U.S. patent application number 11/432281 was filed with the patent office on 2006-11-30 for stent with nanoporous surface.
Invention is credited to Kareen Looi, Whye-Kei Lye, Michael L. Reed.
Application Number | 20060271169 11/432281 |
Document ID | / |
Family ID | 32313109 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060271169 |
Kind Code |
A1 |
Lye; Whye-Kei ; et
al. |
November 30, 2006 |
Stent with nanoporous surface
Abstract
Methods for fabricating a medical device having at least one
porous layer include providing a medical device having at least one
alloy and removing at least one component of the alloy to form the
porous layer. Although methods may be used to make stent devices
with porous layers, any other suitable medical device may be made
having one or more porous layers. An alloy may include any suitable
combination of metals and sometimes a combination of metal and
non-metal. In some embodiments, one or more of the most
electrochemically active component(s) of an alloy are removed by
the dissolving (or "dealloying") process, to leave a porous matrix
behind. The porous matrix layer may then be infused with one or
more therapeutic agents for enhancing treatment of a patient.
Inventors: |
Lye; Whye-Kei; (US) ;
Looi; Kareen; (US) ; Reed; Michael L.;
(US) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
32313109 |
Appl. No.: |
11/432281 |
Filed: |
May 11, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10713244 |
Nov 13, 2003 |
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11432281 |
May 11, 2006 |
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60426106 |
Nov 13, 2002 |
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Current U.S.
Class: |
623/1.39 ;
148/713; 427/2.21; 623/1.42; 623/23.5 |
Current CPC
Class: |
A61L 31/146 20130101;
A61L 31/16 20130101; A61L 2300/41 20130101; A61F 2/86 20130101;
Y10S 623/901 20130101; Y10T 428/12458 20150115; A61L 31/082
20130101; A61L 2300/416 20130101 |
Class at
Publication: |
623/001.39 ;
623/001.42; 623/023.5; 427/002.21; 148/713 |
International
Class: |
A61F 2/82 20060101
A61F002/82; A61F 2/28 20060101 A61F002/28 |
Claims
1. A method of fabricating an implantable medical device having at
least one porous layer for releasably containing at least one
therapeutic agent, the method comprising: providing an implantable
medical device comprising at least one alloy; and dealloying at
least a portion of the implantable medical device to form at least
one porous layer.
2. A method as in claim 1, wherein the at least one alloy is
cobalt-chromium.
3. A method as in claim 1, wherein providing the implantable
medical device comprises providing a stent having an outer surface
and an inner surface.
4. A method as in claim 1, wherein the stent is integrally formed
from the at least one alloy.
5. A method as in claim 4, wherein the stent comprises
cobalt-chromium.
6. A method as in claim 1, wherein providing the implantable
medical device includes depositing the at least one alloy on at
least one surface of the medical device.
7. A method as in claim 1, wherein the alloy is disposed along an
outer surface of the implantable medical device, such that the
removing step forms the porous layer on the outer surface of the
device.
8. A method as in claim 1, wherein the alloy comprises at least one
metal selected from the group consisting of gold, silver, nitinol,
steel, chromium, iron, nickel, copper, aluminum, titanium,
tantalum, cobalt, tungsten, palladium, vanadium, platinum and
niobium.
9. A method as in claim 1, wherein dealloying comprises dissolving
a most electrochemically active component of the alloy.
10. A method as in claim 1, further comprising introducing the at
least one therapeutic agent into the porous layer.
11. A method as in claim 10, wherein the at least one therapeutic
agent comprises at least one anti-restenosis agent or
anti-inflammatory agent for inhibiting restenosis of a coronary
artery.
12. A method as in claim 3, further comprising forming a porous
layer on the inner surface of the stent.
13. A method for treating a blood vessel using a stent, the method
comprising: providing a dealloyed stent having at least one porous
layer for releasably containing at least one drug; and placing the
stent within the blood vessel at a desired location, wherein the
stent releases the at least one drug from the at least one porous
layer after placement.
14. An implantable medical device having at least one porous layer,
at least one the at least one porous layers comprising: at least
one remaining metal component of an alloy comprising at least two
metal components; and interstitial spaces, wherein the interstitial
spaces comprise at least one removed metal component space of the
alloy.
15. An implantable medical device as in claim 14, wherein at least
one of the at least two metal components is selected from the group
consisting of gold, silver, nitinol, steel, chrome, iron, nickel,
copper, aluminum, titanium, tantalum, cobalt, tungsten, palladium,
vanadium, platinum and niobium.
16. An implantable medical device as in claim 14, wherein the at
least one removed metal component comprises a most
electrochemically active component of the alloy.
17. A method for forming a porous medical component, comprising:
providing a medical device component comprising a metallic surface;
chemically dealloying the metallic surface; and thermally annealing
the metallic surface.
18. The method for forming a porous medical component in claim 17,
further comprising altering the surface charge of the metallic
surface.
19. The method for forming a porous medical component in claim 17,
further comprising altering the hydrophobicity of the metallic
surface.
20. The method for forming a porous medical component in claim 17,
further comprising applying a binder to the metallic surface.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 10/713,244 filed on Nov. 13, 2003, which
claims priority under 35 U.S.C. .sctn.119(e) to U.S. Provisional
Application No. 60/426,106 filed on Nov. 13, 2002, the disclosures
of which are incorporated by reference herein in their
entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention relates generally to medical devices
and methods for making same. More specifically, the invention
relates to implantable medical devices having at least one porous
layer, and methods for making such devices.
[0003] Implantable medical devices are increasingly being used to
deliver one or more therapeutic agents to a site within a body.
Such agents may provide their own benefits to treatment and/or may
enhance the efficacy of the implantable device. For example, much
research has been conducted into the use of drug eluting stents for
use in percutaneous transluminal coronary angioplasty (PTCA)
procedures. Although some implantable devices are simply coated
with one or more therapeutic agents, other devices include means
for containing, attaching or otherwise holding therapeutic agents
to provide the agents at a treatment location over a longer
duration, in a controlled-release manner, or the like.
[0004] Porous materials, for example, are commonly used in medical
implants as matrices for the retention of therapeutic agents.
Materials that have been used for this purpose include ceramics
such as hydroxyapatites and porous alumina, as well as sintered
metal powders. Polymeric materials such as poly(ethylene
glycol)/poly(L-lactic acid) (PLGA) have also been used for this
purpose. These materials are typically applied as coatings to the
medical implant, raising issues regarding coating adhesion,
mechanical properties, and material biocompatibility. Further,
application of these coatings introduces additional complexity to
the fabrication process, increasing overall production costs.
[0005] Therefore, it would be advantageous to have improved
implantable medical devices with porous layers and methods for
fabricating those devices. Such methods would ideally produce a
more adherent and mechanically robust porous layer while
simplifying device manufacture. Methods would also ideally provide
porous layers having desired pore sizes and densities. At least
some of these objectives will be met by the present invention.
BRIEF SUMMARY OF THE INVENTION
[0006] Methods of the present invention provide means for
fabricating an implantable medical device having at least one
porous layer. In one aspect, a method of fabricating an implantable
medical device having a porous layer for releasably containing at
least one therapeutic agent includes providing an implantable
medical device comprising at least one alloy and removing at least
one component of the alloy to form the porous layer. In some
embodiments, the component is removed to form the porous layer as a
biocompatible material, such as gold. In some embodiments, the
medical device comprises a tubular stent device having an outer
surface and an inner surface. For example, the stent device may
comprise a coronary artery stent for use in a percutaneous
transluminal coronary angioplasty (PTCA) procedure. In some of
these embodiments, the alloy is disposed along the outer surface of
the stent device.
[0007] Optionally, providing the implantable medical device may
also include depositing the alloy on at least one surface of the
medical device. In various embodiments, the alloy may be disposed
along an outer surface of the implantable medical device, such that
the dissolving step forms the porous layer on the outer surface of
the device. In some embodiments, the alloy includes one or more
metals, such as but not limited to gold, silver, nitinol, steel,
chromium, iron, nickel, copper, aluminum, titanium, tantalum,
cobalt, tungsten, palladium, vanadium, platinum and/or niobium. In
other embodiments, the alloy comprises at least one metal and at
least one non-metal. Optionally, before the dissolving step at
least one substance may be embedded within the alloy. For example,
a salt or an oxide particle may be embedded in the alloy to enhance
pore formation upon dissolution.
[0008] Dissolving one or more components of the alloy may involve
exposing the alloy to a dissolving substance. For example, a
stainless steel alloy may be exposed to sodium hydroxide in one
embodiment. Typically, one or more of the most electrochemically
active components of the alloy are dissolved. After the dissolving
step, additional processing may be performed. For example, the
device may be coated after the dissolving step with titanium, gold
and/or platinum. Some embodiments further include introducing at
least one therapeutic agent into the porous layer. For example, the
therapeutic agent may be introduced by liquid immersion, vacuum
dessication, high pressure infusion or vapor loading in various
embodiments. The therapeutic agent may be any suitable agent or
combination of agents, such as but not limited to anti-restenotic
agent(s) or anti-inflammatory agent(s), such as Rapamycin,
Sirolimus, Taxol, Prednisone, and/or the like. In other
embodiments, live cells may be encapsulated by the porous layer,
thereby allowing transport of selected molecules, such as oxygen,
glucose, or insulin, to and from the cells, while shielding the
cells from the immune system of the patient. Some embodiments may
optionally include multiple porous layers having various porosities
and atomic compositions.
[0009] In another aspect, a method for treating a blood vessel
using an implantable medical device having a porous layer for
releasably containing at least one therapeutic agent includes:
providing at least one implantable stent having a porous layer for
releasably containing at least one therapeutic agent; and placing
the stent within the blood vessel at a desired location, wherein
the stent releases the at least one therapeutic agent from the
porous layer after placement. For example, in one embodiment the
desired location may comprise an area of stenosis in the blood
vessel, and the at least one therapeutic agent may inhibit
re-stenosis of the blood vessel. Again, the therapeutic agent in
some embodiments may be one or more anti-restenosis agents,
anti-inflammatory agents, or a combination of both. In one
embodiment, the blood vessel may be a coronary artery. In such
embodiments, the placing step may involve placing the stent so as
to contact the porous layer with at least one of a stenotic plaque
in the blood vessel and an inner wall of the blood vessel.
[0010] In still another aspect, an implantable medical device has
at least one porous layer comprising at least one remaining alloy
component and interstitial spaces, wherein the interstitial spaces
comprise at least one removed alloy component space of an alloy,
the alloy comprising the at least one remaining alloy component and
the at least one removed alloy component. In some embodiments, the
porous layer comprises a matrix. Also in some embodiments, the
implantable medical device comprises an implantable stent device
having an outer surface and an inner surface, and the porous layer
is disposed along the outer surface. For example, the stent device
may comprise a coronary artery stent for use in a percutaneous
transluminal coronary angioplasty procedure. As described above,
the alloy may comprise one or more metals selected from the group
consisting of gold, silver, nitinol, steel, chromium, iron, nickel,
copper, aluminum, titanium, tantalum, cobalt, tungsten, palladium,
vanadium, platinum and/or niobium. For example, the alloy may
comprise stainless steel and the porous layer may comprise iron and
nickel.
[0011] In some embodiments, the component (or components) that is
dissolved comprises a most electrochemically active component of
the alloy. Generally, the device further includes at least one
therapeutic agent disposed within the at least one porous layer.
Any such agent or combination of agents is contemplated. Finally,
the device may include a titanium or platinum coating over an outer
surface of the device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a perspective view of an implantable stent device
having a porous layer according to one embodiment of the present
invention.
[0013] FIGS. 2A-2B are electron micrographs of a porous layer
formed by dissolving silver from a gold-silver alloy, according to
one embodiment of the present invention.
[0014] FIGS. 3A-3C are cross-sectional side views showing a method
of making an implantable stent device having a porous layer,
according to one embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Methods of the present invention provide means for
fabricating an implantable medical device having at least one
porous layer. Generally, the methods involve providing an
implantable medical device containing an alloy and removing at
least one component of the alloy to form the porous layer. In some
embodiments, an alloy may first be deposited on an implantable
device and one or more components of the alloy may then be removed
to form the porous layer. Such methods are often referred to as
"dealloying." For a general description of dealloying methods,
reference may be made to "Evolution of nanoporosity in dealloying,"
Jonah Erlebacher et al., Nature 410, pp. 450-453, March 2001, the
entire contents of which are hereby incorporated by reference.
Dealloying a layer of an implantable device provides a porous
layer, which may then be infused with one or more therapeutic
agents for providing delivery of an agent into a patient via the
device. Use of dealloying methods will typically provide more
adherent and mechanically robust porous layers on medical
implantables than are currently available, while also simplifying
device manufacture.
[0016] Although the following description often focuses on the
example of implantable stent devices for use in PTCA procedures,
any suitable implantable medical device may be fabricated with
methods of the invention. Other devices may include, but are not
limited to, other stents, stent-grafts, implantable leads, infusion
pumps, vascular access devices such as implantable ports,
orthopedic implants, implantable electrodes, and the like.
Similarly, devices fabricated via methods of the present invention
may be used to deliver any suitable therapy or combination of
therapies in a patient care context, veterinary context, research
setting or the like. Therapeutic agents may include, for example,
drugs, genes, anti-restenosis agents, anti-thrombogenic agents,
antibiotic agents, anti-clotting agents, anti-inflammatory agents,
cancer therapy agents and/or the like. Thus, the following
description of specific embodiments is provided for exemplary
purposes only and should not be interpreted to limit the scope of
the invention as set forth in the appended claims.
[0017] Referring now to FIG. 1, an implantable medical device
fabricated by methods of the present invention may include an
elongate stent device 10, having two or more layers 12, 14 and a
lumen 16. In one embodiment, stent device 10 includes an outer
porous layer 12 and an inner non-porous layer 14. Other embodiments
may suitably include an inner porous layer 12 and an outer
non-porous layer 14, multiple porous layers 12, multiple non-porous
layers 14, a porous coating over an entire surface of a medical
device, or any combination of porous and non-porous surfaces,
layers, areas or the like to provide a desired effect. In one
embodiment, for example, multiple porous layers may be layered over
one another, with each layer having a different porosity and atomic
composition. Porous layer 12 and non-porous layer 14 may have any
suitable thicknesses in various embodiments. In some embodiments,
for example, a very thin porous layer 12 may be desired, such as
for delivery of a comparatively small amount of therapeutic agent.
In another embodiment, a thicker porous layer 12 may be used for
delivery of a larger quantity of therapeutic agent and/or for a
longer duration of agent delivery. Any suitable combination and
configuration of porous layer 12 and non-porous layer 14 is
contemplated. In one embodiment, porous layer 12 may comprise the
entire thickness of stent device 10, so that the device is
completely porous. Again, stent device 10 is only one example of a
device with which porous layers may be used. Other devices may not
have a lumen, for example, but may still be suitable for use in the
present invention.
[0018] As mentioned above, any medical device may be fabricated
with one or more porous layers 12 according to embodiments of the
present invention. Where the device is an implantable stent device
10, any suitable type, size and configuration of stent device may
be fabricated with one or more porous layers 12. In one embodiment,
stent device 10 comprises an expandable stent for implantation in a
coronary artery during a PTCA procedure. Such a stent device 10 may
be fabricated from any suitable material or combination of
materials. In one embodiment, stent device 10 comprises a stainless
steel non-porous layer 14 arid an iron and nickel porous layer 12.
In some embodiments, porous layer 12 may be formed of a
biocompatible material, such as gold. In other embodiments, porous
layer 12 may be formed from a cobalt-chromium alloy such as L605.
Any other suitable material or combination of materials is
contemplated. Furthermore, stent device 10 may include a layer or
coating comprising a biocompatible material such as titanium, gold
or platinum, which may provide biocompatibility, corrosion
resistance or both.
[0019] With reference now to FIGS. 2A and 2B, a porous layer 12 is
shown in greater detail. Porous layer 12 in these figures was made
by selectively dissolving silver from a gold-silver alloy. As can
be seen from the scanning electron micrographs, porous layer 12
comprises a matrix of pores and structural elements. In any given
embodiment, the size and density of such pores may be varied by
varying one or more elements of a method for making the device and
forming porous layer 12. For example, one or more components of an
alloy, a substance used to selectively dissolve the alloy, duration
time of exposing the alloy to the dissolving substance, or the like
may be chosen to give porous layer 12 certain desired
characteristics. Thermal anneals prior or subsequent to the
dealloying process may also be performed to vary pore size and
density. Any suitable combination of porous layer thickness, pore
size, pore density and the like is contemplated within the scope of
the present invention.
[0020] Although not shown in FIGS. 1 and 2, any implantable medical
device of the present invention may include one or more therapeutic
agents disposed within one or more porous layers 12. As discussed
above, any agent or combination of agents may be included.
Additionally, as described further below, any suitable method for
introducing an agent into a porous layer may be used.
[0021] Referring now to FIGS. 3A through 3C, a method for
fabricating an implantable medical device 20 having a porous layer
suitably includes providing an implantable device comprising at
least one alloy and removing at least one component of the alloy to
form the porous layer. As shown in the cross-sectional FIG. 3A, a
medical device 20 such as a stent may include a precursor alloy
layer 22, a substrate layer 24 and a lumen. Precursor alloy layer
22 can be deposited onto substrate layer 24 by various processes,
including but not limited to physical vapor deposition, ion
implantation, sputter deposition, thermal or electron beam
evaporation, chemical vapor deposition, pulsed laser deposition, or
the like. Using such techniques, precursor alloy layer 22 may be
synthesized in situ from various materials, as described
previously, such that exposure to the dealloying process will
remove the sacrificial component of precursor alloy layer 22,
leaving behind a porous matrix. In another embodiment, precursor
alloy layer 22 and substrate layer 24 may be made from the same
material. As previously described, medical device 20 may comprise
any suitable stent or other device and precursor alloy layer 22,
substrate layer 24 and/or other layers may be given any suitable
configurations, thicknesses and the like. In some embodiments,
precursor alloy layer 22 is disposed along an outer surface of
device 20, while in others precursor alloy layer 22 may be disposed
along an inner surface, both inner and outer surfaces, or the like.
The alloy used to form precursor alloy layer 22 may comprise any
suitable alloy and may be a metal-metal alloy or a metal-non-metal
alloy. In various embodiments, for example, components of precursor
alloy layer 22 may include steel, nitinol, chromium, brass, copper,
iron, nickel, aluminum, titanium, gold, silver, tantalum, cobalt,
tungsten, palladium, vanadium, platinum and/or niobium. In some
embodiments, one or more additional substances may be embedded
within precursor alloy layer 22 to cause or enhance pore formation
during the fabrication process. For example, a salt, an oxide
particle or the like may be added to precursor alloy layer 22 to
enhance pore formation.
[0022] As shown in FIG. 3B, implantable medical device 20 is
typically exposed to a substance (arrows) to dissolve or otherwise
remove at least one component of the alloy to form the porous layer
from precursor alloy layer 22. In various embodiments, any suitable
substance may be used for removing at least one component of the
alloy. In one embodiment, for example, the alloy comprises
stainless steel, such as 316L stainless steel, and dissolving at
least one component of the steel comprises exposing the steel to
hot sodium hydroxide to dissolve chromium and leave iron and nickel
as the porous layer. In another embodiment, a silver-gold alloy may
be exposed to nitric acid to dissolve the silver and leave the gold
as the porous layer (as shown in FIGS. 2A and 2B). In another
embodiment, a cobalt-chromium alloy, such as L605, is modified by
the addition of a sacrificial material such as silver, copper or
aluminum, which is subsequently removed by processing in an
appropriate solvent, such as nitric acid, sulphuric acid or
phosphoric acid, to leave a porous film of the original
cobalt-chromium alloy. In another embodiment, a platinum-copper
alloy is dealloyed in the presence of sulphuric acid to produce
porous platinum. In some embodiments, nitinol may be dissolved by a
suitable dissolving substance to leave a porous layer. The
dissolving process may include the use of electrochemical cells to
bias device 20 in solution so as to facilitate the dealloying
process. Any other suitable combination of alloy and dissolving or
component-removing substance is contemplated. Furthermore, any
means for exposing medical device 20 to a dissolving substance is
contemplated. For example, medical device 20 may be immersed in,
sprayed with, coated with, etc. any suitable substance or
combination of substances.
[0023] As shown in FIG. 3C, one or more components of precursor
alloy layer 22 are selectively removed to form a porous layer 23.
In some embodiments, removing at least one component of the alloy
comprises dissolving one or more of the most electrochemically
active components of the alloy. For example, in a steel alloy the
chromium component may be dissolved, leaving the iron and nickel
components. Additional processing of medical device 20 may include
introduction of one or more therapeutic agents into porous layer
23. Any suitable agent(s) may be introduced and they may be
introduced by any desired method. For example, methods for
introducing therapeutic agents include, but are not limited to,
liquid immersion, vacuum dessication, high pressure infusion, vapor
loading, and the like.
[0024] In another embodiment, multiple therapeutic agents may be
introduced into a porous matrix composed of a plurality of porous
layer 23. As described previously, the plurality of porous layers
may vary in atomic composition, as well as in pore size and
density. Compositional variations may allow for preferential
binding to occur between the therapeutic agent and the coating,
changing the elution kinetics of the agent. Pore size and density
will also affect the transport kinetics of therapeutics from and
across each layer. The use of a plurality of porous layers may thus
allow for controlling elution kinetics of multiple therapeutic
agents. In a further embodiment, live cells may be encapsulated
within lumen 26 of device 20. In one such embodiment, the entire
device may be made porous (such that the internal lumen and the
exterior of the device are separated by a porous layer). Live cells
(such a pancreatic islet cells) can be encapsulated within the
internal lumen, and the porosity of the layer adjusted to allow
transport of selected molecules (such as oxygen, glucose; as well
as therapeutic cellular products, such as insulin, interferon),
while preventing access of antibodies and other immune system
agents that may otherwise attack or compromise the encapsulated
cells. In some embodiments, a protective layer or coating may be
formed or added to medical device 20, such as a titanium, gold or
platinum layer or coating. If there is a concern that porous layer
23 may not be biocompatible, a passivation layer may be deposited
into porous layer 23 to enhance biocompatibility. For instance, a
very thin layer of gold may be electroplated into the dealloyed
porous layer 23. Electroless deposition may also be used to achieve
the same effect. Depending on the composition of porous layer 23,
the porous coating may also be passivated chemically or in a
reactive ion plasma.
[0025] Although the present invention has been described in full,
in relation to various exemplary embodiments, various additional
embodiments and alterations to the described embodiments are
contemplated within the scope of the invention. Thus, no part of
the foregoing description should be interpreted to limit the scope
of the invention as set forth in the following claims.
* * * * *