U.S. patent application number 10/911968 was filed with the patent office on 2005-02-10 for surface features of an implantable medical device.
Invention is credited to Chen, Charlene, Guruwaiya, Judy A., Harish, Sameer, Hossainy, Syed, Mirzaee, Daryush, Sanders-Millare, Deborra, Wu, Steven Z..
Application Number | 20050033411 10/911968 |
Document ID | / |
Family ID | 33132093 |
Filed Date | 2005-02-10 |
United States Patent
Application |
20050033411 |
Kind Code |
A1 |
Wu, Steven Z. ; et
al. |
February 10, 2005 |
Surface features of an implantable medical device
Abstract
An implantable medical device, such as a stent or graft, having
asperities on a designated region of its outer surface is
disclosed. The asperities can serve to improve retention of one or
more layers of a coating on the device and to increase the amount
of coating that can be carried by the device. The asperities can be
formed by using a stream of pressurized grit to roughen the
surface. The asperities can also be formed by removing material
from the outer surface, for example, by chemical etching with or
without a patterned mask. Alternatively, the asperities can be
formed by adding material to the outer surface, for example, by
welding powder particles to the outer surface or sputtering.
Inventors: |
Wu, Steven Z.; (Santa Clara,
CA) ; Harish, Sameer; (Fremont, CA) ;
Sanders-Millare, Deborra; (San Jose, CA) ; Guruwaiya,
Judy A.; (San Jose, CA) ; Mirzaee, Daryush;
(Sunnyvale, CA) ; Hossainy, Syed; (Fremont,
CA) ; Chen, Charlene; (Redondo Beach, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
33132093 |
Appl. No.: |
10/911968 |
Filed: |
August 4, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10911968 |
Aug 4, 2004 |
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09675092 |
Sep 28, 2000 |
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6805898 |
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Current U.S.
Class: |
623/1.15 |
Current CPC
Class: |
A61F 2/91 20130101; A61F
2/0077 20130101; A61F 2250/0068 20130101; A61F 2/915 20130101; A61F
2/848 20130101; A61F 2230/0013 20130101; A61F 2002/91533 20130101;
A61F 2250/0067 20130101; Y10S 623/901 20130101 |
Class at
Publication: |
623/001.15 |
International
Class: |
A61F 002/06 |
Claims
1-21. (canceled).
22. An implantable medical device comprising a substrate having an
outer surface, the outer surface including asperities on a
designated region of the outer surface so as to provide for a
roughness factor greater than 40 nm.
23. The device of claim 22, wherein the substrate is a generally
tubular structure having an inner surface opposite the outer
surface, and the inner surface having a roughness factor less than
40 nm.
24. The device of claim 22, wherein the a roughness factor is
greater than 100 nm.
25. The device of claim 22, wherein the designated region comprises
the entire outer surface.
26. The device of claim 22, wherein the designated region comprises
a portion of the outer surface in only a middle section of the
device.
27. The device of claim 22, wherein the asperities are formed by
material deposited on the outer surface of the device.
28. The device of claim 27, wherein the material is
radioopaque.
29. The device of claim 22, wherein the asperities comprise sharp
tips.
30. The device of claim 22, further comprising a layer of a
material overlaying the asperities of the designated region of the
outer surface.
31. The device of claim 30, wherein the layer comprises a
therapeutic substance.
32. The device of claim 22, wherein the device is a stent or a
graft.
33. The device of claim 22, wherein the device further comprises a
plurality of depots in the outer surface, and wherein a layer of
material fills the depots and covers the asperities, the material
comprising a therapeutic substance.
34. A stent comprising a generally tubular structure having a
surface with a roughness factor greater than 40 nm.
35. The stent of claim 34, wherein the surface is covered by a
layer of material comprising a therapeutic substance.
36. The device of claim 22, the device being a stent comprising an
inner surface opposite the outer surface and a side wall between
the outer and inner surfaces, wherein the side wall has a roughness
factor less than 40 nm.
37. The device of claim 22, wherein the asperities comprise tips
having a shape selected from the group of (a) sharp, (b) rounded,
(c) square or (d) a combination thereof.
38. The device of claim 22, wherein the roughness factor is between
50 nm and 50 .mu.m.
39. The device of claim 29, wherein the sharp tips have a height
between 0.1 .mu.m and 10 .mu.m.
40. The device of claim 30, wherein the layer is a first layer,
further comprising a second layer of material overlaying a portion
of the first layer.
41. The stent of claim 34, wherein the structure has an inner
surface opposite an outer surface, and wherein the inner surface
has a roughness factor less than 40 nm.
42. The stent of claim 34, wherein the roughness factor is greater
than 100 nm.
43. The stent of claim 34, wherein the surface comprises an entire
outer surface of the structure.
44. The stent of claim 34, wherein the surface comprises a portion
of an outer surface of the structure in only a middle section of
the stent.
45. The stent of claim 34, wherein the surface is covered by a
material comprising a radioopaque substance.
46. The stent of claim 34, wherein the surface comprises asperities
including sharp tips.
47. The stent of claim 46, wherein the sharp tips have a height
between 0.1 .mu.m and 10 .mu.m.
48. The stent of claim 34, comprising an inner surface opposite an
outer surface, and a side wall between the outer and inner
surfaces, wherein the side wall has a roughness factor less than 40
nm.
49. The stent of claim 34, wherein the surface comprises asperities
including tips having a shape selected from the group of (a) sharp,
(b) rounded, (c) square or (d) a combination thereof.
50. The stent of claim 34, wherein the roughness factor is between
50 nm and 50 .mu.m.
51. The stent of claim 35, wherein the layer is a first layer,
further comprising a second layer of material overlaying a portion
of the first layer.
52. An implantable medical device, comprising: a surface including
protrusions and indentations, the protrusions having a height; and
a coating material deposited on the surface so that the height of
some of the protrusion is greater than the thickness of the
material deposited on the surface.
53. The device of claim 52, wherein the coating material is a
therapeutic substance.
54. The device of claim 52, wherein the protrusions include sharp
tips.
55. The device of claim 54, wherein the sharp tips have a height
between 0.1 .mu.m and 10 .mu.m.
56. The device of claim 52, wherein the protrusions and
indentations form a roughened surface having a roughness factor
greater than 40 nm.
57. The device of claim 52, wherein the protrusions and
indentations form a roughened surface having a roughness factor
between 50 nm and 50 .mu.m.
58. The device of claim 52, wherein the protrusions include tips
having a shape selected from the group of (a) sharp, (b) rounded,
(c) square or (d) a combination thereof.
59. The device of claim 52, wherein the coating material is a first
coating material, further comprising a second coating material
overlaying a portion of the first coating material so that the
protrusions are completely covered by the second coating
material.
60. The device of claim 52, wherein the device is a stent or a
graft.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to surface features of implantable
medical devices, for example stents and grafts, and to methods for
forming such surface features.
[0003] 2. Description of the Background
[0004] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A catheter assembly having a
balloon portion is introduced into the cardiovascular system of a
patient via the brachial or femoral artery. The catheter assembly
is advanced through the coronary vasculature until the balloon
portion is positioned across the occlusive lesion. Once in position
across the lesion, the balloon is inflated to a predetermined size
to radially compress against and remodel the artery wall for
dilating the lumen. The balloon is then deflated to a smaller
profile to allow the catheter to be withdrawn from the patient's
vasculature.
[0005] A problem associated with the procedure includes formation
of intimal flaps or torn arterial linings that can collapse and
occlude the conduit after the balloon is deflated. Moreover,
thrombosis and restenosis of the artery may develop over several
months after the procedure, which may require another angioplasty
procedure or a surgical by-pass operation. To reduce the partial or
total occlusion of the artery by the collapse of arterial lining
and to reduce the chance of the development of thrombosis and
restenosis, an implantable device, an example of which includes an
expandable stent, is implanted in the lumen to maintain the
vascular patency. Stents are scaffoldings, usually cylindrical or
tubular in shape, functioning to physically hold open, and if
desired, to expand the wall of the passageway. Typically stents are
compressed for insertion through small cavities via small
catheters, and then expanded to a larger diameter once at the
desired location. Examples in patent literature disclosing stents
include U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.
4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued
to Wiktor.
[0006] A problem encountered with intravascular stents is that,
once implanted into the blood stream, platelets and other blood
components tend to adhere to any portion of the stent surfaces
having roughness or irregularity. Adhesion and aggregation of
platelets and other blood components can lead to thrombosis and
restenosis. Therefore, an important aspect of manufacturing and
finishing stents is ensuring that all stent surfaces are made
extremely smooth, without roughness and irregularities. This is
accomplished by highly polishing the entire surface of the stent
material, typically by electropolishing or by using an abrasive
slurry, as described in U.S. Pat. No. 5,746,691 titled "Method for
Polishing Surgical Stents" issued to Frantzen and U.S. Pat. No.
5,788,558 "Apparatus and method for Polishing Lumenal Prostheses"
issued to Klein.
[0007] To further fight against thrombosis and restenosis, and in
treating the damaged vascular tissue, therapeutic substances can be
administered. For example, anticoagulants, antiplatelets and
cytostatic agents are commonly used to prevent thrombosis of the
coronary lumen, to inhibit development of restenosis, and to reduce
post-angioplasty proliferation of the vascular tissue,
respectively. To provide an efficacious concentration to the
treated site, systemic administration of these drugs often produces
adverse or toxic side effects for the patient. Local delivery is a
highly suitable method of treatment in that smaller levels of
medication, as compared to systemic dosages, are concentrated at a
specific site. Local delivery therefore produces fewer side effects
and achieves more effective results.
[0008] One commonly applied technique for the local delivery of
therapeutic substances is through the use of medicated stents. A
well-known method for medicating stents involves the use of a
polymeric carrier coated onto the body of the stent, as disclosed
in U.S. Pat. No. 5,464,650 issued to Berg et al., U.S. Pat. No.
5,605,696 issued to Eury et al., U.S. Pat. No. 5,865,814 issued to
Tuch, and U.S. Pat. No. 5,700,286 issued to Tartaglia et al. The
therapeutic substances are impregnated in, located on, or provided
underneath the polymeric coating for release in situ once the stent
has been implanted.
[0009] An obstacle often encountered with the use of stent coatings
is poor adhesion of the polymeric coating to the surface of a
stent. During stent delivery, a poorly adhering coating can be
rubbed and peeled off of the stent if the coating contacts an
arterial wall while the stent is being moved into position. Also,
when a coated stent is expanded in situ, the distortion the stent
undergoes as it expands can cause the coating to peel, crack, or
tear, and disengage from the stent. Poor adhesion of the coating
material can promote thrombosis and restenosis, by providing
additional surfaces for platelets and other blood components to
adhere. Additionally, poor adhesion and loss of the coating also
leads to loss of a significant amount of the drugs to be delivered
from the coating.
[0010] Another technical challenge in using stent coatings to
deliver drugs is loading enough drug onto the stent, so that an
effective amount of the drug or drug combination is delivered to
the treatment site. The total amount of a drug that can be loaded
onto a stent in a polymeric coating is limited by the amount of
drug that can be mixed into the polymer (the concentration of the
drug in the polymer), and the amount of polymer and drug mixture
that can be coated onto the stent (the thickness of the coating on
the stent for a given stent size). Therefore, a stent that carries
more coating can deliver greater amounts of drugs. However,
increasing the thickness of a stent coating can be difficult,
particularly if the coating does not adhere well to the stent
material.
[0011] When delivering drugs from a stent, it is also desirable to
control the timing and rate of release of the drugs being
delivered. Controlled release can be achieved by coating a stent
with a number of layers. For instance, each layer can contain a
different drug or be made of a polymer that releases drugs at
different rates. However, additional layers tend to adhere poorly
to underlying layers. The additional layers peel off either during
application of the additional layer over an underlying layer, or,
as described above, when the stent is delivered and expanded within
the artery.
[0012] Another complication for drug delivery from a stent is that
the arterial wall tissue the stent is compressed against can be
tough and fibrotic, preventing medication released from the stent
from penetrating the tissue in which the medication may be
therapeutically beneficial.
SUMMARY
[0013] An implantable medical device capable of delivering
therapeutic substances from a coating is provided, which provides a
high retention of one or more layers of coating material. The
implantable device also allows a greater total amount of coating to
be carried by the device, allowing for greater amounts of
therapeutic substances to be delivered from the device. In some
embodiments the implantable device can penetrate the arterial wall
to enhance delivery of therapeutic substances into the arterial
wall.
[0014] In one embodiment within the present invention, the
implantable medical device has a generally tubular structure with
an inner surface and an outer surface. The outer surface has
asperities on designated regions that have roughness factors, Ra,
of greater than 40 nm. The designated regions can be the entire
outer surface, a middle section of the outer surface, or ends of
the outer surface. Typically, the inner surface is smooth.
[0015] In various embodiments, the outer surface, or portion
thereof, can be coated with a coating containing a therapeutic
substance or substances, a polymer, or a combination of therapeutic
substances and polymer. The coating can be made of one or more
layers and the layers can hold different therapeutic substances,
polymers, or combination of therapeutic substances and
polymers.
[0016] The asperities may have surface protrusions and indentations
of various shapes. In some embodiments, the asperities can have
sharp tips, be rounded, be square, or a combination of these
shapes.
[0017] Exemplary embodiments are made by polishing the inner
surface of the implantable medical device and forming asperities on
the designated region of the outer surface. In some embodiments,
the inner surface is polished before the asperities are formed and
the inner surface is protected while the asperities are being
formed.
[0018] In some embodiments, the asperities are formed by projecting
grit, which can be beads or sand, at the designated region of the
outer surface.
[0019] In some embodiments, the asperities are formed by depositing
material onto the designated region. In one method, the material is
deposited by adding particles to the designated region and bonding
the particles, for instance by sintering, to the designated region.
In one method, the material is deposited by sputtering. In some
embodiments, the material added to the outer surface is
radio-opaque.
[0020] In some embodiments, the asperities are formed by applying a
chemical etchant to the designated region and rinsing the chemical
etchant off of the region after a predetermined period of time. The
chemical etchant can by applied by sponging or spraying the etchant
onto the outer surface. In some embodiments, a patterned mask,
which has openings, is applied to the outer surface and then the
chemical etchant is applied, allowing the chemical etchant to etch
through the openings.
[0021] In some embodiments, the asperities are formed by machining
or laser cutting.
[0022] These and other features and aspects of the various
embodiments of the present invention may be better understood in
view of the drawings and the following detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0023] FIG. 1A is a perspective view of an example of a stent in an
expanded state.
[0024] FIG. 1B is a cross-sectional side view of a stent implanted
in a lumen.
[0025] FIG. 1C is a side view of a graft.
[0026] FIG. 1D is a cross-sectional side view of a graft implanted
in a damaged blood vessel.
[0027] FIG. 1E illustrates a portion of the struts of the stent of
FIG. 1A, which shows depots formed therein.
[0028] FIG. 1F is a cross-sectional side view of a stent strut,
taken in the direction of the arrows and along the plane of line
1F-1F of FIG. 1E, illustrating a depot formed in strut.
[0029] FIG. 1G illustrates the strut of FIG. 1F in which a material
has been deposited into the depot.
[0030] FIG. 2 graphically depicts elements used in determining the
roughness factor, Ra, of a surface.
[0031] FIGS. 3A, 3B, 3C, 3D, 3E, 3F, and 3G are cross-sectional
views of portions of implantable medical devices with exemplary
asperities. FIGS. 3F and 3G also show depots.
[0032] FIG. 4A, 4B, 4C, 4D and 4E are cross-sectional views of
portions of implantable medical devices with exemplary asperities
covered with a coating.
[0033] FIG. 4F is a cross-sectional view of a portion of a
conventional implantable medical device that is coated.
[0034] FIG. 5A, 5B, 5C, 5D, and 5E are cross-sectional views of
portions of implantable medical devices with exemplary asperities
covered with two or three layers of coatings.
[0035] FIG. 5F is a cross-sectional view of a portion of a
conventional implantable medical device that has two layers of
coating.
[0036] FIG. 5G is a cross-sectional view of a portion of an
implantable medical device with exemplary asperities and a depot.
The depot contains a material and the material and the asperities
are covered with a coating.
[0037] FIG. 6A is a schematic representation of the method of using
a pressurized grit source to create asperities on the outer surface
of a stent while protecting the inner surface of the stent.
[0038] FIG. 6B is a schematic representation of a stent having
asperities on a middle portion.
[0039] FIG. 6C is a schematic representation of a stent having
asperities adjacent to the ends of the stent.
[0040] FIGS. 7A and 7B are scanning electron micrograph photographs
of portions of stent surfaces on which asperities have been created
by bead blasting.
[0041] FIG. 8 is a perspective view of a portion of a stent with
asperities on the top surface deposited by sputtering material onto
the top surface.
DETAILED DESCRIPTION
[0042] The present invention includes surface treatments for
implantable medical devices, such as stents and grafts, often
referred to as endoprostheses. FIGS. 1A and 1B illustrate an
exemplary stent 100 in accordance with one embodiment. Stents are
scaffoldings, usually cylindrical or tubular in shape, which are
inserted into an anatomical passageway and operate to physically
hold open and, if desired, to expand or replace the wall of a
passageway. Stents are capable of being compressed for insertion
through small cavities via balloon-catheters, positioned in a
desired location, then expanded to a larger diameter. Stents can be
either balloon expandable or self-expanding.
[0043] Referring to FIG. 1A, exemplary stent 100 is a patterned
tubular device that includes a plurality of radially expanding
cylindrical struts 102 disposed generally coaxially and
interconnected by connecting struts 104 that are disposed between
and connect adjacent cylindrical struts 102. Struts 102 and 104 can
be any suitable thickness T between the stent outer surface 110 and
inner surface 112. Typically thickness T is in the range of
approximately 50 .mu.m (0.002 inches) to 200 .mu.m (0.008 inches).
A specific choice of thickness depends on the anatomy and size of
the target lumen.
[0044] FIG. 1B illustrates stent 100 of FIG. 1A implanted in a
lumen 106. The stent struts 102 and 104 define a stent body having
an outer surface 110 in contact with inner surface of the lumen
115, and an inner surface 112 in contact with the fluid stream
through the lumen 117. For example, when stent 100 is implanted in
a blood vessel, the outer surface is in contact with the blood
vessel wall, and the inner surface is in contact with the blood
flowing through the vessel.
[0045] An exemplary graft 120 is illustrated in FIG. 1C. Grafts are
typically placed in a blood vessel to either replace a diseased
segment that has been removed, or, as illustrated in FIG. 1D, to
form a bypass conduit through a damaged segment of the vessel wall,
for instance, an aneurysm 126. The graft 120 has a tubular portion
122, which spans the site of the damaged tissue and through which
the blood flows. The graft has sections, 124 and 125, at both ends
of tube 122 that are used to secure the graft to the inside of the
vessel wall 115. The graft also has an outer surface 130, portions
of which are in contact with inner surface of the blood vessel wall
115, and an inner surface 132, in contact with the blood flowing
through the vessel 117.
[0046] In some embodiments, the implantable device may include a
single depot, or a plurality of depots, formed in an outer surface
thereof. The materials may be filled, fully or partially, with a
material, such as a therapeutic substance or polymer, as discussed
below.
[0047] FIGS. 1E, 1F, and 1G illustrate a portion of stent struts
102, 104 of the exemplary stent 100 having depots 130 formed in an
outer surface thereof. Depots 130, which may also be referred to as
a pores or a cavities, can be formed in virtually any implantable
device structure. Depots 130 are formed by a manufacturer at any
preselected location and have any preselected depth, size, and
geometrical configuration. The location of depots 130 on the outer
surface of the implantable device varies according to intended
usage and application. The depth and size of depots 130 typically
depend on the material and dimensions of the implantable device,
the type and amount of materials deposited within depot 130, and
the clinical purpose and usage of the device. Typically, depots
have a depth, D, that is between 10% and 90%, e.g. 40% to 60%, of
the strut thickness, T (illustrated in FIG. 1F). The depth and size
of the individual depots 130 formed on a single device can vary
relative to one another. Depots 130 may be formed in a variety of
selected geometrical shapes including, but not limited to,
generally cylindrical shapes, generally conical shapes, and
elongated trenches.
[0048] In some embodiments, depots 130 contain material 132, as
depicted in FIG. 1G. Depots 130 may contain a material that is the
same, or different than the device covering material, as described
in detail below with respect to implantable medical device covers
for delivering therapeutic substances.
[0049] The conventional practice of having highly polished
implantable medical device surfaces contributes to the poor
adhesion problem and other problems mentioned above that are
associated with coatings used on implantable devices and drug
delivery from such coatings. Therefore, in accordance with the
present invention, asperities are created on a designated region or
regions of the surface of the implantable devices. The asperities
cause the designated region to have a roughness factor, Ra, defined
below, greater than about 40 nm (nanometers), which is the upper
limit of roughness factors typical of polished stent surfaces.
Typically, the asperities so formed cause the designated region to
have a roughness factor, Ra, greater than about 100 nm.
[0050] It is often desirable for the inner surface of the
implantable medical device, which contacts the blood flowing
through the vessel, to be smooth, in order to prevent aggregation
of platelets from the blood on the stent. The outer surface of the
implantable devices, which contacts the arterial wall, need not be
smooth. Therefore, the designated region or regions having the
asperities are typically on the outer surface of the implantable
device.
[0051] A roughness factor, Ra, is used to quantify the surface
roughness. In FIG. 2, a surface having asperities is outlined in
two-dimensions by the profile 210. Profile 210 outlines the
irregular protrusions 211 and indentations 212 of a surface having
asperities. The roughness factor, Ra, is defined herein as the
arithmetic mean of the absolute values of the profile departures
213 from a centerline 214 through profile 210, within an evaluation
length 215. For a three-dimensional surface, centerline 214 becomes
a mean plane and Ra is defined as the arithmetic mean of the
absolute values of the surface departures from the mean plane
within an evaluation area. The digital approximation for the
three-dimensional Ra over an evaluation area is given in Equation
1: 1 R a = 1 MN j = 1 M i = 1 N Z ji Equation 1
[0052] M and N are the number of data points in the X and Y
directions, respectively, of the evaluation area, and Z is the
surface height of each point relative to the mean plane.
[0053] The roughness factor, Ra, of asperities on an implantable
medical device within the present invention may be measured, for
example, by using a commercially available Veeco Metrology Group
(Tucson, Ariz.) WYKO NT-2000 system, which is a non-contact optical
profiler. VSI (vertical scanning interferometer) mode is used. For
cylindrical implantable medical devices, such as stents, cylinder
and tilt terms are removed so the stent surface appears flat. A low
pass filter is used which removes the effects of high spatial
frequency roughness, smoothing over features that are smaller than
a nine pixel window. A 50.times. objective and 2.0.times. FOV
converter sense are used to produce an effective magnification of
100.times.. This objective and converter combination profiles a
0.58 .mu.m.times.0.44 .mu.m evaluation area, at a spatial sampling
interval of 159.13 nm. For statistical purposes, samples are
measures at five separate locations. Equation 1 is used to
calculate a value of Ra.
[0054] In general, outer surface asperities in accordance with the
present invention can have a variety of shapes, some examples of
which are illustrated in FIGS. 3A-3E. FIGS. 3A-3E illustrate
cross-sectional views of portions of implantable devices (for
example, portions of stent struts, 102 or 104) with average
thicknesses 310 and inner surfaces 312. Outer surface asperities
314 can be random and irregular, as exemplified in FIGS. 3A and 3B.
The asperities 314 can also be more regular and well-defined, as
exemplified in FIGS. 3C, 3D, and 3E. The asperities of the
embodiments can be formed by protrusions and indentations in the
surface that can have a variety of shapes and sizes, for example,
the rounded shape 318 of FIG. 3B, the pointed shape 319 of FIG. 3D,
or the rectangular shape 315 of FIG. 3E. In the exemplary surface
of FIG. 3E, the protrusion and indentations cause the surface to
have ridges 316 and channels 317. The protrusions and indentations
can also have different densities on the surface, as illustrated by
the difference between FIGS. 3C and 3D.
[0055] As illustrated by the exemplary surfaces in FIGS. 3F and 3G,
the asperities 314 may be formed on an implantable medical device
that has depots 330. Note that depots 330 have a greater depth than
the asperities 314. The depot surface 333 may be smooth, as
illustrated in FIG. 3F, or depot surface 333 may contain asperities
314, as illustrated in FIG. 3G.
[0056] FIGS. 4A-4E illustrate coatings 401 covering the example
surfaces illustrated in FIGS. 3A-3E. Coating 401 may be, for
example, a polymeric coating that contains a therapeutic substance,
as described in detail below. As compared to the coated smooth
surface 410 (FIG. 4F) of a conventional coated implantable medical
device, the asperities of the present invention provide a
mechanical hold for the coating and help to prevent the coating
from slipping or peeling off of the implantable device. The
asperities also provide greater surface area on the implantable
device, increasing the amount of coating that can be put onto the
surface. The greater amount of coating allows the implantable
device to carry more therapeutic substance, so more medicine can be
delivered from the implantable device in situ. The coating may
fully cover the asperities or the peaks of the asperities may
extend through the coating.
[0057] The asperities can also allow two or more layers of a
coating to adhere to an implantable device, as illustrated in FIGS.
5A-5E. A first layer 510 is coated onto the surface and then
covered with a second layer, 512, or even third layer 514 (FIG.
5C). The first coating 510 partially fills the depth of the areas
between the asperities, but the peaks of some or all of the
asperities extend above the coating 510. Because of the asperities,
the second (and third) layer can adhere to both the first layer and
protruding implantable device material, as can be seen by
comparison to a conventional smooth stent with two layers, FIG.
5F.
[0058] The multiple coating layers of FIGS. 5A-5E can be used to
achieve different therapeutic substance release profiles. For
example, if it is desired to release two therapeutic substances
sequentially, one followed by the other, two layers as illustrated
in FIG. 5A, 5B, 5D, and 5E can be used. A therapeutic substance in
the outer layer 510 will be released first, as the outer layer
dissolves, and a therapeutic substance in the underlying layer 512
will be released after the outer layer 510 has wholly or partially
dissolved. This release profile is sometimes referred to as a "late
burst", especially if the second therapeutic substance to be
released (that in the underlying layer 512) is in a highly soluble
form, for instance, pure crystalline form. It should also be noted
that, in accordance with the present invention, the underlying
layer can be made of a material that does not adhere well to the
surface, because the outer layer can be used to hold the underlying
layer onto the implantable device. As shown in FIGS. 5A-5E, the
outer layer 512 can adhere to portions of the surface not covered
by the underlying layer, and thus act as a seal for an underlying
layer.
[0059] If the implantable device contains depots 330 (as
illustrated in FIG. 5G), the therapeutic substance release profile
can be manipulated even further. The coating layer 512 on the outer
surface of the implantable device and over depots 330 will need to
partially or wholly dissolve before the material 520 deposited in
depots 330 is exposed and can begin to dissolve and release the
therapeutic substance. Thus, release of the material deposited in
the depots 330 can be delayed by application of the coating layer
512.
[0060] If the asperities are sharp, having, for instance, sharp
protrusions as in 319, FIG. 3D, or sharp edges, they can also
penetrate the tissue of the lumen once the implantable device is
expanded. The penetration may enhance the ability of therapeutic
substances released from the coating to reach target cells. Sharp
asperities may also help to hold the implantable device in place in
the lumen, which may be particularly useful with grafts, which need
to be affixed to the lumen at the distal and proximal end of the
damaged tissue. In these cases, the asperities can be formed on the
distal and proximal ends of the graft.
[0061] In the discussion that follows, methods are described for
forming asperities on the outer surface of a stent, as an example
of an implantable medical device. It is to be understood that, in
accordance with the invention, these methods can be applied to any
implantable medical device, including grafts and other implantable
devices.
[0062] In one method for manufacturing a stent, a thin-walled,
small diameter, cylindrical tube is cut to produce the desired
stent pattern. Cutting is typically accomplished through laser
cutting, as described in U.S. Pat. No. 5,759,192 "Method and
Apparatus for Direct Laser Cutting of Metal Stents" to Saunders, or
chemical etching, as described in U.S. Pat. No. 6,056,776
"Expandable Stents and method of Making Same" to Lau et al. Other
methods of cutting stent lattice patterns can be used. Instead of
cutting the pattern into a tube, the stent lattice pattern can be
cut into on a flat sheet of material, which is then roll and joined
in a cylindrical configuration.
[0063] The tube or flat sheet used to form the stent may be made of
any suitable biocompatible material such as a metallic material or
an alloy, examples of which include, but not limited to, stainless
steel, "MP35N," "MP20N," elastinite (Nitinol), tantalum,
nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or
combinations thereof. "MP35N" and "MP20N" are trade names for
alloys of cobalt, nickel, chromium and molybdenum available from
standard Press Steel Co., Jenkintown, Pa. "MP35N" consists of 35%
cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N"
consists of 50% cobalt, 20% nickel, 20% chromium, and 10%
molybdenum. The stent also may be made from bioabsorbable or
biostable polymers.
[0064] Often, cutting the stent lattice pattern, especially by
laser, leaves scrap that must be removed, in a process known as
descaling, to reveal the lattice pattern of the stent. Descaling is
typically accomplished by ultrasonically cleaning the stent in
heated acid, as described in U.S. Pat. No. 5,759,192. The stent is
also polished so the stent surfaces are made as smooth as possible.
In conventional processes, a cleaning or rinsing step, usually with
an alcohol solution, follows the polishing step to remove any of
the polishing solution that may be left on the stent.
[0065] Another method that is used to manufacture stents is to mold
the stent into the desired shape. This method is especially useful
if the stent is made from a polymeric material. Polishing is
sometimes done after molding to ensure smooth stent surfaces.
[0066] Depots 130, 330 may be formed as a laser trench on the
implantable device by exposing the surface to an energy discharge
from a laser, such as an excimer laser. Alternative methods of
forming such depots 130, 330 include, but are not limited to,
physical and chemical etching techniques. Techniques of laser
fabrication or etching to form depots are well-known to one of
ordinary skill in the art. Depots 130, 330 may be added before or
after the asperities are formed
[0067] In general, the asperities may be added to the outer surface
of the stent at any point in the stent manufacturing process,
provided that subsequent processing does not remove the asperities
desired in the completed stent.
[0068] For example, in one embodiment, the asperities on the stent
outer surface are created after the stent has been polished. In
this case the smooth inner surface is protected during creation of
the asperities to preserve the smoothness of the inner surface.
This may be done, for example, by inserting a mandrel or a hypo
tube inside the stent or inserting and inflating a balloon inside
the stent. The inner surface can also be masked with a temporary
protective coating, which is removed after the asperities have been
added to the outer surface of the stent. For example, a poly vinyl
alcohol (PVA) solution (80% by weight dissolved in hot water at
100.degree. C.) can be applied to the inner surface with a syringe
and allowed to air dry, and can be removed by soaking in water. In
another embodiment, the asperities are created before the stent
pattern is cut. In these cases, the asperities need to be preserved
when the stent is cut, descaled, and polished, and therefore this
embodiment works well with asperities that are not likely to be
destroyed in subsequent processing. If subsequent processing might
destroy the asperities, a temporary protective coating can be
applied to the outer surface of the stent to preserve the
asperities.
[0069] If the stent contains depots, the asperities can be formed
either before or after formation of the depots, depending on the
methods used to form the depots and the asperities. In some
methods, if the asperities are formed after the depots, the surface
of the depots may also be roughened.
[0070] Methods of Treating the Surface
[0071] A. Mechanical Methods for Creating Asperities
[0072] A variety of methods can be used to create the asperities on
the outer surface of the stent. FIG. 6A illustrates one embodiment,
in which a pressurized stream of grit material is directed upon the
outer surface 110 of stent 100 to create asperities on the outer
surface of the stent. Examples of such processes include bead
blasting and sand blasting. Bead blasting refers to the use of
pressurized gas to project beads of a relatively uniform diameter
at an object at a high velocity. The bead may be made of a variety
of materials, such as latex, aluminum oxide, or silicon oxide. In
sand blasting, the grit projected does not have as uniform a
diameter as in bead blasting. Both bead blasting and sand blasting
are techniques that are well known in the art.
[0073] In FIG. 6A, the stent 100, which has been polished, is
mounted onto a mandrel 612 to protect the stent's inner surface
during blasting. The stent is then rotated while the grit 616, e.g.
beads, is projected at the stent outer surface from the pressurized
grit source 618. The grit is projected at the stent at an
approximately 30.degree. angle 620 to the vertical axis of the
stent, and is passed up and down over the outer surface 110 of the
stent until the desired pattern, type, and number of asperities
have been created. The visual appearance of the surface can be used
to indicate that it is roughened appropriately. The outer surface
of the stent is smooth, shiny, and reflective before the process,
but becomes dull, non-reflective, and of a darker color shade after
the roughening process. Subsequently, the stent is removed from the
mandrel and cleaned, for example by immersion and sonication in an
isopropyl alcohol bath for approximately 20 minutes.
[0074] The roughness factor achieved using a pressurized grit
source can be controlled by the size of the grit, e.g., the
diameter of the beads, the pressure used, the distance between the
grit source and the stent surface, and the length of time the grit
is blasted at the surface. By way of example and not limitation,
the grit can be beads having a diameter of between 10 .mu.m and 50
.mu.m. Pressures of 30 PSI (pounds per square inch) to 60 PSI can
be used to project the beads from a distance of approximately 3-10
cm from the stent. The grit source is passed very quickly, in
approximately 1-3 seconds, down and up over the stent outer
surface. The stent is then rotated 120.degree. and the process
repeated twice so the entire stent is roughened.
[0075] Average roughness values achieved are typically in a range
of 100 nm to 300 nm, and usefully in a range of 130 nm to 210
nm.
[0076] Note also, that the entire outer surface need not be
roughened. For example, the grit may be projected at only a middle
region 624 (FIGS. 6A and 6B) of the stent, so that the asperities
are formed only in a middle region of the stent's outer surface,
and not adjacent to the opposing ends of the stent, FIG. 6B. Or, as
illustrated in FIG. 6C, the grit may be projected only at the ends
of the stent, to create asperities at one or both ends, 625 and
626.
[0077] If the stent contains depots, the depots may be in regions
where there are asperities, may be in regions where there are not
asperities, or both.
[0078] FIGS. 7A and 7B are scanning electron micrograph photographs
of portions of stent struts (e.g. 102 of FIG. 1A) having asperities
created by bead blasting (as described above). The stent material
in the examples shown in the photographs is 316L stainless steel.
The photographs show the outer surface of the struts, which have
been roughened. The asperities in FIG. 7A were created using a
pressure of 60 PSI, and the asperities in FIG. 7B were created
using a pressure of 30 PSI. The photographs also show the surfaces
of the sides of the struts, which were also roughened during the
bead blasting process. In other embodiments, the sides of the
struts may be left smooth or asperities can be added to only a
portion thereof.
[0079] In another embodiment, the asperities may be formed by
grinding the tubular stent between two sanding plates or using
sandpaper to scratch the outer surface. In this method, the
roughness factor achieved depends on the grain size of the surface
of the sanding plates. This method may be particularly useful with
polymer stents or stents made from relatively soft materials.
Typically, this method is used to create asperities after the stent
pattern has been cut into the hypotube (or cut into a flat piece of
material and the material rolled into a tube), and after the stent
has been descaled, if descaling is necessary, and polished.
[0080] B. Creating Asperities by Removal of Stent Material
[0081] In another embodiment, chemical etching is used to create
asperities on the outer surface of a stent. Chemical etching
methods are known to those of ordinary skill in the art. The
chemical etchant solution typically includes an acid that degrades
and dissolves the material from which the stent is made. The
chemical etchant is applied to the outer surface, and then rinsed
off of the surface after a predetermined period of time. The length
of time the etchant is left on the surface depends on the etch rate
and the depth of etch desired.
[0082] The roughness factor produced by the chemical etchant
depends on the method of application of the etchant. In one
embodiment, the chemical etchant is applied to the stent outer
surface with a fine sponge or by spraying a mist of the chemical
etchant onto the stent. A temporary protective coating, e.g., poly
vinyl alcohol dissolved in water, is applied to the inner surface
of the stent to protect the inner surface from the etchant to keep
the inner surface smooth. The chemical etchant is rinsed off of the
stent, leaving a rough outer surface. The roughness factor will
depend on the stent material and the chemical etchant used, the
amount and length of time the etchant was applied, and how the
etchant was applied.
[0083] In one embodiment, the stent is made of a composite material
where one of the components of the composite material can be easily
dissolved by the chemical etchant. For example, a metal alloy, such
as stainless steel can be used to form the stent and nitric acid
can be applied to the outer surface to create the asperities. A
hydrochloric acid solution, 37% by volume in water, can also be
used to create the asperities.
[0084] In another embodiment, a patterned mask that has openings is
applied to the stent outer surface before the chemical etchant is
applied. The etchant is then applied in a uniform manner and
allowed to etch the stent material through the openings of the
mask. The use of patterned masks with chemical etchants is known to
those of ordinary skill in the art. Because it is usually easier to
mask and etch a flat piece of material than a hypo-tube, the mask
is typically applied to a flat piece of the stent material and the
resulting outer surface pattern etched into the surface. Then, the
flat piece of stent material is cut, rolled and joined into a
stent. The flat piece of stent material may be polished before the
mask and etch process, so that the asperities created by the mask
and etch are not degraded in a subsequent polishing process.
Additionally, a cutting process that does not leave scrap between
the stent struts can be used to eliminate the descaling step, which
may also damage the asperities. For example, the stent pattern can
be cut using another chemical etching step where the second mask,
which protects the asperities, is in the pattern of the stent and
the etchant is allowed to dissolve all material not masked.
[0085] In this embodiment, the patterned mask can be used to make
asperities that are composed of more regular and well-defined
shapes. The shapes can be chosen depending on the eventual
application of the stent. In one example, a patterned masking
followed by etching is used to create asperities composed of
relatively sharp tips (319 of FIG. 3D), or ridges and channels (316
and 317, respectively, of FIG. 3E). The sharp tips 319 can have a
height between 0.1 .mu.m and 10 .mu.m. The sharp tips can be of any
density on the surface, although a higher density produces more
surface area, provides better mechanical hold of the coating, and
has more tips to penetrate the tissue. The asperities made by this
method typically have a roughness factor between 50 nm and 5
.mu.m.
[0086] If, when creating the asperities by chemical etching, a
significant amount of stent material will be removed, for instance
to reduce the average thickness T of the stent strut by more than
10%, a thicker material can be used to form the stent.
[0087] Therefore, the finished stent has the desired strut
thickness T after etching so that the structural integrity of the
stent is not compromised by creating the asperities.
[0088] In other embodiments, asperities are formed by machining or
laser cutting the outer surface. These methods can also be used to
make asperities composed of more regular and well-defined shapes.
For example, a laser discharge machine tool can be programmed to
cut a desired pattern into the outer surface of a stent.
[0089] Because machining and laser cutting will typically remove
material from the stent, a thicker material can be used to form the
stent, resulting in a completed stent having the desired average
strut thickness.
[0090] C. Creating Asperities by Adding Material
[0091] In another embodiment, additional material is deposited onto
the outer surface of the stent to create the asperities. In one
method, the additional material, which is typically a metal, is
first made into a powder. The powder particles are then bonded to
the outer surface to form the asperities. The powder can be made,
for example, by grinding the metal to form particles of a
predetermined size. The particles are then put onto the outer
surface of the stent, for example, by rolling the stent in the
powdered metal or spaying the powdered metal onto the stent. The
stent can be electrostatically charged to a charge, typically
negative, that is opposite that of the powdered metal, to improve
the adhesion of the powder to the stent.
[0092] The stent coated with the particles is then heated to weld
the particles to the stent by methods, for example sintering in a
furnace or with a flame, known to those of skill in the art.
Typically, the stent material, particle material, and sintering
temperature are chosen so that melting temperatures of the
materials allow the particles to be welded to the stent without
distortion of the stent by the heat treatment. For example, the
stent material may be 316L stainless steel and the particles may be
gold, aluminum, or copper. The sintering temperature would have to
be below the melting temperature of 316L stainless steel,
1388.degree. C.
[0093] In this method, the inner surface can be protected by
inserting a mandrel or applying a temporary coating to the inner
surface that prevents the particles from contacting and staying on
the inner surface when they are applied to the stent. The coating,
typically a polymeric material, will burn off of the stent in the
subsequent heat treatment. The temporary coating can also be used
on the outer surface of the stent if it is desired to create
asperities on only designated regions of the outer surface. For
example, if it is desired to have the asperities adjacent to the
ends of the stent (as illustrated in FIG. 6B), the temporary
coating can be applied to the middle portion of the stent before
the particles are applied to the stent.
[0094] The roughness factor, Ra, achieved using this method depends
on the size of the particles in the powder and is in the range of
50 nm to 5 .mu.m.
[0095] The additional material may also be added via physical
deposition processes, for example, sputtering, which is known to
those of ordinary skill in the art. In sputtering, an energy beam,
for instance an ion beam, is directed at a target formed of the
material which is to be deposited on the substrate. The energy beam
dislodges atoms of the target material. The target material atoms
are transported to the substrate, which in this instance is the
stent on which asperities are being formed. Once at the substrate,
the atoms form "islands", or small nodules of the deposition
material on the substrate. FIG. 8 illustrates the "islands" 812
formed on an illustrative portion of the substrate 810,
corresponding to the stent outer surface (310 of FIG. 3).
[0096] Conventionally, sputtering is used to form a thin film of
the deposition material over the substrate, and sputtering
conditions are used such that the "islands" grow, spread, and
condense on the substrate to form a thin film. To form the
asperities, however, the sputtering process conditions are set so
that instead of creating a uniform film over the substrate, the
"islands" do not grow, spread, and condense, leaving a rough
surface. Process conditions in which a lower pressure and shorter
deposition time than is typically used for thin film deposition are
used to form the asperities.
[0097] Typically, a cut stent is inserted into the sputtering
chamber, with inner surface protected, and rotated while material
is deposited on the outer surface. Alternatively, material can be
deposited onto the hypo-tube before the stent pattern is cut into
it, or flat piece of stent material before it is cut and rolled
into stent. If the subsequent processing of the stent will destroy
the added asperities, a temporary protective coating can be applied
to protect them.
[0098] The sputtering, however, may only loosely deposit the
material onto the outer surface of the stent. In such cases, to
further enhance attachment of the deposited material to the
substrate, a heat treatment, for instance sintering can be
performed. As discussed above, the temperature ranges for heating
will depend on the deposition material and the stent material. The
roughness factor achieved in this embodiment will have a lower
value of approximately 50 nm and an upper value of approximately
200 nm.
[0099] Typically, material is added to the outer surface after the
stent is polished, although it can be done at any point in the
process provided the subsequent processes do not remove the
asperities. This will again depend on the material that is used to
manufacture stent and the material deposited on the stent.
[0100] In one embodiment, radiopaque materials are deposited on the
stent, to not only create asperities on the stent, but to allow
visualization of the stent after implantation. For example, the
radio-opaque material can be applied adjacent to the ends of the
stent.
[0101] Coatings for Delivering Therapeutic Substances
[0102] Methods of coating an implantable medical device with a
therapeutic substance or substance, or with a polymer containing
one or more therapeutic substances are known to one of ordinary
skill in the art. One or more therapeutic substances can be added
to an implantable medical device by dissolving or mixing the
therapeutic substances in a solvent and applying the therapeutic
substance and solvent mixture to the implantable medical device. To
cover the implantable device with a polymer containing the
therapeutic substance or substance combination, a solution of the
polymeric material and one or more therapeutic substances are
mixed, often with a solvent, and the polymer mixture is applied to
the implantable device. An implantable device can also be coated
with a polymer which does not contain a therapeutic substance, for
example, to form a sealant layer over an underlying layer, which
does contain a therapeutic substance.
[0103] Methods of applying the therapeutic substance, polymer, or
therapeutic substance and polymer mixture to the implantable
medical device are known to those of skill in the art. Methods
include, but are not limited to, immersion, spray-coating,
sputtering, and gas-phase polymerization. Immersion, or
dip-coating, entails submerging the entire implantable device, or
an entire section of the implantable device, in the mixture. The
implantable device is then dried, for instance in a vacuum or oven,
to evaporate the solvent, leaving the therapeutic substance or
therapeutic substance and polymer coating on the implantable
device. Similarly, spray-coating requires enveloping the entire
device, or an entire section of the device, in a large cloud of the
mixture, and then allowing the solvent to evaporate, to leave the
coating. Sputtering typically involves placing a polymeric coating
material target in an environment, and applying energy to the
target such that polymeric material is emitted from the target. The
polymer emitted deposits onto the device, forming a coating.
Similarly, gas phase polymerization typically entails applying
energy to a monomer in the gas phase within a system set up such
that the polymer formed is attracted to a stent, thereby creating a
coating around the stent.
[0104] If the implantable device contains depots (130 of FIGS. 1E,
1F, and 1G), it is desirable to first deposit material (132 of FIG.
1G) into the depots before coating the outer surface of the device.
Materials deposited into the depots are similar to those used to
cover the device, and include, for example polymers, therapeutic
substances, or combination thereof.
[0105] Materials 132 may be deposited into depots using any
suitable method. In an exemplary method of depositing material 132
into depots 130, material 132 is added to a first solvent. Material
132 is dispersed throughout the first solvent so that material 132
is in a true solution, saturated or supersaturated with the first
solvent or suspended in fine particles in the first solvent. The
first solvent can be virtually any solvent that is compatible with
material 132. A high capillary permeation and a viscosity not
greater than about ten centipoise allows the first solvent to
penetrate into depots 130 more quickly, eliminating a requirement
to apply the first solvent to the implantable device for a
prolonged period of time. Examples of suitable first solvents
include, but are not limited to, acetone, ethanol, methanol,
isopropanol, tetrahydrofuran, and ethyl acetate. The first solvent
containing material 132 is applied to the implantable device, for
example by immersing or spraying the solvent using procedures that
are well-known to one having ordinary skill in the art. The first
solvent containing material 132 is applied for a predetermined
period of time, the specific time depending on the capillary
permeation and viscosity of the first solvent, the volume of depots
130, and the amount of material 132 to be deposited.
[0106] After applying the first solvent containing material 132 for
a selected duration, the first solvent is removed from the
implantable device using conventional techniques, such as
evaporation in ambient pressure, room temperature and anhydrous
atmosphere and/or by exposure to mild heat (e.g., 60.degree. C.)
under vacuum condition. The implantable device typically has a
clustered or gross formation of material 132 gathered on the body
surface. The cluster is generally removed by immersing the device
in a non-solvent and agitating the implantable device via
mechanical perturbation techniques, such as vortexing or vigorous
shaking. The non-solvent can have a low capillary permeation or a
contact angle greater than about 90.degree. and a viscosity not
less than about 0.5 centipoise so that the second fluid is not
capable of significantly penetrating into depots 130 during the
process of agitation. Examples of a suitable non-solvent include,
but are not limited to, saturated hydrocarbons or alkanes, such as
hexane, heptane, and octane.
[0107] The implantable device is rinsed in a second solvent to
facilitate dissolution of material 132. The second solvent
generally has a low capillary permeation and a viscosity of not
less than about 1.0 centipoise and is therefore incapable of
significantly penetrating into depots 130 during the rinsing stage.
The rinsing is conducted rapidly for example in a range from 1
second to about 15 seconds, the exact duration depending on the
solubility of material 132 in the second solvent. Extended duration
of exposure of the implantable device to the second solvent may
lead to the penetration of the second solvent into depots 130. The
rinsing step is repeated, if desired, until all traces of material
132 are removed from the surface of the implantable device. The
second solvent removes excess material 132 from the surface of the
implantable device body. Useful examples of second solvents
include, but are not limited to, dimethylsulfoxide (DMSO), water,
DMSO in an aqueous solution, glyme, and glycerol. The second
solvent is removed from the implantable device body using
conventional techniques. The first and second solvents as well as
the non-solvent are selected to not adversely affect the
characteristics and composition of material 132. Although one
method of depositing material 132 into depots 130 has been
described here, depots 130 may be filled using any suitable
method.
[0108] Once the depots have been filled, a coating can be applied
to the outer surface of the implantable device, as described
above.
[0109] The polymer used for coating the implantable device and
filling depots is typically either bioabsorbable or biostable. A
bioabsorbable polymer bio-degrades or breaks down in the body and
is not present sufficiently long after implantation to cause an
adverse local response. Bioabsorbable polymers are gradually
absorbed or eliminated by the body by hydrolysis, metabolic
process, bulk, or surface erosion. Examples of bioabsorbable,
biodegradable materials include but are not limited to
polycaprolactone (PCL), poly-D, L-lactic acid (DL-PLA),
poly-L-lactic acid (L-PLA), poly(lactide-co-glycolide),
poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),
polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid),
poly(glycolic acid-cotrimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly (amino acids), cyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate),
copoly(ether-esters), polyalkylene oxalates, polyphosphazenes,
polyiminocarbonates, and aliphatic polycarbonates. Biomolecules
such as heparin, fibrin, fibrinogen, cellulose, starch, and
collagen are typically also suitable. Examples of biostable
polymers include Parylene.RTM., Parylast.RTM., polyurethane (for
example, segmented polyurethanes such as Biospan.RTM.),
polyethylene, polyethlyene teraphthalate, ethylene vinyl acetate,
silicone and polyethylene oxide.
[0110] Therapeutic substances can include, but are not limited to,
antineoplastic, antimitotic, antiinflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antiproliferative,
antibiotic, antioxidant, and antiallergic substances as well as
combinations thereof. Examples of such antineoplastics and/or
antimitotics include paclitaxel (e.g., TAXOL.RTM. by Bristol-Myers
Squibb Co., Stamford, Conn.), docetaxel (e.g., Taxoteree from
Aventis S. A., Frankfurt, Germany) methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride
(e.g., Adriamycin.RTM. from Pharmacia & Upjohn, Peapack N.J.),
and mitomycin (e.g., Mutamycin.RTM. from Bristol-Myers Squibb Co.,
Stamford, Conn.) Examples of such antiplatelets, anticoagulants,
antifibrin, and antithrombins include sodium heparin, low molecular
weight heparins, heparinoids, hirudin, argatroban, forskolin,
vapiprost, prostacyclin and prostacyclin analogues, dextran,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, and thrombin inhibitors
such as Angiomax.TM. (Biogen, Inc., Cambridge, Mass.) Examples of
such cytostatic or antiproliferative agents include angiopeptin,
angiotensin converting enzyme inhibitors such as captopril (e.g.,
Capoten.RTM. and Capozide.RTM. from Bristol-Myers Squibb Co.,
Stamford, Conn.), cilazapril or lisinopril (e.g., Prinivil.RTM. and
Prinzide.RTM. from Merck & Co., Inc., Whitehouse Station,
N.J.); calcium channel blockers (such as nifedipine), colchicine,
fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty
acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA
reductase, a cholesterol lowering drug, brand name Mevacor.RTM.
from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal
antibodies (such as those specific for Platelet-Derived Growth
Factor (PDGF) receptors), nitroprusside, phosphodiesterase
inhibitors, prostaglandin inhibitors, suranin, serotonin blockers,
steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF
antagonist), and nitric oxide. An example of an antiallergic agent
is permirolast potassium. Other therapeutic substances or agents
that may be used include alpha-interferon, genetically engineered
epithelial cells, and dexamethasone. In other examples, the
therapeutic substance is a radioactive isotope for implantable
device usage in radiotherapeutic procedures. Examples of
radioactive isotopes include, but are not limited to, phosphoric
acid (H.sub.3P.sup.32O.sub.4), palladium (Pd.sup.103), cesium
(Cs.sup.131), and iodine (I.sup.125). While the preventative and
treatment properties of the foregoing therapeutic substances or
agents are well-known to those of ordinary skill in the art, the
substances or agents are provided by way of example and are not
meant to be limiting. Other therapeutic substances are equally
applicable for use with the disclosed methods and compositions.
[0111] The following example illustrates a method for creating
asperities on an outer surface of a stent, and then coating the
stent. The results are compared to the result obtained for a stent
coated in the same manner but without a roughened outer surface.
The example is given by way of illustration and not limitation.
EXAMPLE
[0112] Stents # 1-5 were fabricated by cutting, descaling, and
polishing a 316L stainless steel hypo-tube as described in U.S.
Pat. No. 5,759,192. The inner surface of stents # 1-#4 were
protected by inserting a mandrel, hypotube, or inflated balloon
into the interior of the stent to protect the inner surface. The
outer surface of each stent was bead blasted, using bead diameters
in the range of 10 .mu.m to 50 .mu.m. Stents #1 and #2 were bead
blasted at 60 PSI pressure and stents #3 and #4 were bead blasted
at 30 PSI pressure, as indicated in Table 1. Bead blasting was done
at a distance of approximately 5 cm from the stent. The beads were
passed very quickly, in approximately 1-3 seconds, down and up over
the stent outer surface. The stent was then rotated 120.degree. and
the process repeated twice so the entire stent was roughened. After
bead blasting, stents # 1-# 4 were cleaned by immersion in an
ultrasonic isopropyl alcohol bath for 20 minutes and allowed to
dry. Stent #5 was also cleaned in an ultrasonic isoproply alcohol
bath for 20 minutes and allowed to dry. Uncoated stents #1-#5 were
weighed.
[0113] A coating solution was made by adding EVOH (ethylene vinyl
alcohol copolymer) to DMSO (dimethysulfoxide) in a weight ratio of
1:4 EVOH:DMSO. Tetrahydrofuran (THF) was added to the EVOH:DMSO
solution. Tetrahydrofuran constituted 20% by weight of the total
weight of the solution. The solution was vortexed and placed in a
tube. Stents #1-#5 were each dipped into the solution. The coated
stents were passed over a hot plate, for about 3-5 seconds, with a
temperature setting of about 60.degree. C. The coated stents were
cured in a convection over at 60.degree. C. for one hour. The
coating stents were then re-dipped into the solution, passed again
over the hot plate as above and cured in the convention over at
60.degree. C. for four hours. The coated stents were weighed and
the weight difference between the coated and non-coated stent was
calculated. The results are shown in Table 1 below. For the stents
#1-#4 the amount of coating on the stent is greater than that of
stent #5.
1 Pressure Used Weight difference between in Bead coated and
uncoated stent Stent Blast (PSI) (weight of coating) (mg) #1 60
0.187 #2 60 0.160 #3 30 0.168 #4 30 0.158 #5 none 0.090
[0114] To test the adherence of the coating, stents # 1-# 5 were
expanded on a balloon and examined visually with a microscope. No
peeling or defects in the stent coatings were observed.
[0115] While particular embodiments of the present invention have
been shown and described, it will be clear to those of ordinary
skill in the art that changes and modifications can be made without
departing from this invention in its broader aspects and,
therefore, the appended claims are to encompass within their scope
all such changes and modifications as fall within the true spirit
and scope of this invention.
* * * * *