U.S. patent application number 15/244030 was filed with the patent office on 2016-12-08 for coating for a surface.
The applicant listed for this patent is W. L. Gore & Associates, Inc.. Invention is credited to Charles D. Claude, Paul D. Drumheller.
Application Number | 20160355688 15/244030 |
Document ID | / |
Family ID | 51528025 |
Filed Date | 2016-12-08 |
United States Patent
Application |
20160355688 |
Kind Code |
A1 |
Drumheller; Paul D. ; et
al. |
December 8, 2016 |
Coating For A Surface
Abstract
Coatings for a surface, especially a priming coating, of the
present invention have been found to be durable, resistant to
oxidative degradation, erosion and depolymerisation, stable to
sterilization and low particulating, and are easily applied to the
required surface of a substrate in a surface-independent manner.
Such coatings, when used as priming coatings to be coated with a
subsequent coating, in at least some embodiments, form exterior
coatings which are also highly durable and are stable to
sterilisation and aging.
Inventors: |
Drumheller; Paul D.;
(Flagstaff, AZ) ; Claude; Charles D.; (Flagstaff,
AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
W. L. Gore & Associates, Inc. |
Newark |
DE |
US |
|
|
Family ID: |
51528025 |
Appl. No.: |
15/244030 |
Filed: |
August 23, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14209866 |
Mar 13, 2014 |
9447304 |
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15244030 |
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61785999 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2420/06 20130101;
A61L 29/085 20130101; C09D 131/04 20130101; A61L 31/16 20130101;
A61L 31/10 20130101; C09D 179/02 20130101; A61L 27/34 20130101;
B05D 1/18 20130101; Y10T 428/31725 20150401; A61L 2420/02 20130101;
B05D 3/067 20130101; B05D 3/065 20130101; B05D 1/02 20130101; B05D
7/58 20130101; C09D 7/63 20180101; B05D 5/086 20130101; Y10T
428/31544 20150401; C09D 5/002 20130101; A61L 27/34 20130101; C08L
79/02 20130101; A61L 29/085 20130101; C08L 79/02 20130101; A61L
31/10 20130101; C08L 79/02 20130101 |
International
Class: |
C09D 5/00 20060101
C09D005/00; A61L 31/16 20060101 A61L031/16; A61L 31/10 20060101
A61L031/10; C09D 179/02 20060101 C09D179/02; C09D 131/04 20060101
C09D131/04 |
Claims
1. A surface having a coating comprising a mixture of components A
and B, wherein component A is a polymer formed by
self-polymerisation of a molecule comprising catechol functionality
and amine and/or amide and/or hydroxyl functionality; and component
B comprises a polymer comprising photosensitive or thermosensitive
moieties at least some of which moieties form covalent bonds with
component A and which polymer forms an interpenetrating network
with component A.
2. A surface having a coating according to claim 1, wherein
component B is a mixture of a cross-linking molecule comprising two
or more photosensitive or thermosensitive moieties, at least some
of which moieties form covalent bonds with component A, and a
polymer comprising photosensitive or thermosensitive moieties at
least some of which moieties form covalent bonds with component A
and which polymer forms an interpenetrating network with component
A.
3. A surface having a coating according to claim 1, wherein
component A is a catecholamine capable of self-polymerisation.
4. A surface having a coating according to claim 3, wherein
component A is dopamine.
5. A surface having a coating according to claim 1, wherein the
coating is covalently bonded to the surface.
6. A surface having a coating according to claim 1, wherein the one
or more photosensitive or thermosensitive moieties component B are
capable of hydrogen abstraction.
7. A surface having a coating according to claim 6, wherein the
surface comprises abstractable hydrogen atoms and the coating is
covalently bonded to the surface via abstraction of hydrogen atoms
from the surface by at least some of the photosensitive or
thermosensitive moieties of component B.
8. A surface having a coating according to claim 1, wherein
component B comprises one or more photosensitive moieties.
9. A surface having a coating according to claim 8, wherein the one
or more photosensitive moieties are selected from the group
consisting of aryl ketone, diaryl ketone, aryl azide, alkenyl and
alkynyl.
10. A surface having a coating according to claim 8, wherein the
one or more photosensitive moiety is a Type I or Type II
photoinitiator,
11. A surface having a coating according to claim 10, wherein the
one or more photosensitive moiety is a Type II photoinitiator.
12. A surface having a coating according to claim 11, wherein one
or more photosensitive moiety is a diaryl ketone.
13. A surface having a coating according to claim 11, wherein the
one or more photosensitive moiety is benzophenone.
14. A surface having a coating according to claim 1, wherein
component B comprises one or more thermosensitive moieties.
15. A surface having a coating according to claim 1, wherein
component B comprises one or more photosensitive or thermosensitive
moieties capable of forming a carbene or nitrene.
16. A surface having a coating according to claim 1, wherein the
surface has a subsequent coating,
17. A surface having a coating according to claim 16, wherein the
subsequent a coating is selected from the group consisting of a
synthetic or naturally occurring organic or inorganic polymer or
material, such as polyolefins, polyesters, polyurethanes,
polyamides, polyether block amides, polycarbonates, polyphenylene
sulfides, polyphenylene oxides, polyethers, silicones,
polycarbonates, polyhydroxyethylmethacrylate polyvinyl pyrrolidone,
polyvinyl alcohol, rubber, silicone rubber, polyhydroxyacids,
polyallylamine, polyallylalcohol, polyacrylamide, polyamelic acid,
styrenic polymers, polytetrafluoroethylene and copolymers thereof,
bioresorbables, such as poly(D,L-lactide), polyglycolids and
copolymers thereof, non-woven, bioabsorbable web materials
comprising a tri-block copolymer such as
poly(glycolide-co-trimethylene carbonate) tri-block copolymer
(PGA:TMC), nylon 12, nylon 11, nylon 9, nylon 6/9 and nylon 6/6,
polyetheresteramide, polyethylene terephthalate and polybutylene
terephthalate, polyester ethers, polyester elastomer copolymers,
block copolymer elastomers such as those copolymers having styrene
end blocks, and midblocks formed from butadiene, isoprene,
ethylene/butylene, ethylene/propene, styrenic block copolymers
including acrylonitrile-styrene and acrylonitrile-butadiene-styrene
block copolymers, polystyrenes, poly(methyl)methacrylates,
polyacrylonitriles, poly(vinylacetates), poly(vinyl alcohols),
chlorine-containing polymers such as poly(vinyl) chloride,
polyoxymethylenes, polycarbonates, polyamides, polyimides,
polyurethanes, phenolics, amino-epoxy resins, polyesters,
silicones, cellulose-based plastics, rubber-like plastics,
fluorinated polymers such as fluoropolymers, e.g. expanded
polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE),
fluorinated ethylene-propylene (FEP), perfluorocarbon copolymers,
e.g. tetrafluoroethylene perfluoroalkylvinyl ether (TFE/PAVE)
copolymers, copolymers of tetrafluoroethylene (TFE) and
perfluoromethyl vinyl ether (PMVE), copolymers of TFE with
functional monomers that comprise acetate, alcohol, amine, amide,
sulfonate, functional groups, expanded polyethylene,
polyvinylchloride, polyurethane, silicone, polyethylene,
polypropylene, polyurethane, polyglycolic acid, polyesters,
polyamides, elastomers and their mixtures, blends and copolymers or
derivatives.
18. A surface having a coating according to claim 16, wherein the
coating is covalently bonded to the subsequent coating.
19. A surface having a coating according to claim 16, wherein the
subsequent coating comprises a therapeutic agent.
20. A surface having a coating according to claim 19, wherein the
therapeutic agent is selected from the group consisting of an
anti-thrombogenic agent, a hemostatic agent, an anti-angiogenic
agent, an angiogenic agents, an anti-microbial agent, an
anti-proliferative agent, a proliferative agent and an
anti-inflammatory agent, or a combination thereof.
21. A surface having a coating according to claim 21, wherein the
surface is the surface of a substrate comprising a medical
device.
22. A surface having a coating according to claim 21, wherein the
medical device is selected from the group consisting of stents
including bifurcated stents, balloon expandable stents and
self-expanding stents, stent-grafts including bifurcated
stent-drafts, grafts including vascular grafts and bifurcated
grafts, dialators, vascular occluders, embolic filters, embolectomy
devices, catheters including microcatheters, central venous
catheters, peripheral intravenous catheters and hemodialysis
catheters, artificial blood vessels, sheaths including retractable
sheaths, blood indwelling monitoring devices, artificial heart
valves, pacemaker electrodes, guidewires, cardiac leads,
cardiopulmonary bypass circuits, cannulae, plugs, drug delivery
devices, balloons, tissue patch devices and blood pumps.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a coating for a surface,
especially a priming coating, and to methods for preparing such a
coating.
BACKGROUND OF THE INVENTION
[0002] A priming coating is a preparatory coating that is applied
to a surface before a subsequent coating is applied. Priming
coatings are used in a broad range of applications, inter alia, to
improve the adhesion between the subsequent coating and the
surface, to increase the durability of the subsequent coating, and
to provide additional protection for the surface being coated.
[0003] The use of polydopamine as a primer has attracted great
interest since the discovery that simple immersion of a substrate
in a dilute aqueous solution of dopamine, buffered to alkaline pH,
results in the spontaneous deposition of a polydopamine film on the
substrate, Messersmith et al. (Science, 2007, 318, 426-430)
demonstrated that a polydopamine coating is able to form on a
variety of substrate surfaces, including metals, metal oxides,
ceramics, synthetic polymers and a wide range of other hydrophilic
and hydrophobic materials. Polydopamine coatings have been used as
a platform for the conjugation of synthetic polymers or
biomolecules to a surface, as illustrated in WO2011/005258 which
discloses the attachment of amine-functionalised polyethylene
glycol ("PEG-NH.sub.2") to a polydopamine coating, to provide a
hydrophilic outer layer for the prevention of biofilm formation.
US2008/0149566 discloses that a substrate treated with a
surface-modifying agent (SMA) such as polydopamine can be treated
with a secondary reactive moiety to impart specific functionalities
to the substrate. The secondary moiety is described as an
"ad-layer" and may be applied by various means, including by
nucleophilic addition and by free radical graft polymerisation.
[0004] However, the use of polydopamine as a coating such as a
priming coating has certain drawbacks. Polydopamine is known to
degrade under oxidative conditions and is also susceptible to
degradation under sterilising conditions, thereby reducing its
utility for coating medical devices. Although the exact nature of
the interaction between a polydopamine coating and the surface
which it coats is unknown and is likely to be surface dependent, it
is acknowledged the polydopamine layer is not covalently bound to
the surface. This has implications for the durability of any
subsequent coating that is applied to the polydopamine layer
Furthermore, it has been observed that when a substrate is dipped
in a solution of polydopamine, over time particulates of
polydopamine are observed in the solution. Particulation is
undesirable in most coating applications that require a long-term
or permanent, stable coating.
[0005] In summary, there remains a need for improved coatings for
surfaces, particularly priming coatings. Preferably, such coatings
are durable, sterilizable, low particulating, biocompatible and
readily applied to a surface.
SUMMARY OF THE INVENTION
[0006] In one aspect, the invention provides a surface having a
coating comprising a mixture of components A and B, wherein [0007]
component A is a polymer formed by self-polymerisation of a
molecule comprising catechol functionality and amine and/or amide
and/or hydroxyl functionality; and [0008] component B is [0009] (i)
a cross-linking molecule comprising two or more photosensitive or
thermosensitive moieties, at least some of which moieties form
covalent bonds with component A; or [0010] (ii) a polymer
comprising photosensitive or thermosensitive moieties at least some
of which moieties form covalent bonds with component A and which
polymer forms an interpenetrating network with component A; or a
mixture thereof.
[0011] In another aspect, the invention provides a surface having a
coating comprising a cross-linked copolymer of components A and B,
wherein
[0012] component A is a molecule capable of self-polymerisation
comprising catechol functionality and amine and/or amide and/or
hydroxyl functionality; and
[0013] component B is a molecule comprising one or more groups
capable of participating in the polymerisation of component A,
wherein said molecule comprises one or more photosensitive or
thermosensitive moieties capable of forming covalent bonds with
component A, at least some of which moieties form covalent bonds
with component A in the copolymer.
[0014] In a further aspect, the invention provides a method of
coating a surface, comprising the steps of: [0015] (a) contacting
the surface with a mixture comprising components A and B, [0016]
wherein [0017] component A is a molecule capable of
self-polymerisation comprising, catechol functionality and amine
and/or amide and/or hydroxyl functionality; and [0018] component B
is [0019] (i) a cross-linking molecule comprising two or more
photosensitive or thermosensitive moieties capable of forming
covalent bonds with component A; or [0020] (ii) a polymer
comprising photosensitive or thermosensitive moieties capable of
forming covalent bonds with component A; [0021] or a mixture
thereof; [0022] such that component A self-polymerises in the
presence of component B and in the case of (ii) forms an
interpenetrating network with component B; and [0023] (b)
activating the photosensitive or thermosensitive moieties of
component B such that at least some of said moieties form covalent
bonds with component A.
[0024] In a still further aspect, the invention provides a method
of coating a surface, comprising the steps of: [0025] (a)
contacting the surface with a mixture comprising components A and
B, [0026] wherein [0027] component A is a molecule capable of
self-polymerisation comprising catechol functionality and amine
and/or amide and/or hydroxyl functionality; and [0028] component B
is a molecule comprising one or more groups capable of
participating in the polymerisation of component A, wherein said
molecule comprises one or more photosensitive or thermosensitive
moieties capable of forming covalent bonds with component A such
that a copolymer of components A and B is formed; and [0029] (b)
activating the photosensitive or thermosensitive moieties of
component B in the copolymer such that at least some of said
moieties form covalent bonds with component A.
[0030] As explained in the Examples, coatings of the present
invention, in at least some embodiments, have been found to be
durable, resistant to oxidative degradation, erosion and
depolymerisation, stable to sterilization and low particulating,
and are easily applied to the required surface of a substrate in a
surface-independent manner. Such coatings, when used as priming
coatings to be coated with a subsequent coating, in at least some
embodiments, form exterior coatings which are also highly durable
and are stable to sterilisation and aging.
BRIEF DESCRIPTION OF THE FIGURES
[0031] FIG. 1: shows various proposed structures for
polydopamine.
[0032] FIG. 2: shows Embodiment 1a of the invention, wherein
component B is a cross-linking molecule comprising two or more
photosensitive or thermosensitive moieties capable of forming
covalent bonds with component A;
[0033] FIG. 3: shows Embodiment 1 b of the invention, wherein
component B is a polymer comprising photosensitive or
thermosensitive moieties capable of forming covalent bonds with
component A;
[0034] FIG. 4: shows Embodiment 2 of the invention, wherein
component B is a molecule comprising one or more groups capable of
participating in the polymerisation of component A, wherein said
molecule comprises a photosensitive or thermosensitive moiety
capable of forming covalent bonds with component A such that a
copolymer of components A and B is formed;
[0035] FIG. 5: shows Embodiment 2 of the invention, wherein the
resulting coating is covalently bonded to the surface;
[0036] FIG. 6: shows Embodiment 2 of the invention, wherein a
subsequent coating is covalently bonded to the priming coating of
the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention relates to a coating, especially a
priming coating, which is applied to a surface. In one embodiment
the surface is the surface of a substrate.
Substrate
[0038] Suitable substrates may include, but are not limited to,
industrial and consumer articles such as membranes and fabrics,
medical devices, analytical devices, separation devices. The
present invention also has applications in diagnostic devices such
as nanoarrays and microarrays.
Medical Devices
[0039] For the purposes of this invention, the term "medical
device" refers to intracorporeal or extra-corporeal devices but
more usually to intracorporeal medical devices.
[0040] Thus, in one embodiment, the surface is the surface of a
substrate comprising a medical device. In another embodiment, the
surface is the surface of a substrate comprising an intracorporeal
medical device. In a further embodiment, the surface is the surface
of substrate comprising an extracorporeal medical device. In
another embodiment, the surface is the surface of a substrate which
is a component of a medical device.
[0041] Examples of intracorporeal medical devices which can be
permanent or temporary intracorporeal medical devices include
stents including bifurcated stents, balloon expandable stents,
self-expanding stents, stent-grafts including bifurcated
stent-grafts, grafts including vascular grafts, bifurcated grafts,
dialators, vascular occluders, embolic filters, embolectomy
devices, artificial blood vessels, blood indwelling monitoring
devices, artificial heart valves (leaflet, frame, and/or cuff),
pacemaker electrodes, guidewires, cardiac leads, cardiopulmonary
bypass circuits, cannulae, plugs, drug delivery devices, balloons,
tissue patch devices, blood pumps, patches, cardiac leads, chronic
infusion lines, arterial lines, devices for continuous subarachnoid
infusions, feeding tubes, CNS shunts (e.g., a ventriculopleural
shunt, a VA shunt, or a VP shunt), ventricular peritoneal shunts,
ventricular atrial shunts, portosystemic shunts and shunts for
ascites.
[0042] Further examples of intracorporeal medical devices which can
be permanent or temporary are catheters. Examples of catheters
include, but are not limited to, central venous catheters,
peripheral intravenous catheters, hemodialysis catheters, catheters
such as coated catheters include implantable venous catheters,
tunnelled venous catheters, coronary catheters useful for
angiography, angioplasty, or ultrasound procedures in the heart or
in peripheral veins and arteries, hepatic artery infusion
catheters, CVC (central venous catheters), peripheral intravenous
catheters, peripherally inserted central venous catheters (PIC
lines), flow-directed balloon-tipped pulmonary artery catheters,
total parenteral nutrition catheters, chronic dwelling catheters
(e.g., chronic dwelling gastrointestinal catheters and chronic
dwelling genitourinary catheters), peritoneal dialysis catheters,
CPB catheters (cardiopulmonary bypass), urinary catheters and
microcatheters (e.g., for intracranial application).
[0043] Medical devices include endovascular device delivery systems
such as stents, occluders, valves, etc., diagnostics catheters
containing spectroscopic or imaging capabilities, placement wires,
catheters or sheaths.
[0044] In a specific embodiment, the surface is the surface of a
substrate comprising a medical device selected from the group
consisting of stents including bifurcated stents, balloon
expandable stents and self-expanding stents, stent-grafts including
bifurcated stent-grafts, grafts including vascular grafts and
bifurcated grafts, dialators, vascular occluders, embolic filters,
embolectomy devices, catheters including microcatheters, central
venous catheters, peripheral intravenous catheters and hemodialysis
catheters, artificial blood vessels, sheaths including retractable
sheaths, blood indwelling monitoring devices, artificial heart
valves, pacemaker electrodes, guidewires, cardiac leads,
cardiopulmonary bypass circuits, cannulae, plugs, drug delivery
devices, balloons, tissue patch devices and blood pumps.
[0045] Examples of extracorporeal medical devices are
non-implantable devices such as extracorporeal blood treatment
devices, and transfusion devices. Devices may have neurological,
peripheral, cardiac, orthopedal, dermal and gynecological
application, inter alia.
[0046] In another embodiment, the above-mentioned stents can be
used in cardiac, peripheral or neurological applications. In
another embodiment, said stent-grafts can be used in cardiac,
peripheral or neurological applications.
[0047] In another embodiment, the above-mentioned sheaths can be an
interventional diagnostic and therapeutic sheath, large and
standard bore endovascular delivery sheaths, arterial introducer
sheaths with and without hemostatic control and with or without
steering, micro-introducer sheaths, dialysis access sheaths,
guiding sheaths, and percutaneous sheaths; all for access in
carotid, renal, transradial, transseptal, pediatric and micro
applications.
[0048] In another embodiment, said medical device can be used in
neurological, peripheral, cardiac, orthopedic, dermal, or
gynaecologic applications.
Analytical Devices
[0049] An analytical device can be, for example, a solid support
for carrying out an analytical process such as chromatography or an
immunological assay, reactive chemistry or catalysis. Examples of
such devices include slides, beads, well plates and membranes.
Separation Devices
[0050] A separation device can be, for example, a solid support for
carrying out a separation process such as protein purification,
affinity chromatography or ion exchange. Examples of such devices
include filters, beads, particles, packed beds, arrays, nanoarrays,
channels, microfluidics channels, and columns.
[0051] The surface to be coated can be the entire surface, of the
substrate, or only a portion of the surface of the substrate.
Certain substrates may have an external surface and an internal
surface, either or both of which can be coated. For example,
tubular substrates such as artificial blood vessels have an
internal surface, or lumen, which can be coated independently from
the external surface. A surface comprising an internal and an
external surface may only require the internal surface to the
coated. Conversely, only the external surface may require the
coating. Using the method of the invention, it is possible to apply
a different coating to e.g. the external and internal surfaces of
the substrate.
[0052] In one embodiment, up to 99%, for example up to 95%, 90%,
75%, 50% or 25% of the surface of the substrate is coated with the
coating. In one embodiment, both the external and internal surfaces
of the substrate are coated. In another embodiment, only the
external surface of the substrate is coated. In one embodiment, the
substrate to be coated is tubular in shape having an internal
surface or lumen, which can be coated independently from the
external surface. The surface of the substrate can be porous or
non-porous.
Substrate Materials Useful Within this Invention
[0053] The substrate may comprise or be formed of a metal or a
synthetic or naturally occurring organic or inorganic polymer or a
ceramic material, inter alia.
[0054] Thus, for example, it can be formed from a synthetic or
naturally occurring organic or inorganic polymer or material,
including but not limited to materials such as polyolefins,
polyesters, polyurethanes, polyamides, polyether block amides,
polyimides, polycarbonates, polyphenylene sulfides, polyphenylene
oxides, polyethers, silicones, polycarbonates,
polyhydroxyethylmethacrylate, polyvinyl pyrrolidone, polyvinyl
alcohol, rubber, silicone rubber, polyhydroxyacids, polyallylamine,
polyallylalcohol, polyacrylamide, and polyacrylic acid, styrenic
polymers, polytetrafluoroethylene and copolymers thereof,
derivatives thereof and mixtures thereof. Some of these classes are
available both as thermosets and as thermoplastic polymers. As used
herein, the term "copolymer" shall be used to refer to any polymer
formed from two or more monomers, e.g. 2, 3, 4, 5 and so on and so
forth. Bioresorbables, such as poly(D,L-lactide) and polyglycolids
and copolymers thereof are also useful Non-woven, bioabsorbable web
materials comprising a tri-block copolymer such as
poly(glycolide-co-trimethylene carbonate) tri-block copolymer
(PGA:TMC) are also useful (as described in U.S. Pat. No. 7,659,219;
Biran et al.). Useful polyamides include, but are not limited to,
nylon 12, nylon 11, nylon 9, nylon 6/9 and nylon 6/6. Examples of
some copolymers of such materials include the
polyether-block-amides, available from Elf Atochem North America in
Philadelphia, Pa. under the tradename of PEBAX.RTM.. Another
suitable copolymer is a polyetheresteramide. Suitable polyester
copolymers, include, for example, polyethylene terephthalate and
polybutylene terephthalate, polyester ethers and polyester
elastomer copolymers such as those available from DuPont in
Wilmington, Del. under the tradename of HYTREL. Block copolymer
elastomers such as those copolymers having styrene end blocks, and
midblocks formed from butadiene, isoprene, ethylene/butylene,
ethylene/propene, and so forth may be employed herein. Other
styrenic block copolymers include acrylonitrile styrene and
acrylonitrile-butadiene-styrene block copolymers. Also, block
copolymers wherein the particular block copolymer thermoplastic
elastomers in which the block copolymer is made up of hard segments
of a polyester or polyamide and soft segments of polyether may also
be employed herein. Other useful substrates are polystyrenes,
poly(methyl)methacrylates, polyacrylonitriles, poly(vinylacetates),
poly(vinyl alcohols), chlorine-containing polymers such as
poly(vinyl) chloride, polyoxymethylenes, polycarbonates,
polyamides, polyimides, polyurethanes, phenolics, amino-epoxy
resins, polyesters, silicones, cellulose-based plastics, and
rubber-like plastics.
[0055] Combinations of these materials can be employed with and
without cross-linking.
[0056] Polymeric substrates may optionally be blended with fillers
and/or colorants.
[0057] In one embodiment, said the substrate is biocompatible and
comprises or consists of a polyether-block-amides, such as
PEBAX.RTM..
[0058] Fluorinated polymers such as fluoropolymers, e.g. expanded
polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE),
fluorinated ethylene-propylene (FEP), perfluorocarbon copolymers,
e.g. tetrafluoroethylene perfluoroalkylvinyl ether (TFE/PAVE)
copolymers, copolymers of tetrafluoroethylene (TFE) and
perfluoromethyl vinyl ether (PMVE), copolymers of TFE with
functional monomers that comprise acetate, alcohol, amine, amide,
sulfonate, functional groups and the like, as well as combinations
thereof and combinations of the above with and without crosslinking
between the polymer chains, expanded polyethylene,
polyvinylchloride, polyurethane, silicone, polyethylene,
polypropylene, polyurethane, polyglycolic acid, polyesters,
polyamides, elastomers and their mixtures, blends and copolymers or
derivatives thereof may be useful.
[0059] Other suitable substrate materials include proteins, such as
silk and wool, agarose and alginate. Bio-derived materials, such as
cellulose, oxidized cellulose, collagen, gelatin, albumin, elastin,
keratin, agar, and the like. Substrates comprising or consisting of
fabric are also contemplated. Suitable fabrics may include natural
and/or synthetic materials, and may be in woven, non-woven or
knitted form, and combinations thereof, and may be selected based
on the end use requirements contemplated. Fabrics can be coated
with durable water repellent (DWR) or other suitable coatings,
again depending on the end use requirements contemplated.
[0060] Also, substrates comprising or consisting of certain metals
and ceramics can be used in the present invention. Suitable metals
include, but are not limited to, biocompatible metals, titanium,
stainless steel, high nitrogen stainless steel, gold, silver,
rhodium, zinc, platinum, rubidium, copper and magnesium, and
combinations thereof. Suitable alloys include cobalt-chromium
alloys such as L-605, MP35N, Elgiloy, nickel-titanium alloys (such
as Nitinol), tantalum, and niobium alloys, such as Nb-1% Zr, and
others. Ceramic substrates include, but are not limited to,
silicone oxides, aluminum oxides, alumina, silica,
hydroxyapapitites, glasses, calcium oxides, polysilanols, and
phosphorous oxide.
[0061] In one embodiment, said metal biocompatible and is a
nickel-titanium alloy, such as Nitinol.
Coating of the Invention
[0062] The present invention relates to the discovery that the
problems associated with polydopamine coatings outlined above can,
at least in some embodiments, be overcome by the addition of an
additive during the coating formation. The additive is a molecule
which is functionalised with a photosensitive or thermosensitive
moiety and also comprises functionality which enables it to be
covalently incorporated within the coating. The resulting coating
then comprises photosensitive or thermosensitive groups within the
bulk of the coating, which, when activated, form covalent bonds
within the coating. As such, at least in some embodiments, the
coating of the invention is more durable than a pure polydopamine
coating. In some embodiments, the coating of the invention is more
stable to sterilisation and to oxidative conditions than a pure
polydopamine coating. In some embodiments, the coating of the
invention is less susceptible to particulation than a pure
polydopamine coating.
[0063] The coating of the invention comprises photosensitive or
thermosensitive groups on the surface of the coating, as well as
within and throughout the bulk of the coating. If the surface being
coated has complementary functionality to the photosensitive or
thermosensitive groups, then in some embodiments the coating of the
invention will be covalently bonded to the surface. For example, if
the photosensitive or thermosensitive group is capable of hydrogen
abstraction and subsequent covalent bond formation, and if the
surface being coated has abstractable hydrogen atoms, then the
resulting coating will be covalently bonded to the surface.
Likewise, if a subsequent coating which is applied on the surface
has complementary functionality to the photosensitive or
thermosensitive groups, then in some embodiments the coating of the
invention will be covalently bonded to the subsequent coating which
is subsequently applied to the surface. In both cases, the
durability of the coating can be enhanced. In the latter case, the
durability of the subsequent coating can be enhanced.
Component A
[0064] Broadly speaking, component A is a polymer which is formed
from a monomer which can self-polymerise. In certain embodiments,
component A is defined as polymer, while in other embodiments,
component A is defined as a monomer which forms said polymer, via
self-polymerisation. Thus, in one embodiment, component A is a
polymer formed by self-polymerisation of a molecule comprising
catechol functionality and amine and/or amide and/or hydroxyl
functionality. In another embodiment, component A is a molecule
capable of self-polymerisation comprising catechol functionality
and amine and/or amide and/or hydroxyl functionality.
[0065] "Catechol functionality" refers to any functionality
comprising a 1,2-dihydroxybenzene, "Amine functionality" refers to
primary amines, secondary amines, tertiary amines and quaternary
amines. "Amide functionality" refers to any functionality
comprising --NH--(CO)-- or --N(R)--CO-- groups (wherein R is a
substituent other than hydrogen). "Hydroxyl functionality" refers
to an --OH group. In one embodiment, component A is a molecule of
formula (I):
##STR00001##
wherein, R.sup.a, R.sup.b, R.sup.c, R.sup.d and R.sup.e are
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8alkynyl, --OH, --CO.sub.2H, --C(O)--(C.sub.1-C.sub.8
alkyl), --C(O)--(C.sub.2-C.sub.8 alkenyl),
--C(O)--(C.sub.2-C.sub.8alkynyl); and [0066] X is C.sub.1-C.sub.8
alkyl optionally substituted with one or more groups selected from
the groups consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --OH, --CO.sub.2H,
--C(O)--(C.sub.1-C.sub.8alkyl), --C(O)--(C.sub.2-C.sub.8 alkenyl),
--C(O)--(C.sub.2-C.sub.8alkynyl); wherein optionally one or more
carbon atoms of the C.sub.1-C.sub.8 functionality is/are replaced
with a group selected from --O--, --S--, --NH--,
--N(C.sub.1-C.sub.8 alkyl)-, --NHC(O)-- and --N(C.sub.1-C.sub.8
alkyl)C(O)--. Suitably, one or more of R.sup.a, R.sup.b, R.sup.c,
R.sup.d and R.sup.e are H.
[0067] In one embodiment, component A is a molecule of formula
(II):
##STR00002##
wherein, R.sup.a', R.sup.b', R.sup.c', R.sup.d', R.sup.e', R.sup.f,
R.sup.g, R.sup.h and R.sup.i are independently selected from the
group consisting of: H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8 alkynyl, --OH, --CO.sub.2H,
--C(O)--(C.sub.1-C.sub.8 alkyl), --C(O)--(C.sub.2-C.sub.8 alkenyl),
--C(O)--(C.sub.2-C.sub.8 alkynyl). Suitably, one or more of
R.sup.1-R.sup.9 are not H.
[0068] Suitably, component A comprises at least one abstractable
hydrogen atom.
[0069] In one embodiment, component A is a catecholamine.
Catecholamine is a compound that comprises catechol and a
side-chain amine.
[0070] In one embodiment, component A is dopamine. Dopamine is a
catecholamine of formula:
##STR00003##
[0071] In another embodiment, component A is a dopamine analogue.
Dopamine analogues include molecules involved in the same or
similar biochemical pathways as dopamine and/or those that are
similar in structure to dopamine, including, oxidised derivatives
of tyrosine.
[0072] Naturally occurring dopamine analogues include:
##STR00004##
[0073] In one embodiment, component A is based on melanin. In
another embodiment, component A is based on eumelanin.
[0074] In embodiments, where component A is referred to as being a
polymer, rather than a molecule (i.e. a monomer), component A being
a polymer of any of the above monomers/molecules is envisaged.
[0075] In one embodiment, component A is a polymer formed by
self-polymerisation of a molecule comprising catechol functionality
and amine and/or amide and/or hydroxyl functionality. In another
embodiment, component A is a polymer formed by self-polymerisation
of a molecule comprising catechol functionality and amine. In a
further embodiment, component A is a polymer formed by
self-polymerisation of a catecholamine. Suitably, component A is
polydopamine.
[0076] In one embodiment, component A is a molecule capable of
self-polymerisation comprising catechol functionality and amine
and/or amide and/or hydroxyl functionality. In another embodiment,
component A is a molecule capable of self-polymerisation comprising
catechol functionality and amine functionality. In a further
embodiment, component A is a catecholamine capable of self
polymerisation. Suitably, component A is dopamine.
[0077] The exact structure of polydopamine is not well understood,
and a number of structures have been proposed, as illustrated in
FIG. 1.
[0078] Polymerisation of dopamine occurs under alkaline and
oxidative conditions, and mere exposure to the air (i.e. oxygen) is
sufficient to initiate polymerisation under alkaline conditions. It
is generally acknowledged that the initial oxidation of dopamine
occurs on the catechol moiety, which then reacts with another
molecule of dopamine, or can undergo an intermolecular cyclisation
(via the pendant primary amine) to form a nitrogen-containing
bicycle. Structure A of polydopamine (as described in
WO2010/006196) suggests that polydopamine consists of repeating
5,6-dihydroxy-3H-indole units, cross-linked through positions 4 and
7. Structure B (as described by Zhao et al. Polym. Chem., 2010, 1,
1430-1433) suggests a similar polymer, but every other
5,6-dihydroxy-3H-indole unit is replaced with a
5,6-dihydroxyindoline unit. Structure C is proposed by the present
inventors as another possible structure for polydopamine, which
again is similar to Structure A, but every other
5,6-dihydroxy-3H-indole unit is replaced with an un-cyclised
dopamine molecule. This structure of polydopamine therefore
comprises primary amine functionalities. Structure D (described in
Kang et al. Langmuir, 2009, 25, 9656-9659) is also proposed by the
present inventors and suggests attachment between dopamine
molecules at the five-membered nitrogen ring, as well as between
the catechol rings. This structure also suggests that quinone rings
as well as catechol rings are present in the polymeric structure.
Finally, Structure E (described by Dreyer et al. Langmuir, 2012,
28, 6428-6435) illustrates a completely different structure in
which polydopamine is not a covalent polymer but is instead a
supramolecular aggregate of monomers, consisting primarily of
5,6-dihydroxyindoline and its dione derivative. It should be noted
that despite the disparity in the proposed structures for
polydopamine, all of the structures share the common feature of
having a plurality of abstractable hydrogen atoms.
[0079] Component A will polymerise in the presence of air, or a
source of O.sub.2.
Component B
[0080] Broadly speaking, component B is a molecule or polymer which
comprises photosensitive or thermosensitive moieties and is capable
of forming covalent bonds with component A.
[0081] Thus, in one embodiment, component B is a cross-linking
molecule comprising two or more photosensitive or thermosensitive
moieties, at least some of which moieties form covalent bonds with
component A.
[0082] In another embodiment, component B is a polymer comprising
photosensitive or thermosensitive moieties at least some of which
moieties form covalent bonds with component A and which polymer
forms an interpenetrating network with component A.
[0083] In a further embodiment, component B is a mixture of a
cross-linking molecule comprising two or more photosensitive or
thermosensitive moieties, at least some of which moieties form
covalent bonds with component A, and a polymer comprising
photosensitive or thermosensitive moieties at least some of which
moieties form covalent bonds with component A and which polymer
forms an interpenetrating network with component A.
[0084] In a further embodiment, component B is a molecule
comprising one or more groups capable of participating in the
polymerisation of component A, wherein said molecule comprises one
or more photosensitive or thermosensitive moieties capable of
forming covalent bonds with component A, at least some of which
moieties form covalent bonds with component A in the copolymer.
[0085] In one embodiment, component B is a monomer. In another
embodiment, component B is a polymer.
Photosensitive and Thermosensitive Moieties
[0086] Photosensitive moieties are moieties which undergo a change
upon exposure to certain wavelengths of light. In one embodiment,
the photosensitive moiety undergoes a change upon exposure to UV
light. Thermosensitive moieties are moieties which undergo a change
on exposure to heat. In the context of the present invention, when
photosensitive or thermosensitive moieties are exposed to light or
heat respectively, covalent bond formation with component A
results.
[0087] In one embodiment, component B comprises one or more
photosensitive moieties. In another embodiment, component B
comprises one or more thermosensitive moieties.
[0088] In certain embodiments, the surface to be coated has
complementary functionality to the photosensitive or
thermosensitive groups, which results in the coating being
covalently bonded to the surface.
[0089] In certain embodiments, a subsequent coating which is
applied on the surface has complementary functionality to the
photosensitive or thermosensitive groups, which results in the
coating of the invention being covalently bonded to the subsequent
coating which is subsequently applied to the surface.
[0090] In one embodiment, the photosensitive moiety is a
photoinitiator. A photoinitiator is a compound that yields free
radicals when exposed to UV or visible light. Based on the
mechanism of radical formation, photoinitiators are generally
divided into two classes: Type I photoinitiators undergo a
unimolecular bond cleavage upon irradiation to yield free radicals.
Type II photoinitiators undergo a bimolecular reaction where the
excited state of the photoinitiator interacts with a second
molecule (a coinitiator, usually a H-donor) to generate free
radicals via hydrogen abstraction mechanisms. Subsequent
polymerisation is usually initiated by the radicals produced from
the coinitiator, UV photoinitiators of both Type I and Type II are
available. However, visible light photoinitiators belong almost
exclusively to the Type II class of photoinitiators. Thus, in one
embodiment, the one or more photosensitive moiety is a Type I or
Type II initiator. In another embodiment, the one or more
photosensitive moiety is a Type I initiator. In a further
embodiment, the one or more photosensitive moiety is a Type II
initiator.
[0091] In one embodiment, the one or more photosensitive moiety is
capable of hydrogen abstraction.
[0092] In one embodiment, the one or more photosensitive moiety is
an aryl ketone.
[0093] In one embodiment, the one or more photosensitive moiety is
a diaryl ketone. Suitably, the diaryl ketone is a substituted
diaryl ketone. As is known to the art, diaryl ketones tend to react
via Type II mechanisms i.e. upon excitation with UV light, the
diaryl ketone enters an excited state and can interact with a
second molecule via hydrogen abstraction to form a covalent bond
with the second molecule via free radical recombination as shown in
Scheme 1, infra. In one embodiment, the one or more photosensitive
moiety is benzophenone. Suitably, the benzophenone is a substituted
benzophenone. Benzophenone may be substituted or functionalised on
one phenyl ring or both phenyl rings, in various positions. In one
embodiment, the one or more photosensitive moiety is a benzophenone
of formula (III):
##STR00005##
wherein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently
selected from --H, --OH, --NO.sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.8 alkyl), --O(C.sub.1-C.sub.4alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8
alkyl).sub.2, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, phenyl, --O-phenyl, --S-phenyl, F, Cl, Br
and I, or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 taken together
form a cyclic anhydride; wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are optionally independently substituted with one or more
of --OH, --NO.sub.2, --CO.sub.2H, --CO.sub.2(C.sub.1-C.sub.8
alkyl), --O(C.sub.1-C.sub.4 alkyl), --NH.sub.2,
--NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8 alkyl).sub.2,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, phenyl, --O-phenyl, S-phenyl, F, Cl, Br or I.
[0094] In one embodiment, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
not capable of participating in the polymerisation of component
A.
[0095] Examples of benzophenone moieties include, but are not
limited to, benzophenone, benzophenone-3,3'-4,4'-tetracarboxylic
dianhydride, 4-benzoylbiphenyl, 4,4'-bis(diethylamino)benzophenone,
4,4'-bis[2-(1-propenyl)phenoxy]benzophenone,
4-(diethylamino)benzophenone, 4,4'-dihydroxybenzophenone,
4-(dimethylamino)benzophenone, 3,4-dimethylbenzophenone,
4-aminobenzophenone, 4,4'-diaminobenzaphenone,
3-hydroxybenzophenone, 4-hydroxybenzophenone,
4,4'-dihydroxybenzophenone, 3,4-diaminobenzophenone,
2-methylbenzophenone, 3-methylbenzophenone, 4-methylbenzophenone,
and Michler's ketone.
[0096] The benzophenone can form part of component B by attachment
(at one or more points) via one phenyl ring or both phenyl rings.
Alternatively, component B may be the benzophenone molecule
itself.
[0097] In one embodiment, component B comprises or consists of a
polymeric initiator. Polymer initiators comprise a polymer backbone
and multiple pendant initiator groups. For example, a polymeric
initiator can comprise multiple diaryl ketone, e.g. benzophenone
moieties (polybenzophenone). Thus, in one embodiment, component B
comprises, or consists of, a polydiaryl ketone, e.g.
polybenzophenone. Omnipol and Omnirad are trade names for a class
of polybenzopheones comprising poly(alkylene
glycol)-dibenzophenone.
[0098] In one embodiment, the photosensitive moiety is
phthalimide.
[0099] In one embodiment, the photosensitive moiety is an aryl
azide, for example an aryl azide of formula (IV):
##STR00006##
wherein, R.sup.5 and R.sup.6 are independently selected from the
group consisting of --H, --OH, --NO.sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.8 alkyl), --O(C.sub.1-C.sub.4 alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8
alkyl).sub.2, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, phenyl, --O-phenyl, --S-phenyl, F, Cl, Br
and I; wherein R.sup.5 and R.sup.6 are optionally independently
substituted with one or more of --OH, --NO.sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.8 alkyl), --O(C.sub.1-C.sub.4alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8
alkyl).sub.2, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, phenyl, --O-phenyl, --S-phenyl, F, Cl, Br
and I.
[0100] In one embodiment, R.sup.5 and R.sup.8 are not capable of
participating in the polymerisation of component A.
[0101] The aryl azide can form part of component B via attachment
(at one or more points) via the phenyl ring. Alternatively,
component B may be the aryl azide itself.
[0102] In one embodiment, the photosensitive moiety is a diazirine,
for example a diazirine of formula (V):
##STR00007##
wherein, both R.sup.7 and R.sup.8 are points of attachment via
which the diazirine forms part of component B, or one of R.sup.7
and R.sup.8 is a point of attachment via which the diazirine forms
part of component B, and the remaining R.sup.7 or R.sup.8 is
selected from the group consisting of H and C.sub.1-C.sub.8
alkyl.
[0103] In an alternative embodiment, R.sup.7 and R.sup.8 are
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, --(C.sub.1-C.sub.8
alkyl)-CO.sub.2-(succinimide), alkyl)-C(O)NH--(C.sub.1-C.sub.8
alkyl)-(succinimide) and --(C.sub.1-C.sub.8
alkyl)-C(O)NH--(C.sub.1-C.sub.8 alkyl)-S--S--(C.sub.1-C.sub.8
alkyl)-(succinimide), wherein succinimide is optionally substituted
with --SO.sub.3Na. In this embodiment, component B is the diazirine
molecule itself.
[0104] In one embodiment, the photosensitive moiety is a
furocoumarin, for example psoralen.
[0105] In one embodiment, the photosensitive moiety is
C.sub.2-C.sub.8 alkenyl or C.sub.2-C.sub.8 alkynyl.
[0106] In one embodiment, the one or more photosensitive moieties
are selected from the group consisting of aryl ketone, diaryl
ketone, aryl azide, alkenyl and alkynyl. In another embodiment, the
one more photosensitive moiety is a diaryl ketone or alkenyl. In a
further embodiment, the one or more photosensitive moiety is
benzophenone or C.sub.2-C.sub.8 alkenyl.
[0107] Reactivity of Photosensitive and Thermosensitive
Moieties
[0108] The photosensitive or thermosensitive moieties of component
B, when activated, will react in such a way so as to form a
covalent bond with component A.
[0109] In one embodiment, the photosensitive or thermosensitive
moiety, once activated, is capable of hydrogen abstraction. For
example, diaryl ketones such as benzophenone can react via a Type
II reaction mechanism to abstract hydrogen atoms. A representative
reaction scheme of the activation of a component B which comprises
benzophenone is illustrated in Scheme 1 below:
##STR00008##
[0110] As shown in Scheme 1, when exposed to UV light the triplet
excited state of benzophenone is formed, which can abstract a
hydrogen from another molecule (represented as H--R) to form a
ketyl radical and a radical R.. The radical intermediate then
collapses to form a covalent bond between the benzophenone molecule
and molecule R. Thus, component B and R are covalently bonded. The
H-abstraction mechanism illustrated in Scheme 1 is a widely known
photochemical mechanism which has utility in grafting
processes.
[0111] H--R in Scheme 1 represents component A. In same
embodiments, H--R also represents the surface to be coated. In this
embodiment, the resulting coating is covalently bonded to the
surface. In some embodiments, H--R also represents a subsequent
coating which is applied on the surface. In this embodiment, the
coating of the invention is covalently bonded to the subsequent
coating.
[0112] Certain photosensitive or thermosensitive moieties, once
activated, form carbenes or nitreries. Thus, in one embodiment,
component B comprises one or more photosensitive or thermosensitive
moieties capable of forming a carbene or nitrene. A carbene is a
molecule containing a neutral carbon atom with a valence of two and
two unshared valence electrons, of general formula R--(C:)--R' or
R.dbd.C:. Alternatively, a carbene can be defined as a molecule
containing a carbon atom with an unpaired free electron i.e. a free
radical. A nitrene is a nitrogen analogue of a carbene. Carbenes
and nitrenes can initiate addition reactions with double bonds and
undergo insertion into C--H and N--H bonds, leading to covalent
bond formation and in some cases ring expansion.
[0113] Groups Capable of Participating in Catecholamine
Polymerisation
[0114] In one embodiment, component B comprises one or more groups
capable of participating in the polymerisation of component A. In
this embodiment, when components A and B are mixed in solution,
they will polymerise to form a co-polymer of components A and
B.
[0115] In one embodiment, the one or more groups capable of
participating in polymerisation of component A are independently
selected from the group consisting of amino, hydroxyl, catechol,
thiol, hydrazine, hydrazone, oxime, keto, aldehyde, carboxyl,
imino, amido, alkenyl (such as C.sub.2-C.sub.8 alkenyl) and alkynyl
(such as C.sub.2-C.sub.8 alkynyl). Suitably, the one of the one or
more groups capable of participating in the polymerisation of
component A are selected from the group consisting of amino,
hydroxyl, catechol, amido and C.sub.2-C.sub.8 alkenyl.
Examples of Component B
[0116] In one embodiment, component B is of formula (VI), formula
(VII), formula (VIII), formula (IX), formula (X) or formula
(XI):
##STR00009##
wherein, [0117] each Z is independently a photosensitive or
thermosensitive group, as described above; [0118] each X is a
moiety comprising a functional group capable of participating in
the polymerisation of component A; and [0119] each Y is
independently selected from the group consisting of a covalent
bond, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(CH.sub.2CH.sub.2O).sub.1-20--,
--C(O)--NH--(C.sub.1-C.sub.8 alkyl)-, --NH--C(O)--(C.sub.1-C.sub.8
alkyl)-, --C(O)--NH--(C.sub.1-C.sub.8 alkyl)-NH--(C(O)--,
--NH--C(O)--(C.sub.1-C.sub.8 alkyl)-C(O)--NH--,
--NH--C.sub.1-C.sub.8 alkyl-NH(CO)--, --N(C.sub.1-C.sub.8
alkyl-NH(CO)--).sub.2, N(C.sub.1-C.sub.8 alkyl-NH(CO)--).sub.3,
phenyl and --(C.sub.1-C.sub.8 alkyl)-phenyl; wherein, each Y is
optionally independently substituted with C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl or --O(C.sub.1-C.sub.8 alkyl); [0120] q is
1-4; [0121] r is 1-4; [0122] m is 1-5000; and [0123] n is 1-100;
wherein the ratio of m:n is from about 1:1 to about 1:0.02.
[0124] In one embodiment, each Z is independently selected from the
group consisting of benzophenone and C.sub.2-C.sub.8 alkenyl.
Suitably each Z is benzophenone, such as a benzophenone of formula
(III).
[0125] In one embodiment, each X is independently selected from the
group consisting of amino, hydroxyl, catechol, thiol, hydrazine,
hydrazone, oxime, keto, aldehyde, carboxyl, imino, amido,
C.sub.2-C.sub.8 alkenyl and C.sub.2-C.sub.8 alkynyl. Suitably, each
X is selected from the group consisting of amino, hydroxyl,
catechol, amido and C.sub.2-C.sub.8 alkenyl.
[0126] In one embodiment, each Y is independently selected from the
group consisting of a covalent bond, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, --(CH.sub.2CH.sub.2O).sub.1-20--,
--C(O)--NH--(C.sub.1-C.sub.8 alkyl)-, --NH--C(O)--(C.sub.1-C.sub.8
alkyl)-, C(O)--NH--(C.sub.1-C.sub.8 alkyl)-NH--(C(O)-- and phenyl;
wherein each Y is optionally independently substituted with
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl or
--O(C.sub.1-C.sub.8 alkyl).
[0127] In one embodiment, q is 1-3, 1-2, 4, 3, 2 or 1.
[0128] In one embodiment, r is 1-3, 1-2, 4, 3, 2 or 1.
[0129] In one embodiment, m is 1-4500, for example 100-4000 or
1000-3000.
[0130] In one embodiment, n is 10-100, for example 10-80, 20-80 or
50-80.
[0131] In one embodiment, ratio of m:n is from about 1:1 to about
1:0.05, for example 1:1 to about 1:0.1, for example 1:1 to about
1:0.5.
Formula (VI)
[0132] In one embodiment, component B is of formula (VI):
##STR00010##
wherein Z, X, Y and q are as defined above.
[0133] In one embodiment, component B is of formula (VI) wherein Z
is benzophenone or C.sub.2-C.sub.8 alkenyl; each Y is independently
selected from the group consisting of a covalent bond,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
--(CH.sub.2CH.sub.2O).sub.1-20--, --C(O)--NH--(C.sub.1-C.sub.8
alkyl)-, --NH--C(O)--(C.sub.1-C.sub.8 alkyl)-,
--C(O)--NH--(C.sub.1-C.sub.8 alkyl)-NH--(C(O)--, or
--NH--C(O)--(C.sub.1-C.sub.8 alkyl)-C(O)--NH--, phenyl and
--(C.sub.1-C.sub.8 alkyl)-phenyl; wherein each Y is optionally
independently substituted with C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl or --O(C.sub.1-C.sub.8 alkyl); X is
selected from the group consisting of amino, hydroxyl, catechol,
thiol, hydrazine, hydrazone, oxime, keto, aldehyde, carboxyl,
imino, amido, C.sub.2-C.sub.8 alkenyl and C.sub.2-C.sub.8 alkynyl;
and q is 1-4.
[0134] In one embodiment, component B is of formula (VI), wherein Z
is a benzophenone of formula (III) or C.sub.2-C.sub.8 alkenyl; Y is
a covalent bond, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
--(CH.sub.2CH.sub.2O).sub.1-20--, --C(O)--NH--(C.sub.1-C.sub.8
alkyl)-, --NH--C(O)--(C.sub.1-C.sub.8 alkyl)-,
--C(O)--NH--(C.sub.1-C.sub.8 alkyl)-NH--(C(O)--, or
--NH--C(O)--(C.sub.1-C.sub.8 alkyl)-C(O)--NH--, phenyl or
--(C.sub.1-C.sub.8 alkyl)-phenyl, wherein each Y is optionally
independently substituted with C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl or --O(C.sub.1-C.sub.8 alkyl); X is
selected from the group consisting of amino, hydroxyl, catechol,
thiol, hydrazine, hydrazone, oxime, keto, aldehyde, carboxyl,
imino, amide, C.sub.2-C.sub.8 alkenyl and C.sub.2-C.sub.8 alkynyl;
and q is 1-4.
[0135] In another embodiment, component B is of formula (VI),
wherein Z is a benzophenone of formula (III) or C.sub.2-C.sub.8
alkenyl; Y is a covalent bond or --(C.sub.1-C.sub.8 alkyl)-phenyl,
wherein each Y is optionally independently substituted with
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl or
--O(C.sub.1-C.sub.8 alkyl); X is selected from the group consisting
of amino, hydroxyl, C.sub.2-C.sub.8 alkenyl and catechol; and q is
1-4, suitably 1-2.
[0136] In one embodiment, component B is selected from the group
consisting of: [0137] dopamine benzoyl benzamide ("dopa-BBA"; see
Example 2a)
[0137] ##STR00011## [0138] 3-amido(4-benzoylbenzoyl)propyl
methacrylamide ("ABBPMA"; see Example 2c)
##STR00012##
[0139] In one embodiment, component B is dopamine benzoyl
benzamide.
Formula VII
[0140] In one embodiment, component B is of formula (VII):
##STR00013##
wherein, Z, Y and r are as defined above.
[0141] In one embodiment, component B is of formula (VII) wherein Z
is a benzophenone of formula (III) or C.sub.2-C.sub.8 alkenyl; Y is
selected from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(CH.sub.2CH.sub.2O).sub.1-20--, --C(O)--NH--(C.sub.1-C.sub.8
alkyl)-, --NH--C(O)--(C.sub.1-C.sub.8 alkyl)-,
--C(O)--NH--(C.sub.1-C.sub.8 alkyl)-NH--(C(O)--,
--NH--C(O)--(C.sub.1-C.sub.8 alkyl)-C(O)--NH--,
--NH--C.sub.1-C.sub.8 alkyl-NH(CO)--, --N(C.sub.1-C.sub.8
alkyl-NH(CO)--).sub.2, N(C.sub.1-C.sub.8 alkyl-NH(CO)--).sub.3,
phenyl and --(C.sub.1-C.sub.8 alkyl)-phenyl; and r is 1-4.
[0142] In another embodiment, component B is of formula (VII)
wherein Z is a benzophenone of formula (III), Y is
N(C.sub.1-C.sub.8 alkyl-NH(CO)--).sub.3; and r is 3.
[0143] In one embodiment, component B is
tris-[amino(ethylbenzoylbenzamide)] ("tris-BBA"; synthesis
described in Example 2b)
##STR00014##
[0144] In one embodiment, component B is of formula (VII) wherein,
Z and Y are as previously defined and r is 2. In this embodiment,
component B forms cross-linkages within component A.
Formula (VIII)
[0145] In one embodiment, component B is of formula (VIII):
X--Y--Z--Y--X (VIII)
wherein, X, Y and Z are as defined above.
Formula (IX)
[0146] In one embodiment, component B is of formula (IX):
##STR00015##
wherein, X, Y, Z, m and n are as defined above.
[0147] In one embodiment, component B is of formula (IX) wherein Z
is a photosensitive group as described above; each X is a moiety
comprising a functional group capable of participating in the
polymerisation of component A; and each Y is independently selected
from the group consisting of a covalent bond, C.sub.1-C.sub.8
alkyl, C.sub.2-C.sub.8 alkenyl and C.sub.2-C.sub.8 alkynyl, wherein
each Y is optionally independently substituted with C.sub.1-C.sub.8
alkyl, C.sub.2-C.sub.8 alkenyl or --O(C.sub.1-C.sub.8 alkyl); m is
1-5000; and n is 1-100.
[0148] In another embodiment, component B is of formula (IX)
wherein Z is a benzophenone, X is a moiety comprising an amide
moiety, and is suitably pyrrolidone; each Y is C.sub.1-C.sub.8
alkyl, optionally substituted with C.sub.1-C.sub.8 alkyl; m is
100-4000; and n is 10-80.
[0149] In one embodiment, component B is
poly(vinylpyrrolidone-co-amido(4-benzoylbenzoyl)propyl methacrylate
("VP-co-BBA"; see Example 2d)
##STR00016##
Formula (X)
[0150] In one embodiment, component B is of formula (X).
##STR00017##
wherein, X, Y, Z and m are as defined above.
Formula (XI)
[0151] In one embodiment, component B is of formula (XI):
##STR00018##
wherein, Y, Z and m are as defined above.
[0152] Further Examples of Component B
[0153] In one embodiment, component B is of formula (XII):
##STR00019##
wherein, R.sup.x is selected from the group consisting of --H,
--OH, --NO.sub.2, --CO.sub.2H, --CO.sub.2(C.sub.1-C.sub.8 alkyl),
--O(C.sub.1-C.sub.4alkyl), --NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl),
--N(C.sub.1-C.sub.8 alkyl).sub.2, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, phenyl,
--O-phenyl, --S-phenyl; R.sup.y is selected from the group
consisting of --H, --OH, --NO.sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.8 alkyl), --O(C.sub.1-C.sub.4alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8
alkyl).sub.2, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, phenyl, --O-phenyl, --S-phenyl, wherein
R.sup.x and R.sup.y are optionally independently substituted with
one or more of --OH, --NO.sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.8 alkyl), --O(C.sub.1-C.sub.4alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8
alkyl).sub.2, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, phenyl, --O-phenyl or --S-phenyl; Q is
selected from the group consisting of a covalent bond,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl and
--C(O)--(C.sub.1-C.sub.8 alkyl)-; and W is a covalent bond or
phenyl, wherein phenyl is optionally substituted with one or more
R.sup.y.
[0154] In one embodiment, component B is of formula (XII), wherein
R.sup.x is selected from the group consisting of --H, --OH,
--CO.sub.2H, --CO.sub.2(C.sub.1-C.sub.8 alkyl),
--O(C.sub.1-C.sub.4alkyl), --NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl),
--N(C.sub.1-C.sub.8 alkyl).sub.2, and C.sub.1-C.sub.8 alkyl.
[0155] In one embodiment, R.sup.y is selected from the group
consisting of --H, --OH, --CO.sub.2H, --CO.sub.2(C.sub.1-C.sub.8
alkyl), --O(C.sub.1-C.sub.4alkyl), --NH.sub.2, --NH(C.sub.1-C.sub.8
alkyl), --N(C.sub.1-C.sub.8 alkyl).sub.2, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, and phenyl.
[0156] In one embodiment, R.sup.x and R.sup.y are optionally
independently substituted with one or more of --OH, --NO.sub.2,
--CO.sub.2H, --CO.sub.2(C.sub.1-C.sub.8 alkyl),
--O(C.sub.1-C.sub.4alkyl), --NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl),
--N(C.sub.1-C.sub.8 alkyl).sub.2, or C.sub.1-C.sub.8 alkyl.
[0157] In one embodiment, Q is selected from the group consisting
of a covalent bond, C.sub.2-C.sub.4 alkyl, C.sub.2-C.sub.8 alkenyl
and --C(O)--(C.sub.1-C.sub.4 alkyl)-.
[0158] In one embodiment, W is a covalent bond.
[0159] In one embodiment, component B is selected from the group
consisting of dopamine benzoyl benzamide ("dopa-BBA"),
3-amido(4-benzoylbenzoyl)propyl methacrylamide ("ABBPMA"),
tris-[amino(ethylbenzoylbenzamide)] ("tris-BBA"),
4-aminobenzophenone, eugenol, 4,4'-diaminobenzophenone,
4,4'-dihydroxybenzophenone, 3,4-diaminobenzapheneone and a
polymeric photoinitiator such as a polydiaryl ketone e.g. a
polybenzophenone.
[0160] In one embodiment, component B has molecular weight of
1-1000 kDa, such as 1-500 kDa, 20-450 kDa or 50-400 kDa.
[0161] In one aspect, the present invention provides a surface
having a coating comprising a mixture of components A and B,
wherein [0162] component A is a polymer formed by
self-polymerisation of a molecule comprising catechol functionality
and amine and/or amide and/or hydroxyl functionality; and [0163]
component B is a cross-linking molecule comprising two or more
photosensitive or thermosensitive moieties, at least some of which
moieties form covalent bonds with component A.
[0164] In another aspect, the present invention provides a surface
having a coating comprising a mixture of components A and B,
wherein [0165] component A is a polymer formed by
self-polymerisation of a molecule comprising catechol functionality
and amine and/or amide and/or hydroxyl functionality; and [0166]
component B is a polymer comprising photosensitive or
thermosensitive moieties at least some of which moieties form
covalent bonds with component A and which polymer forms an
interpenetrating network with component A.
[0167] In a further aspect, the present invention provides a
surface having a coating comprising A a mixture of components A and
B, wherein component A is a polymer formed by self-polymerisation
of a molecule comprising catechol functionality and amine and/or
amide and/or hydroxyl functionality; and [0168] component B is a
mixture of: [0169] (iii) a cross-linking molecule comprising two or
more photosensitive or thermosensitive moieties, at least some of
which moieties form covalent bonds with component A; and [0170]
(iv) a polymer comprising photosensitive or thermosensitive
moieties at least some of which moieties form covalent bonds with
component A and which polymer forms an interpenetrating network
with component A.
[0171] In one aspect, the present invention provides a surface
having a coating comprising a cross-linked copolymer of components
A and B, wherein component A is a catecholamine capable of
self-polymerisation; and component B is a molecule comprising one
or more groups selected from the group consisting of amino,
hydroxyl, catechol, thiol, hydrazine, hydrazone, oxime, keto,
aldehyde, carboxyl, imino, amido, alkenyl and alkynyl, wherein said
molecule also comprises one or more photosensitive moieties
selected from the group consisting of aryl ketone, diaryl ketone,
aryl azide, alkenyl and alkynyl.
[0172] In one aspect, the present invention provides a surface
having a coating comprising a cross-linked copolymer of components
A and B, wherein component A is a catecholamine capable of
self-polymerisation; and component B is a molecule comprising one
or more groups selected from the group consisting of amino,
hydroxyl, amido and alkenyl, wherein said molecule also comprises
one or more benzophenone groups.
[0173] In one embodiment, the coating comprises catecholamine and
benzophenone throughout its bulk.
Methods of the Invention
[0174] The present invention provides a method of coating a
surface, for which there are three main embodiments 1a, 1b and 2,
depending on the nature of component B. It should be noted that all
embodiments relating to components A and B described above with
reference to the surface having a coating of the invention also
apply to the methods of the invention.
Embodiments 1a and 1b
[0175] In one aspect of the invention is provided a method of
coating a surface, comprising the steps of: [0176] (a) contacting
the surface with a mixture comprising components A and B, wherein
[0177] component A is a molecule capable of self-polymerisation
comprising catechol functionality and amine and/or amide and/or
hydroxyl functionality; and component B is [0178] (i) a
cross-linking molecule comprising two or more photosensitive or
thermosensitive moieties capable of forming covalent bonds with
component A; or [0179] (ii) a polymer comprising photosensitive or
thermosensitive moieties capable of forming covalent bonds with
component A; [0180] such that component A self-polymerises in the
presence of component B and in the case of (ii) forms an
interpenetrating network with component B; and [0181] (b)
activating the photosensitive or thermosensitive moieties of
component B such that at least some of said moieties form covalent
bonds with component A.
[0182] In Embodiment 1a, component B is a cross-linking molecule
comprising two or more photosensitive or thermosensitive moieties
capable of forming covalent bonds with component A. Embodiment 1a
is illustrated in FIG. 2, which shows that when components A and B
are mixed together in step (a), component A polymerises in solution
but component B does not. In step (b), once activated, component B
forms covalent bonds to component A and forms cross-linkages within
the bulk of component A because it is functionalised with two
photosensitive or thermosensitive moieties.
[0183] An example of a component B which is suitable for Embodiment
1a is a compound of formula (VII) wherein, Z and Y are as
previously defined and r is 2.
[0184] In Embodiment 1b, component B is a polymer comprising
photosensitive or thermosensitive moieties capable of forming
covalent bonds with component A; and when component A
self-polymerises in the presence of component B, component A forms
an interpenetrating network with component B. Embodiment 1b is
illustrated in FIG. 3, which shows that when components A and B are
mixed together in step (a) component A polymerises in solution and
entanglement with component B (which is also a polymer) results. In
step (b), upon activation, component B forms covalent bonds to
component A, to produce a cross-linked polymer of components A and
B.
[0185] An example of a component B which is, suitable for
embodiment 1b is a compound of formula (XI):
##STR00020##
wherein, Y, Z and m are as defined above.
Embodiment 2
[0186] In another aspect of the invention is provided a method of
coating a surface comprising the steps of: [0187] (a) contacting
the surface with a mixture comprising components A and B, wherein
[0188] component A is a molecule capable of self-polymerisation
comprising catechol functionality and amine and/or hydroxyl
functionality; and [0189] component B is a molecule comprising one
or more groups capable of participating in the polymerisation of
component A, wherein said molecule comprises one or more
photosensitive or thermosensitive moieties capable of forming
covalent bonds with component A such that a copolymer of components
A and B is formed; and [0190] (b) activating the photosensitive or
thermosensitive moieties of component B in the copolymer such that
at least some of said moieties form covalent bonds with component
A.
[0191] In Embodiment 2, component B is a molecule comprising one or
more groups capable of participating in the polymerisation of
component A, wherein said molecule comprises one or more
photosensitive or thermosensitive moieties capable of forming
covalent bonds with component A such that a copolymer of components
A and B is formed. Embodiment 2 is illustrated in FIG. 4, which
shows that when components A and B are mixed together in step (a),
components A and B will polymerise to form a copolymer. In step
(b), upon activation, component B forms covalent bonds to component
A, resulting in a cross-linked copolymer of components A and B.
[0192] Examples of suitable molecules which are suitable for
Embodiment 2, but are not limited to, compounds of formula (VI),
(VIII), (IX), (X):
##STR00021##
wherein, Z, Y, X, m and n are as defined above.
Activation of Photosensitive and Thermosensitive Moieties
[0193] In step (b), activation of the one or more photosensitive or
thermosensitive moieties of component B results in at least some of
the component B moieties forming covalent bonds with component A.
Photosensitive moieties, for example aryl ketones, are activated on
exposure to particular wavelengths of light. In one embodiment, the
one or more photosensitive moieties are activated by exposure of
the coated surface to UV light. Thermosensitive moieties, for
example aryl azides, are activated on exposure to heat. In one
embodiment, component B comprises one or more moieties which are
both photosensitive and thermosensitive.
Particular Embodiments of the Method of the Invention
[0194] In one aspect, the present invention provides a method of
coating a surface, comprising the steps of: [0195] (a) contacting
the surface with a mixture comprising components A and B, wherein
[0196] component A is a molecule capable of self-polymerisation
comprising catechol functionality and amine and/or amide and/or
hydroxyl functionality; and [0197] component B is a cross-linking
molecule comprising two or more photosensitive or thermosensitive
moieties capable of forming covalent bonds with component A; [0198]
such that component A self-polymerises in the presence of component
B and in the case of (ii) forms an interpenetrating network with
component B; and [0199] (b) activating the photosensitive or
thermosensitive moieties of component B such that at least some of
said moieties form covalent bonds with component A.
[0200] In another aspect, the present invention provides a method
of coating a surface, comprising the steps of: [0201] (a)
contacting the surface with a mixture comprising components A and
B, wherein [0202] component A is a molecule capable of
self-polymerisation comprising catechol functionality and amine
and/or amide and/or hydroxyl functionality; and [0203] component B
is a polymer comprising photosensitive or thermosensitive moieties
capable of forming covalent bonds with component A; [0204] such
that component A self-polymerises in the presence of component B
and forms an interpenetrating network with component B; and [0205]
(b) activating the photosensitive or thermosensitive moieties of
component B such that at least some of said moieties form covalent
bonds with component A.
[0206] A method of coating a surface, comprising the steps of:
[0207] (a) contacting the surface with a mixture comprising
components A and B, wherein [0208] component A is a molecule
capable of self-polymerisation comprising catechol functionality
and amine and/or amide and/or hydroxyl functionality; and component
B is a mixture of [0209] (i) a cross-linking molecule comprising
two or more photosensitive or thermosensitive moieties capable of
forming covalent bonds with component A; and [0210] (ii) a polymer
comprising photosensitive or thermosensitive moieties capable of
forming covalent bonds with component A; [0211] such that component
A self-polymerises in the presence of component B and forms an
interpenetrating network with component B; and [0212] (b)
activating the photosensitive or thermosensitive moieties of
component such that at least some of said moieties form covalent
bonds with component A.
[0213] In one aspect, the present invention provides a method of
coating a surface, comprising the steps of: [0214] (a) contacting
the surface with a mixture comprising components A and B, wherein
[0215] component A is a catecholamine capable of
self-polymerisation; and [0216] component B is a molecule
comprising one or more groups selected from the group consisting of
amino, hydroxyl, catechol, thial, hydrazine, hydrazone, keto,
aldehyde, carboxyl, imino, amido, alkenyl and alkynyl, wherein said
molecule also comprises one or more photosensitive moieties
selected from the group consisting of aryl ketone, diaryl ketone,
aryl azide, alkenyl and alkynyl; [0217] such that a copolymer of
components A and B is formed; and [0218] (b) activating the
photosensitive moieties of component B in the copolymer such that
at least some of said moieties form covalent bonds with component
A.
Properties of the Coating
[0219] The coating of the invention comprises components A and B,
wherein component B is an additive molecule which is functionalised
with a photosensitive or thermosensitive moiety and also comprises
functionality which enables it to be covalently bonded to component
A.
[0220] As shown in Examples the addition of component B enhances
the durability of the coating and prevents depolymerisation of the
coating under oxidative conditions (such as on exposure to
peroxide, chlorite or hypochlorite). As described in Example 3,
Pebax/BaSO.sub.4 tubing was contacted with mixtures of various
compounds comprising a photosensitive moiety (as component B) and
dopamine (as component A), to form a coating of a copolymer of
components A and B (step (a); Embodiment 2, as described above).
The coated tubing was then activated/cured as described in Example
4, by exposing the coating to UV light. It is clear from comparing
Tables 1 and 2 of Example 5 that coatings which underwent UV curing
(i.e. step (b)) were more resistant to oxidative conditions that
those which did not, as evidenced by the fact that coatings which
underwent UV curing (step (b)) retained their coating colouration,
while those coatings which did not undergo UV curing lost
colouration, indicating degradation and erosion of the coating.
[0221] During this experiment it was observed that coatings of the
invention had various colours ranging from dark grey, dark brown,
brown yellow, yellow brown, yellow orange and yellow. The coating
were observed to retain their colouration over time. This is
surprising, since the prior art teaches that dopamine
polymerisation solutions become grey or black during dopamine
polymerization, and produce grey or black, rather than coloured,
coatings (E Herlinger, J Chem Soc Perkin Trans, vol. 2, p. 259,
1995). In one embodiment, the coating of the invention reflects
electromagnetic radiation of red to yellow wavelengths.
[0222] As discussed above, the coating of the invention is durable
and resistant to degradation, erosion and depolymerisation under
oxidative conditions such as peroxide, chlorite and hypochlorite.
Thus, in one embodiment, the coating of the invention does not
appreciatively depolymerise under oxidative conditions, such as
exposure to a chlorite compound. In another embodiment, the coating
of the invention comprising components A and B is more durable than
the corresponding coating consisting solely of component A.
[0223] As shown in Examples 6 and 7, the coating of the invention
was applied to many different surfaces, all of which were found to
be resistant to oxidative depolymerisation.
Covalent Bonding to the Surface
[0224] As the coating of the invention comprises photosensitive or
thermosensitive groups on the surface of the coating as well as
within the bulk of the coating, if the surface being coated has
complementary functionality to the photosensitive or
thermosensitive groups, then in some embodiments the coating of the
invention will be covalently bonded to the surface. FIG. 5
illustrates a variant of Embodiment 2, wherein the surface being
coated has complementary functionality (CZ) to the photosensitive
or thermosensitive group of component B (Z). Upon activation of
group Z, component B will form covalent bonds with component A to
form cross-linkages within the bulk of the coating, and Z groups
which are in proximity to the surface will form covalent bonds with
the surface. It should be noted that the above also applies to
Embodiments 1a and 1b. This variant of the coating of the invention
is expected to be particularly durable because of the cross-linking
within the coating and because of the covalent bonding to the
surface. In some embodiments, component A is also capable of
reacting with the surface.
[0225] For example, if the photosensitive or thermosensitive moiety
is capable of hydrogen abstraction and subsequent covalent bond
formation, and if the surface being coated has abstractable
hydrogen atoms, then the resulting coating will be covalently
bonded to the surface. Alternatively, the photosensitive or
thermosensitive moiety, once activated, could generate a nitrene or
carbene. Suitable complementary reactive groups for nitrenes and
carbenes include, but are not limited to, alkyl, alkenyl and
alkynyl.
[0226] Thus, in one embodiment, the coating of the invention is
covalently bonded to the surface. In another embodiment, the
surface comprises abstractable hydrogen atoms and the coating is
covalently bonded to the surface via abstraction of hydrogen atoms
from the surface by at least some of the photosensitive or
thermosensitive moieties of component B.
[0227] The surface may have "intrinsic" complementary functionality
(CZ) to the photosensitive or thermosensitive group of component B
(Z), meaning the material from which the surface is made (prior to
any coating process) comprises the complementary functionality.
Alternatively, the surface may be pre-treated to place a population
of CZ, e.g. a surface treatment such as plasma, corona, heat
treatment, ozonation, silanizing, ion implantation, surfactant
adsorption, etc. (as per below).
[0228] In one embodiment, the surface to be coated comprises
abstractable hydrogen atoms.
[0229] "Abstractable hydrogen atoms" are defined as covalently
bound hydrogen atoms that can be abstracted or removed by an
entity, being in an excited state, and thereby generating a free
radical (at least initially) at the atom which was previously
covalently bound to the hydrogen atom (see Scheme 1, supra).
[0230] Examples of surface materials having an intrinsic surface
comprising abstractable hydrogen atoms include, but are not limited
to aliphatic polymers, vinyl polymers, condensation polymers;
fluorinated copolymers (although not perfluoropolymers), silanated
metals and ceramics, biopolymers.
[0231] Surfaces lacking such complementary functionality can be
covered, at least in part, with a polymeric covering material
having a multiplicity of reactive chemical groups thereon to which
said component B (and optionally component A) can react. Polymeric
substrates can also be modified along their surface, or along their
polymer backbone using a variety of methods, including hydrolysis,
aminolysis, photolysis, etching, plasma modification, plasma
polymerization, carbene insertion, nitrene insertion, etc. In the
resulting coatings of the invention, component B (and optionally
component A) are covalently attached, or bound, to the polymeric
covering material through the reactive chemical groups of the
covering material or directly to a substrate that has been
modified. The polymeric covering material may form at least one
layer on at least a portion of a substrate. Thus, in one
embodiment, prior to applying the coating of the invention the
surface is coated with a polymeric covering material comprising
complementary functionality.
Subsequent Coatings
[0232] The coating of the invention is suitably a priming coating
upon which subsequent coatings may be applied. Thus, in one
embodiment, the surface has a subsequent coating. In another
embodiment, the method of the invention further comprises the step
of (c) applying a subsequent coating to the surface.
[0233] Subsequent coatings that can be applied to the surface
include, but are not limited to a synthetic or naturally occurring
organic or inorganic polymer or material, including but not limited
to materials such as polyolefins, polyesters, polyurethanes,
polyamides, polyether block amides, polyimides, polycarbonates,
polyphenylene sulfides, polyphenylene oxides, polyethers,
silicones, polycarbonates, polyhydroxyethylmethacrylate, polyvinyl
pyrrolidone, polyvinyl alcohol, rubber, silicone rubber,
polyhydroxyacids, polyallylamine, polyallylalcohol, polyacrylamide,
and polyacrylic acid, styrenic polymers, polytetrafluoroethylene
and copolymers thereof, derivatives thereof and mixtures thereof.
Some of these classes are available both as thermosets and as
thermoplastic polymers. As used herein, the term "copolymer" shall
be used to refer to any polymer formed from two or more monomers,
e,g. 2, 3, 4, 5 and so on and so forth. Bioresorbables, such as
poly(D,L-lactide) and polyglycolids and copolymers thereof are also
useful. Non-woven, bioabsorbable web materials comprising a
tri-block copolymer such as poly(glycolide-co-trimethylene
carbonate) tri-block copolymer (PGA:TMC) are also useful (as
described in U.S. Pat. No. 7,659,219: Biran at al.). Useful
polyamides include, but are not limited to, nylon 12, nylon 11,
nylon 9, nylon 6/9 and nylon 6/6. Examples of some copolymers of
such materials include the polyether-block-amides, available from
Elf Atochem North America in Philadelphia, Pa. under the tradename
of PEBAX.RTM.. Another suitable copolymer is a polyetheresteramide.
Suitable polyester copolymers, include, for example, polyethylene
terephthalate and polybutylene terephthalate, polyester ethers and
polyester elastomer copolymers such as those available from DuPont
in Wilmington, Del. under the tradename of HYTREL.RTM.. Block
copolymer elastomers such as those copolymers having styrene end
blocks, and midblocks formed from butadiene, isoprene,
ethylene/butylene, ethylene/propene, and so forth may be employed
herein. Other styrenic block copolymers include
acrylonitrile-styrene and acrylonitrile-butadiene-styrene block
copolymers. Also, block copolymers wherein the particular block
copolymer thermoplastic elastomers in which the block copolymer is
made up of hard segments of a polyester or polyamide and soft
segments of polyether may also be employed herein. Other useful
substrates are polystyrenes, poly(methyl)methacrylates,
polyacrylonitriles, poly(vinylacetates), poly(vinyl alcohols),
chlorine-containing polymers such as poly(vinyl) chloride,
polyoxymethylenes, polycarbonates, polyamides, polyimides,
polyurethanes, phenolics, amino-epoxy resins, polyesters,
silicones, cellulose-based plastics, and rubber-like plastics.
[0234] Subsequent coating that may be applied to the surface also
include, but are not limited to, fluorinated polymers such as
fluoropolymers, e.g. expanded polytetrafluoroethylene (ePTFE),
polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene
(FEP), perfluorocarbon copolymers, e.g. tetrafluoroethylene
perfluoroalkylvinyl ether (TFE/PAVE) copolymers, copolymers of
tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE),
copolymers of TFE with functional monomers that comprise acetate,
alcohol, amine, amide, sulfonate, functional groups and the like,
as well as combinations thereof, and combinations of the above with
and without crosslinking between the polymer chains, expanded
polyethylene, polyvinylchloride, polyurethane, silicone,
polyethylene, polypropylene, polyurethane, polyglycolic acid,
polyesters, polyamides, elastomers and their mixtures, blends and
copolymers or derivatives thereof may be useful.
[0235] This aspect of the invention is illustrated in Example 8,
wherein a stent, to which had been applied a coating of the
invention (dopa-BBA priming layer) was subsequently coated with a
fluoro-copolymer. The adhesion of the coated stent (primed
according to the invention) was found to be far superior to that of
a stent which was coated directly with the fluoropolymer, as
described in Example 9.
[0236] FIG. 6 illustrates a variant of Embodiment 2, wherein a
subsequent coating has complementary functionality (CZ) to the
photosensitive or thermosensitive group of component B (Z). Upon
activation of group Z, component B forms covalent bonds with
component A to form cross-linkages within the bulk of the coating,
and Z groups which are in proximity to the subsequent coating will
form covalent bonds with the subsequent coating. It should be noted
that the above also applies to Embodiments 1a and 1b. This variant
of the coating of the invention is expected to be particularly
durable because of the cross-linking within the coating and because
of the covalent bonding to the subsequent coating. In some
embodiments, component A is also capable of reacting with the
subsequent coating.
[0237] Thus, in certain embodiments, a subsequent coating which is
applied on the surface has complementary functionality to the
photosensitive or thermosensitive groups, which results in the
coating of the invention being covalently bonded to a coating which
is subsequently applied to the surface.
[0238] Thus, in embodiments wherein the coating of the invention is
covalently bonded to subsequent coating, the subsequent coating can
be expected to have enhanced durability (when compared with the
durability of the same coating which is applied directly to the
surface). In certain embodiments, the uniformity of the subsequent
coating may also be improved (when compared with the uniformity of
the same coating which is applied directly to the surface).
[0239] In one embodiment, the subsequent coating comprises a
therapeutic agent. Suitably, the therapeutic agent is selected from
the group consisting of an anti-thrombogenic agent, a hemostatic
agent, an anti-angiogenic agent, an angiogenic agents, an
anti-microbial agent, an anti-proliferative agent, a proliferative
agent and an anti-inflammatory agent, or a combination thereof.
Other Aspects of the Coating
[0240] In one embodiment, the mass ratio of component A:component B
is between 100:1 and 1:100, such as 100:1 to 1:5, such as 10:1 to
1:5, such as 5:1 to 1:2, such as 1:1.
[0241] The above mentioned ratios refer to the mass ratio of
components A and B present in the reaction mixture before component
B covalently bonds to component A. The ratio of components A and B
present in the resulting coating may reasonably be expected to be
substantially similar to the mass ratio of the individual
components in the mixture of components before the coating is
formed.
[0242] The dry thickness of the coating on the substrate can be
controlled by limiting the quantities of components A and B and/or
by limiting the time for step (a). Suitably, the coating is at
least 100 nm thick when dry, for example at least 50 m, 25 nm, 10
nm, 5 nm, 1 nm, 0.5 nm or 0.1 nm. In one embodiment, the coating is
0.1-80 nm thick, for example 0.1-50 nm or 0.5-25 nm.
[0243] It should be noted that all aspects of the invention as
described above and herein refer equally to the surface of the
invention and the method of the invention.
[0244] The coating of the invention is formed by contacting the
surface with a solution comprising components A and B. Suitably,
the reaction solvent is an aqueous-solvent mixture such as a
water-alcohol mixture or a water-buffer solution. Suitable alcohols
include, but are not limited to, methanol, ethanol, propanol and
isopropanol. Other suitable solvents include DMSO, DMF, acetone,
acetonitrile, dioxane, THF, and the like. Suitable buffers include,
but are not limited to, tris buffer and Trizma base (tris buffer
and HCl).
[0245] The surface to be coated is first contacted with a solution
of components A and B for a given length of time before being
removed, and suitably dried (step (a)). If component A is water
soluble but component B is not (or visa versa), then components A
and B are separately dissolved in water and organic solvent,
respectively, before being combined to form an emulsion. The
photosensitive or thermosensitive moieties of component B are then
activated by any suitable means. Certain photosensitive moieties
can be activated by exposure to UV light. When UV light is used to
initiate photoactivation, any suitable UV source can be used, for
example a Fusion UV-lamp or Oriel UV-lamp providing UV-A and/or
UV-B and/or UV-C radiation, or a pulsed UV lamp source (Xenon,
XC-500) with broad UVA and UVB emission. Thermosensitive moieties
may be activated using heat provided by any suitable means such as
an oven or a heating element or forced air convection. When
component B comprises a photosensitive moiety, suitably step (b)
proceeds at room temperature.
[0246] Step (a) of the method (polymerisation reaction) is suitably
carried out at pH 7-10, for example pH 7.5-9, or pH 8.5. As
discussed above, a buffer such as tris buffer may be added to the
solution to maintain the solution or emulsion at a particular pH.
Other possible buffers include MES, ACES, PIPES, MOPSO, Bis-Tris
propane, BES, MOPS, TES and HEPES. The pH of the solution can
alternatively be adjusted using any suitable acid or base, such as
HCl or NaOH, respectively.
[0247] In step (a) the reaction mixture must be open to the air (or
have a source of O.sub.2), as component A will generally
self-polymerise via an oxidation process. The present inventors
have found that, unusually, when component B comprises a
benzophenone moiety as photosensitive moiety, step (b) (activation
and formation of covalent bonds with component A) will proceed in
the presence of polymerized Component A. As the presence of
dopamine and polydopamine usually scavenge free radicals, which can
lead to insufficient crosslinking, this is particularly surprising.
See Ju et al., Biomacromolecules, 2011, Vol. 12, pages 625-632
which teaches that dopamine and polydopamine are free radical
scavengers.
[0248] The rate of formation of the coating of components A and B
in step (a) may be increased by the addition of an oxidant to the
solution. Suitable oxidants include but are not limited to oxygen
gas, ammonium persulfate and sodium persulfate.
[0249] The time required to form a coating of components A and B in
step (a) will vary depending on the specific reaction conditions
used. The coating of step (a) is preferably formed within a time
period that is feasible for efficient manufacture. For example,
within 48 hours, 24 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3
hours, 2 hours, 1 hour or 30 min. As a general principle, the
longer the polymerisation time, the thicker the coating. The time
required to activate the photosensitive or thermosensitive moieties
of component B in order to form covalent bonds with component A
(step (b) of the method) will also vary depending on the specific
reaction conditions used, but the time required for step (b) will
usually be shorter than the time required for step (a). For
example, when component B comprises photosensitive moieties which
are activated by UV light, the coated surface of step (a) only
requires UV irradiation for around 6 minutes.
Further Aspects of the Method of the Invention
[0250] The speed of the self-polymerisation reaction in step (a) of
the methods of the invention may be increased by the addition of an
oxidant such as a stream of O.sub.2, ammonium persulfate or
ammonium persulfate.
[0251] Prior to coating, the surface of the substrate can be
cleaned or pretreated in order to improve adhesion of the coating
(be that the coating of the invention or a coating comprising CZ
groups). Prior cleaning or pretreatment of the surface may also
improve the uniformity of the coating.
[0252] Suitable cleaning agents or pre-treatment agents include
solvents as ethanol or isopropanol (IPA), solutions with high pH
such as solutions comprising a mixture of an alcohol and an aqueous
solution of a hydroxide compound (e.g. sodium hydroxide), sodium
hydroxide solution per se, solutions containing tetramethyl
ammonium hydroxide (TMAH), basic Piranha (ammonia and hydrogen
peroxide), acidic Piranha (a mixture of sulfuric acid and hydrogen
peroxide), and other oxidizing agents including sulfuric acid and
potassium permanganate or different types of peroxysulfuric acid or
peroxydisulfuric acid solutions (also as ammonium, sodium, and
potassium salts e.g. ammonium persulfate), or combinations
thereof.
Properties of the Coating
[0253] Coatings according to the invention, in at least some
embodiments, are expected to have one or more advantages of: [0254]
having high durability [0255] having good coating uniformity;
[0256] being stable to oxidation degradation, erosion and
depolymerisation [0257] being stable to sterilisation; [0258] wide
applicability, as the coating is surface independent.
Definitions and Abbreviations
[0259] `C.sub.1-C.sub.8 alkyl` is defined as a straight or branched
aliphatic carbon chain containing 1-8 carbon atoms, for example
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
pentyl, isopentyl, hexyl, heptyl and octyl and the corresponding
alkylene radicals such as methylene, ethylene, etc.
[0260] `C.sub.2-C.sub.8 alkenyl` is defined as a straight or
branched aliphatic carbon chain containing 2-8 carbon atoms and at
least one carbon-carbon double bond. Examples include, but are not
limited to, vinyl, acrylate, acrylamide, methacrylate,
methacrylamide, and the like.
[0261] `C.sub.2-C.sub.8 alkynyl` is defined as a straight or
branched aliphatic carbon chain containing 2-8 carbon atoms and at
least one carbon-carbon triple bond. [0262] ABBPMA
3-amido(4-benzoylbenzoyl)propyl methacrylamide [0263] AIBN
2,2'-azobis(2-methylpropionitrile) [0264] BP benzophenone [0265]
BBA-Cl 4-benzoylbenzoyl chloride [0266] dopa-BBA dopamine benzoyl
benzamide [0267] DMSO dimethyl sulfoxide [0268] d.i. deionised
[0269] GPC gas phase chromatography [0270] hr hour [0271] IPA
isopropanol [0272] min minute [0273] MES
2-(N-morpholino)ethanesulfonic acid [0274] ePTFE expanded
polytetrafluoroethylene [0275] PEG polyethylene glycol [0276]
TFE-co-VAc copolymer comprising tetrafluoroethylene-co-vinyl
acetate [0277] tris tris(hydroxymethyl)aminomethane [0278] tris-BBA
tris-[amino(ethylbenzoylbenzamide)] [0279] QCM quartz crystal
microbalance [0280] VP-co-BBA
poly(vinylpyrrolidone-co-amido(4-benzoylbenzoyl)propyl
methacrylamide
EXAMPLES
General Procedures
Chemicals
[0281] Dopamine HCl, 4-benzoylbenzoic acid, thionyl chloride,
N-vinyl pyrrolidone and AIBN were purchased from Sigma.
Tris(2-aminoethyl)amine, 4-aminobenzophenone,
4,4'-diaminobenzaphenone, 4,4'-dihydroxybenzophenone,
3,4-diaminobenzophenone and eugenol were purchased from Aldrich.
3-Aminopropylmethacrylamide was purchased from Polysciences.
Materials
[0282] Single wire nitinol stents interconnected by an ePTFE
structure were obtained from W.L. Gore & Associates, Inc.,
Flagstaff, Ariz. under the trade name GORE.RTM. TIGRIS Vascular
Stent. Quartz glass slides (72250-03) were purchased from Electron
Microscopy Sciences, Hatfield, Pa. ePTFE membrane (GMM-406,
GORE.RTM. Microfiltration Media) was supplied by W.L. Gore &
Associates, Inc., Flagstaff, Ariz. Pebax tubing (72D) was purchased
from Arkema, King of Prussia, Pa.). FEP tubing (600036-05) was
purchased from Zeus, Orangeburg, S.C.
Evaluation Methods
[0283] The parameter being evaluated by each method is given in
parentheses.
Time-of-Flight Secondary Ion Mass Spectrometry (TOF-SIMS: Coating
Composition)
[0284] TOF-SIMS uses a pulsed primary ion beam to desorb and ionize
species from a sample surface. The resulting secondary ions are
accelerated into a mass spectrometer, wherein they are mass
analyzed by measuring their time-of-flight from the sample surface
to the detector. For coatings of the present invention, one would
expect to detect fragments of component B, especially tertiary
hydroxyl groups (a reaction product in embodiments where component
B abstracts hydrogen via activation of a ketone group, Scheme 1,
supra).
Nanomechanical Testing (Coating Coverage and Adhesion)
[0285] This testing involved nanoscratch testing, imaging of the
scratch region, and nanoindent testing, to record quasi-static
reduced modulus values, which were then converted into adhesive
critical failure load values (a routine test procedure which is
well known to the skilled person). Testing was carried out using a
Hysitron 950 Triboindenter (Hysitron Inc., Eden Prairie, Minn.). 5
stents of each coating formulation were tested at random locations.
This technique can be used to investigate the extent of cross
linking (formed by component B forming covalent bonds with
component A) throughout the thickness of the coating. If only the
outermost for innermost) sections of the coating are cross-linked,
then these sections will have a different modulus and/or adhesion
strength, while a coating which is cross-linked throughout its full
thickness will have a uniform modulus and/or adhesion strength.
X-Ray Photoelectron Spectroscopy with Depth Profiling (XPS)
(Coating Composition)
[0286] Samples were irradiated with mono-energetic X-rays causing
photoelectrons to be emitted from the top 1-10 nm of the sample
surface. An electron energy analyzer determined the binding energy
of the photoelectrons. Qualitative and quantitative analysis of all
elements except hydrogen and helium was possible, at detection
limits of .about.0.1-0.2 atomic percent. Analysis spot sizes ranged
from 10 .mu.m to 1.5 mm. It is also possible to generate surface
images of features using elemental and chemical state mapping.
Depth profiling was possible using angle-dependent measurements to
obtain non-destructive analyses within the top 10 nm of a surface,
or throughout the coating depth using destructive analysis such as
ion etching or C60 sputtering. Carbon, oxygen, and nitrogen X-ray
spectra were normalized to the carbon 285 eV peak. For coatings of
the present invention comprising aryl ketone moieties, in
particular benzophenone, the aromatic groups were detectable on the
carbon spectrum at 290-293 eV.
Visual Inspection (Coating Coverage and Adhesion)
[0287] Coatings of the invention, at least in some embodiments were
coloured. Coatings wherein component A was dopamine may vary in
colours from dark grey through to yellow. The coating colouring was
used to assess the durability of the coating, as if the coating was
degraded, eroded or depolymerized then the colour changed.
Degradation, erosion and depolymerisation was indicated by a
lighter coloured coating, a less intense colour or the absence of
the original colour.
Scanning Electron Microscopy (SEM) (Coating Coverage and
Adhesion)
[0288] SEM images of coated samples were captured using a Zeiss
Supra 35 VP SEM. SEM imaging and EDS (energy dispersive X-ray
spectroscopy) were used to provide information on the extent,
distribution, and uniformity of the coating.
Quartz Crystal Microbalance (QCM) (Coating Coverage, Thickness and
Adhesion)
[0289] Quartz Crystal Microbalance techniques (QCM) may be used to
evaluate the thickness of coating layer. Comparing the thickness
before and after subjecting the surface to oxidation conditions
provides an indication of the coating adhesion.
Particulation (Coating Adhesion)
[0290] Particulation on the surface of the coating may be
indicative of erosion or degradation of the coating, and may be
observed after purposeful abrasion of the coated surface in a test
protocol, intended to mimic in-service use. Particles in the
collection media can be analyzed by an Accusizer Particle Sizer
(780/SIS PSS NICOMP, Santa Barbara, Calif. USA) according to test
method described by United States Pharmacopeia (USP) monograph 788
for small volume injectables. More durable coatings will have less
particulation after abrasion.
Example 1a
Evaluation of Dopamine Polymerization in Water Buffer Compared to
Water/Alcohol Emulsion
[0291] The ability of dopamine to coat a substrate was examined
using systems involving aqueous buffer or water/alcohol emulsion.
The substrate comprised tubing of Pebax72D loaded with 20% w/w
BaSO.sub.4 powder, that had been cleaned by sonication in
isopropanol for 10 min and air dried.
[0292] An aqueous tris buffer was formed by dissolving tris at 10
mM in deionized water and adjusting the pH to 8.5 with HCl. A
water/alcohol emulsion was formed by mixing 1 part aqueous tris
buffer (50 mM) to 4 parts methanol, to give a final concentration
of 10 mM Trizma, and adjusting the pH to 8.5 with HCl. Dopamine-HCl
was dissolved at 2 mg per 5 ml in the aqueous buffer and in the
water/alcohol emulsion. A 4 cm sample of the Pebax/BaSO.sub.4
tubing was immersed into 5 ml of each dopamine solution to
completely wet the sample. Air was bubbled through each solution
for 20 seconds. The solutions were left undisturbed for 72 hr.
[0293] Sample substrates were vigorously rinsed in deionized water
and dried in an oven at 50.degree. C. The normally bright white
Pebax/BaSO.sub.4 tubing was a light-to-dark grey colour for both
solutions, indicating deposition of a polydopamine coating stable
to water rinsing.
Example 1b
XPS Analysis of Coatings Comprising Dopamine Polymerized in Water
Compared to Water/Alcohol Emulsion
[0294] The coated samples of Example 1a were examined with X-ray
photoelectron spectroscopy. Carbon, oxygen, and nitrogen x-ray
spectra were normalized to the carbon 285 eV peak. In the regions
of 280-298 eV (carbon), 524-540 eV (oxygen), and 392-410 eV
(nitrogen), the dopamine/buffer spectrum overlapped the
dopamine/emulsion spectrum, indicating that the polydopamine
coating is unaltered by the use of aqueous buffer or water-alcohol
emulsion.
Example 2a
Synthesis of Dopamine Benzoyl Benzamide ("dopa-BBA")
[0295] 4-Benzoylbenzoyl chloride was first prepared by the reaction
of 4-benzoylbenzoic acid with excess thionyl chloride in refluxing
anhydrous dimethylformamide (note: all reactions involving
photosensitive reagents were performed in a UV/blue light-shielded
fume hood). The 4-benzoylbenzoyl chloride product ("BBA-Cl") was
recovered by rotary evaporation and recrystallization from
hexane/toluene (4:1).
[0296] The BBA-Cl product was dissolved in pyridine:chloroform
(1:4). Dopamine HCl was dissolved in chloroform. The two solutions
were reacted (BBA-Cl in excess) under argon for about 24 hours with
stirring. The resulting suspension was washed with aqueous acid and
with water, dried over sodium sulfate, and the organic solvent
removed under rotary evaporation. The dopamine benzoyl benzamide
("dopa-BBA") product was recrystallized from toluene: chloroform
(4:1). Proton-NMR characterization demonstrated 85% purity, with
the remainder comprising 4-benzoylbenzoic acid and dopamine
Example 2b
Synthesis of tris-[amino(ethylbenzoylbenzamide)] ("tris-BBA")
[0297] The BBA-Cl of Example 2a was dissolved in chloroform.
Tris(2-aminoethyl)amine was dissolved in aqueous base. The BBA-Cl
solution was added (in excess) to the tris(2-aminoethyl)amine
solution, dropwise with vortexing, and reacted an additional 30 min
with vortexing. The emulsion was allowed to separate, the organic
layer washed with aqueous base, dried over sodium sulfate, and the
organic solvent removed under rotary evaporation. The final
product, tris(benzoylbenzamide ethyl)amine ("tris-BBA), was
characterized by proton NMR.
Example 2c
Synthesis of 3-amido(4-benzoylbenzoyl)propyl methacrylamide
"ABBPMA"
[0298] A monomer comprising a benzophenone moiety and a
methacrylamide moiety was prepared.
[0299] The BBA-Cl of Example 2a was reacted with
3-aminopropylmethacrylamide in chloroform/triethylamine (5:1) for
4.5 hrs. The solution was washed with dilute aqueous HCl and then
water, and the organic fraction dried over sodium sulfate. The
product, 3-amido(4-benzoylbenzoyl)propyl methacrylamide (ABBPMA),
was recovered by rotary evaporation and recrystallization from
toluene/chloroform (4:1).
Example 2d
Synthesis of poly(vinylpyrrolidone-co-amido(4-benzoylbenzoyl)propyl
methacrylamide ("VP-co-BBA")
[0300] The title polybenzophenone copolymer VP-co-BBA was prepared
by free radical polymerization of the ABBPMA form Example 2c with
N-vinyl pyrrolidone (freshly vacuum distilled), using AIBN
initiator, at a mass ratio of 92.3:7.5:0.2 respectively, in
dimethylsulfoxide, under argon, 65.degree. C., 3 days. The
copolymer product was recovered via sequential dialysis (MWCO 10
KDa) against toluene, ethanol, then water, and lyophilized. The
copolymer product was characterized by proton NMR and GPC. The
final product,
poly(vinylpyrrolidone-co-amido(4-benzoylbenzoyl)propyl
methacrylate) ("VP-co-BBA"), contained contained 2.7% mole fraction
benzophenone-bearing groups, and a number average molecular weight
of 284 KDa.
Example 3
Coating of Dopamine with Functionalized UV Compounds onto Various
Substrates
[0301] The following functionalized UV compounds were examined for
their ability to engraft and UV crosslink into a polydopamine
coating: [0302] dopa-BBA (Example 2a) [0303] tris-BBA (Example 2b)
[0304] ABBPMA monomer (Example 2c) [0305] VP-co-BBA (Example 2d)
[0306] 4-aminobenzophenone ("4NH.sub.2") [0307] Eugenol [0308]
4,4'-diaminobenzophenone ("44'NH2") [0309]
4,4'-dihydroxybenzophenone ("44'OH") [0310] 3,4-diaminobenzophenone
("34NH.sub.2").
[0311] Briefly, the functionalized UV compound was dissolved in
methanol, dopamine-HCl was dissolved in Trizma buffer, and the two
combined with vortexing. Final concentrations were 10 mM Trizma, 2
mg dopamine, and 10 mg functionalized UV compound per 5 ml
solution. A 4 cm sample of sonicated and dried Pebax/BaSO.sub.4
tubing was immersed into 5 ml of each solution to completely wet
the sample. Air was bubbled through each solution for 20 sec. The
solutions were left undisturbed for 48 hr. Sample substrates were
vigorously rinsed in deionized water, methanol, water:methanol, and
finally water and were than dried in an oven at 50.degree. C.
Example 4
UV Curing of Example 1a and 3
[0312] The coated tubing samples of Example 3 were exposed to UV
light to effect covalent crosslinking of the polydopamine coating.
The coated tubing samples of Example 1a were also exposed to UV
light as a comparison.
[0313] The coated tubing samples of Example 1a and 3 were exposed
to a pulsed UV lamp source (Xenon, XC-500) with broad UVA and UVB
emission. They were exposed to 15 mW/cm.sup.2 intensity light (at
254 nm) for 6 minutes with 60 rpm axial rotation to ensure even
exposure along the outer circumference of the coated tubing sample,
for a total dose of 2.7 J/cm.sup.2.
Example 5
Oxidation Stability of Examples 1a, 3 and 4
[0314] It is known that oxidation, such as immersion into
hypochlorite, can degrade polydopamine coatings (Del Frari, Polym
Degrad Stab, 97, 1844, 2012; B P Lee, Ann Rev Mater Res, 41, 99,
2011). To evaluate stability against oxidation as a dependence upon
incorporation of the functionalized UV compound, the non-UV-cured
tubing samples of Examples 1a and 3 and the UV-cured tubing samples
of Example 4 were immersed in NaClO (Clorox) dissolved in water (6%
wiv), for 15 sec, rinsed vigorously in deionized water, then air
dried in an oven at 50.degree. C. The colour of the coating against
the white background of the tubing was noted.
TABLE-US-00001 TABLE 1 no UV curing Coating composition Colour
before oxidation Colour after oxidation dopa/buffer brown-grey None
dopa/alcohol dark gray None tris-BBA brown-gray None VP-co-BBA
brown-gray None ABPMA yellow-brown faint brown
[0315] The results of Table 1 demonstrate that the dopamine
coatings, and the dopamine coatings comprising a functionalized UV
compound that were not irradiated with UV to induce covalent
crosslinking of the coating, were not resistant to oxidation by
hypochlorite.
TABLE-US-00002 TABLE 2 UV curing Coating composition Colour before
oxidation Colour after oxidation dopa/buffer brown-grey None
dopa/alcohol dark grey None dopa-BBA brown-yellow brown-yellow
Eugenol dark brown dark brown 44'NH.sub.2 yellow yellow 44'OH
yellow-orange yellow-orange 34NH.sub.2 yellow yellow 4NH.sub.2
yellow-brown yellow-brown tris-BBA brown-grey brown-grey VP-co-BBA
brown-grey brown-grey ABPMA yellow-brown yellow-brown
[0316] The results of Table 2 demonstrate that dopamine coatings
which were irradiated with UV were not resistant to oxidation by
hypochlorite. The results further demonstrate that the dopamine
coatings comprising a functionalized UV compound that were
irradiated with UV to induce covalent crosslinking of the coating,
were resistant to oxidation by hypochlorite, as indicated by no
change in their coloration.
[0317] It was observed that coatings retained their original colour
over time periods at least as long as 8 months, even after exposure
to bleach. As discussed in the detailed description, to the best of
the inventors' knowledge this Example is the first demonstration of
polydopamine coatings with stable colours other than grey or
black.
Example 6
Coating of Other Substrates
[0318] Other substrates were coated with dopamine from emulsion,
and with dopamine comprising UV functionalized compounds. These
coated substrates were coated as per Examples 1a and 3, and UV
cured as per Example 4.
[0319] A variety of substrates were coated, including quartz glass
slides, ePTFE membrane, Pebax tubing (72D). FEP tubing (600036-05,
Zeus, Orangeburg, S.C.), and low density polyethylene (LOPE)
tubing.
[0320] After coating and UV curing, the substrates had different
colours, indicating the deposition of the dopamine or the dopamine
comprising UV functionalized compounds. The samples were exposed to
hypochlorite as per Example 5. The coated samples comprising
dopamine prepared as per Example 1a were unstable to oxidation as
indicated by a loss of colour. The coated samples comprising
dopamine comprising UV functionalized compounds, and exposed to UV,
were stable to oxidation, as indicated by a stable colour.
Example 7
Priming of a Stent with a Dopa-BBA Primer Layer
[0321] The dopa-BBA of Example 2a was primed onto a single wire
nitinol stent interconnected by an ePTFE structure. The dopa-BBA
was dissolved (3.5 mg per 5 ml) in an aqueous buffer as per Example
2a. The stent was then immersed into the dopa-BBA solution, with
gentle shaking, for about 24 hr. The stent was rinsed multiple
times with deionized water, and dried at 60.degree. C. for about 1
hr. The coated stent was exposed to UV as per Example 4.
Example 8
Coating of a Stent Comprising a Dopa-BBA Primer Layer with a
Topcoat Comprising a Fluoro-Copolymer
[0322] The dopa-BBA primed stent of Example 7 was coated with a
fluoro-copolymer comprising tetrafluoroethylene-co-vinyl acetate.
As such, a copolymer comprising tetrafluoroethylene-co-vinyl
acetate ("TFE-co-VAc"), at a mole ratio of 20:80, was first
prepared. To a nitrogen purged 1 L pressure reactor under vacuum
were added d.i. water (500 g), 20% aqueous ammonium
perfluorooctanoate (2 g), distilled vinyl acetate (30 ml),
n-butanol (10 g), and ammonium persulfate (0.2 g).
Tetrafluoroethylene monomer was fed into the reactor until the
reactor pressure reached 1500 KPa. The mixture was stirred and
heated to 50.degree. C. When a pressure drop was observed, vinyl
acetate (25 ml) was slowly fed into the reactor. The reaction was
stopped when the pressure dropped another 150 KPa after vinyl
acetate addition. The copolymer was obtained from freeze-thaw
coagulation of the latex emulsion, cleaned with methanol/water
extraction, and dried under vacuum. The TFE-co-VAc copolymer was
dissolved at 1.5 mg/ml in a solution of
methylpentanone/cyclohexanone/acetone (1:1.5:7.5).
[0323] The primed stent of Example 7 was coated with the TFE-co-VAc
solution, by evenly spraying a fine mist of the TFE-co-VAc solution
onto the primed stent with rotation. The solvent was removed by
heating at 120.degree. C. for 10 min. An average of 1.5 mg of
copolymer was coated onto the stents at an average thickness of 0.7
um
[0324] For comparison, an unprimed stent not comprising the
dopa-BBA primer was coated with the TFE-co-VAc solution. The fine
mist was observed largely not to adhere to the stent surface, and
produced a highly discontinuous coating that readily flaked off the
stent surface.
Example 9
Adhesion of a Stent Primed with Dopa-BBA and Coated with
TFE-co-VAc
[0325] Adhesion testing of the primed and unprimed stents and
coated with TFE-co-VAc was performed by nanomechanical testing
(Hysitron, Eden Prairie, Minn.).
[0326] For those stents primed with dopa-BBA, exposed to UV
radiation, and coated with TFE-co-VAc, the average critical load
failure was 26.1 mN with a standard deviation of about 10% among
the tested locations. For those stents not primed with dopa-BBA,
and coated with TFE-co-VAc nanomechanical testing was not possible
due to the poor quality of the coating.
[0327] These results demonstrate the H-abstraction capability of
the dopa-BBA primer layer improved the coating consistency of the
sprayed topcoat solution, improved the adhesive strength of the
topcoat layer, and generated a homogeneous coating with little
deviation in adhesive strength across the stent surface area.
[0328] All references referred to in this application, including
patent and patent applications, are incorporated herein by
reference to the fullest extent possible.
[0329] Throughout the specification and the claims which follow,
unless the context requires otherwise, the word `comprise`, and
variations such as `comprises` and `comprising`, will be understood
to imply the inclusion of a stated integer, step, group of integers
or group of steps but not to the exclusion of any other integer,
step, group of integers or group of steps.
* * * * *