U.S. patent number RE39,438 [Application Number 10/679,965] was granted by the patent office on 2006-12-19 for thromboresistant coated medical device.
This patent grant is currently assigned to Medtronic Vascular, Inc.. Invention is credited to Chirag B Shah, Laurel L Wolfgang.
United States Patent |
RE39,438 |
Shah , et al. |
December 19, 2006 |
Thromboresistant coated medical device
Abstract
Coatings are provided in which biopolymers may be covalently
linked to a substrate. Such biopolymers include those that impart
thromboresistance and/or biocompatibility to the substrate, which
may be a medical device. Coatings disclosed herein include those
that permit coating of a medical device in a single layer,
including coatings that permit applying the single layer without a
primer. Suitable biopolymers include heparin complexes, and linkage
may be provided by a silane having isocyanate functionality.
Inventors: |
Shah; Chirag B (North
Attleboro, MA), Wolfgang; Laurel L (Townsend, MA) |
Assignee: |
Medtronic Vascular, Inc. (Santa
Rosa, CA)
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Family
ID: |
22482124 |
Appl.
No.: |
10/679,965 |
Filed: |
October 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
09138464 |
Aug 21, 1998 |
06248127 |
Jun 19, 2001 |
|
|
Current U.S.
Class: |
623/1.15;
428/34.7; 428/425.6; 428/425.8; 428/36.91; 428/35.7; 428/35.2;
428/442; 428/447; 428/450; 428/451; 428/458; 428/463; 428/480;
428/522; 427/2.1 |
Current CPC
Class: |
A61L
29/085 (20130101); A61L 31/10 (20130101); A61L
33/0029 (20130101); A61L 29/085 (20130101); C08L
83/04 (20130101); A61L 29/085 (20130101); C08L
83/00 (20130101); A61L 29/085 (20130101); C08L
83/08 (20130101); A61L 31/10 (20130101); C08L
83/04 (20130101); A61L 31/10 (20130101); C08L
83/00 (20130101); A61L 31/10 (20130101); C08L
83/08 (20130101); A61L 33/0029 (20130101); C08L
83/00 (20130101); A61L 33/0029 (20130101); C08L
83/08 (20130101); A61L 33/0029 (20130101); C08L
83/04 (20130101); Y10T 428/31667 (20150401); Y10T
428/31681 (20150401); Y10T 428/31699 (20150401); Y10T
428/31551 (20150401); Y10T 428/31601 (20150401); Y10T
428/31935 (20150401); Y10T 428/31786 (20150401); Y10T
428/31663 (20150401); Y10T 428/31649 (20150401); Y10T
428/31605 (20150401); Y10T 428/1334 (20150115); Y10T
428/1393 (20150115); Y10T 428/1352 (20150115); Y10T
428/1321 (20150115); Y10T 428/1317 (20150115) |
Current International
Class: |
A61F
2/06 (20060101) |
Field of
Search: |
;427/2.1
;428/34.7,35.2,35.7,36.9,425.6,425.8,442,447,450,451,458,463,480,522
;623/1.15 |
References Cited
[Referenced By]
U.S. Patent Documents
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EP |
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WO |
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WO |
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Other References
Scott et al, Concise Encyclopedia Biochemistry and Molecular
Biology, Waler de Gruyter Berlin. New York 1997, Third Edition, p.
287. cited by examiner.
|
Primary Examiner: Nakarani; D. S.
Claims
We claim:
1. A medical device having a coating comprising the product of the
reaction of: a silane having at least one functional group selected
from the group consisting of an isocyanate, an .[.isothiocvanate.].
.Iadd.isothiocyanate.Iaddend., .[.an ester, an anhydride, an acyl
halide, an alkyl halide, an epoxide and an aziridine.]. .Iadd.an
anhydride, an acyl halide and an aziridine.Iaddend., and a
biopolymer.Iadd., wherein the coating adheres to a surface of the
medical device by covalent attachment of said silane to said
surface.Iaddend..
2. The medical device of claim 1, wherein the weight ratio of said
silane to said biopolymer is from about 1:4 to about 2:1.
3. The medical device of claim 2, wherein said weight ratio is 1:4,
1:1 or 2:1.
4. The medical device of claim 2, wherein said biopolymer is
heparin or a complex thereof.
5. The medical device of claim 4, wherein said biopolymer is
selected from the group consisting of
heparin-tridodecylmethylammonium chloride, heparin-benzalkonium
chloride, heparin stearalkonium chloride,
heparin-poly-N-vinyl-pyrrolidone, heparin lecithin,
heparin-didodecyldimethyl ammonium bromide, heparin-pyridinium
chloride and heparin-synthetic glycolipid.
6. The medical device of claim 2, further comprising at least one
additive selected from the group consisting of wetting agents,
surface active agents and film forming agents.
7. The medical device of claim 6, wherein said film-forming agent
is selected from the group consisting of cellulose esters,
polydialkyl siloxanes, polyurethanes, acrylic polymers, elastomers,
biodegradable polymers, polylactic acid, polyglycolic acid,
copolymers of polylactic acids, copolymers of polyglycolic acid and
poly(e-caprolactone).
8. The medical device of claim 1, wherein said device is selected
from the group consisting of stents, catheters, prostheses, tubing
and blood storage vessels.
9. The medical device of claim 8, wherein said device is made of at
least one material selected from stainless steel, nitinol,
tantalum, glass, ceramic, nickel, titanium or aluminum.
10. The medical device according to claim 1, wherein said at least
one functional group is an isocyanate.
11. The medical device according to claim 10, wherein said
biopolymer is heparin or a complex thereof.
12. The medical device according to claim 11, wherein said
biopolymer is selected from the group consisting of
heparin-tridodecylmethylammonium chloride, heparin-benzalkonium
chloride, heparin stearalkonium chloride,
heparin-poly-N-vinyl-pyrrolidone, heparin lecithin,
heparin-didodecyldimethyl ammonium bromide, heparin-pyridinium
chloride and heparin-synthetic glycolipid.
13. The method device according to claim 12, wherein said
biopolymer is heparin-tridodecylmethylammonium chloride.
.Iadd.14. A medical device having a coating consisting essentially
of the product of the reaction of: a silane having at least one
functional group selected from the group consisting of an
isocyanate, an isothiocyanate, an anhydride, an acyl halide and an
aziridine; and a biopolymer. .Iaddend.
.Iadd.15. The medical device of claim 14, wherein the weight ratio
of said silane to said biopolymer is from about 1:4 to about 2:1.
.Iaddend.
.Iadd.16. The medical device of claim 15, wherein said weight ratio
is 1:4, 1:1 or 2:1. .Iaddend.
.Iadd.17. The medical device of claim 15, wherein said biopolymer
is heparin or a complex thereof. .Iaddend.
.Iadd.18. The medical device of claim 17, wherein said biopolymer
is selected from the group consisting of
heparin-tridodecylmethylammonium chloride, heparin-benzalkonium
chloride, heparin stearalkonium chloride,
heparin-poly-N-vinyl-pyrrolidone, heparin lecithin,
heparin-didodecyldimethyl ammonium bromide, heparin-pyridinium
chloride and heparin-synthetic glycolipid. .Iaddend.
.Iadd.19. The medical device of claim 15, further comprising at
least one additive selected from the group consisting of wetting
agents, surface active agents and film forming agents.
.Iaddend.
.Iadd.20. The medical device of claim 14, wherein said device is
selected from the group consisting of stents, catheters,
prostheses, tubing and blood storage vessels. .Iaddend.
.Iadd.21. The medical device of claim 20, wherein said device is
made of at least one material selected from stainless steel,
nitinol, tantalum, glass, ceramic, nickel, titanium or aluminum.
.Iaddend.
.Iadd.22. The medical device of claim 19, wherein said film-forming
agent is selected from the group consisting of cellulose esters,
polydialkyl siloxanes, polyurethanes, acrylic polymers, elastomers,
biodegradable polymers, polylactic acid, polyglycolic acid,
copolymers of polylactic acid, copolymers of polyglycolic acid and
poly(e-caprolactone). .Iaddend.
.Iadd.23. The medical device according to claim 14, wherein said at
least one functional group is an isocyanate. .Iaddend.
.Iadd.24. The medical device according to claim 23, wherein said
biopolymer is heparin or a complex thereof. .Iaddend.
.Iadd.25. The medical device according to claim 24, wherein said
biopolymer is selected from the group consisting of
heparin-tridodecylmethylammonium chloride, heparin-benzalkonium
chloride, heparin stearalkonium chloride,
heparin-poly-N-vinyl-pyrrolidone, heparin lecithin,
heparin-didodecyldimethyl ammonium bromide, heparin-pyridinum
chloride and heparin-synthetic glycolipid. .Iaddend.
.Iadd.26. The medical device according to claim 25, wherein said
biopolymer is heparin-tridodecylmethylammonium chloride. .Iaddend.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application relates to the field of medical devices and more
particularly to the field of coatings for medical devices.
2. Description of Related Art
Arteriosclerosis is a condition that detrimentally affects many
individuals. Untreated, arteriosclerosis may lead to sever
consequences, including heart damage, heart attack and death. Known
treatments for arteriosclerosis have had limited success.
Transluminal balloon angioplasty, wherein a balloon is inserted via
a catheter into the artery of the patient and expanded, thereby
simultaneously expanding the partially closed artery to a more open
state, is a well-known treatment for arteriosclerosis, but
long-term benefits of balloon angioplasty are limited by the
problems of occlusion and restenosis, which result in re-closure of
the artery.
A variety of intravascular stents and prostheses have been
developed to support diseases arteries and thereby inhibit arterial
closure after angioplasty. In particular, expandable intraluminal
stents have been developed in which a catheter is used to implant a
stent into the artery of the patient in a minimally invasive
manner.
Like other foreign bodies placed into arteries, stents can result
in coagulation of thrombosis in the intravascular environment.
Thrombosis can inhibit blood flow through the stent, diminishing
its effectiveness, or can cause clotting, which can threaten the
life of the patient. Accordingly, methods of reducing thrombotic
activity have been sought to reduce the negative side effects
caused by certain stents.
A number of coatings have been developed for medical devices that
are intended to promote compatibility between a particular medical
device and the environment in which the medical device resides.
Some of these coatings, known as thromboresistant coatings, are
intended to reduce the thrombosis often associated with insertion
of a foreign object, such as a medical device, into the interior of
the body.
Heparin, or heparinic acid, arteven, or leparan, is a
glycosaminoglycan with well-known anticoagulant activity. Heparin
is biosynthesized and stored in mast cells of various animal
tissues, particularly the liver, lung and gut. Heparin is known to
have antithrombotic activity as a result of its ability to bind and
activate antithrobmin III; a plasma protein which inhibits several
enzymes in the coagulation cascade. It has been hoped that heparin
coatings, by inhibiting thrombogenesis, can improve the therapeutic
outcomes derived from intra-vascular medical devices, such as
stents.
However, known heparin coatings are subject to a number of defects,
including incompabitility with the organism and/or microscopic
features of the surface to be coated, excessive thickness,
difficulty in application, and insufficient durability. For
example, several known coatings are based upon simultaneous
coulombic interactions between heparin and
tri(dodecyl)methylammonium chloride, which is also referred to
herein as heparin-TDMAC, and hydrophobic interactions between the
quaternary ammonium ion of heparin-TDMAC and the surface of the
device. Due to the relative weaknesses of hydrophobic interactions,
such coatings typically leach away from the substrate to which they
are applied within a few hours; coatings of this type, therefore,
are not generally durable enough to provide beneficial therapeutic
results.
Other known coatings comprise silanes having a pendent amino or
vinyl functionality. In the fabrication of these coatings, a base
layer of silane is applied initially to the surface, followed by
the application to the base layer of a second layer comprising
antithrombogenic biomolecules, such as heparin. It is necessary
that the pendent groups of the base layer of silane be both
complementary and accessible to groups on heparin. In some such
coatings, a silane with terminal amino functionality is applied to
a substrate to form a first layer, followed by application of
heparin in solution to form the second layer. In certain examples
of this strategy, the amino functionality of the silane base layer
reacts with an aldehyde-containing heparin derivative to form a
Schiff base and thereby covalently attach the biomolecule to the
base layer. In another group of coatings of this general class, a
base layer comprising a silane with a vinyl functional group is
applied to a surface, followed by covalent attachment, via free
radical chemistry, of a heparin-containing derivative to the base
layer.
Some of the known coatings have been found lacking in
bioeffectiveness and stability. Modifications made in these
coatings utilize additional coatings of the polymeric matrices
comprising reactive functionalities. The multi-step process
required to fabricate the polymeric matrices necessary in these
approaches increases the thickness of the resulting coatings. Thick
coatings present a number of difficulties. First, thick coatings
increase the profile of the medical device in the intravascular
environment. A stent with a thick profile, for example, can reduce
blood flow, thereby undermining the therapeutic benefit of the
stent. A thick coating may also render the coating itself more
vulnerable to pitting, chipping, cracking, or peeling when the
stent is flexed, crimped, expanded, or subjected to intravascular
forces. Any of the foregoing results of excessively thick coatings
may reduce the antithrombogenic characteristics of the stent.
Moreover, the likelihood of pitting is hypothesized to be greater
in thick coatings, and pits in a coating may increase the
susceptibility to galvanic corrosion of the underlying surface.
Because their fabrication requires additional steps, coatings
comprising multiple layers may also be more difficult and expensive
to manufacture.
Accordingly, a need exists for a thromboresistant coating that is
thin, durable, and biocompatible, and that may be applied in a
single coating.
SUMMARY OF THE INVENTION
Coatings are provided herein in which biopolymers may be covalently
linked to a substrate. Such biopolymers include those that impart
thromboresistance and/or biocompatibility to the substrate, which
may be a medical device. Coatings disclosed herein include those
that permit coating of a medical device in a single layer,
including coatings that permit applying the single layer without a
primer. It should be understood that it may be advantageous in some
circumstances to apply double layers of the coatings, such as to
cover an area of a medical device that is used to hold the device
while a first layer is applied. Thus, single, double and multiple
layers of coatings are encompassed by the coatings disclosed
herein.
The coatings disclosed herein include those that use an adduct of
heparin molecules to provide thromboresistance. The heparin
molecules may comprise heparin-tri(dodecyl) methylammonium chloride
complex. Uses of these term "heparin" herein should be understood
to include heparin, as well as any other heparin complex, including
heparin-tri (dodecyl)methylammonium chloride complex.
The coatings described herein further include those that use a
silane to covalently link a biopolymer to a substrate. The coatings
include those derived from silanes comprising isocyanate
functionality.
The disclosed coatings include those that can be applied without a
base or primer layer.
Coatings are also included that provide a thin and durable coating
wherein the thickness of said coating can be controlled by
application of single or multiple layers.
Coatings are provided wherein thromboresistance activity can be
modified by choice of appropriate amounts of heparin-TDMAC complex
and silane.
Thin, durable coatings are provided having controllable
bioactivity.
Single of multi-layer, coatings disclosed herein are designed to
impart thromboresistance and/or biocompatibility to a medical
device. In one embodiment, the coating provides for covalent
linking of heparin to the surface of the medical device.
One coating formulation of the present invention initially consists
of heparin-TDMAC complex, organic solvent and silane. Wetting
agents may be added to this formulation. A silane is chosen that
has an organic chain between isocyanate and silane functionalities.
The isocyanate functionality reacts with an amino or hydroxyl group
on the heparin molecule. After the reaction, the formulation
contains covalent adducts of heparin and silane, in addition to
organic solvent and other additives. Unreacted silane or
heparin-TDMAC complex may be present in the formulation, depending
on the relative amounts of the reagents utilized.
Once the coating formulation is applied to a device, the silane end
group of the adduct mentioned above adheres to the substrate
surface, and a network, or film, containing heparin-TDMAC complexes
is related on the surface of a substrate. Heparin molecules is the
heparin-TDMAC complex are known to have anticoagulant properties.
When exposed to blood, heparin molecules inactivate certain
coagulation factors, thus preventing thrombus formation.
The direct adherence of the silane end group to the substrate means
that the coating may be applied to a wide range of medical device
materials without the use of a base/primer layer. The covalent bond
between the surface and the solution of the silane comprising the
heparin-TDMAC complex provides superior durability compared to
known coatings.
The coating can be applied by dip coating, spray coating, painting
or wiping. Dip coating is a preferred mode.
The coating can be thin and durable. The coating thickness can be
controlled in a number of ways, e.g., by the application of single
or multiple layers. Since the coating process described herein may
be a one-step process, coating thickness is not increased as a
result of the need to apply multiple layers, as in certain known
coating methods.
The bioeffectiveness of the coatings can be controlled by selecting
appropriate amounts of reactants. In particular, the
thromboresistance activity of the coating can be controlled by
modifying the amount of heparin-TDMAC complex in the coating.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Single or multi-layer coatings are provided herein that are
designed to impart thromboresistance and/or biocompatibility to a
medical device. In an embodiment of the invention, the coating
provides for the covalent linking of heparin molecules to a
substrate.
A heparin molecule is understood to contain a specific
art-recognized pentasaccharide unit that displays antithrombogenic
qualities. Covalent linkage of a heparin molecule to a surface is
understood to affect at least one, but not all, of the hydroxyl and
amino moieties comprised by that molecule; the covalently linked
heparin, therefore, presents a thromboresistant surface to the
environment surrounding the coated substrate. Different methods and
formulations for covalently linking heparin to the surface may
affect different sites on the heparin molecules, so that different
formulations will provide different levels of
anti-thrombogenicity.
One coating formulation of the present invention initially consists
of heparin-TDMAC complex, organic solvent and a silane. Other
biopolymers may be used in place of or in addition to heparin-TDMAC
complex, and such biopolymers may be covalently linked to a
substrate according to the present invention. Such biopolymers may
be those that provide thromboresistance, or those that have other
desired bioactivity.
The silane provided may have functionality capable of reacting with
a nucleophilic group, e.g., a hydroxyl or amino group. In
particular, the silane may comprise isocyanate, isothiocyanate,
ester, anhydride, acyl halide, alkyl halide, epoxide, or aziridine
functionality. In certain embodiments described herein, the silane
comprises isocyanate functionality.
The silane comprising isocyanate functionality may be linked
covalently to any biopolymer that provides anti-thrombogenicity.
The selected biopolymer may be selected from a group of heparin
complexes, including heparin-tridodecylmethylammonium chloride,
heparin-benzalkonium chloride, heparin-steralkonium chloride,
heparin-poly-N-vinyl-pyrrolidone, heparin-lecithin,
heparin-didodecyldimethyl ammonium bromide, heparin-pyridinium
chloride, and heparin-synthetic glycolipid complexes. The selected
biopolymer may also be another biopolymer that has hydroxyl or
amine functional groups that can react with the isocyanate
functionality of the silane.
The selected biopolymer is preferably capable of dissolving in an
organic solvent, as opposed to biopolymers that dissolve only in
water. Solubility in organic solvents confers a number of
advantages, e.g., elimination of water-mediated decomposition of
the isocyanate-containing silane. In one preferred embodiment, the
selected biopolymer is heparin-tri(dodecyl)methylammonium chloride
complex.
Wetting agents and other additives may be added to the coatings
described herein, to improve the adherence to the substrate, to
improve the ease of adding the coatings to a substrate, or for
other purposes. A variety of organic solvents may be used,
including tetrahydrofuran (THF). Additives may include surface
active agents, such as Triton.
The selected silanes may have an organic chain between the
isocyanate functionality, which covalently links to the heparin
molecule, and an end group that is capable of linking to a
substrate surface. The end group may link to pendant oxide groups
on the substrate surface; in some cases, the pendant oxide groups
may be obtained by oxidation of the substrate.
The bioactivity, including thromboresistance, of the disclosed
coatings may be selectively modified by controlling the amounts of
heparin-indodecylmethylammonium chloride complex, silane comprising
isocyanate functionality, and organic solvent, as well as other
constituents, to provide the desired thromboresistance. In an
embodiment of the coatings, the concentration of the silane in the
formulation is between about one-half percent and about four
percent. In an embodiment, the concentration of
heparin-tridodecylmethylammonium chloride in the formulation is
between about one-tenth percent and about four percent. One
preferred coating is a solution with a formulation of silane of
about five-tenths percent and a formulation of the
heparin-tridodecylmethyl-ammonium chloride complex of about
two-tenths percent. In one such preferred solution, the organic
solvent is tetrahydrofuran.
Heparin molecules, including those in heparin-TDMAC, complex are
known to have anticoagulant properties. When exposed to blood,
structural elements of heparin molecules inactive certain
coagulation factors, thus preventing thrombus formation.
The coatings described herein may be applied in a single layer. The
layer can be formed by reacting silane having isocyanate
functionality within a heparin in an organic solvent to form a
silane-heparin complex, which can be applied directly to a
substrate, such as a metal substrate, in a single-layer coating
that can be applied without a primer. The single layer can thus be
made sufficiently thin to minimize the problems of peeling,
cracking, and other problems that characterize some thicker
coatings that require multiple layers, primers, or polymeric
matrices for binding to the solution. Thus, the layers may perform
better under the mechanical crimping or expansion of a medical
device, such as a stent, to which they are applied, and may perform
better in the intravascular environment.
The silane end groups of the monomer that yield the coatings react
with oxides or hydroxyl groups on the surface of stainless steel.
The stainless steel surface may be oxidized or cleaned and
pre-treated, such as with sodium hydroxide, to increase the number
of appropriate sites for linking the silane end groups.
To improve hydrolytic stability, non-functional silanes can be
added to the formulations disclosed herein. Other silanes may be
used to link to substrates, such as trihalosilanes, and silanes
having methoxy and ethoxy groups. Silanes having triethoxy,
trialkoxy, trichloro, and other groups may be provided to yield the
covalent linkages present in the coatings disclosed herein. The
non-functional silanes may be selected from the group consisting of
chain alkyltrialkoxysilanes and phenyltrialkoxysilanes.
In an embodiment, the amount of functional silane is preferably
selected to provide substantially complex coverage of the substrate
surface; that is, it may be desirable to have the single layer
cover all of the surface that would otherwise be exposed to the
environment in which the substrate will be placed.
The adherence of the silane end group to the substrate means that
the coating may be applied to a wide range of medical device
materials without the use of base primer layer. The covalent bond
between the heparin-TDMAC complex and the substrate provides a thin
and durable coating. The coating's thickness can be controlled,
e.g. by choice of the length of the chain connecting the silane and
isocyanate functionalities.
The bioeffectiveness and/or bioactivity of the thromboresistant
coating can be controlled by selecting appropriate amounts of
reactants. In particular, the thromboresistance activity of the
coating can be modified by modifying the amounts of heparin-TDMAC
complex and silane in the coating.
Single layers have further advantages in that problems may arise in
the extra steps required for the deposition of multiple layers. For
example, dust or other particulates may appear between coatings in
two-step processes. Also, application of a second layer may tend to
reduce reactivity of the first layer in an unpredictable way.
Coatings of the present invention may be applied to medical devices
that are placed in the body of a human, or that remain outside the
body. Coated medical devices that are placed in the human body may
include stents, catheters, prostheses and other devices. Coated
medical devices that remain outside the human body may include
tubing for the transport of blood and vessels for the storage of
blood. Substrates of medical devices on which the coatings
described herein may be applied can include a wide variety of
materials, including stainless steel, nitinol, tantalum, glass,
ceramics, nickel, titanium, aluminum and other materials suitable
for manufacturer of a medical device.
The coatings disclosed herein may further include a film-forming
agent for the coating. The film-forming agents could slow any
leaching of the biopolymers from the coating. The film
forming-agent could be added in a second layer, or dissolved
simultaneously with the silane and the biopolymer. Appropriate
film-forming agents could include cellulose esters, polydialkyl
siloxanes, polyurethanes, acrylic polymers or elastomers, as well
as biodegradable polymers such as polylactic acid (PLA),
polyglycolic acid (PGA), copolymers of PLA and PGA, known as PLGA,
poly(e-caprolactone), and the like.
To create coatings of the present invention, the silanes and
heparin complexes are dissolved in a solvent, which may be an
organic solvent. The solution preferably should be substantially
anhydrous, because water tends to react with isocyanate groups of
the silane molecule. The water may be added after mixing the
silane-isocyanate with heparin. In certain embodiments, the silane
and heparin are combined in solution, the resulting solution is
aged for about one day, the pH is adjusted with a weak acid, and
then water is added to hydrolyze silane. The pH of the solution may
be adjusted with aqueous acetic acid. Instead of adding water, it
is possible to hydrolyze the silane groups by exposure to moist
atmosphere conditions. It is desirable to mix the silane and
heparin complex in a manner so as to include a slight excess of
heparin molecules, so that all of the isocyanate is reacted,
preventing adverse reactions between the isocyanate and any water.
Moreover, it is desirable to have a single heparin react with each
silane isocyanate functional group; this goal is most easily
accomplished by starting with an excess of heparin.
Based on experimental results, it was found that, in certain
embodiments, solution of about two-lengths percent heparin complex
and about five-tenths percent silane provided effective coatings.
However, coatings in a fairly wide range may be effective. Thus,
coatings are likely to have some effectiveness in cases in which
heparin complex is present in concentrations ranging from about
one-length of a percent to about twenty percent. Coatings with
heparin in concentrations of less than ten percent may be
preferable in some formulations. Coatings with heparin in
concentrations of less than five percent may be preferable in other
formulations. Coatings may be expected to be effective in
formulations in which silane is present in a wider range of
concentrations as well, including concentrations ranging from about
one-tenth of a percent silane to about twenty percent silane.
The thromboresistant characteristics of heparin coatings can be
assessed qualitatively and quantitatively, so that methods can be
developed that provide uniform coating with a desired amount of
bioactivity. Successfully heparinized surfaces give a purple stain
when exposed to toluidine blue. After coating, the surface is
exposed to a saline solution for a number of days or weeks, and
thromboresistance activity is measured as a function of time.
Stents and coupons coated as disclosed herein were shown
experimentally to display long-lived thromboresistant properties;
bioactivity persisted for periods on the order of months, and it
will probably endure much longer.
The heparin activity of a sample may be quantified based on its
ability to inactive thrombin. To quantify heparin activity in
experimental assays, heparin may be first mixed with human
antithrombin III, which binds to create a complex. The
heparin-antithrombin III complex can then be mixed with thrombin to
produce a ternary complex comprising heparin, thrombin, and
antithrombin. The heparin then departs this complex and is free to
react again with available antithrombin and thrombin to create
additional thrombin-antithrombin complexes. Thus, heparin acts as a
catalyst for the antithrombin-mediated deactivation of thrombin.
The reaction of the active thrombin still left in the solution with
a substrate produces a proportional amount of p-nitro aniline
exhibiting color. Thus, an assay may be conducted for a
spectrophotometric analysis of color, to determine the amount of
thrombin left in solution. The more thrombin left in solution, the
lower the bioactivity of the heparin A low level of thrombin in
solution indicates a high degree of catalysis of the
thrombin-antithrombin reaction; which indicates a high level of
thromboresistance provided by the heparin. A baseline comparison
for the assay is the very slow reaction of thrombin-antithrombin in
the absence of heparin. The result of the assay can be quantified
using spectrophotometry. The assay mimics the reaction that occur
in the human bloodstream, where thrombin and antithrombin circulate
at all times. The reaction between antithrombin and thrombin in the
body, which is catalyzed by the heparin of the coatings of the
present invention helps suppress the coagulation that results from
thrombogenesis on a medical device.
Various methods of making coatings of the present invention are
possible, and examples of such methods and certain resulting
coatings are as follows. Such methods and coatings are disclosed by
way of example, and are not intended to be limiting, as other
examples may be readily envisioned by one or ordinary skill in the
art. The following examples include methods of providing coatings
of the present invention in a single layer, without the need for a
primer layer as well as methods of controlling the bioactivity of
the resulting coating. In some instances, experimental results are
provided showing sustained bioactivity for the particular
coating.
Coatings can be applied in a wide variety of conventional ways,
including painting, spraying, dipping vapor deposition, epitaxial
growth and other methods known to those of ordinary skill in the
art.
To test coatings disclosed herein, infrared scans were performed to
demonstrate changes in the isocyanate functionality, through
observation of the isocyanate peak (NCO, 2260 or 2270 cm-1) over
time. Isocyanatosiliane was formulated with different components,
including heparin-tridodecylmethylammonium chloride complex
(Heparin-TDMAC complex), tetrahydrofuran ("THF") and Triton (as
optional, surface active agent) in solution to determine whether
the intensity of the isocyanate peak changed over time. Table 1
shows the observation of the isocyanate functionality for different
solution constituents:
TABLE-US-00001 TABLE 1 Solution Observation 1) Silane + THF No
change in peak with time 2) Silane + THF + TDMAC No change in peak
with time 3) Silane + THF + Triton No change in peak with time 4)
Silane + THF + Heparin-TDMAC Peak disappears with time complex
depending on the concentration of silane and heparin-TDMAC
complex
The observation that the isocyanate peak disappears with time in
the solution that includes silane, THF and Heparin-TDMAC complex
suggests that a reaction occurs between functional groups on
heparin and the isocyanate group of silane.
In embodiments of the present invention, the coating formulations
contains the following constituents, which may vary in
concentrations in different embodiments: Heparin-TDMAC complex, an
organic solvent, such as THF, a silane, such as 3-isocyanatopropyl
triethoxysilane (OCN--(CH.sub.2).sub.3Si(OEt).sub.3), and Triton
(x-100). In a first embodiment, a solution of these constituents
was mixed and allowed to sit in order to permit a reaction to
occur. Allowing the solution to sit for one day allowed the
reaction to occur, but shorter reaction times may well be
effective. Before coating the substrate with the solution, the pH
was adjusted. Solutions of the above constituents were adjusted to
a pH between 4.5 and 5.5 using a solution of acetic acid and water.
After adjusting, pH, it is desirable to wait for a period of time,
such as fifteen minutes, before applying the coating. Once the
coating was applied, it was dried in air and cured in an oven. In
particular, coatings of the above constituents were dried in air
for about twenty minutes and then cured in an oven at eight-five
degree Celsius for about one hour.
Coatings, derived from the above-described solutions, on coupons
and stents were tested in various ways. First, as a qualitative
test, coated coupons and stents were dipped in toluidine blue
solution and then were screened for the presence of a purple stain.
As mentioned above, the presence of a purple stain in this assay
indicates the presence of heparin in the sample being assayed.
Additionally, the intensity of the purple stain observed in this
assay is proportional to the amount of heparin in the sample.
Therefore, a comparison of the intensities of the purple stains
produced in this assay by a set of samples allows an assignment of
the relative amounts of heparin comprised by the coatings of those
samples.
As a quantitative test for heparin activity, a heparin activity
assay was conducted according to a conventional thrombin inhibition
assay techniques. The heparin assay permitted determination of the
ability of the heparin coating to deactivate thrombin and thus to
provide thromboresistance. The purpose of the protocol was to assay
for heparin activity based on thrombin inhibition. A number of
different reactions are understood to take place in order to
determine heparin activity. In the first reaction: Heparin+ATIII
(excess)-[Heparin*ATIII] Heparin reacts with Human Antithrombin III
("ATIII") to yield a Heparin-Antithrobmin III complex. In the
second reaction: [Heparin*ATIII]+Thrombin
(excess)-[Heparin*ATIH*Thrombin]+Thrombin the Heparin-Antithrombin
complex reacts with Thrombin to yield a
Heparin-Antithrombin-Thrombin complex. In the third reaction:
S2238+Thrombin--peptide--nitroaniline (measured at 405 nm) the
amount of the thrombin was measured. As a result, the size of the
p-nitroaniline peak measured at 405 nm is inversely proportional to
the amount of heparin present Exemplification
The invention now being generally described, it will be more
readily understood by reference to the following examples which are
included merely for purposes of illustration of certain aspects and
embodiments of the present invention, and are not intended to limit
the invention.
General Procedures
In the following examples, heparin activity on coated coupons or
stents was measured after exposing the coated object to a
continuous flow of saline at thirty-seven degrees Celsius for a
selected time period. Stainless steel coupons and stents were
cleaned before coating. The coupons or stents were cleaned with
several organic solvents, such as hexane and isopropanol, followed
by rinsing with distilled water. The cleaning procedure was carried
out in an ultrasonic bath for fifteen minutes. After this
procedure, the coupons or stents were placed in sodium hydroxide
solution (1.0 N) for fifteen minutes and then washed thoroughly
with distilled water. Samples were air dried before coating.
It should be noted that thrombin inhibition assay techniques are
notoriously subject to significant sample error; accordingly, it is
not unusual to obtain variable experimental results for a given
sample. The examples below identify results for multiple samples
under a variety of conditions and thus indicate in the aggregate
that the coatings described herein are likely to provide
therapeutic levels of thromboresistance. However, results from any
single formulation were found to vary somewhat depending on
particular sample conditions. In cases where more than one set of
data is provided for a given sample, the individual data sets
reflect measurements taken at distinct positions on that sample;
the data sets in these cases, therefore, do not necessarily reflect
a lack of precision in the measurements.
EXAMPLE 1
Stainless steel coupons were coated with a formulation of 1%
heparin-TDMAC complex, 2% silane and 97% THF. The coupons were
dipped once in the formulation with a dwell time of five seconds at
a coating speed of 10 in/min, to give a single layer of coating.
Results are set forth in Table 2.
TABLE-US-00002 TABLE 2 Activity, mU/cm.sup.2 Sample Unwashed 7 days
wash 97-080-90C <10 <10 97-080-90C <15 <10 97-080-90D
<15 <5 97-080-90D <15 <5
The coating showed toluidine blue stain before and after washing
with water. The coating showed heparin activity after one week of
exposure to saline.
EXAMPLE 2
Stainless steel coupons were dipped once, at coating speeds of 10
in/min and 42 in/min and for a dwell time of five seconds, and
resulting in single layer coatings of different thickness, in the
following formulations: 1) 7% heparin-TDMAC complex, 2% silane and
91% THF and a small amount of Triton; and 2) 2% heparin-TDMAC
complex, 2% silane and 96% THF and a small amount of Triton. Sample
pieces were cut from coupons and were either washed or not washed
before being measured under the indicated conditions after the
indicated amounts of time. Results are set forth in Table 3:
TABLE-US-00003 TABLE 3 Activity, mU/cm.sup.2 1 day 2 days 1 day 2
days 7 days Sample unwashed unwashed wash wash wash 97-100-9A
<50 <75 <15 <25 <25 97-100-9A <50 <75 <15
<25 <25 97-100-9B <50 <75 <25 <50 <50
97-100-9B <75 <75 <15 <50 <10
A toludine blue stain was present before and after washing, and the
coupons showed heparin activity after seven days of washing.
Combined with Example 1, the results showed that heparin activity
can be varied using different coating formulations and coating
processes.
EXAMPLE 3
Stainless steel coupons were dipped once, at speeds of 10 in/min
and 42 in/min, and for dwell times of five seconds, two minutes and
fifteen minutes, and resulting in coatings of different thickness,
in the following formulations: 1) 7% heparin-TDMAC complex, 2%
silane and 91% THF and a small amount of Triton; and 2) 2%
heparin-TDMAC complex, 2% silane and 96% THF and a small amount of
Triton. Results are shown in Table 4.
TABLE-US-00004 TABLE 4 Activity, mU/cm.sup.2 Sample 1 day unwashed
1 day wash 7 days wash 97-100-15A <150 <10 <5 97-100-15A
<100 <10 <10 97-100-15B <50 <10 <25 97-100-15B
<25 <1 <25 97-100-15C <75 <25 97-100-15C <100
<50 97-100-15D <150 <50 97-100-15D <150 <50
97-100-15E <150 <10 <10 97-100-15E <150 <25 <25
97-100-15F <150 <10 <25 97-100-15F <200 <25 <25
97-100-15G <150 <25 97-100-15G <150 <25 97-100-15H
<150 <50 97-100-15H <150 <50 97-100-15I <200 <100
<50 97-100-15I <200 <75 <75 97-100-15J <200 <100
97-100-15J <250 <100
Seven day results were for certain pieces measured at the one day
point and then placed back into a flusher for additional days of
washing. Toluidine blue stains were present before and after wash,
with shades differing with thickness. Heparin activity was present
after seven days of washing. In combinations with Examples 1 and 2,
this example demonstrated that heparin activity can be varied using
different coating formulation and coating processes.
EXAMPLE 4
Stainless steel coupons were dipped once, at speeds of 10 in/min
for dwell times of one-half, one, two, five, ten and fifteen
minutes, in the following formulation: 2% heparin-TDMAC complex, 2%
silane. 96% THF and a small amount of Triton. Certain coupons were
dipped into toluidine blue solution and rubbed under water. The
coupons were then redipped in toluidine blue and checked for the
presence of a stain. Results are shown in Table 5.
TABLE-US-00005 TABLE 5 Toluidine blue Toluidine blue stain before
rub stain after Sample Appearance test rub test 97-100-30A Good
coating, thin Uniform, light Uniform, light 97-100-30B Good
coating, thin Uniform, light Uniform, light 97-100-30C Good
coating, thin Uniform, light Uniform, light 97-100-30D Good
coating, thin Uniform, light Uniform, light 97-100-30E Good
coating, thin Uniform, light Uniform, light 97-100-30F Good
coating, thin Dark gritty stain Uniform, light, some peeling
A qualitative assessment of the effect of different solvents on
coating was also performed, by dipping a coated sample in solvent
for 60 seconds and then washing it with water and staining it with
toluidine blue. Results are shown in Table 6.
TABLE-US-00006 TABLE 6 Solvent Hot water Hot water (high (high
pressure pressure Sample IPA Toluene flow) flow) Acetone 97-100-30G
Good purple No stain Light stain Light stain Good stain stain
Heparin activity is displayed in Table 7.
TABLE-US-00007 TABLE 7 Activity, mU/cm.sup.2 Sample 1 day unwashed
1 days wash 97-100-30A <150 <25 97-100-30A <150 <25
97-100-30B <75 -- 97-100-30B <75 -- 97-100-30C <50 --
97-100-30C <50 -- 97-100-30D <50 -- 97-100-30D <50 --
97-100-30E <10 -- 97-100-30E <25 -- 97-100-30F <10 --
97-100-30F <25 -- 97-100-30G <25 <25 97-100-30G <25
<25
This example indicated that coating thickness may be dependent on
dwell time, that rubbing does not remove the coating as indicated
by stains after rubbing, that washing with various solvents has a
different effect on coating durability, and that heparin activity
was present after washing. The example provided further evidence
that heparin activity can be varied using different coating
processes.
EXAMPLE 5
Stainless steel coupons were dipped once, at speeds of 10 in/min,
and for dwell times of two and fifteen minutes, in the following
formulations: 1) 2% heparin-TDMAC complex, 4% silane and 94% THF
and a small amount of Triton; 2) 2% heparin-TDMAC complex, 8%
silane and 90% THF and a small amount of Triton; 3) 4%
heparin-TDMAC complex, 4% silane and 92% THF and a small amount of
Triton; and 4) Diluted 4% heparin-TDMAC complex, 4% silane and 92%
THF and a small amount of Triton.
Coated coupons were dipped in toluidine blue solution and rubbed
with fingers under water, then redipped in toluidine blue and
checked for stains. Results are displayed in Table
TABLE-US-00008 TABLE 8 Toluidine blue Toluidine blue stain before
stain after Sample Appearance rub test rub test 97-100-36A (2 min)
Good coating Uniform stain Uniform 97-100-36A (15 min) Good coating
Uniform stain Uniform 97-100-36B (2 min) Good coating Uniform stain
Uniform 97-100-36B (15 min) Good coating Uniform stain Uniform
97-100-36C (2 min) Good coating Very thick, Uniform, gritty some
peeling 97-100-36C (15 min) Good coating Very thick, Uniform,
gritty some peeling 97-100-36D (2 min) Good coating Uniform stain
Uniform 97-100-36D (15 min) Good coating Uniform stain Uniform,
some peeling
Heparin activity for this example is displayed in Table 9.
TABLE-US-00009 TABLE 9 Coating Activity, mU/cm.sup.2 (%/% 30 87
heptdmac/ 1 day 30 days 1 day days days Sample silane) unwashed
unwashed wash wash wash 97-100-36A 2.0/4.0 <150, <50 <25,
<5 <1, (2 min dwell) <125 <25 <1 97-100-36B 4.0/8.0
<25, <25 <25, <5 <1, (2 min) <25 <25 <1
97-100-36C 4.0/4.0 <175, <150 <50, <5 <1, (2 min)
<150 <25 <1 97-100-36C Diluted, <50, <150 <25,
<5 0, (2 min) 4.0/4.0 <100 <25 <1
This example demonstrated that for thin coatings thickness is not
strongly dependent on dwell time. Also, rubbing does not remove the
coating, as indicated by stains after rubbing. Long term durability
of the coating is evident from heparin activity results. Again,
heparin activity can be varied using different coating formulation
and processes.
EXAMPLE 6
Stainless steel coupons were dipped once, at speeds of 10 in/min
and for a dwell time of two minutes, in the following formulation:
2% heparin-TDMAC complex, 2% silane and 96% THF and a small amount
of Triton. The coupons were then either left unsterilized, or
sterilized with ethylene oxide or gamma radiation,
Results for non-sterile coupons are in Table 10.
TABLE-US-00010 TABLE 10 Coating Activity, mU/cm.sup.2 (%/% 7 28
heptdmac/ unwashed Unwashed days days Sample silane) Dip 7 days 28
days wash wash 97-100-66A 2.0/2.0 Single <125, >10, <10,
<2, <100 >12 <10 <1 97-100-66E 2.0/2.0 Single
<100, >10, <10, <1, <125 >16 <10 0
Results for ethylene oxide sterile coupons are in Table 11.
TABLE-US-00011 TABLE 11 Coating (%/% Activity, mU/cm.sup.2
heptdmac/ 3 day 14 days 14 Sample silane) Dip unwashed unwashed 1
day days 97-100-66A 2.0/2.0 Single >12 >16, >16 <15
<2, <2 97-100-66E 2.0/2.0 Single >12 >16, >16 <10
<3, <2
Results for gamma radiation sterilized coupons are in Table 12.
TABLE-US-00012 TABLE 12 Coating (%/% Activity, mU/cm.sup.2
heptdmac/ 1 day 14 days 20 days 1 day 14 days 20 Sample silane) Dip
unwashed unwashed unwashed wash wash days 97-100-66A 2.0/2.0 Single
<200, >16 >16 <20, <1, <1, <200 <20 <1
<2 97-100-66E 2.0/2.0 Single <200, >16 >16 0, <2,
<2, <200 0 <2 <2
The resulting coatings were thin, with long term durability as
evident by heparin activity results. Sterilization did not appear
to affect coating properties, regardless of the sterilization
mode.
EXAMPLE 7
Stainless steel coupons were dipped once, dipped twice, or dipped,
washed, and then dipped again, at coating speeds of 10 in/min and
for dwell times of two minutes, in the following formulations: 1)
0.5% heparin-TDMAC complex, 0.5% silane, 99% THF & small
amounts of Triton, 2) 0.5% heparin-TDMAC complex, 2.0% silane,
97.5% THF & small amount of Triton; 3) 2.0% heparin-TDMAC
complex, 0.5% silane, 97.5% THF & small amount of Triton; and
4) 2.0% heparin-TDMAC complex, 2.0% silane, 96% THF & small
amount of Triton.
Heparin activity is shown in Table 13.
TABLE-US-00013 TABLE 13 Activity, mU/cm.sup.2 Coating (%/% 12 days
18 days 12 day 18 day 26 day 72 day Sample heptdmac/silane) Dip
unwashed unwashed wash wash wash wash 97-100-69A 0.5/0.5 Single
>10 <175 0 <5 -- 0 97-100-69B 0.5/0.5 Double >10
<150 <2 <2 -- <1 97-100-69C 0.5/0.5 Dip/wash/Dip >10
<125 <2 <2 <1 <1 97-100-69D 0.5/2.0 Single <10
<25 <1 <5 -- <1 97-100-69E 0.5/2.0 Double <5 <5
<1 <5 -- <1 97-100-69F 0.5/2.0 Dip/wash/Dip <2 <5
<2 <5 <2 <1 97-100-69G 2.0/0.5 Single -- <15 --
<5 -- <1, <1 97-100-69H 2.0/0.5 Double -- <5 -- <5
-- <1, <1 97-100-69I 2.0/0.5 Dip/wash/Dip -- <2 -- <5
<2, <2 0, <1 97-100-69J 2.0/2.0 Single -- <150 -- <5
-- <1, <1 97-100-69K 2.0/2.0 Double -- <200 -- <5 --
<1, <1 97-100-69K 2.0/2.0 Dip/wash/Dip -- <250 -- <5
<3, <2 <1, <1
The resulting thin coatings demonstrated heparin activity,
including light strains before and after rubbing. The long term
durability of the coatings were evident through heparin activity
results. Coating properties were variable according to different
coating methods.
EXAMPLE 8
Stainless steel coupons were dipped twice, or were dipped, washed
then dipped again, at speeds of 10 in/min and for dwell times of
two minutes, in the following formulations; 1) 0.5% heparin-TDMAC
complex, 0.,5% silane, 99% THF; and 2) 0.5% heparin-TDMAC complex,
2.0% silane, 97.5% THF. The pH of the coatings was adjusted using
acetic acid.
Heparin activity is shown in Table 14.
TABLE-US-00014 TABLE 14 Coating (%/% Activity, mU/cm.sup.2
heptdmac/ 1 day Sample silane) Dip unwashed 1 day 43 days
97-100-93A 0.5/0.5 Double <75 <2 <2, <1 97-100-93B
0.5/0.5 Dip/wash/Dip <50 <3 <1, <1 97-100-93C 0.5/2.0
Double <50 <2 <2, <2 97-100-93D 0.5/2.0 Dip/wash/Dip
<1 <1 <2, <2
The resulting thin coatings demonstrated heparin activity including
light stains before and after rubbing. The long term durability of
the coatings were evident through heparin activity results. Coating
properties were variable according to different coating
methods.
EXAMPLE 9
Stainless steel coupons and stainless steel stents were dipped
twice, or were dipped, washed with saline and distilled water, and
dipped again, at coating speeds of 10 in/min and for dwell times of
two minutes. Coating pH was adjusted formulations were prepared: 1)
0.5% heparin-TDMAC complex, 0.5% silane, 99% THF; and 2) 0.5%
heparin-TDMAC complex, 2.0% silane, 97.5% THF.
Heparin activity is shown in Table 15.
TABLE-US-00015 TABLE 15 Activity, mU/cm.sup.2 1 11 1 11 25 43
Coating (%/% day days day days days days Sample heptdmac/silane)
Dip unwashed unwashed washed wash wash wash 97-100-92A 0.5/0.5
Double <25 <25, <25 <2 <1, <1 <1, <1, --
<5, <2, <2, <2 97-100-92B 0.5/0.5 Dip/wash/ <25
<10, <25 <2 <1, <1 <2, <2, -- Dip <2,
<2, <1, <2 97-100-92D 0.5/2.0 Double <10 <5 --
<5, <2 <1, <2 97-100-92E 0.5/2.0 Dip/wash/ <25 <2
-- <2, <2 <1, Dip <1
Persistence of heparin activity after an increasing number of days
suggests that most unattached heparin washes away immediately, but
that attached heparin does not easily wash away even after
prolonged exposure.
Activity on stents is disclosed in Table 16.
TABLE-US-00016 TABLE 16 Activity, mU/cm.sup.2 Coating (%/% 1 day
Sample heptdmac/silane) Dip unwashed 1 day 97-100-92C 0.5/0.5
Dip/wash/Dip <125 <50 97-100-92F 0.5/2.0 Dip/wash/Dip <50
<10
The resulting thin coatings showed light stains before and after
rubbing. The coatings were durable as evident from heparin activity
results. Coating properties were variable depending on different
coating methods.
EXAMPLE 10
Stainless steel coupons and stainless steel stents were dipped,
washed with IPA and dipped again, at coating speeds of 10 in/min
and for a dwell time of two minutes, in the following formulations:
1) 0.1% heparin-TDMAC complex, 0.5% silane, 99.4% THF; and 2) 0.2%
heparin-TDMAC complex, 0.5% silane, 99.3% THF.
Heparin activity on coupons is shown in Table 17.
TABLE-US-00017 TABLE 17 Coating (%/% Activity, mU/cm.sup.2
heptadmac/ 2 days 2 days 34 days Sample silane) Dip unwashed wash
wash 97-101-25A, 0.1/0.5 Double <25 <1 <2 Red 97-101-25A,
0.1/0.5 Double <25 <1 <2 Red 97-101-25B, 0.1/0.5
Dip/wash/dip <75 0 <2 green 97-101-25B, 0.1/0.5 Dip/wash/dip
<50 0 <2 green 97-101-25A, 0.2/0.5 Double <50 <1 <5
yellow 97-101-25A, 0.2/0.5 Double <25 <1 <5 yellow
97-101-25B, 0.2/0.5 Dip/wash/dip <50 <1 <2 brown
97-101-25B, 0.2/0.5 Dip/wash/dip <25 <1 <2 brown
Heparin activity on stents is shown in Table 18
TABLE-US-00018 TABLE 18 Coating (%/% Activity, mU/cm.sup.2
heptdmac/ 2 days 2 days 16 days Sample silane) Dip unwashed wash
wash 97-101-25A, 0.1/0.5 Double <225 <5 <2 Red 97-101-25A,
0.1/0.5 Double <225 0 <3 Red 97-101-25B, 0.1/0.5 Dip/wash/dip
<125 <1 <2 green 97-101-25B, 0.1/0.5 Dip/wash/dip <100
0 <5 green 97-101-25C, 0.2/0.5 Double <200 <15 <3
yellow 97-101-25C, 0.2/0.5 Double <100 <5 <10 yellow
97-101-25D, 0.2/0.5 Dip/wash/dip <200 <5 <10 brown
97-101-25D, 0.2/0.5 Dip/wash/dip <225 <10 <5 brown
The resulting thin coatings showed light stains before and after
rubbing. The coatings were durable as evident from heparin activity
resins. Coating properties were variable depending on different
coating methods.
EXAMPLE 11
Stainless steel stents were dipped once, at coating speeds of 10
in/min for dwell times of five seconds and two minutes, in the
following formulations: 1) 4.0% heparin-TDMAC complex, 8.0% silane,
88% THF, small amount of Triton; 2) 4.0% heparin-TDMAC complex,
4.0% silane, 92% THF; small amount of Triton; and 3) 2.0%
heparin-TDMAC complex, 2.0% silane, 96% THF, small amount of
Triton.
Heparin activity is shown in Table 19.
TABLE-US-00019 TABLE 19 Coating (%/% Activity, mU/cm.sup.2 Sample
heptdmac/silane) Dip Unwashed 3/4 days 97-100-50A 4/8 Single
<175 <50 97-101-50B 4/4 Single <150 <125 97-100-54B 2/2
Single <225 <25 (4 days)
Again, coating properties varied using different coating
methods.
EXAMPLE 12
Stainless steel stents were dipped twice, at coating speeds of 10
in/min and at a dwell time of two minutes in the following
formulations: 1) 0.2% heparin-TDMAC complex, 0.5Silane; 2) 0.5%
heparin-TDMAC complex, 0.5% silane; 3) 0.5% heparin-TDMAC complex,
1.0% silane; 4) 1.0% heparin-TDMAC complex, 1.0% silane; and 5)
1.0% heparin-TDMAC complex, 2.0% silane. Stents were either left
unsterilized or were sterilized with gamma radiation.
Table 20 shows results for non-sterile stents.
TABLE-US-00020 TABLE 20 Coating %/% Activity, mU/cm.sup.2 Sample
heptdmac/silane Dip 4 days unwashed 4 days 97-101-86A 0.2/0.5
Double <100 <1 97-101-86A 0.2/0.5 Double <125 <1
97-101-86B 1.0/2.0 Double <200 <10 97-101-86B 1.0/2.0 Double
<225 <5 97-101-86C 1.0/1.0 Double <225 <5 97-101-86C
1.0/1.0 Double <225 <5 97-101-86D 0.5/1.0 Double <200
<5 97-101-86D 0.5/1.0 Double <225 <5 97-101-86E 0.5/0.5
Double <225 <5 97-101-86E 0.5/0.5 Double <200 <5
97-101-86F 0.5/1.0 Sutton Double <125 <1 97-101-86F 0.5/1.0
Sutton Double <125 <5
Table 21 shows activity for sterile stents.
TABLE-US-00021 TABLE 21 Coating %/% Activity, mU/cm.sup.2 Sample
heptdmac/silane Dip 4 days unwashed 4 days 97-101-86A 0.2/0.5
Double >200 <1 97-101-86A 0.2/0.5 Double >200 <5
97-101-86B 1.0/2.0 Double >200 <10 97-101-86B 1.0/2.0 Double
>200 <5 97-101-86C 1.0/1.0 Double >200 <10 97-101-86C
1.0/1.0 Double >200 <10 97-101-86D 0.5/1.0 Double >200
<5 97-101-86D 0.5/1.0 Double >200 <5 97-101-86E 0.5/0.5
Double >200 <5 97-101-86E 0.5/0.5 Double >200 <5
97-101-86F 0.5/1.0 Sutton Double >200 <5 97-101-86F 0.5/1.0
Sutton Double >200 <5
Sterilization showed no effect on coating properties. The coatings
were durable on stents, as evident by heparin activity after
several days of washing.
EXAMPLE 13
Several coupons and stents were coated with 0.2% heparin-TDMAC
complex, 0.5% silane and 99.3% THF. These pieces were sterilized by
gamma radiation and sent to NAMSA for biocompatibility testing.
Three tests, Hemolysis, Cytotoxicity and Thromboresistance, were
conducted. The coating pass all three tests.
In addition to the foregoing examples, various other methods and
coatings may be envisioned in the spirit of the present disclosure.
For example, heparin might be covalently linked to a substrate with
a silane identified as capable of being soaked into a stainless
steel surface. The silane compound could have amino or epoxy
terminal groups. The silane could thus be used to link heparin
molecules to the substrate in a manner similar to the silane if
isocyanate functionality disclosed herein. Heparin could then be
prepared with an aldehyde positive group that mixed with an NH2
group to provide an end linkable to heparin without affecting its
activity. The procedure to make degraded heparin is well known to
those of ordinary skill in the art.
A coating system may also be provided in which heparin can be
covalently linked or can be incorporated into a matrix to obtain
variable rate of elution. A silicon fluid, such as Dow Corning MDS
4-4159 is used, with the active silicon being an amino functional
polydimethyl siloxane copolymer. The coating may be used to coat
stainless steel guide wires. This working can be utilized for
heparin covalent-bonding as described below.
First, a solution of heparin (deaminated) in water or other solvent
may be provided. A wire coated with a silicon fluid in a solvent
may be placed in the solution for some time, for example two hours.
The heparin has an aldehyde group that can link to the amino
functionality in the silicon copolymer. Other amino functionalized
silicon polymers, or copolymers, can be used to achieve covalent
bonding of heparin to the substrate.
Equivalents
While the invention has been disclosed in connection with the
preferred embodiments shown and described in detail, various
modifications and improvements thereon will become readily apparent
to those skilled in the art. Accordingly, the spirit and scope of
the present invention is to be limited only by the following
claims.
* * * * *