto the
activated substrates from a 1% solution in THF. The first
(hydrophobic) polymer cast (i.e., PSF or PHFA) was grafted at
170.degree. C. for 50 min in vacuum. After removing the non-grafted
polymer, the second (hydrophilic) polymer (i.e., PNiPAAm) was cast
grafted under the same conditions over 16 hours. The non-grafted
polymer was again removed. Switching ability of the synthesized
mixed polymer brushes upon exposure to selective solvents was
observed (toluene is selective for PSF and PHFA, whereas ethanol is
selective for PNiPAAm), as was thermally induced switching.
[0057] An example of a "grafting from" technique is described in M.
Motornov et al., "Mixed Polymer Brushes on Polyamide Substrates,"
Polymeric Materials: Science & Engineering 2004, 88, 264-265.
In this technique, polyamide (PA) samples were first treated with
NH.sub.3 plasma. An azo-initiator, 4,4'-azobis(4-cianopentanoic
acid), was then covalently grafted to the plasma modified
substrate, via the reaction of the amino-groups on the substrate
with the hydroxy-groups on the initiator. Grafting of the
polystyrene chains was performed by in situ radical polymerization,
which was initiated by thermal decomposition of the azo-initiator.
After washing, the residual azo-initiator was used to carry out the
graft polymerization of 2-vinylpyridine. A pronounced switching
effect upon exposure to toluene and ethanol was observed.
[0058] Igor Luzinov et al., National Textile Center Annual Report:
November 2003 describe forming a mixed polymer brush on a
poly(glycidylmethacrylate) (PGMA) substrate using a combination of
the "grafting to" and "grafting from" techniques. Specifically,
bromoacetic acid (BAA) molecules were attached to the PGMA surface
from the gaseous phase, whereupon the reaction between the epoxy
groups and carboxyl functionalities of the halogen acid led to
2-bromoisobutyric esters derivatives of the PGMA, which were then
available to act as an ATRP initiator. Next, the synthesis of a
poly(t-butyl acrylate) brush was carried out by melt grafting. The
PTBA melt grafting "buried" the ATRP initiator under the polymer
brush, which had a thickness of 12-20 nm. To complete the
fabrication of the mixed brush, ATRP of styrene was carried out,
initiated by the ATRP intiator. Hydrolysis of PTBA to polyacrylic
acid (PAA) yielded polymer layers having hydrophobic/hydrophilic
properties. The brushes changed their surface morphology, when they
were exposed to solvent with different polarity. See also V. Klep
et al., "Mixed Polymer Layers by `Grafting to`/`Grafting form`
Combination," Polymeric Materials: Science & Engineering 2003,
89, 248, in which a similar procedure was carrier out using
2-bromoisobutyric acid as initiator.
[0059] Luzinov et al. also describe a technique whereby Y-shaped
block copolymers, which contained two incompatible polystyrene (PS)
and polyacrylic acid (PAA) arms and an aromatic functional stem
having a reactive carboxylate group, were grafted to the substrate
surface. It was observed that these arms are capable of local
reversible rearrangements leading to a reversible surface
structural reorganization in different solvents.
[0060] Analogously, switchable diblock and triblock polymers may be
grafted to substrates using "grafting to" methods, "grafting from"
methods, and combinations of the same. For an example of a diblock
copolymer exhibiting switchable behavior see, e.g., S A Prokhorova,
et al., "Can polymer brushes induce motion of nano-objects?" 2003
Nanotechnology 14 1098-1108, in which poly(methyl
methacrylate-b-glycidyl methacrylate) diblock-copolymer brushes are
synthesized by "grafting from" a covalently attached
2-bromoisobutyrate initiator on the surface of a silicon wafer. See
also U.S. Pat. Appln. 2003/0219535 in which nitroxide mediated free
radical polymerization of vaporized vinyl monomers, including
acrylic acid (AAc), styrene (St), N-2-(hydroxypropyl)
methacrylamide (HPMA) and N-isopropyl acrylamide (NIPAAm), on
silicon wafers is demonstrated. A tri-block copolymer of
poly(AAc)-poly(St)-poly(HPMA) is synthesized.
[0061] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
* * * * *