U.S. patent application number 13/088862 was filed with the patent office on 2011-08-11 for coated implantable medical device.
This patent application is currently assigned to Cook Incorporated. Invention is credited to Brian L. Bates, Neal E. Feamot, Thomas G. Kozma, Anthony O. Ragheb, William D. Voorhees, III.
Application Number | 20110196479 13/088862 |
Document ID | / |
Family ID | 32830707 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110196479 |
Kind Code |
A1 |
Bates; Brian L. ; et
al. |
August 11, 2011 |
COATED IMPLANTABLE MEDICAL DEVICE
Abstract
A coated implantable medical device includes a structure adapted
for introduction into the vascular system, esophagus, trachea,
colon, biliary tract, or urinary tract; at least one coating layer
posited on one surface of the structure; and at least one layer of
a bioactive material posited on at least a portion of the coating
layer. Preferably the structure is a stent graft.
Inventors: |
Bates; Brian L.;
(Bloomington, IN) ; Ragheb; Anthony O.; (West
Lafayette, IN) ; Feamot; Neal E.; (West Lafayette,
IN) ; Kozma; Thomas G.; (Alpharetta, GA) ;
Voorhees, III; William D.; (West Lafayette, IN) |
Assignee: |
Cook Incorporated
Bloomington
IN
MED Institute, Inc.
West Lafayette
IN
|
Family ID: |
32830707 |
Appl. No.: |
13/088862 |
Filed: |
April 18, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11810289 |
Jun 5, 2007 |
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13088862 |
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|
10218308 |
Aug 14, 2002 |
7611532 |
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11810289 |
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|
09027054 |
Feb 20, 1998 |
6774278 |
|
|
10218308 |
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|
08645646 |
May 16, 1996 |
6096070 |
|
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09027054 |
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08484532 |
Jun 7, 1995 |
5609629 |
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08645646 |
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60811559 |
Jun 7, 2006 |
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60038459 |
Feb 20, 1997 |
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Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61L 29/085 20130101;
A61L 33/022 20130101; A61F 2/02 20130101; A61L 2420/08 20130101;
A61L 31/16 20130101; A61K 51/1282 20130101; A61F 2/82 20130101;
A61F 2/91 20130101; A61L 2300/416 20130101; A61F 2/24 20130101;
A61L 29/085 20130101; A61L 2300/602 20130101; A61F 2/0077 20130101;
A61P 37/06 20180101; A61L 27/54 20130101; A61N 5/1002 20130101;
A61L 31/10 20130101; A61F 2210/0076 20130101; A61F 2/06 20130101;
A61F 2250/0067 20130101; A61L 27/306 20130101; A61L 29/106
20130101; A61L 2300/608 20130101; A61L 31/10 20130101; A61L 29/16
20130101; A61L 31/088 20130101; A61L 2300/256 20130101; A61L
2300/606 20130101; A61F 2250/0068 20130101; C08L 65/04 20130101;
C08L 65/04 20130101 |
Class at
Publication: |
623/1.42 |
International
Class: |
A61F 2/82 20060101
A61F002/82 |
Claims
1. A medical device, comprising: a structure having at least one
surface and being composed of a base material; at least one coating
layer comprising a polymer posited on the at least one surface of
the structure; and at least one layer comprising a first bioactive
material posited over at least a portion of the at least one
coating layer, wherein the first bioactive material is selected
from the group consisting of vasodilators, antimicrobials,
antibiotics, antimitotics, antiproliferatives, antisecretory
agents, non-steroidal antiinflammatory drugs, immunosuppressive
agents, growth factor antagonists, and antioxidants; wherein said
at least one coating layer provides for a controlled release of the
first bioactive material.
2. The medical device of claim 1, wherein the polymer is selected
from the group consisting of parylene, polyurethanes, silicones and
polyesters.
3. The medical device of claim 2, wherein the polymer is a
polyurethane.
4. The medical device of claim 1, wherein polymer is selected from
the group consisting of polyimide, poly(ethylene oxide),
poly(ethylene glycol), poly(propylene oxide), silicone,
polytetrafluoroethylene, tetramethyldisiloxane, parylene, parylene
derivative, and a polymer of methane.
5. The medical device of claim 1, wherein the polymer is parylene
or a parylene derivative.
6. The medical device of claim 1, wherein the structure is a
stent.
7. The medical device of claim 1, wherein the at least one layer
comprising the first bioactive material is the outermost layer of
the medical device.
8. The medical device of claim 1, wherein the at least one layer
comprising the first bioactive material further comprises a second
bioactive material.
9. The medical device of claim 8, wherein the first bioactive
material is paclitaxel or a paclitaxel derivative.
10. The medical device of claim 9, wherein the second bioactive
material is an anti-inflammatory agent.
11. The medical device of claim 8, wherein one of the first
bioactive material or the second bioactive material is an
anti-inflammatory agent.
12. The medical device of claim 8, wherein the first bioactive
material and the second bioactive material are co-mixed.
13. The medical device of claim 1, wherein the at least one coating
layer comprises a non-porous material.
14. The medical device of claim 1 wherein the at least one coating
layer has a thickness in a range from 50,000 to 500,000
Angstroms.
15. The medical device of claim 1, wherein the polymer is selected
from the group consisting of a polyurethane, silicones, polyesters,
polyimide, poly(ethylene oxide), poly(ethylene glycol),
poly(propylene oxide), silicone, polytetrafluoroethylene,
tetramethyldisiloxane, parylene, and a parylene derivative; wherein
the medical device is a stent; and wherein the first bioactive
material is paclitaxel or a paclitaxel derivative.
16. The medical device of claim 15, wherein the at least one layer
comprising the first bioactive material further comprises a second
bioactive material; and wherein the second bioactive material is an
anti-inflammatory agent.
17. The medical device of claim 16, wherein the at least one layer
of a first bioactive material is the outermost layer of the medical
device.
18. The medical device of claim 1, wherein the polymer is selected
from the group consisting of polyimide, poly(ethylene oxide),
poly(ethylene glycol), poly(propylene oxide), silicone,
polytetrafluoroethylene, tetramethyldisiloxane, parylene, and a
parylene derivative; and wherein the first bioactive material is
paclitaxel or a paclitaxel derivative.
19. The medical device of claim 18, wherein at least one layer
comprising the first bioactive material further comprises a second
bioactive material; and wherein the second bioactive material is an
anti-inflammatory agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/810,289, filed Jun. 5, 2007, which claims
the benefit of the filing date under 35 U.S.C. .sctn.119(e) of U.S.
provisional application Ser. No. 60/811,559, filed Jun. 7, 2006,
and which is also a continuation application of U.S. patent
application Ser. No. 10/218,308, filed Aug. 14, 2002 (now U.S. Pat.
No. 7,611,532, issued Nov. 3, 2009), which is a continuation of
U.S. patent application Ser. No. 09/027,054, filed Feb. 20, 1998
(now U.S. Pat. No. 6,774,278, issued Aug. 10, 2004), which claims
the benefit of the filing date under 35 U.S.C. .sctn.119(e) of U.S.
provisional application Ser. No. 60/038,459, filed Feb. 20, 1997,
and which is also a continuation-in-part application of U.S. patent
application Ser. No. 08/645,646, filed May 16, 1996 (now U.S. Pat.
No. 6,096,070, issued Aug. 1, 2000), which is in turn a
continuation-in-part application of U.S. patent application Ser.
No. 08/484,532, filed Jun. 7, 1995 (now U.S. Pat. No. 5,609,629,
issued Mar. 11, 1997). All of the above-referenced patent
applications are incorporated herein by reference in their
entirety.
TECHNICAL FIELD
[0002] This invention relates generally to human and veterinary
medical devices, and more particularly to devices incorporating
drugs or bioactive agents.
BACKGROUND
[0003] It has become common to treat a variety of medical
conditions by introducing an implantable medical device partly or
completely into the esophagus, trachea, colon, biliary tract,
urinary tract, vascular system or other location within a human or
veterinary patient. For example, many treatments of the vascular
system entail the introduction of a device such as a stent, a
catheter, a balloon, a wire guide, a cannula, or the like. However,
when such a device is introduced into and manipulated through the
vascular system, the blood vessel walls can be disturbed or
injured. Clot formation or thrombosis often results at the injured
site, causing stenosis or occlusion of the blood vessel. Moreover,
if the medical device is left within the patient for an extended
period of time, thrombus often forms on the device itself, again
causing stenosis or occlusion. As a result, the patient is placed
at risk of a variety of complications, including heart attack,
pulmonary embolism, and stroke. Thus, the use of such a medical
device can entail the risk of precisely the problems that its use
was intended to ameliorate.
[0004] Another way in which blood vessels undergo stenosis is
through disease. Probably the most common disease causing stenosis
of blood vessels is atherosclerosis. Atherosclerosis is a condition
which commonly affects the coronary arteries, the aorta, the
iliofemoral arteries and the carotid arteries. Atherosclerotic
plaques of lipids, fibroblasts, and fibrin proliferate and cause
obstruction of an artery or arteries. As the obstruction increases,
a critical level of stenosis is reached, to the point where the
flow of blood past the obstruction is insufficient to meet the
metabolic needs of the tissue distal to (downstream of) the
obstruction. The result is ischemia.
[0005] Many medical devices and therapeutic methods are known for
the treatment of atherosclerotic disease. One particularly useful
therapy for certain atherosclerotic lesions is percutaneous
transluminal angioplasty (PTA). During PTA, a balloon-tipped
catheter is inserted in a patient's artery, the balloon being
deflated. The tip of the catheter is advanced to the site of the
atherosclerotic plaque to be dilated. The balloon is placed within
or across the stenotic segment of the artery, and then inflated.
Inflation of the balloon "cracks" the atherosclerotic plaque and
expands the vessel, thereby relieving the stenosis, at least in
part.
[0006] While PTA presently enjoys wide use, it suffers from two
major problems. First, the blood vessel may suffer acute occlusion
immediately after or within the initial hours after the dilation
procedure. Such occlusion is referred to as "abrupt closure."
Abrupt closure occurs in perhaps five percent or so of the cases in
which PTA is employed, and can result in myocardial infarction and
death if blood flow is not restored promptly. The primary
mechanisms of abrupt closures are believed to be elastic recoil,
arterial dissection and/or thrombosis. It has been postulated that
the delivery of an appropriate agent (such as an antithrombic)
directly into the arterial wall at the time of angioplasty could
reduce the incidence of thrombotic acute closure, but the results
of attempts to do so have been mixed.
[0007] A second major problem encountered in PTA is the
re-narrowing of an artery after an initially successful
angioplasty. This re-narrowing is referred to as "restenosis" and
typically occurs within the first six months after angioplasty.
Restenosis is believed to arise through the proliferation and
migration of cellular components from the arterial wall, as well as
through geometric changes in the arterial wall referred to as
"remodeling." It has similarly been postulated that the delivery of
appropriate agents directly into the arterial wall could interrupt
the cellular and/or remodeling events leading to restenosis.
However, like the attempts to prevent thrombotic acute closure, the
results of attempts to prevent restenosis in this manner have been
mixed.
[0008] Non-atherosclerotic vascular stenosis may also be treated by
PTA. For example, Takayasu arteritis or neurofibromatosis may cause
stenosis by fibrotic thickening of the arterial wall. Restenosis of
these lesions occurs at a high rate following angioplasty, however,
due to the fibrotic nature of the diseases. Medical therapies to
treat or obviate them have been similarly disappointing.
[0009] A device such as an intravascular stent can be a useful
adjunct to PTA, particularly in the case of either acute or
threatened closure after angioplasty. The stent is placed in the
dilated segment of the artery to mechanically prevent abrupt
closure and restenosis. Unfortunately, even when the implantation
of the stent is accompanied by aggressive and precise antiplatelet
and anticoagulation therapy (typically by systemic administration),
the incidence of thrombotic vessel closure or other thrombotic
complication remains significant, and the prevention of restenosis
is not as successful as desired. Furthermore, an undesirable side
effect of the systemic antiplatelet and anticoagulation therapy is
an increased incidence of bleeding complications, most often at the
percutaneous entry site.
[0010] Other conditions and diseases are treatable with stents,
catheters, cannulae and other devices inserted into the esophagus,
trachea, colon, biliary tract, urinary tract and other locations in
the body, or with orthopedic devices, implants, or replacements. It
would be desirable to develop devices and methods for reliably
delivering suitable agents, drugs or bioactive materials directly
into a body portion during or following a medical procedure, so as
to treat or prevent such conditions and diseases, for example, to
prevent abrupt closure and/or restenosis of a body portion such as
a passage, lumen or blood vessel. As a particular example, it would
be desirable to have devices and methods which can deliver an
antithrombic or other medication to the region of a blood vessel
which has been treated by PTA, or by another interventional
technique such as atherectomy, laser ablation, or the like. It
would also be desirable that such devices would deliver their
agents over both the short term (that is, the initial hours and
days after treatment) and the long term (the weeks and months after
treatment). It would also be desirable to provide precise control
over the delivery rate for the agents, drugs or bioactive
materials, and to limit systemic exposure to them. This would be
particularly advantageous in therapies involving the delivery of a
chemotherapeutic agent to a particular organ or site through an
intravenous catheter (which itself has the advantage of reducing
the amount of agent needed for successful treatment), by preventing
stenosis both along the catheter and at the catheter tip. A wide
variety of other therapies could be similarly improved. Of course,
it would also be desirable to avoid degradation of the agent, drug
or bioactive material during its incorporation on or into any such
device.
SUMMARY
[0011] The foregoing problems are solved and a technical advance is
achieved in an illustrative vascular stent or other implantable
medical device that provides a controlled release of an agent, drug
or bioactive material into the vascular or other system, or other
location in the body, in which a stent or other device is
positioned. Applicants have discovered that the degradation of an
agent, a drug or a bioactive material that is applied to such a
device can be avoided by positing a coating layer on one surface of
the device structure. The agent, drug or bioactive material is
posited over at least a portion of the coating layer, wherein the
coating layer provides for a controlled release of the bioactive
material posited thereon. Furthermore, the medical device further
includes a porous layer positioned over the bioactive material
wherein the porous layer is composed of a polymer and the polymer
provides for a controlled release of the bioactive material through
the porous layer.
[0012] In one aspect, the coating layer comprises a non-porous
material of for example a parylene derivative. This coating layer
has a thickness preferably in a range from 50 to 500,000 Angstroms,
more preferably in a range from 100,000 to 500,000 Angstroms, and
illustratively approximately 200,000 Angstroms. In another aspect,
the non-porous material is either an adsorbent or an absorbent
material, where the coating layer of the adsorbent material has a
thickness of approximately 230,000 Angstroms.
[0013] In another aspect, the bioactive material layer includes a
chimeric monoclonal antibody such as an antiplatelet GP IIb/IIIa
antibody.
[0014] In still another aspect, an adhesive promotion layer is
posited on one surface of the structure on which the coating layer
is posited over at least a portion thereof. Preferably the adhesion
promotion layer includes silane having a thickness in range of 0.5
to 5,000 Angstroms.
[0015] Applicants have also discovered that the degradation of an
agent, a drug or a bioactive material applied to such a device may
be avoided by covering the agent, drug or bioactive material with a
porous layer of a biocompatible polymer that is applied without the
use of solvents, catalysts, heat or other chemicals or techniques,
which would otherwise be likely to degrade or damage the agent,
drug or material. Those biocompatible polymers may be applied
preferably by vapor deposition or plasma deposition, and may
polymerize and cure merely upon condensation from the vapor phase,
or may be photolytically polymerizable and are expected to be
useful for this purpose. However, it should be recognized that
other coating techniques may also be employed.
[0016] Preferably, when the device is intended for use in the
vascular system, the bioactive material in the at least one layer
is heparin or another antiplatelet or antithrombotic agent, or
dexamethasone, dexamethasone acetate, dexamethasone sodium
phosphate, or another dexamethasone derivative or anti-inflammatory
steroid. Furthermore, a wide range of other bioactive materials can
be employed, including, but not limited to, the following
categories of agents: thrombolytics, vasodilators, antihypertensive
agents, antimicrobials or antibiotics, antimitotics,
antiproliferatives, antisecretory agents, non-steroidal
anti-inflammatory drugs, immunosuppressive agents, growth factors
and growth factor antagonists, antitumor and/or chemotherapeutic
agents, antipolymerases, antiviral agents, photodynamic therapy
agents, antibody targeted therapy agents, prodrugs, sex hormones,
free radical scavengers, antioxidants, biologic agents,
radiotherapeutic agents, radiopaque agents and radiolabelled
agents. The major restriction is that the bioactive material must
be able to withstand the coating techniques, for example, the
vacuum employed during vapor deposition or plasma deposition of the
at least one porous layer. In other words, the bioactive material
must have a relatively low vapor pressure at the deposition
temperature, typically, near or at room temperature.
[0017] The at least one porous layer is preferably composed of a
polyamide, parylene or a parylene derivative applied by
catalyst-free vapor deposition and is conveniently about 5,000 to
250,000 Angstroms thick, which is adequate to provide a controlled
release of the bioactive material. "Parylene" is both a generic
name for a known group of polymers based on p-xylylene and made by
vapor phase polymerization, and a name for the unsubstituted form
of the polymer; the latter usage is employed herein. More
particularly, parylene or a parylene derivative is created by first
heating p-xylene or a suitable derivative at an appropriate
temperature (for example, at about 950.degree. C.) to produce the
cyclic dimer di-p-xylylene (or a derivative thereof). The resultant
solid can be separated in pure form, and then cracked and pyrolyzed
at an appropriate temperature (for example, at about 680.degree.
C.) to produce a monomer vapor of p-xylylene (or derivative); the
monomer vapor is cooled to a suitable temperature (for example,
below 50.degree. C.) and allowed to condense on the desired object,
for example, on the at least one layer of bioactive material. The
resultant polymer has the repeating structure
CH.sub.2C.sub.6H.sub.4--CH.sub.2--).sub.n, with n equal to about
5,000, and a molecular weight in the range of 500,000.
[0018] As indicated, parylene and parylene derivative coatings
applicable by vapor deposition are known for a variety of
biomedical uses, and are commercially available from or through a
variety of sources, including Specialty Coating Systems (100
Deposition Drive, Clear Lake, Wis. 54005), Para Tech Coating, Inc.
(35 Argonaut, Aliso Viejo, Calif. 92656) and Advanced Surface
Technology, Inc. (9 Linnel Circle, Billerica, Mass.
01821-3902).
[0019] The at least one porous layer can alternatively be applied
by plasma deposition. Plasma is an ionized gas maintained under
vacuum and excited by electrical energy, typically in the
radiofrequency range. Because the gas is maintained under vacuum,
the plasma deposition process occurs at or near room temperature.
Plasma can be used to deposit polymers such as poly(ethylene
oxide), poly(ethylene glycol), and poly(propylene oxide), as well
as polymers of silicone, methane, polytetrafluoroethylene
(including TEFLON brand polymers), tetramethyldisiloxane, and
others.
[0020] While the foregoing represents some preferred embodiments of
certain embodiments of the invention, other polymer systems may
also be employed, e.g., polymers derived from photopolymerizable
monomers. Also, other coating techniques may be utilized, e.g.,
dipping, spraying, and the like.
[0021] The device may include two or more layers of different
bioactive materials atop the structure. However, in some
embodiments, the same bioactive material will generally not be
posited on the different surfaces of the device within the same
layer. In other words, each surface of the device structure will
carry a different bioactive material or materials except where the
bioactive material is the innermost or outermost layer, e.g.
heparin may form the innermost layer or the outermost layer or
both. These additional layers may be placed directly atop one
another or can be separated by additional porous polymer layers
between each of them. Additionally, the layers of bioactive
materials can comprise a mixture of different bioactive materials.
The porous layers are also preferably composed of parylene or a
parylene derivative. Advantageously, the two or more bioactive
materials can have different solubilities, and the layer containing
the less soluble bioactive material (for example, dexamethasone) is
preferably posited above the layer containing the more soluble
bioactive material (for example, heparin). Unexpectedly, this has
been found to increase the in vitro release rate of some relatively
less soluble materials such as dexamethasone, while simultaneously
decreasing the release rate of some relatively more soluble
materials such as heparin.
[0022] While the structure included in the device may be configured
in a variety of ways, the structure is preferably configured as a
vascular stent composed of a biocompatible metal such as stainless
steel, nickel, silver, platinum, gold, titanium, tantalum, iridium,
tungsten, Nitinol, inconel, or the like. An additional
substantially nonporous coating layer of parylene or a parylene
derivative or other biocompatible polymer of about 50,000 to
500,000 Angstroms thick may be posited directly atop the vascular
stent, beneath the at least one layer of bioactive material. The
additional coating layer can merely be relatively less porous than
the at least one porous layer, but preferably is substantially
nonporous, that is, sufficiently nonporous to render the stent
essentially impervious to blood during normal circumstances of
use.
[0023] The device and methods described herein are useful in a wide
variety of locations within a human or veterinary patient, such as
in the esophagus, trachea, colon, biliary tract, urinary tract and
vascular system, as well as for subdural and orthopedic devices,
implants or replacements. They are particularly advantageous for
reliably delivering suitable bioactive materials during or
following an intravascular procedure, and find particular use in
preventing abrupt closure and/or restenosis of a blood vessel. More
particularly, they permit, for example, the delivery of an
antithrombotic, an antiplatelet, an anti-inflammatory steroid, or
another medication to the region of a blood vessel which has been
opened by PTA. Likewise, it allows for the delivery of one
bioactive material to, for example, the lumen of a blood vessel and
another bioactive material to the vessel wall. The use of a porous
polymer layer permits the release rate of a bioactive material to
be carefully controlled over both the short and long terms.
[0024] These and other aspects will be appreciated by those skilled
in the art upon the reading and understanding of the
specification.
[0025] In another aspect, the bioactive material is attached to the
non-porous layer and is advantageously eluted for prolonged periods
of time. The non-porous layer is attached to the base material of
the structure. The non-porous layer can be any of those previously
or subsequently listed herein, and, likewise, the bioactive
material can be any of those previously or subsequently listed
herein. Conveniently, and in a preferred embodiment, a glycoprotein
IIb/IIIa inhibitor such as commercially available ReoPro.TM. is
attached to a non-porous layer of parylene positioned on the outer
surface of the medical device such as a coronary stent. The
ReoPro.TM. is advantageously eluted from the surface of the stent
for prolonged periods of time.
BRIEF DESCRIPTION OF THE DRAWING
[0026] A better understanding of certain embodiments of the
invention will now be had upon reference to the following detailed
description, when read in conjunction with the accompanying
drawing, wherein like reference characters refer to like parts
throughout the several views, and in which:
[0027] FIG. 1 is a cross-sectional view of a first preferred
embodiment of certain embodiments of the invention;
[0028] FIG. 2 is a cross-sectional view of another preferred
embodiment of certain embodiments of the invention;
[0029] FIG. 3 is a cross-sectional view of yet another preferred
embodiment of certain embodiments of the invention;
[0030] FIG. 4 is a cross-sectional view of a further preferred
embodiment of certain embodiments of the invention;
[0031] FIG. 5 is a cross-sectional view of an additional preferred
embodiment of certain embodiments of the invention;
[0032] FIGS. 6A and 6B are cross-sectional views of an additional
preferred embodiment of certain embodiments of the invention;
[0033] FIG. 7 is a cross-sectional view of an additional preferred
embodiment of certain embodiments of the invention;
[0034] FIG. 8 is a partial, enlarged top view of FIG. 7;
[0035] FIG. 9 is an enlarged, sectional view along lines 9-9 of
FIG. 8;
[0036] FIGS. 10A-10D are enlarged cross-sectional views along lines
10-10 of FIG. 8;
[0037] FIG. 11 depicts another aspect of the medical device of FIG.
1 utilizing a polymer coating layer with a bioactive material
attached thereto; and
[0038] FIG. 12 depicts still another aspect of the medical device
of FIG. 11 in which the polymer coating layer is adhered to the
outer surface of the device base material using an adhesive
promotion layer.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0039] With reference now to FIG. 1, an implantable medical device
10 in accordance with one embodiment is shown and first comprises a
structure 12 adapted for introduction into a human or veterinary
patient. "Adapted" means 10 that the structure 12 is shaped and
sized for such introduction. For clarity, only a portion of the
structure 12 is shown in FIG. 1.
[0040] By way of example, the structure 12 is configured as a
vascular stent particularly adapted for insertion into the vascular
system of the patient. However, this stent structure can be used in
other systems and sites such as the esophagus, trachea, colon,
biliary ducts, urethra and ureters, subdural among others. Indeed,
the structure 12 can alternatively be configured as any
conventional vascular or other medical device, and can include any
of a variety of conventional stents or other adjuncts, such as
helical wound strands, perforated cylinders, or the like. Moreover,
the inserted structure 12 need not be an entire device, but can
merely be that portion of a vascular or other device which is
intended to be introduced into the patient. Accordingly, the
structure 12 can be configured as at least one of, or any portion
of, a catheter, a wire guide, a cannula, a stent, a vascular or
other graft, a cardiac pacemaker lead or lead tip, a cardiac
defibrillator lead or lead tip, a heart valve, or an orthopedic
device, appliance, implant, or replacement. The structure 12 can
also be configured as a combination of portions of any of
these.
[0041] Most preferably, however, the structure 12 is configured as
vascular stent such as the commercially available Gianturco-Roubin
FLEX-STENT.RTM. or GR II.TM. coronary stent from Cook Incorporated,
Bloomington, Ind. Such stents are typically about 10 to about 60 mm
in length and designed to expand to a diameter of about 2 to about
6 mm when inserted into the vascular system of the patient. The
Gianturco-Roubin stent in particular is typically about 12 to about
25 mm in length and designed to expand to a diameter of about 2 to
about 4 mm when so inserted.
[0042] These stent dimensions are, of course, applicable to
exemplary stents employed in the coronary arteries. Structures such
as stents or catheter portions intended to be employed at other
sites in the patient, such as in the aorta, esophagus, trachea,
colon, biliary tract, or urinary tract will have different
dimensions more suited to such use. For example, aortic,
esophageal, tracheal and colonic stents may have diameters up to
about 25 mm and lengths about 100 mm or longer.
[0043] The structure 12 is composed of a base material 14 suitable
for the intended use of the structure 12. The base material 14 is
preferably biocompatible, although cytotoxic or other poisonous
base materials may be employed if they are adequately isolated from
the patient. Such incompatible materials may be useful in, for
example, radiation treatments in which a radioactive material is
positioned by catheter in or close to the specific tissues to be
treated. Under most circumstances, however, the base material 14 of
the structure 12 should be biocompatible.
[0044] A variety of conventional materials can be employed as the
base material 14. Some materials may be more useful for structures
other than the coronary stent exemplifying the structure 12. The
base material 14 may be either elastic or inelastic, depending upon
the flexibility or elasticity of the polymer layers to be applied
over it. The base material may be either biodegradable or
non-biodegradable, and a variety of biodegradable polymers are
known. Moreover, some biologic agents have sufficient strength to
serve as the base material 14 of some useful structures 12, even if
not especially useful in the exemplary coronary stent.
[0045] Accordingly, the base material 14 can include at least one
of stainless steel, tantalum, titanium, nitinol, gold, platinum,
inconel, iridium, silver, tungsten, or another biocompatible metal,
or alloys of any of these; carbon or carbon fiber; cellulose
acetate, cellulose nitrate, silicone, polyethylene terephthalate,
polyurethane, polyamide, polyester, polyorthoester, polyanhydride,
polyether sulfone, polycarbonate, polypropylene, high molecular
weight polyethylene, polytetrafluoroethylene, or another
biocompatible polymeric material, or mixtures or copolymers of
these; polylactic acid, polyglycolic acid or copolymers thereof, a
polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or
another biodegradable polymer, or mixtures or copolymers of these;
a protein, an extracellular matrix component, collagen, fibrin or
another biologic agent; or a suitable mixture of any of these.
Stainless steel is particularly useful as the base material 14 when
the structure 12 is configured as a vascular stent.
[0046] Of course, when the structure 12 is composed of a
radiolucent material such as polypropylene, polyethylene, or others
above, a conventional radiopaque coating may and preferably should
be applied to it. The radiopaque coating provides a means for
identifying the location of the structure 12 by X-ray or
fluoroscopy during or after its introduction into the patient's
vascular system.
[0047] With continued reference to FIG. 1, the vascular device 10
can comprise at least one layer 18 of a bioactive material posited
on one surface of the structure 12. In some embodiments, at least
one bioactive material is posited on one surface of the structure
12, and the other surface will either contain no bioactive material
or one or more different bioactive materials. In this manner, one
or more bioactive materials or drugs may be delivered, for example,
with a vascular stent, to the blood stream from the lumen surface
of the stent, and a different treatment may be delivered on the
vessel surface of the stent. A vast range of drugs, medicaments and
materials may be employed as the bioactive material in the layer
18, so long as the selected material can survive exposure to the
vacuum drawn during vapor deposition or plasma deposition.
Particularly useful in the practice of certain embodiments of the
invention are materials which prevent or ameliorate abrupt closure
and restenosis of blood vessels previously opened by stentinq
surgery or other procedures. Thrombolytics (which dissolve, break
up or disperse thrombi) and antithrombogenics (which interfere with
or prevent the formation of thrombi) are especially useful
bioactive materials when the structure 12 is a vascular stent.
Particularly preferred thrombolytics are urokinase, streptokinase,
and the tissue plasminogen activators. Particularly preferred
antithrombogenics are heparin, hirudin, and the antiplatelets.
[0048] Urokinase is a plasminogen activating enzyme typically
obtained from human kidney cell cultures. Urokinase catalyzes the
conversion of plasminogen into the fibrinolytic plasmin, which
breaks down fibrin thrombi.
[0049] Heparin is a mucopolysaccharide anticoagulant typically
obtained from porcine intestinal mucosa or bovine lung. Heparin
acts as a thrombin inhibitor by greatly enhancing the effects of
the blood's endogenous antithrombin III. Thrombin, a potent enzyme
in the coagulation cascade, is key in catalyzing the formation of
fibrin. Therefore, by inhibiting thrombin, heparin inhibits the
formation of fibrin thrombi. Alternatively, heparin may be
covalently bound to the outer layer of structure 12. Thus, heparin
would form the outermost layer of structure 12 and would not be
readily degraded enzymatically, and would remain active as a
thrombin inhibitor.
[0050] Of course, bioactive materials having other functions can
also be successfully delivered by the device 10 of certain
embodiments of the invention. For example, an antiproliferative
agent such as methotrexate will inhibit over-proliferation of
smooth muscle cells and thus inhibit restenosis of the dilated
segment of the blood vessel. The antiproliferative is desirably
supplied for this purpose over a period of about four to six
months. Additionally, localized delivery of an antiproliferative
agent is also useful for the treatment of a variety of malignant
conditions characterized by highly vascular growth. In such cases,
the device 10 of certain embodiments of the invention could be
placed in the arterial supply of the tumor to provide a means of
delivering a relatively high dose of the antiproliferative agent
directly to the tumor.
[0051] A vasodilator such as a calcium channel blocker or a nitrate
will suppress vasospasm, which is common following angioplasty
procedures. Vasospasm occurs as a response to injury of a blood
vessel, and the tendency toward vasospasm decreases as the vessel
heals. Accordingly, the vasodilator is desirably supplied over a
period of about two to three weeks. Of course, trauma from
angioplasty is not the only vessel injury which can cause
vasospasm, and the device 10 may be introduced into vessels other
than the coronary arteries, such as the aorta, carotid arteries,
renal arteries, iliac arteries or peripheral arteries for the
prevention of vasospasm in them.
[0052] A variety of other bioactive materials are particularly
suitable for use when the structure 12 is configured as something
other than a coronary stent. For example, an anti-cancer
chemotherapeutic agent can be delivered by the device 10 to a
localized tumor. More particularly, the device 10 can be placed in
an artery supplying blood to the tumor or elsewhere to deliver a
relatively high and prolonged dose of the agent directly to the
tumor, while limiting systemic exposure and toxicity. The agent may
be a curative, a pre-operative debulker reducing the size of the
tumor, or a palliative which eases the symptoms of the disease. It
should be noted that the bioactive material in certain embodiments
of the invention is delivered across the device 10, and not by
passage from an outside source through any lumen defined in the
device 10, such as through a catheter employed for conventional
chemotherapy. The bioactive material of certain embodiments of the
invention may, of course, be released from the device 10 into any
lumen defined in the device, or to tissue in contact with the
device and that the lumen may carry some other agent to be
delivered through it. For example, tamoxifen citrate, TAXOL.RTM.
(paclitaxel) or derivatives thereof PROSCAR.RTM. (finasteride),
HYTRIN.RTM. (terazosin), or EULEXIN.RTM. (flutamide) may be applied
to the tissue-exposed surface of the device for delivery to a tumor
located, for example, in breast tissue or the prostate.
[0053] Dopamine or a dopamine agonist such as bromocriptine
mesylate or pergolide mesylate is useful for the treatment of
neurological disorders such as Parkinson's disease. The device 10
could be placed in the vascular supply of the thalamic substantia
nigra for this purpose, or elsewhere, localizing treatment in the
thalamus.
[0054] A wide range of other bioactive materials can be delivered
by the device 10. Accordingly, it is preferred that the bioactive
material contained in the layer 18 includes at least one of
heparin, covalent heparin, or another thrombin inhibitor, hirudin,
hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl
ketone, or another antithrombogenic agent, or mixtures thereof;
urokinase, streptokinase, a tissue plasminogen activator, or
another thrombolytic agent, or mixtures thereof; a fibrinolytic
agent; a vasospasm inhibitor; a calcium channel blocker, a nitrate,
nitric oxide, a nitric oxide promoter or another vasodilator;
HYTRIN.RTM. (terazosin) or other antihypertensive agents; an
antimicrobial agent or antibiotic; aspirin, ticlopidine, a
glycoprotein IIb/IIIa inhibitor or another inhibitor of surface
glycoprotein receptors, or another antiplatelet agent; colchicine
or another antimitotic, or another microtubule inhibitor, dimethyl
sulfoxide (DMSO), a retinoid or another antisecretory agent;
cytochalasin or another actin inhibitor; or a remodeling inhibitor;
deoxyribonucleic acid, an antisense nucleotide or another agent for
molecular genetic intervention; methotrexate or another
antimetabolite or antiproliferative agent; tamoxifen citrate,
TAXOL.RTM. (paclitaxel) or the derivatives thereof, or other
anti-cancer chemotherapeutic agents; dexamethasone, dexamethasone
sodium phosphate, dexamethasone acetate or another dexamethasone
derivative, or another anti-inflammatory steroid or non-steroidal
anti-inflammatory agent; cyclosporin or another immunosuppressive
agent; trapidal (a PDGF antagonist), angiopeptin (a growth hormone
antagonist), angiogenin, a growth factor or an anti-growth factor
antibody, or another growth factor antagonist; dopamine,
bromocriptine mesylate, pergolide mesylate or another dopamine
agonist; .sup.60Co (5.3 year half life), .sup.192Ir (73.8 days),
.sup.32P (14.3 days), .sup.111In (68 hours), .sup.90Y (64 hours),
.sup.99mTc (6 hours) or another radiotherapeutic agent;
iodine-containing compounds, barium-containing compounds, gold,
tantalum, platinum, tungsten or another heavy metal functioning as
a radiopaque agent; a peptide, a protein, an enzyme, an
extracellular matrix component, a cellular component or another
biologic agent; captopril, enalapril or another angiotensin
converting enzyme (ACE) inhibitor; ascorbic acid, alpha tocopherol,
superoxide dismutase, deferoxyamine, a 21-aminosteroid (lasaroid)
or another free radical scavenger, iron chelator or antioxidant; a
.sup.14C--, .sup.3H--, .sup.131I--, .sup.32P-- or .sup.36S--
radiolabelled form or other radiolabelled form of any of the
foregoing; estrogen or another sex hormone; AZT or other
antipolymerases; acyclovir, famciclovir, rimantadine hydrochloride,
ganciclovir sodium, NORVIR.RTM. (ritonavir), CRIXIVAN.RTM.
(indinavir), or other antiviral agents; 5-aminolevulinic acid,
meta-tetrahydroxyphenylchlorin, hexadecafluoro zinc phthalocyanine,
tetra methyl hematoporphyrin, rhodamine 123 or other photodynamic
therapy agents; an IgG2 Kappa antibody against Pseudomonas
aeruginosa exotoxin A and reactive with A431 epidermoid carcinoma
cells, monoclonal antibody against the noradrenergic enzyme
dopamine beta-hydroxylase conjugated to saporin or other antibody
targeted therapy agents; gene therapy agents; and enalapril and
other prodrugs; PROSCAR.RTM. (finasteride), HYTRIN.RTM. (terazosin)
or other agents for treating benign prostatic hyperplasia (BHP) or
a mixture of any of these; and various forms of small intestine
submucosa (SIS).
[0055] In a particularly preferred aspect, the layer of bioactive
material contains preferably from about 0.01 mg to about 10 mg and
more preferably from about 0.1 mg to about 4 mg of the bioactive
material per cm5 of the gross surface area of the structure. "Gross
surface area" refers to the area calculated from the gross or
overall extent of the structure, and not necessarily to the actual
surface area of the particular shape or individual parts of the
structure. In other terms, about 100 .mu.g to about 300 .mu.g of
drug per 0.001 inch of coating thickness may be contained on the
device surface.
[0056] When the structure 12 is configured as a vascular stent,
however, particularly preferred materials for the bioactive
material of the layer 18 are heparin, anti-inflammatory steroids
including but not limited to dexamethasone and its derivatives, and
mixtures of heparin and such steroids.
[0057] Still with reference to FIG. 1, the device 10 of certain
embodiments of the invention also comprises at least one porous
layer 20 posited over the layer 18 of bioactive material and the
bioactive-material-free surface. The purpose of the porous layer 20
is to provide a controlled release of the bioactive material when
the device 10 is positioned in the vascular system of a patient.
The thickness of the porous layer 20 is chosen so as to provide
such control.
[0058] More particularly, the porous layer 20 is composed of a
polymer deposited on the bioactive material layer 18, preferably by
vapor deposition. Plasma deposition may also be useful for this
purpose. Preferably, the layer 20 is one that is polymerized from a
vapor which is free of any solvent, catalysts or similar
polymerization promoters. Also preferably, the polymer in the
porous layer 20 is one which automatically polymerizes upon
condensation from the vapor phase, without the action of any
curative agent or activity such as heating, the application of
visible or ultraviolet light, radiation, ultrasound, or the like.
Most preferably, the polymer in the porous layer 20 is polyimide,
parylene or a parylene derivative.
[0059] When first deposited, the parylene or parylene derivative is
thought to form a network resembling a fibrous mesh, with
relatively large pores. As more is deposited, the porous layer 20
not only becomes thicker, but it is believed that parylene or
parylene derivative is also deposited in the previously formed
pores, making the existing pores smaller. Careful and precise
control over the deposition of the parylene or parylene derivative
therefore permits close control over the release rate of material
from the at least one layer 18 of bioactive material. It is for
this reason that the bioactive material lies under the at least one
porous layer 20, rather than being dispersed within or throughout
it. The porous layer 20, however, also protects the bioactive
material layer 18 during deployment of the device 10, for example,
during insertion of the device 10 through a catheter and into the
vascular system or elsewhere in the patient.
[0060] As shown in FIG. 1, the device 10 of certain embodiments of
the invention can further comprise at least one additional coating
layer 16 posited between the structure 12 and the at least one
layer 18 of bioactive material. While the additional coating layer
16 can simply be a medical grade primer, the additional coating
layer 16 is preferably composed of the same polymer as the at least
one porous layer 20. However, the additional coating layer 16 is
also preferably less porous than the at least one porous layer 20,
and is more preferably substantially nonporous. "Substantially
nonporous" means that the additional coating layer 16 is
sufficiently impervious to prevent any appreciable interaction
between the base material 14 of the structure 12 and the blood to
which the device 10 will be exposed during use. The use of an
additional coating layer 16 which is substantially nonporous would
permit the use of a toxic or poisonous base material 14, as
mentioned above. Even if the base material 14 of the structure 12
is biocompatible, however, it may be advantageous to isolate it
from the blood by use of a substantially nonporous coating layer
16.
[0061] Other polymer systems that may find application within the
scope of the invention include polymers derived from
photopolymerizable monomers such as liquid monomers preferably
having at least two cross linkable C--C (Carbon to Carbon) double
bonds and being a non-gaseous addition polymerizable ethylenically
unsaturated compound, having a boiling point above 100.degree. C.,
at atmospheric pressure, a molecular weight of about 100-1500 and
being capable of forming high molecular weight addition polymers
readily. More preferably, the monomer is preferably an addition
photopolymerizable polyethylenically unsaturated acrylic or
methacrylic acid ester containing two or more acrylate or
methacrylate groups per molecule or mixtures thereof. A few
illustrative examples of such multifunctional acrylates are
ethylene glycol diacrylate, ethylene glycol dimethacrylate,
trimethylopropane triacrylate, trimethylopropane trimethacrylate,
pentaerythritol tetraacrylate or pentaerythritol tetramethacrylate,
1,6-hexanediol dimethacrylate, and diethyleneglycol
dimethacrylate.
[0062] Also useful in some special instances are monoacrylates such
as n-butyl-acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate,
lauryl-acrylate, and 2-hydroxy-propyl acrylate. Small quantities of
amides of (meth)acrylic acid such as N-methylol methacrylamide
butyl ether are also suitable, N-vinyl compounds such as N-vinyl
pyrrolidone, vinyl esters of aliphatic monocarboxylic acids such as
vinyl oleate, vinyl ethers of diols such as butanediol-1,4-divinyl
ether and allyl ether and allyl ester are also suitable. Also
included would be other monomers such as the reaction products of
dior polyepoxides such as butanediol-1,4-diglycidyl ether or
bisphenol A diglycidyl ether with (meth)acrylic acid. The
characteristics of the photopolymerizable liquid dispersing medium
can be modified for the specific purpose by a suitable selection of
monomers or mixtures thereof.
[0063] Other useful polymer systems include a polymer that is
biocompatible and minimizes irritation to the vessel wall when the
stent is implanted. The polymer may be either a biostable or a
bioabsorbable polymer depending on the desired rate of release or
the desired degree of polymer stability, but a bioabsorbable
polymer is preferred for this embodiment since, unlike a biostable
polymer, it will not be present long after implantation to cause
any adverse, chronic local response. Bioabsorbable polymers that
could be used include poly(L-lactic acid), polycaprolactone,
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,
polyanhydride, poly(glycolic acid), poly(D,L-lactic acid),
poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly(amino acids), cyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate),
copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates,
polyphosphazenes and biomolecules such as fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid. Also, biostable
polymers with a relatively low chronic tissue response such as
polyurethanes, silicones, and polyesters could be used and other
polymers could also be used if they can be dissolved and cured or
polymerized on the stent such as polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers; acrylic polymers and copolymers,
vinyl halide polymers and copolymers, such as polyvinyl chloride;
polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene
halides, such as polyvinylidene fluoride and polyvinylidene
chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl
aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl
acetate; copolymers of vinyl monomers with each other and olefins,
such as ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers; polyamides, such as Nylon 66 and
polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes;
polyimides; polyethers; epoxy resins, polyurethanes; rayon;
rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate;
cellulose acetate butyrate; cellophane; cellulose nitrate;
cellulose propionate; cellulose ethers; and carboxymethyl
cellulose.
[0064] While plasma deposition and vapor phase deposition may be a
preferred method for applying the various coatings on the stent
surfaces, other techniques may be employed. For example, a polymer
solution may be applied to the stent and the solvent allowed to
evaporate, thereby leaving on the stent surface a coating of the
polymer and the therapeutic substance. Typically, the solution can
be applied to the stent by either spraying the solution onto the
stent or immersing the stent in the solution. Whether one chooses
application by immersion or application by spraying depends
principally on the viscosity and surface tension of the solution;
however, it has been found that spraying in a fine spray such as
that available from an airbrush will provide a coating with the
greatest uniformity and will provide the greatest control over the
amount of coating material to be applied to the stent. In either a
coating applied by spraying or by immersion, multiple application
steps are generally desirable to provide improved coating
uniformity and improved control over the amount of therapeutic
substance to be applied to the stent.
[0065] When the layer 18 of bioactive material contains a
relatively soluble material such as heparin, and when the at least
one porous layer 20 is composed of parylene or a parylene
derivative, the at least one porous layer 20 is preferably about
5,000 to 250,000 Angstroms thick, more preferably about 5,000 to
100,000 Angstroms thick, and optimally about 50,000 Angstroms
thick. When the at least one additional coating layer 16 is
composed of parylene or a parylene derivative, the at least one
additional coating is preferably about 50,000 to 500,000 Angstroms
thick, more preferably about 100,000 to 500,000 Angstroms thick,
and optimally about 200,000 Angstroms thick.
[0066] When the at least one layer 18 of bioactive material
contains a relatively soluble material such as heparin, the at
least one layer 18 preferably contains a total of about 0.1 to 4 mg
of bioactive material per cm5 of the gross surface area of the
structure 12. This provides a release rate for the heparin
(measured in vitro) which is desirably in the range of 0.1 to 0.5
mg/cm5 per day, and preferably about 0.25 mg/cm5 per day, under
typical blood flows through vascular stents. It should, be noted
that the solubility of dexamethasone can be adjusted as desired,
with or without the inclusion of heparin, by mixing it with one or
more of its relatively more soluble derivatives, such as
dexamethasone sodium phosphate.
[0067] FIG. 11 depicts another aspect of device 10 of certain
embodiments of the invention in which coating layer 16 is applied
directly to the outer surface of base material 14 of structure 12.
In this configuration, coating layer 16 is preferably a non-porous
coating layer as previously described. When coating layer 16
comprises a parylene derivative, non-porous coating layer 16 ranges
in thickness from 50,000 to 500,000 Angstroms, more preferably in
the range of 100,000 to 500,000 Angstroms, and optimally about
200,000 Angstroms. In this aspect, non-porous coating layer 16 is
also an adsorbent in which an adsorbent is defined as an agent that
attracts other materials or particles to its surface as indicated
in Dorland's Illustrated Medical Dictionary 26th Edition by W.B.
Saunders Co., Philadelphia, Pa. Bioactive material 18 is then
attached to the surface of coating layer 16. An additional coating
layer 20 can be applied over bioactive material layer 18.
Alternatively, alternating layers of coating material and the same
or different bioactive materials can be applied to the surface of
bioactive material layer 18. However, in this particular aspect,
the outer layer of structure 12 is a bioactive material layer
18.
[0068] In still another aspect of certain embodiments of the
invention as depicted in FIG. 11, coating layer 16 can be
considered an adsorbent layer and/or an absorbent layer in which a
bioactive material is attached thereto. In one particular example,
device 10 is a stainless steel GR II.TM. stent in which the
stainless steel base material 14 of structure 12 is coated with a
polymer and, in particular, parylene. This adsorbent polymer layer
16 of parylene is approximately 230,000 Angstroms thick. Bioactive
material layer 18 of the antiplatelet GP IIb/IIIa antibody (AZ1)
was passively loaded on adsorbent polymer layer 16. The polymer
coated stainless steel stents were immersed for approximately 24
hours in a buffered aqueous solution of AZ1 antibody (1 mg/ml,
pH=7.2) at 37.degree. C. AZ1 is a monoclonal anti-rabbit platelet
glycoprotein (GP) IIb/IIIa antibody. Using radio-labeled AZ1, it
was demonstrated that approximately 0.02 .mu.g antibody was loaded
per mm.sup.2 stent surface area (approximately 2 .mu.g total for a
3.times.20 mm GR II.TM. stent). It was also demonstrated that in an
in-vitro flow system (10 ml/min, 1% BSA in PBS) approximately half
the loaded antibody remained on the stent after approximately 10
days perfusion.
[0069] The mechanism by which the stent is loaded with drug is
thought to include adsorption onto the surface of the polymer layer
and/or absorption into the polymer.
[0070] Previous studies with similar loading and release of AZ1
from cellulose coated stainless steel stents showed inhibition of
platelet aggregation and reduced thrombosis rates in a rabbit model
of deep arterial injury. (Aggarwal et al., Antithrombotic Potential
of Polymer-Coated Stents Eluting Platelet Glycoprotein IIb/IIIa
Receptor Antibody, American Heart Association Circulation Vol. 94
No. 12, Dec. 15, 1996, pp 3311-3317).
[0071] In another example, c7E3 Fab as bioactive material layer 18
is attached to polymer coating layer 16. Bioactive material c7E3
Fab is a chimeric monoclonal antibody that acts upon the Gp
IIa/IIIb integrin on platelets to inhibit their aggregation. This
antibody or receptor blocker can be used in humans intravenously to
prevent thrombosis during coronary angioplasty. This receptor
blocker is also known as ReoPro.TM. available from Eli Lilly,
Indianapolis, Ind. Bioactive material layer 18 of the antiplatelet
GP IIb/IIIa antibody (c7E3 Fab) was passively loaded on adsorbent
polymer layer 16. The polymer coated stainless steel stents were
immersed for approximately 24 hours in a buffered aqueous solution
of c7E3 Fab antibody (1 mg/ml, pH=7.2) at 37.degree. C. c7E3 Fab is
an inhibitor of platelet thrombus in humans. Using radio-labeled
c7E3 Fab, it was demonstrated that approximately 0.010 .mu.g
antibody was loaded per mm.sup.2 stent surface area (approximately
10 .mu.g total for a 3.times.20 mm GR II.TM. stent). It was also
demonstrated that in an in-vitro flow system (10 ml/min, 1% BSA in
PBS) approximately half the loaded antibody remained on the stent
after approximately 10 days perfusion.
[0072] FIG. 12 depicts still another aspect of device 10 of FIG.
11. In this embodiment, a parylene adhesion promotion layer 30 is
first applied to stainless steel base material 14 of structure 12.
By way of example, adhesion promotion layer 30 is a thin layer of
silane having a thickness in the range of, for example, 0.5 to
5,000 Angstroms and preferably, 2 to 50 Angstroms. This silane
promotion layer is preferably A-174 silane including a
gammamethacryloxypropyltrimethoxysilane, which is available from
Specialty Coating Systems Inc., Indianapolis, Ind. In preparing the
outer surface of base material 14, it is first cleaned with
isopropyl alcohol. The stent is then dipped in the silane to apply
a very thin layer thereof to the outer surface of the base
material. Polymer coating layer 16 of parylene is then applied to
the silane layer. Other methods of preparing the outer surface of
base material 14 include plasma etching and grit blasting.
Preparation includes cleaning the outer surface of the base
material with isopropyl alcohol, plasma etching the outer surface
of the base material and applying the silane to the plasma etched
surface. With grit blasting, the outer surface of the base material
is grit blasted and then cleaned with isopropyl alcohol to which
silane is applied to the cleansed grit blasted surface.
[0073] As shown in FIG. 2, the device 10 of certain embodiments of
the invention is not limited to the inclusion of a single layer 18
of bioactive material. The device 10 can, for example, comprise a
second layer 22 of a bioactive material posited over the structure
12. The bioactive material of the second layer 22 can be, but need
not necessarily be, different from the bioactive material of the
first bioactive material layer 18, only that they not be posited on
the same surface of the device 10 without the intermediate porous
layer 24. The use of different materials in the layers 18 and 22
allows the device 10 to perform more than a single therapeutic
function.
[0074] The device 10 can further comprise an additional porous
layer 24 of the polymer posited between each of the layers 18 and
22 of bioactive material. It is reiterated that bioactive material
18 is on one surface of structure 12. The other surface may be free
of bioactive material or may comprise one or more different
bioactive materials. The additional porous layer 24 can give the
bioactive materials in the layers 18 and 22 different release
rates. Simultaneously, or alternatively, the device 10 may employ
bioactive materials in the two layers 18 and 22 which are different
from one another and have different solubilities. In such a case,
it is advantageous and preferred to position the layer 22
containing the less soluble bioactive material above the layer 18
containing the more soluble bioactive material. Alternatively, the
bioactive material 18 may be contained in holes, wells, slots and
the like occurring within the stent surface as illustrated in FIGS.
8-10 and will further be discussed in greater detail.
[0075] For example, when the structure 12 of the device 10 is
configured as a vascular stent, it is advantageous for the at least
one layer 18 to contain relatively soluble heparin, and the second
layer 22 to contain relatively less soluble dexamethasone.
Unexpectedly, the heparin promotes the release of the
dexamethasone, increasing its release rate many times over the
release rate of dexamethasone in the absence of heparin. The
release rate of the heparin is also lowered, somewhat less
dramatically than the increase of the dexamethasone release rate.
More particularly, when dexamethasone is disposed by itself beneath
a porous parylene layer 20 dimensioned as disclosed above, its
release rate is negligible; an adequate release rate is obtained
only when the thickness of the porous layer 20 is reduced by a
factor of ten or more. In contrast, when a layer 22 of
dexamethasone is disposed over a layer 18 of heparin, and beneath a
porous parylene layer 20 dimensioned as above, the dexamethasone
may be released at a desirable rate of about 1 to 10 .phi.g/cm5 per
day. Moreover, and even more unexpectedly, this increased release
rate for the dexamethasone is thought to be maintained even after
all of the heparin has been released from the layer 18.
[0076] The bioactive material layers 18 and/or 22 are applied to
the device 10 independent of the application of the porous polymer
layers 20 and/or 24. Any mixing of a bioactive material from the
layers 18 and/or 22 into the porous layers 20 and/or 24, prior to
introducing the device 10 into the vascular system of the patient,
is unintentional and merely incidental. This gives significantly
more control over the release rate of the bioactive material than
the simple dispersal of a bioactive material in a polymeric
layer.
[0077] The device 10 need not include the additional porous layer
24 when two or more layers 18 and 22 of bioactive material are
present. As shown in FIG. 3, the layers 18 and 22 do not have to be
separated by a porous layer, but can instead lie directly against
one another. It is still advantageous in this embodiment to
position the layer 22 containing the relatively less soluble
bioactive material above the layer 18 containing the relatively
more soluble bioactive material.
[0078] Whether or not the additional porous layer 24 is present, it
is preferred that the layers 18 and 22 contain about 0.05 to 2.0 mg
of each of heparin and dexamethasone, respectively, per 1 cm5 of
the gross surface area of the structure 12. The total amount of
bioactive material posited in the layers 18 and 22 over the
structure 12 is thus preferably in the range of about 0.1 to 10
mg/cm5.
[0079] Some dexamethasone derivatives, such as dexamethasone sodium
phosphate, are substantially more soluble than dexamethasone
itself. If a more soluble dexamethasone derivative is used as the
bioactive material in the device 10, the thickness of the at least
one porous layer 20 (and of the additional porous layer 24) should
be adjusted accordingly.
[0080] The particular structure of the device 10 as disclosed may
be adapted to specific uses in a variety of ways. For example, the
device 10 may include further layers of the same or different
bioactive materials. These additional layers of bioactive material
may or may not be separated by additional porous layers, as
convenient or desired. Alternatively, additional porous layers may
separate only some of the additional layers of bioactive material.
Moreover, one bioactive material may be placed on one portion of
the structure 12 of the device 10, and another bioactive material
placed on a different portion of the structure 12 of the device
10.
[0081] Alternatively, the device 10 need not include the additional
coating layer 16 at all. Such a configuration is shown in FIG. 4,
in which the bioactive material layer 18 is posited directly atop
the base material 14 of the structure 12. In such a case, it may be
highly advantageous to surface process or surface activate the base
material 14, to promote the deposition or adhesion of the bioactive
material on the base material 14, especially before the depositing
of the at least one porous layer 20. Surface processing and surface
activation can also selectively alter the release rate of the
bioactive material. Such processing can also be used to promote the
deposition or adhesion of the additional coating layer 16, if
present, on the base material 14. The additional coating layer 16
itself, or any second or additional porous layer 24 itself, can
similarly be processed to promote the deposition or adhesion of the
bioactive material layer 18, or to further control the release rate
of the bioactive material.
[0082] Useful methods of surface processing can include any of a
variety of such procedures, including: cleaning; physical
modifications such as etching, drilling, cutting, or abrasion; and
chemical modifications such as solvent treatment, the application
of primer coatings, the application of surfactants, plasma
treatment, ion bombardment and covalent bonding.
[0083] It has been found particularly advantageous to plasma treat
the additional coating layer 16 (for example, of parylene) before
depositing the bioactive material layer 18 atop it. The plasma
treatment improves the adhesion of the bioactive material,
increases the amount of bioactive material. that can be deposited,
and allows the bioactive material to be deposited in a more uniform
layer. Indeed, it is very difficult to deposit a hygroscopic agent
such as heparin on an unmodified parylene surface, which is
hydrophobic and poorly wettable. However, plasma treatment renders
the parylene surface wettable, allowing heparin to be easily
deposited on it.
[0084] Any of the porous polymer layers 20 and 24 may also be
surface processed by any of the methods mentioned above to alter
the release rate of the bioactive material or materials, and/or
otherwise improve the biocompatibility of the surface of the
layers. For example, the application of an overcoat of polyethylene
oxide, phosphatidylcholine or a covalently bound bioactive
material, e.g., covalently attached heparin to the layers 20 and/or
24 could render the surface of the layers more blood compatible.
Similarly, the plasma treatment or application of a hydrogel
coating to the layers 20 and/or 24 could alter their surface
energies, preferably providing surface energies in the range of 20
to 30 dyne/cm, thereby rendering their surfaces more
biocompatible.
[0085] Referring now to FIG. 5, an embodiment of the device 10 is
there shown in which a mechanical bond or connector 26 is provided
between (a) anyone of the porous layers 20 and 24, and (b) any or
all of the other of the porous layers 20 and 24, the additional
coating layer 16 and the base material 14. The connector 26
reliably secures the layers 16, 20 and/or 24 to each other, and or
to the base material 14. The connector 26 lends structural
integrity to the device 10, particularly after the bioactive
material layer or layers 18 and/or 20 have been fully released into
the patient.
[0086] For simplicity, the connector 26 is shown in FIG. 5 as a
plurality of projections of the base material 14 securing a single
porous layer 20 to the base material 14. The connector 26 may
alternatively extend from the porous layer 20, through the
bioactive material layer 18, and to the base material 14. In either
case, a single layer 18 of bioactive material, divided into several
segments by the connector 26, is posited between the porous layer
20 and the base material 14. The connectors can also function to
partition the different bioactive agents into different regions of
the device's surface.
[0087] The connector 26 may be provided in a variety of ways. For
example, the connector 26 can be formed as a single piece with the
base material 14 during its initial fabrication or molding into the
structure 12. The connector 26 can instead be formed as a distinct
element, such as a bridge, strut, pin or stud added to an existing
structure 12. The connector 26 can also be formed as a built-up
land, shoulder, plateau, pod or pan on the base material 14.
Alternatively, a portion of the base material 14 between the
desired locations of plural connectors 26 may be removed by
etching, mechanical abrasion, or the like, and the bioactive
material layer 18 deposited between them. The connector 26 can also
be formed so as to extend downwards towards the base material 14,
by wiping or etching away a portion of a previously applied
bioactive material layer 18, and allowing the porous layer 20 to
deposit by vapor deposition or plasma deposition directly on the
bare portions of the base material 14. Other ways to expose a
portion of the base material 14 to direct connection to the porous
layer 20 will be evident to those skilled in this area.
[0088] In another preferred embodiment, as illustrated in FIGS. 6A,
6B and 7, a bioactive material 18 is posited on the one surface of
base material 14 making up structure 12 in FIG. 6A. FIG. 7 shows a
stent 10 in its flat or planar state prior to being coiled and
showing porous layer 20 applied to its outermost surface. FIGS. 6A
and 6B are section views along line 6-6 of FIG. 7. The bioactive
material 18 posited on the one surface of base material 14 in FIG.
6A may be a number of different therapeutic and/or diagnostic
agents. For example, the device 10 may be a stent which is placed
in the body of a patient near a tumor to deliver a chemotherapeutic
agent; such as tamoxifen citrate or Taxol.RTM. (paclitaxel),
directly to the tumor. A porous layer 20 is posited over the
bioactive material 18 to provide a smoother surface as well as a
more controlled release of the bioactive material 18. As further
illustrated in FIG. 6A, the opposite surface of the device may
have, for example, heparin 18' covalently bonded to porous layer
20, particularly where this surface faces, for example, the lumen
of a blood vessel, to provide antithrombotic effect and blood
compatibility. It is pointed out, as has been discussed herein, a
third but different bioactive material may be posited (not shown)
on the opposite surface of base material 14 from the first
bioactive material 18 and on the same side of base material 14 as
the covalently bound heparin or any other bioactive material
including other covalently bound bioactive materials and separated
by porous layer 20.
[0089] A variation of the embodiment shown in FIG. 6A is
illustrated in FIG. 6B, where two bioactive materials 18 and 18'
are posited on the same surface of base material 14 of structure
12. A porous layer 20 may be deposited over the bioactive materials
18 and 18' as well as the bioactive-material-free surface of based
material 14. This embodiment illustrates a situation where it may
be desirable to deliver two agents to the tissue to which the
particular surface of device 10 is exposed, e.g., an
anti-inflammatory agent and an antiviral agent. Moreover, the
opposite surface of the device free of bioactive material is
available for positing one or more bioactive materials or
therapeutic agents, e.g., an antithrombotic agent.
[0090] As has been previously discussed, multiple layers of
bioactive materials and porous layers may be applied to the device
10 where the limiting factors become the total thickness of the
device, the adhesion of multiple layers and the like.
[0091] In still another embodiment, the device can include
apertures within the device for containing the bioactive material.
This embodiment is illustrated in FIGS. 8, 9, 10A, 10B, 10C and
10D. FIG. 8 shows an arm of the stent of FIG. 7 wherein the arm
includes holes 28 into which a bioactive material is contained.
FIG. 9 shows a section of the arm of the stent along lines 9-9 of
FIG. 8. Bioactive material 18 is contained within the hole 28 where
the base material 14 contains coating 16 and further where porous
layer 20 forms the outer most layer for the bioactive material 18
to diffuse through. In an alternative embodiment, wells 28' may be
cut, etched or stamped into the base material 14 of the device in
which a bioactive material 18 may be contained. This embodiment is
illustrated in FIGS. 10A, 10B, 10C and 10D which are sectional
FIGs. taken along line 10-10 of FIG. 8. The wells 28' may also be
in the form of slots or grooves in the surface of the base material
14 of the medical device. This aspect provides the advantage of
better controlling the total amount of the bioactive material 18 to
be released as well as the rate at which it is released. For
example, a V-shape well 28', as illustrated in FIG. 10D, will
contain less quantity of bioactive material 18 and release the
material at geometric rate as compared to a square shaped well 28',
as illustrated in FIG. 10B, which will have a more uniform, linear
release rate.
[0092] The holes, wells, slots, grooves and the like, described
above, may be formed in the surface of the device 10 by a variety
of techniques. For example, such techniques include drilling or
cutting by utilizing lasers, electron-beam machining and the like
or employing photoresist procedures and etching the desired
apertures.
[0093] All the bioactive materials discussed above that may be
coated on the surface of the device 10 may be used to be contained
within the apertures of this aspect. Likewise, layers of bioactive
materials and porous layers may be applied and built up on the
exterior surfaces of the device as described previously with regard
to other aspects of the invention, e.g., heparin, may be covalently
bound to one surface of the device illustrated in FIG. 9.
[0094] The method of making the device 10 according to certain
embodiments of the invention may now be understood. In its simplest
form, the method comprises the steps of depositing the at least one
layer 18 of bioactive material over the structure 12, followed by
depositing the at least one porous layer 20, preferably by vapor
deposition or plasma deposition, over the at least one bioactive
material layer 18 on the one surface of structure 12. The at least
one porous layer 20 being composed of a biocompatible polymer and
being of a thickness adequate to provide a controlled release of
the bioactive material. Preferably, the at least one additional
coating layer 16 is first posited by vapor deposition directly on
the base material 14 of the structure 12. Such deposition is
carried out by preparing or obtaining di-p-xylylene or a derivative
thereof, sublimating and cracking the di-p-xylylene or derivative
to yield monomeric p-xylylene or a monomeric derivative, and
allowing the monomer to simultaneously condense on and polymerize
over the base material 14. The deposition step is carried out under
vacuum, and the base material 14 maintained at or near room
temperature during the deposition step. The deposition is carried
out in the absence of any solvent or catalyst for the polymer, and
in the absence of any other action to aid polymerization. One
preferred derivative for carrying out the deposition step is
dichloro-di-p-xylylene. The parylene or parylene derivative is
preferably applied at the thickness disclosed above, to yield a
coating layer 16 which is substantially nonporous, but in any event
less porous than the at least one porous layer 20 to be applied. If
required by the composition of the coating layer 16, the layer 16
is then surface processed in an appropriate manner, for example, by
plasma treatment as disclosed above.
[0095] The at least one layer 18 of the desired bioactive material
or materials is then applied to the one surface of the structure
12, and in particular, onto the additional coating layer 16. This
application step can be carried out in any of a variety of
convenient ways, such as by dipping, rolling, brushing or spraying
a fluid mixture of the bioactive material onto the additional
coating layer 16, or by electrostatic deposition of either a fluid
mixture or dry powder of the bioactive material, or by any other
appropriate method. Different bioactive agents may be applied to
different sections or surfaces of the device.
[0096] It can be particularly convenient to apply a mixture of the
bioactive material or materials and a volatile fluid over the
structure, and then remove the fluid in any suitable way, for
example, by allowing it to evaporate. When heparin and/or
dexamethasone or its derivatives serve as the bioactive
material(s), the fluid is preferably ethyl alcohol. The bioactive
material is preferably applied in an amount as disclosed above.
[0097] Other methods of depositing the bioactive material layer 18
over the structure 12 would be equally useful. Without regard to
the method of application, however, what is important is that the
bioactive material need only be physically held in place until the
porous layer 20 is deposited over it. This can avoid the use of
carriers, surfactants, chemical binding and other such methods
often employed to hold a bioactive agent on other devices. The
additives used in such methods may be toxic, or the additives or
methods may alter or degrade the bioactive agent, rendering it less
effective or even toxic itself. Nonetheless, if desired these other
methods may also be employed to deposit the bioactive material
layer 18 of certain embodiments of the invention.
[0098] The bioactive material may, of course, be deposited on the
one surface of the structure 12 as a smooth film or as a layer of
particles. Moreover, multiple but different bioactive materials may
be deposited in a manner that different surfaces of the device
contain the different bioactive agents. In the latter case, the
particle size may affect the properties or characteristics of the
device 10, such as the smoothness of the uppermost porous coating
20, the profile of the device 10, the surface area over which the
bioactive material layer 18 is disposed, the release rate of the
bioactive material, the formation of bumps or irregularities in the
bioactive material layer 18, the uniformity and strength of
adhesion of the bioactive material layer 18, and other properties
or characteristics. For example, it has been useful to employ
micronized bioactive materials, that is, materials which have been
processed to a small particle size, typically less than 10 .mu.m in
diameter. However, the bioactive material may also be deposited as
microencapsulated particles, dispersed in liposomes, adsorbed onto
or absorbed into small carrier particles, or the like.
[0099] In still another embodiment according to certain embodiments
of the invention, the bioactive material may be posited on the one
surface of structure 12 in a specific geometric pattern. For
example, the tips or arms of a stent may be free of bioactive
material, or the bioactive material may be applied in parallel
lines, particularly where two or more bioactive materials are
applied to the same surface.
[0100] In any event, once the bioactive material layer 18 is in
place, the at least one porous layer 20 is then applied over the at
least one bioactive material layer 18 in the same manner as for the
application of the at least one additional coating 16. A polymer
such as parylene or a parylene derivative is applied at the lesser
thickness disclosed above, however, so as to yield the at least one
porous layer 20.
[0101] Any other layers, such as the second bioactive material
layer 22 or the additional porous layer 24, are applied in the
appropriate order and in the same manner as disclosed above. The
steps of the method are preferably carried out with any of the
bioactive materials, structures, and base materials disclosed
above.
[0102] Of course, polyimide may be deposited as any or all of the
porous and additional coating layers 20, 24 and/or 16 by vapor
deposition in a manner similar to that disclosed above for parylene
and its derivatives. Techniques for the plasma deposition of
polymers such as poly(ethylene oxide), poly(ethylene glycol),
poly(propylene oxide), silicone, or a polymer of methane,
tetrafluoroethylene or tetramethyl-disiloxane on other objects are
well-known, and these techniques may be useful in the practice of
certain embodiments of the invention.
[0103] Another technique for controlling the release of the
bioactive material may include depositing monodispersed polymeric
particles, i.e., referred to as porogens, on the surface of the
device 10 comprising one or more bioactive materials prior to
deposition of porous layer 20. After the porous layer 20 is
deposited and cured, the porogens may be dissolved away with the
appropriate solvent, leaving a cavity or pore in the outer coating
to facilitate the passage of the underlying bioactive
materials.
[0104] The method of using the device 10 in medically treating a
human or veterinary patient can now be easily understood as well.
The method can be an improvement over previous methods which
include the step of inserting into a patient an implantable
vascular device 10, the device 10 comprising a structure 12 adapted
for introduction into the vascular system of a patient, and the
structure 12 being composed of a base material 14. The method
according to certain embodiments of the invention comprises the
preliminary steps of depositing at least one layer 18 of a
bioactive material on one surface of the structure 12, followed by
depositing at least one porous layer 20 over the at least one
bioactive material layer 18, the porous layer 20 being composed of
a polymer and having a thickness adequate to provide a controlled
release of the bioactive material when the device 10 is positioned
in the patient's vascular system.
[0105] The method can further entail carrying out the two
depositing steps with the various embodiments of the device 10
disclosed above, in accordance with the method of making the device
10 disclosed above. More particularly, the step of depositing the
at least one porous layer 20 can comprise polymerizing the at least
one layer 20 from a monomer vapor, preferably a vapor of parylene
or a parylene derivative, free of any solvent or catalyst. The
method can also comprise the step of depositing the at least one
additional coating layer 16 between the structure 12 and the at
least one bioactive material layer 18.
[0106] The method of treatment according to certain embodiments of
the invention is completed by inserting the device 10 into the
vascular system of the patient. The at least one porous layer 20
and any additional porous layers 24 automatically release the
bioactive material or materials in a controlled fashion into the
patient.
[0107] The remaining details of the method of medical treatment are
the same as those disclosed with respect to the method of making
the device 10 of certain embodiments of the invention; for the sake
of brevity, they need not be repeated here.
[0108] In view of the disclosure above, it is clear that certain
embodiments of the invention provides an implantable medical device
which achieves precise control over the release of one or more
bioactive materials contained in the device. Moreover, the
polyimide, parylene, parylene derivative or other polymeric layers
16, 20 and/or 24 can be remarkably thin, in comparison to the
thicknesses required for other polymer layers. The bulk or
substantial majority of the overall coating on the structure 12 can
therefore consist of bioactive material. This allows the supply of
relatively large quantities of bioactive material to the patient,
much greater than the amounts supplied by prior devices. These
quantities of bioactive material can be supplied to any of a wide
variety of locations within a patient during or after the
performance of a medical procedure, but are especially useful for
preventing abrupt closure and/or restenosis of a blood vessel by
the delivery of an antithrombic or other medication to the region
of it which has been opened by PTA. The invention permits the
release rate of a bioactive material to be carefully controlled
over both the short and long terms. Most importantly, any
degradation of the bioactive material which might otherwise occur
by other polymer coating techniques is avoided.
[0109] The other details of the construction or composition of the
various elements of the disclosed embodiment of certain embodiments
of the invention are not believed to be critical to the achievement
of the advantages of certain embodiments of the invention, so long
as the elements possess the strength or flexibility needed for them
to perform as disclosed. The selection of these and other details
of construction are believed to be well within the ability of one
of ordinary skills in this area, in view of the present
disclosure.
INDUSTRIAL APPLICABILITY
[0110] Certain embodiments of the invention is useful in the
performance of vascular surgical procedures, and therefore finds
applicability in human and veterinary medicine.
[0111] It is to be understood, however, that the above-described
device is merely an illustrative embodiment of the principles of
this invention, and that other devices and methods for using them
may be devised by those skilled in the art, without departing from
the spirit and scope of the invention. It is also to be understood
that the invention is directed to embodiments both comprising and
consisting of the disclosed parts. It is contemplated that only
part of a device need be coated. Furthermore, different parts of
the device can be coated with different bioactive materials or
coating layers. It is also contemplated that different sides or
regions of the same part of a device can be coated with different
bioactive materials or coating layers.
* * * * *