U.S. patent application number 11/127968 was filed with the patent office on 2005-11-24 for medical devices and methods of making the same.
Invention is credited to Weber, Jan.
Application Number | 20050261760 11/127968 |
Document ID | / |
Family ID | 34969489 |
Filed Date | 2005-11-24 |
United States Patent
Application |
20050261760 |
Kind Code |
A1 |
Weber, Jan |
November 24, 2005 |
Medical devices and methods of making the same
Abstract
Medical devices, such as endoprostheses, and methods of making
the devices are described. In some embodiments, the invention
features a medical device including a generally tubular body
including a biodisintegrable material, and a polyelectrolyte on the
generally tubular body. The polyelectrolyte can be used to delay
and/or slow the disintegration of the biodisintegrable
material.
Inventors: |
Weber, Jan; (Maple Grove,
MN) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
34969489 |
Appl. No.: |
11/127968 |
Filed: |
May 12, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11127968 |
May 12, 2005 |
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10985242 |
Nov 10, 2004 |
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11127968 |
May 12, 2005 |
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10849742 |
May 20, 2004 |
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Current U.S.
Class: |
623/1.38 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
35/00 20180101; A61L 2300/624 20130101; A61L 2300/608 20130101;
A61P 29/00 20180101; A61L 29/16 20130101; A61L 29/085 20130101;
A61P 3/06 20180101; A61P 23/00 20180101 |
Class at
Publication: |
623/001.38 |
International
Class: |
A61F 002/06 |
Claims
What is claimed is:
1. A medical device, comprising: a generally tubular body
comprising a biodisintegrable material; and a first polyelectrolyte
on the generally tubular body.
2. The medical device of claim 1, wherein the first polyelectrolyte
is biodisintegrable.
3. The medical device of claim 1, wherein the first polyelectrolyte
comprises a polyacid.
4. The medical device of claim 3, wherein the polyacid is selected
from the group consisting of polyphosphoric acids,
polyvinylsulfuric acids, polyvinylsulfonic acids,
polyvinylphosphonic acids, and polyacrylic acids.
5. The medical device of claim 1, wherein the first polyelectrolyte
comprises a polybase.
6. The medical device of claim 5, wherein the polybase comprises
polyallylamine, polyethylimine, polyvinylamine, and
polyvinylpyridine.
7. The medical device of claim 1, wherein the first polyelectrolyte
comprises a polycation.
8. The medical device of claim 7, wherein the polycation is
selected from the group consisting of poly(allylamine)polycations,
polyethyleneimine polycations, polydiallyldimethylammonium
polycations, protamine sulfate polycations, chitosan polycations,
gelatin polycations, spermidine polycations, poly(N-octyl-4-vinyl
pyridinium iodide) polycations, and albumin polycations.
9. The medical device of claim 1, wherein the first polyelectrolyte
comprises a polyanion.
10. The medical device of claim 9, wherein the polyanion is
selected from the group consisting of poly(styrene
sulfonate)polyanions, polyacrylic acid polyanions, sodium alginate
polyanions, eudragit polyanions, gelatin polyanions, hyaluronic
acid polyanions, carrageenan polyanions, chondroitin sulfate
polyanions, and carboxymethylcellulose polyanions.
11. The medical device of claim 1, wherein the first
polyelectrolyte comprises a polymer selected from the group
consisting of heparin, proteins, polyglycolic acid, polylactic
acid, polyamides, poly-2-hydroxy-butyrate, polycaprolactone, and
poly(lactic-co-glycolic)ac- id.
12. The medical device of claim 1, wherein the biodisintegrable
material comprises a metal.
13. The medical device of claim 1, wherein the biodisintegrable
material comprises a metal selected from the group consisting of
alkali metals, alkaline earth metals, iron, zinc, and aluminum.
14. The medical device of claim 1, wherein the biodisintegrable
material comprises iron.
15. The medical device of claim 1, wherein the biodisintegrable
material comprises magnesium.
16. The medical device of claim 1, wherein the biodisintegrable
material comprises a metal alloy.
17. The medical device of claim 1, wherein the biodisintegrable
material comprises an iron alloy.
18. The medical device of claim 1, wherein the biodisintegrable
material comprises a magnesium alloy.
19. The medical device of claim 1, wherein the biodisintegrable
material comprises a first component selected from the group
consisting of magnesium, titanium, zirconium, niobium, tantalum,
zinc, and silicon, and a second component selected from the group
consisting of lithium, sodium, potassium, calcium, iron, and
manganese.
20. The medical device of claim 1, wherein the biodisintegrable
material comprises a non-metal.
21. The medical device of claim 1, wherein the biodisintegrable
material comprises a polymer.
22. The medical device of claim 1, wherein the medical device
comprises a first layer comprising the first polyelectrolyte, the
first layer being supported by the generally tubular body.
23. The medical device of claim 22, wherein the first layer has a
thickness of at most about 500 nanometers.
24. The medical device of claim 23, wherein the first layer has a
thickness of at least about 0.2 nanometer.
25. The medical device of claim 22, wherein the first layer defines
at least one opening.
26. The medical device of claim 22, wherein the first layer
contacts the generally tubular body.
27. The medical device of claim 22, further comprising a second
layer that is supported by the generally tubular body.
28. The medical device of claim 27, wherein the second layer
contacts the first layer.
29. The medical device of claim 27, wherein the medical device
comprises a plurality of first layers and a plurality of second
layers.
30. The medical device of claim 29, wherein at least two of the
first layers are spaced from each other by one or more second
layers.
31. The medical device of claim 27, wherein the second layer
comprises a second polyelectrolyte.
32. The medical device of claim 31, wherein the second
polyelectrolyte is different from the first polyelectrolyte.
33. The medical device of claim 31, wherein the first
polyelectrolyte is positively charged and the second
polyelectrolyte is negatively charged.
34. The medical device of claim 1, wherein the medical device
further comprises a second polyelectrolyte on the generally tubular
body.
35. The medical device of claim 34, wherein the first
polyelectrolyte and the second polyelectrolyte are cross-linked to
each other.
36. The medical device of claim 35, wherein the first
polyelectrolyte and the second polyelectrolyte are cross-linked to
each other by at least one covalent bond.
37. The medical device of claim 1, wherein the medical device
comprises a plurality of layers.
38. The medical device of claim 37, wherein a first portion of the
medical device comprises a greater number of layers than a second
portion of the medical device.
39. The medical device of claim 38, wherein the first portion
includes at least 20 layers.
40. The medical device of claim 39, wherein the second portion
includes at least 10 layers.
41. The medical device of claim 37, wherein the plurality of layers
has a total thickness of at most 1500 nanometers.
42. The medical device of claim 41, wherein the plurality of layers
has a total thickness of at least five nanometers.
43. The medical device of claim 37, wherein the medical device
comprises at least 10 layers.
44. The medical device of claim 43, wherein the medical device
comprises at most 300 layers.
45. The medical device of claim 1, wherein the medical device
comprises an endoprosthesis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of, and claims
priority under 35 U.S.C. .sctn. 120 to, U.S. patent application
Ser. No. 10/985,242, filed on Nov. 10, 2004, and entitled "Medical
Devices and Methods of Making the Same", and U.S. patent
application Ser. No. 10/849,742, filed on May 20, 2004, and
entitled "Medical Devices Having Multiple Layers", both of which
are incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The invention relates to medical devices, such as, for
example, endoprostheses, and methods of making the devices.
BACKGROUND
[0003] The body includes various passageways such as arteries,
other blood vessels, and other body lumens. These passageways
sometimes become occluded or weakened. For example, the passageways
can be occluded by a tumor, restricted by plaque, or weakened by an
aneurysm. When this occurs, the passageway can be reopened or
reinforced, or even replaced, with a medical endoprosthesis. An
endoprosthesis is typically a tubular member that is placed in a
lumen in the body. Examples of endoprostheses include stents,
stent-grafts, and covered stents.
[0004] An endoprosthesis can be delivered inside the body by a
catheter that supports the endoprosthesis in a compacted or
reduced-size form as the endoprosthesis is transported to a desired
site. Upon reaching the site, the endoprosthesis is expanded, for
example, so that it can contact the walls of the lumen.
[0005] The expansion mechanism may include forcing the
endoprosthesis to expand radially. For example, the expansion
mechanism can include the catheter carrying a balloon, which
carries a balloon-expandable endoprosthesis. The balloon can be
inflated to deform and to fix the expanded endoprosthesis at a
predetermined position in contact with the lumen wall. The balloon
can then be deflated, and the catheter withdrawn.
[0006] In another delivery technique, the endoprosthesis is formed
of an elastic material that can be reversibly compacted and
expanded (e.g., elastically or through a material phase
transition). During introduction into the body, the endoprosthesis
is restrained in a compacted condition. Upon reaching the desired
implantation site, the restraint is removed, for example, by
retracting a restraining device such as an outer sheath, enabling
the endoprosthesis to self-expand by its own internal elastic
restoring force.
[0007] To support a passageway and keep the passageway open,
endoprostheses are sometimes made of relatively strong materials,
such as stainless steel or Nitinol (a nickel-titanium alloy),
formed into struts or wires.
SUMMARY
[0008] In one aspect, the invention features medical devices (e.g.,
endoprostheses) that include one or more biodisintegrable
materials, and methods of making the devices. The medical devices
may include at least one region that is formed of one or more
biodisintegrable materials, or may be formed entirely of one or
more biodisintegrable materials. The disintegration of the
biodisintegrable materials in the medical devices can be
controlled. For example, in some embodiments, the medical devices
can include one or more polyelectrolytes, which can be used to
control the disintegration of the biodisintegrable materials. In
certain embodiments, the polyelectrolytes can be in the form of
layers. The layers can, for example, limit or prevent water
molecules and/or certain ions (e.g., in body fluid) from contacting
the biodisintegrable materials, thereby delaying and/or slowing the
disintegration of the biodisintegrable materials. In some
embodiments, the layers can limit the movement of the water
molecules and/or ions, and/or can slow the rate at which the water
molecules and/or ions access and contact the biodisintegrable
materials.
[0009] In another aspect, the invention features a medical device
including a generally tubular body that includes a biodisintegrable
material, and a first polyelectrolyte on the generally tubular
body.
[0010] In an additional aspect, the invention features a medical
device that includes a substrate including a biodisintegrable
material and a layer supported by the substrate, the layer
including one or more charges.
[0011] In a further aspect, the invention features a method of
making a medical device, the method including forming a first layer
on a generally tubular body including a biodisintegrable material.
The first layer includes a polyelectrolyte.
[0012] In another aspect, the invention features a method of making
a medical device, the method including forming a layer on a
substrate including a biodisintegrable material. The layer includes
one or more charges.
[0013] In a further aspect, the invention features a medical device
including a generally tubular body that includes a biostable
material, and a polyelectrolyte on the generally tubular body. In
some embodiments, the medical device can further include a
non-polyelectrolyte biodisintegrable coating.
[0014] In an additional aspect, the invention features a medical
device including a generally tubular body that includes a
biodisintegrable material, a polyelectrolyte on the generally
tubular body, and a non-polyelectrolyte biodisintegrable
coating.
[0015] Embodiments may include one or more of the following
features.
[0016] The polyelectrolyte can be biodisintegrable.
[0017] In some embodiments, the polyelectrolyte can be a polyacid,
such as a polyphosphoric acid, a polyvinylsulfuric acid, a
polyvinylsulfonic acid, a polyvinylphosphonic acid, or a
polyacrylic acid. In certain embodiments, the polyelectrolyte can
be a polybase, such as polyallylamine, polyethylimine,
polyvinylamine, or polyvinylpyridine.
[0018] In some embodiments, the polyelectrolyte can be a
polycation, such as a poly(allylamine)polycation, a
polyethyleneimine polycation, a polydiallyldimethylammonium
polycation, a protamine sulfate polycation, a chitosan polycation,
a gelatin polycation, a spermidine polycation, a
poly(N-octyl-4-vinyl pyridinium iodide) polycation, or an albumin
polycation. In certain embodiments, the polyelectrolyte can be a
polyanion, such as a poly(styrene sulfonate)polyanion, a
polyacrylic acid polyanion, a sodium alginate polyanion, a
polystyrene sulfonate polyanion, a eudragit polyanion, a gelatin
polyanion, a hyaluronic acid polyanion, a carrageenan polyanion, a
chondroitin sulfate polyanion, or a carboxymethylcellulose
polyanion.
[0019] The polyelectrolyte can include a polymer, such as heparin,
a protein, polyglycolic acid, polylactic acid, a polyamide,
poly-2-hydroxy-butyrate, polycaprolactone, or
poly(lactic-co-glycolic)aci- d.
[0020] The layer can include a polyelectrolyte. The layer can be
biodisintegrable or biostable.
[0021] The medical device can have a first layer that includes the
polyelectrolyte. The first layer can be supported by the generally
tubular body. In some embodiments, the first layer can contact the
generally tubular body. The first layer can have a thickness of at
most about 500 nanometers (e.g., at most about 300 nanometers, at
most about 100 nanometers, at most about 50 nanometers, at most
about 10 nanometers, at most about five nanometers, at most about
one nanometer, at most about 0.5 nanometer) and/or at least about
0.2 nanometer (e.g., at least about 0.5 nanometer, at least about
one nanometer, at least about five nanometers, at least about 10
nanometers, at least about 50 nanometers, at least about 100
nanometers, at least about 300 nanometers). In some embodiments,
the first layer can have at least one (e.g., at least two, at least
five, at least 10) opening in it (e.g., in a wall of the first
layer).
[0022] The medical device can further include a second layer that
can be supported by the generally tubular body. In some
embodiments, the second layer can contact the first layer. The
second layer can include a polyelectrolyte that can be the same as,
or different from, the polyelectrolyte in the first layer. In
certain embodiments, the polyelectrolyte in one layer of the
medical device can be positively charged and the polyelectrolyte in
another layer (e.g., an adjacent layer) of the medical device can
be negatively charged.
[0023] In some embodiments, the medical device can include a
plurality of layers, such as a plurality of first layers and a
plurality of second layers. In certain embodiments, at least two of
the first layers can be spaced from each other by one or more
second layers.
[0024] In certain embodiments, the medical device can further
include a second polyelectrolyte on the generally tubular body. In
some embodiments, the first polyelectrolyte and the second
polyelectrolyte can be cross-linked to each other (e.g., by at
least one covalent bond).
[0025] In certain embodiments, the non-polyelectrolyte
biodisintegrable coating may cover all or a portion of the
polyelectrolyte.
[0026] In some embodiments, the method can include forming a second
layer on the first layer. The second layer can include a
polyelectrolyte. In certain embodiments, the method can include
cross-linking the polyelectrolyte in the first layer to the
polyelectrolyte in the second layer (e.g., by applying heat and/or
UV radiation to the first and second layers). In certain
embodiments, the method can include forming a plurality of first
layers and a plurality of second layers.
[0027] The medical device can include at least 10 layers (e.g., at
least 20 layers, at least 50 layers, at least 100 layers, at least
200 layers), and/or at most 300 layers (e.g., at most 200 layers,
at most 100 layers, at most 50 layers, at most 20 layers). The
plurality of layers can have a total thickness of at most 1500
nanometers (e.g., at most 1000 nanometers, at most 500 nanometers,
at most 100 nanometers, at most 50 nanometers, at most 10
nanometers), and/or at least five nanometers (e.g., at least 10
nanometers, at least 50 nanometers, at least 100 nanometers, at
least 500 nanometers, at least 1000 nanometers). In some
embodiments, one portion of the medical device can include a
greater number of layers than another portion of the medical
device. In certain embodiments, one portion of the medical device
can include at least 10 layers (e.g., at least 20 layers, at least
30 layers, at least 40 layers), and/or another portion of the
medical device can include at least 20 layers (e.g., at least 30
layers, at least 40 layers, at least 50 layers). In some
embodiments, one portion of the medical device can include 10
layers while another portion of the medical device can include 20
layers.
[0028] The medical device can be an endoprosthesis, a catheter, a
graft, or a filter.
[0029] The biodisintegrable material can be a metal, a metal alloy,
and/or a non-metal. In some embodiments, the biodisintegrable
material can be an alkali metal, an alkaline earth metal (e.g.,
magnesium), iron, zinc, aluminum, or an alloy (e.g., an iron alloy,
a magnesium alloy). In certain embodiments, the biodisintegrable
material can include one component (e.g., magnesium, titanium,
zirconium, niobium, tantalum, zinc, silicon), and another,
different, component (e.g., lithium, sodium, potassium, calcium,
iron, manganese). In some embodiments, the biodisintegrable
material can be a polymer.
[0030] Embodiments may include one or more of the following
advantages.
[0031] In certain embodiments, the medical device may be used to
temporarily treat a subject without permanently remaining in the
body of the subject. For example, in some embodiments, the medical
device can be used for a certain period of time (e.g., to support a
lumen of a subject), and then can disintegrate after that period of
time. In certain embodiments, as a medical device disintegrates,
the Magnetic Resonance Imaging (MRI) visibility and/or Computed
Tomography (CT) visibility of the region (e.g., a body lumen) in
which the medical device is located can increase.
[0032] In some embodiments in which the medical device includes one
or more polyelectrolytes, the polyelectrolytes can be used to
control the disintegration (e.g., corrosion) of biodisintegrable
materials in the medical device. The polyelectrolytes can, for
example, be in the form of layers that can limit or prevent water
molecules and/or certain ions from accessing the biodisintegrable
materials. In certain embodiments, the polyelectrolytes can prevent
the biodisintegrable materials from disintegrating prematurely
(e.g., during delivery and/or deployment of the medical device to a
target site).
[0033] In certain embodiments in which the medical device includes
one or more polyelectrolyte layers, different regions of the
medical device can include different numbers of polyelectrolyte
layers. In some embodiments, the biodisintegrable material in a
region of the medical device that includes a relatively high number
of polyelectrolyte layers may begin to disintegrate after, and/or
more slowly than, the biodisintegrable material in a region of the
medical device that includes a relatively low number of
polyelectrolyte layers. Thus, the polyelectrolyte layers on a
medical device may be used to provide different disintegration
rates of biodisintegrable material in different regions of the
medical device. In some embodiments, an endoprosthesis can include
an arrangement of polyelectrolyte layers that causes one or both of
the ends of the endoprosthesis to start disintegrating before the
middle of the endoprosthesis. This may limit the likelihood of the
medical device breaking apart into two or more pieces during
disintegration.
[0034] In certain embodiments, an endoprosthesis can include two or
more polyelectrolyte layers that are cross-linked to each other.
The cross-linked polyelectrolyte layers may be used, for example,
to confine biodisintegrable material in the endoprosthesis. In
certain embodiments, this confinement of the biodisintegrable
material may limit the likelihood that one or more pieces of the
biodisintegrable material will break away from the endoprosthesis
during use and move to a location other than the target site.
[0035] Other aspects, features, and advantages are in the
description, drawings, and claims.
DESCRIPTION OF DRAWINGS
[0036] FIG. 1 is a perspective view of an embodiment of an
endoprosthesis.
[0037] FIG. 2 is a detailed cross-sectional illustration of the
endoprosthesis of FIG. 1, taken along line 2-2.
[0038] FIG. 3 is a flow chart of an embodiment of a method of
making a medical device.
[0039] FIG. 4 is a perspective view of an embodiment of an
endoprosthesis.
[0040] FIG. 5 is a detailed cross-sectional illustration of the
endoprosthesis of FIG. 4, taken along line 5-5.
[0041] FIG. 6 is a detailed cross-sectional illustration of the
endoprosthesis of FIG. 4, taken along line 6-6.
DETAILED DESCRIPTION
[0042] FIG. 1 shows a stent 20 that is in the form of a tubular
structure 21 including a biodisintegrable material. Tubular
structure 21 is defined by a plurality of bands 22 and a plurality
of connectors 24 that extend between and connect adjacent bands.
Tubular structure 21 has a lumen 23. As shown in FIG. 2, stent 20
(as shown, a portion of a band 22) is coated with a multi-layered
structure 26 that includes a plurality of first charged layers 27
and a plurality of second charged layers 30. Multi-layered
structure 26 is capable of delaying and/or slowing the
disintegration of tubular structure 21 (e.g., during delivery
and/or use of stent 20 at a target site).
[0043] In some embodiments, layers 27 and/or 30 can include one or
more polyelectrolytes. For example, layers 27 can include a charged
polyelectrolyte and layers 30 can include an oppositely charged
polyelectrolyte, to maintain charge balance with the charged
polyelectrolyte in layers 27. Each of layers 27 and/or layers 30
may include one type of polyelectrolyte or may include multiple
different types of polyelectrolytes. Without wishing to be bound by
theory, it is believed that polyelectrolyte anion/cation pairs in
layers 27 and 30 can bind water molecules and certain ions (e.g.,
chlorine ions, metal ions), thereby limiting or preventing movement
of the water molecules and ions, and/or limiting or preventing the
water molecules and ions from contacting tubular structure 21 of
stent 20.
[0044] The movement of water molecules and ions within layers 27
and 30, and/or the extent of contact between tubular structure 21
of stent 20 and the water molecules and ions, may depend on any of
a number of different factors.
[0045] As an example, in certain embodiments, as the electrostatic
attraction between the anion/cation pairs in layers 27 and 30
increases, the strength of the bonds holding the water molecules
and ions can also increase. As a result, the movement of water
molecules and ions within layers 27 and 30 may decrease, and/or
tubular structure 21 of stent 20 may have less contact with water
molecules and ions. The relative electrostatic attraction between
anion/cation pairs in polyelectrolyte layers can be estimated by,
for example, measuring the zeta potential of one polyelectrolyte
layer and then measuring the zeta potential of another
polyelectrolyte layer that is formed upon the first polyelectrolyte
layer. In some embodiments, the electrostatic attraction between
anion/cation pairs in adjacent polyelectrolyte layers can be
relatively high, such as embodiments in which the anionic
polyelectrolyte layer has a zeta potential of less than -40
millivolts and the cationic polyelectrolyte layer has a zeta
potential of more than 40 millivolts. The zeta potential of a
polyelectrolyte can be measured using laser doppler electrophoresis
(e.g., using a ZetaPALS system from Brookhaven Instruments Corp.,
Holtsville, N.Y.).
[0046] As another example, in some embodiments, as the temperature
of the environment surrounding stent 20 increases, the movement of
water molecules and ions within layers 27 and 30 may increase,
and/or tubular structure 21 of stent 20 may have less contact with
water molecules and ions. In some embodiments in which layers 27
and/or 30 are biodisintegrable, as described below, the increased
temperature may result in a higher disintegration rate of layers 27
and/or 30, allowing increased access of water molecules and ions to
tubular structure 21 of stent 20.
[0047] As an additional example, in certain embodiments, as the pH
of the environment surrounding stent 20 increases, the movement of
water molecules and ions within layers 27 and 30 may decrease,
and/or the amount of contact between water molecules and ions and
tubular structure 21 of stent 20 may decrease. The pH of the
environment surrounding stent 20 may change, for example, as the
biodisintegrable material in tubular structure 21 disintegrates.
For example, in some embodiments in which stent 20 includes
magnesium, oxidation of the magnesium can cause the pH of the
environment surrounding stent 20 to increase.
[0048] Polyelectrolytes are polymers having charged (e.g.,
ionically dissociable) groups. The number of these groups in the
polyelectrolytes can be so large that the polymers are soluble in
polar solvents (including water) when in ionically dissociated form
(also called polyions). Depending on the type of dissociable
groups, polyelectrolytes can be classified as polyacids or
polybases.
[0049] When dissociated, polyacids form polyelectrolyte anions
(polyanions), with protons being split off. Polyacids include
inorganic, organic and biopolymers. Examples of polyacids include
polyphosphoric acids, polyvinylsulfuric acids, polyvinylsulfonic
acids, polyvinylphosphonic acids and polyacrylic acids. Examples of
the corresponding salts, which are called polysalts, include
polyphosphates, polyvinylsulfates, polyvinylsulfonates,
polyvinylphosphonates and polyacrylates.
[0050] Polybases contain groups that are capable of accepting
protons (e.g., by reaction with acids), with a salt being formed.
Examples of polybases having dissociable groups within their
backbone and/or side groups include polyallylamine,
polyethyleneimine, polyvinylamine and polyvinylpyridine. By
accepting protons, polybases form polyelectrolyte cations
(polycations).
[0051] Some polyelectrolytes have both anionic and cationic groups,
but nonetheless have a net positive or negative charge. An example
of such a polyelectrolyte is gelatin. Whether a polyelectrolyte
having both anionic and cationic groups has a net positive or
negative charge can depend, for example, of the pH of the
environment surrounding the polyelectrolyte.
[0052] In some embodiments, polyelectrolytes can be based on
biopolymers. Examples include alginic acid, gummi arabicum, nucleic
acids, pectins and proteins, chemically modified biopolymers such
as carboxymethylcellulose and lignin sulfonates, and synthetic
polymers such as polymethacrylic acid, polyvinylsulfonic acid,
polyvinylphosphonic acid and polyethyleneimine.
[0053] Polyelectrolytes may be linear or branched. The use of
branched polyelectrolytes on stent 20 can lead to less compact
polyelectrolyte multilayers having a higher degree of wall
porosity. In some embodiments, polyelectrolyte molecules can be
crosslinked within and/or between individual polyelectrolyte layers
(e.g., by crosslinking amino groups with aldehydes). The
cross-linking may enhance the stability of the polyelectrolyte
layers.
[0054] In certain embodiments, polyelectrolytes can be amphiphilic.
For example, polyelectrolytes may include amphiphilic block or
random copolymers having partial polyelectrolyte character.
Amphiphilic polyelectrolytes can be used, for example, to affect
permeability towards polar molecules. In some embodiments, a layer
including an amphiphilic polyelectrolyte may be more permeable to
polar molecules than a layer including a polyelectrolyte that is
not amphiphilic.
[0055] Other examples of polyelectrolytes include low-molecular
weight polyelectrolytes (e.g., polyelectrolytes having molecular
weights of a few hundred Daltons) up to macromolecular
polyelectrolytes (e.g., polyelectrolytes of synthetic or biological
origin, which commonly have molecular weights of several million
Daltons).
[0056] Specific examples of polyelectrolyte cations (polycations)
include protamine sulfate polycations, poly(allylamine) polycations
(e.g., poly(allylamine hydrochloride) (PAH)),
polydiallyldimethylammonium polycations, polyethyleneimine
polycations, chitosan polycations, gelatin polycations, spermidine
polycations and albumin polycations.
[0057] Specific examples of polyelectrolyte anions (polyanions)
include poly(styrenesulfonate)polyanions (e.g., poly(sodium styrene
sulfonate) (PSS)), polyacrylic acid polyanions, sodium alginate
polyanions, eudragit polyanions, gelatin polyanions, hyaluronic
acid polyanions, carrageenan polyanions, chondroitin sulfate
polyanions, and carboxymethylcellulose polyanions.
[0058] In some embodiments, biodisintegrable polyelectrolytes can
be used in layers 27 and/or 30. As used herein, a "biodisintegrable
material" is a material that undergoes dissolution, degradation,
absorption, erosion, corrosion, resorption and/or other
disintegration processes over the period that a device including
the biodisintegrable material is designed to reside in a patient.
As the biodisintegrable polyelectrolytes in layers 27 and/or 30
disintegrate, they may provide less protection for tubular
structure 21 of stent 20. As a result, tubular structure 21 can
begin to disintegrate or can disintegrate at a faster rate.
[0059] Examples of biodisintegrable polyelectrolytes include
heparin, polyglycolic acid (PGA), polylactic acid (PLA),
polyamides, poly-2-hydroxy-butyrate (PHB), polycaprolactone (PCL),
poly(lactic-co-glycolic)acid (PLGA), protamine sulfate,
polyallylamine, polydiallyldimethylammonium species (e.g.,
poly(diallyldimethylammonium chloride) (PDADMA, Aldrich)),
polyethyleneimine, chitosan, eudragit, gelatin, spermidine,
albumin, polyacrylic acid, sodium alginate, poly(styrene sulfonate)
(PSS, Scientific Polymer Products), hyaluronic acid, carrageenan,
chondroitin sulfate, carboxymethylcellulose, polypeptides,
proteins, DNA, and poly(N-octyl-4-vinyl pyridinium iodide) (PNOVP).
Polyelectrolytes are described, for example, in Tarek R. Farhat and
Joseph B. Schlenoff, "Corrosion Control Using Polyelectrolyte
Multilayers", Electrochemical and Solid State Letters, 5 (4)
B13-B15 (2002).
[0060] In some embodiments, a layer formed of a biodisintegrable
polyelectrolyte can disintegrate over a period of at least about
one second (e.g., at least about 10 seconds, at least about 30
seconds, at least about one minute, at least about 10 minutes, at
least about one hour, at least about five hours, at least about 10
hours, at least about one day, at least about two days, at least
about four days, at least about six days), and/or most about one
week (e.g., at most about six days, at most about four days, at
most about two days, at most about one day, at most about 10 hours,
at most about five hours, at most about one hour, at most about 10
minutes, at most about one minute, at most about 30 seconds, at
most about 10 seconds).
[0061] In certain embodiments, a biodisintegrable polyelectrolyte
in a layer can be cross-linked (e.g., using heat and/or UV
radiation) to another biodisintegrable polyelectrolyte in another
layer. In some embodiments, cross-linking between polyelectrolytes
in different layers can cause the polyelectrolytes to disintegrate
at a slower rate than they would otherwise. In certain embodiments,
a layer including a cross-linked polyelectrolyte can disintegrate
over a period of at least about one week (e.g., at least about two
weeks, at least about three weeks, at least about four weeks, at
least about six weeks, at least about eight weeks, at least about
10 weeks, at least about 12 weeks, at least about 14 weeks, at
least about 16 weeks, at least about 18 weeks, at least about 20
weeks, at least about 22 weeks), and/or at most about 24 weeks
(e.g., at most about 22 weeks, at most about 20 weeks, at most
about 18 weeks, at most about 16 weeks, at most about 14 weeks, at
most about 12 weeks, at most about 10 weeks, at most about eight
weeks, at most about six weeks, at most about four weeks, at most
about three weeks, at most about two weeks).
[0062] As the biodisintegrable polyelectrolytes disintegrate, the
biodisintegrable material of tubular structure 21 can, for example,
become more exposed to water. This increased exposure to water can
cause tubular structure 21 to begin to disintegrate or to
disintegrate more rapidly. Eventually, tubular structure 21 may
disintegrate entirely.
[0063] In certain embodiments, biodisintegrable polyelectrolytes
can be used near the outer surface of stent 20 to release a
therapeutic agent into the subject at a rate that is dependent upon
the rate of disintegration of the polyelectrolyte layers. Examples
of therapeutic agents are described below.
[0064] In some embodiments, layers 27 and/or 30 may include
biodisintegrable polyelectrolytes that may disintegrate at a slower
rate than the biodisintegrable material of tubular structure 21 of
stent 20. As tubular structure 21 disintegrates, it may break into
multiple pieces. Because layers 27 and/or 30 are formed of
biodisintegrable materials that disintegrate at a slower rate than
the biodisintegrable material of tubular structure 21, at least
some of layers 27 and/or 30 may limit or prevent movement of these
pieces to other places in the body, causing the pieces to
disintegrate instead at the target site within the body.
[0065] While layers formed of biodisintegrable polyelectrolytes
have been described, in some embodiments, polyelectrolytes in
different layers of a medical device can be sufficiently
cross-linked to each other to make the layers biostable. As used
herein, a "biostable material" is a material that does not undergo
substantial dissolution, degradation, corrosion, resorption and/or
other disintegration processes over the period that a device
including the biostable material is designed to reside in a
patient. Thus if, for example, layers 27 and 30 are cross-linked to
each other so that multi-layered structure 26 is biostable, tubular
structure 21 may disintegrate over a period of time, while
multi-layered structure 26 remains in the body of the subject.
[0066] As an example, a polyelectrolyte layer including diazonium
cations may be covalently cross-linked to a polyelectrolyte layer
including sulfonate groups or acrylic acid groups, using UV
radiation or heat. As another example, a polyelectrolyte layer
including a diazo resin may be cross-linked to a polyelectrolyte
layer including polyoxometalates. As an additional example,
ammonium groups in one polyelectrolyte layer may be covalently
bonded to carboxylate groups in another polyelectrolyte layer. In
certain embodiments, polyelectrolyte layers including
poly(allylamine hydrochloride) (PAH) can be covalently bonded to
polyelectrolyte layers including poly(acrylic acid) (PAA).
Cross-linking of polyelectrolyte layers is described, for example,
in Zhang et al., "Improving multilayer films endurance by
photoinduced interaction between Dawson-type polyoxometalate and
diazo resin", Materials Chemistry and Physics 90 (2005), 47-52, and
in Zhang et al., "Ways for fabricating stable layer-by-layer
self-assemblies: combined ionic self-assembly and post chemical
reaction", Colloids and Surfaces A: Physicochemical and Engineering
Aspects 198-200 (2002), 439-442.
[0067] In some embodiments, one or more of the top polyelectrolyte
layers on a medical device can be cross-linked. This can, for
example, limit or prevent dissolution of the polyelectrolyte layers
on the medical device in the body. For example, multiple layers of
polyallylamine hydrochloride (PAH) and polyacrylic acid (PAA) can
be deposited on a plurality of other polyelectrolyte layers. The
entire multi-layered structure can then be heated at 130.degree. C.
for about an hour under a nitrogen atmosphere to crosslink the
ammonium groups of the PAH and the carboxylic groups of the PAA to
form amide bonds. A nylon-like top film that is impermeable to
liquids can be created. In certain embodiments, this
liquid-impermeable top film can later be removed (e.g., using
excimer ablation).
[0068] In some embodiments, a liquid-impermeable layer (such as a
top layer) may be formed on a biodisintegrable medical device, such
as a biodisintegrable stent (e.g., a biodisintegrable abdominal
aortic aneurysm (AAA) stent) or a biodisintegrable vessel graft. As
an example, in certain embodiments, a biodisintegrable stent (e.g.,
a biodisintegrable stent formed of iron or magnesium) may have
certain desirable properties. For example, magnesium has a
relatively low mass attenuation factor, and the CT visibility of
the region (e.g., a body lumen) in which a magnesium stent is
located can be relatively high. Thus, it may be desirable for the
stent not to disintegrate in the body. A liquid-impermeable layer
can be formed over the stent to limit or prevent disintegration of
the stent.
[0069] In certain embodiments in which multi-layered structure 26
is biostable, layers 27 and 30 may have one or more (e.g., two,
three, four, five, 10, 15, 20, 25) holes in them. In some
embodiments, one or more holes can be added to a layer using a
laser. The holes can, for example, provide water and/or ions with
limited access to tubular structure 21, thereby helping cause
tubular structure 21 to disintegrate. As discussed above, as
tubular structure 21 disintegrates, it may break into multiple
pieces. Because multi-layered structure 26 is biostable,
multi-layered structure 26 may limit or prevent movement of these
pieces to other places in the body, causing the pieces to
disintegrate instead at the target site within the body. In certain
embodiments, a biostable multi-layered structure including one or
more holes in at least one of its layers can be coated with a
biodisintegrable coating. The biodisintegrable coating can, for
example, be used to limit or prevent corrosion of a structure
(e.g., tubular structure 21) underlying the multi-layered structure
until the biodisintegrable coating has substantially or entirely
disintegrated.
[0070] In some embodiments, one or more regions of a
polyelectrolyte layer may be cross-linked to one or more regions of
another polyelectrolyte layer (e.g., by selectively irradiating
certain regions of the polyelectrolyte layers), while the
polyelectrolyte layers may not be cross-linked to each other in
other regions.
[0071] In some embodiments, a medical device can include a
structure (e.g., a multi-layered structure) having a combination of
cross-linked polyelectrolytes and biodisintegrable
polyelectrolytes, to provide further tailoring of the
disintegration of the device.
[0072] In certain embodiments, layers 27 and/or 30 can include one
or more polyoxometalates, anions that can be used to provide a
negative charge to a layer. In some embodiments, the presence of
polyoxometalates in layers 27 and/or 30 can enhance the MRI
visibility of material in lumen 23 of tubular structure 21 of stent
20. In certain embodiments, the presence of polyoxometalates in
layers 27 and/or 30 can enhance the X-ray visibility of tubular
structure 21 of stent 20. Polyoxometalates are nanosized inorganic
oxygen clusters, such as inorganic metal oxygen clusters, that can
be strictly uniform at the atomic level. The clusters are discrete
molecular units with well-defined molecular formulas, in contrast
to nanosized particles having infinite, extended lattice
structures. Depending on the number of different types of
non-oxygen atoms, polyoxometalates can be classified as
isopolyanions or heteropolyanions. Isopolyanions can be described
by the formula [M.sub.xO.sub.y].sup.-p; and heteropolyanions can be
described by the formula [X.sub.aM.sub.bO.sub.c].sup.-q, where M
and X are different metals. Examples of metals include gadolinium,
dysprosium, molybdenum, tungsten, vanadium, niobium, tantalum,
cobalt, iron, ruthenium, titanium, nickel, chromium, platinum,
zirconium, iridium, silicon, and boron. In some embodiments, the
polyoxometalates are magnetic, for example, ferromagnetic,
diamagnetic (e.g., including copper or bismuth), paramagnetic, or
superparamagnetic. Examples of polyoxometalates include
[Co.sub.4(H.sub.2O).sub.2(PW.sub.9O.sub.34).sub.2].sup.10-;
[Co.sub.4(H.sub.2O).sub.2(P.sub.2W.sub.15O.sub.56).sub.2].sup.16-;
Keggin POMs (such as [XM.sub.12O.sub.40].sup.3-/4-, where X can be
P or Si, and M can be W, Mo, Fe, Mn, Cr, Ni, or Ru); Preyssler POMs
(such as [M(H.sub.2O)P.sub.5W.sub.30O.sub.110].sup.14/12-, where M
can be Na or Eu); Lindqvist POMs (such as
[M.sub.6O.sub.19].sup.2-); and Anderson POMs (such as
[XM.sub.6O.sub.24].sup.m-). Other examples of polyoxometalates are
described, for example, in Casan-Pastor et al., Frontiers in
Bioscience 9, 1759-1770, May 1, 2004; Clemente-Leon et al., Adv.
Mater. 2001, 13, No. 8, April 18, 574-577; Liu et al., Journal of
Cluster Science, Vol. 14, No. 3, September 2003, 405-419; Hu
Changwen et al., "Polyoxometalate-based Organic-inorganic Hybrid
Materials" Chemical Journal on Internet, Vol. 3, No. 6, page 22
(Jun. 1, 2001); Kurth et al., Chem. Mater., 2000, 12, 2829-2831;
and the entire issue of Chem. Rev. 1998, 98, 1. One or more layers
27 can include one type of molecular magnetic cluster or different
types of clusters. Polyoxometalates also are described, for
example, in U.S. patent application Ser. No. 10/985,242, filed on
Nov. 10, 2004, and entitled "Medical Devices and Methods of Making
the Same".
[0073] Layers 27 can be assembled with layers 30 using a
layer-by-layer technique in which the layers electrostatically
self-assemble. In the layer-by-layer technique, a first layer
having a first surface charge is deposited on an underlying
substrate, followed by a second layer having a second surface
charge that is opposite in sign to the surface charge of the first
layer. Thus, the charge on the outer layer is reversed upon
deposition of each sequential layer. Additional first and second
layers can then be alternatingly deposited on the substrate to
build multi-layered structure 26 to a predetermined or targeted
thickness. The layer-by-layer technique allows structure 26 to be
formed on tubular structure 21 directly and/or, for example, on a
flexible sleeve (e.g., a polymer sleeve) carried by the tubular
structure. As a result, structure 26 is capable of controlling the
disintegration of tubular structure 21, while allowing stent 20 to
remain flexible and adaptable to the vessel in which stent 20 is
implanted.
[0074] Layers 27 may have the same thickness or different
thicknesses. In some embodiments, the thickness of a layer may
depend on the molecular weight of the polyelectrolyte(s) included
in the layer, and/or the presence of other materials (e.g.,
nanoparticles) in the layer. For example, a layer including a
relatively low molecular weight polyelectrolyte, such as low
molecular weight heparin (e.g., heparin having a molecular weight
of from about 1,000 Daltons to about 10,000 Daltons) may relatively
thin. In certain embodiments, the thickness of a layer may depend
on the conditions (e.g., salt concentration and/or pH) during the
deposition of the layer. In some embodiments, an individual layer
27 and/or an individual layer 30 may have a thickness of at least
about 0.2 nanometer (e.g., at least about 0.5 nanometer, at least
about one nanometer, at least about five nanometers, at least about
10 nanometers, at least about 50 nanometers, at least about 100
nanometers, at least about 300 nanometers), and/or at most about
500 nanometers (e.g., at most about 300 nanometers, at most about
100 nanometers, at most about 50 nanometers, at most about 10
nanometers, at most about five nanometers, at most about one
nanometer, at most about 0.5 nanometer).
[0075] As described above, tubular structure 21 of stent 20 is
formed of a biodisintegrable material, such as a biodisintegrable
metal, a biodisintegrable metal alloy, or a biodisintegrable
non-metal. Examples of biodisintegrable metals include alkali
metals, alkaline earth metals (e.g., magnesium), iron, zinc,
aluminum. In some embodiments, a biodisintegrable metal can be
sintered. Examples of biodisintegrable metal alloys include alkali
metal alloys, alkaline earth metal alloys (e.g., magnesium alloys),
iron alloys (e.g., alloys including iron and up to seven percent
carbon), zinc alloys, and aluminum alloys. Examples of
biodisintegrable non-metals include biodisintegrable polymers, such
as polyiminocarbonates, polycarbonates, polyarylates, polylactides,
or polyglycolic esters.
[0076] In certain embodiments, a biodisintegrable material can
include at least one metallic component and at least one
non-metallic component, or at least two different metallic
components. In some embodiments, a biodisintegrable material can
include at least one of the following: manganese, cobalt, nickel,
chromium, copper, cadmium, lead, tin, thorium, zirconium, silver,
gold, palladium, platinum, rhenium, silicon, calcium, lithium,
aluminum, zinc, iron, carbon, and sulfur. In certain embodiments, a
biodisintegrable material can include magnesium, titanium,
zirconium, niobium, tantalum, zinc, or silicon, and lithium,
sodium, potassium, calcium, iron, or manganese.
[0077] In certain embodiments, a medical device that is formed of
one or more biodisintegrable materials can disintegrate at a rate
of at least about 0.2 micron per day (e.g., at least about 0.5
micron per day, at least about one micron per day, at least about
two microns per day, at least about three microns per day, at least
about four microns per day) and/or at most about five microns per
day (e.g., at most about four microns per day, at most about three
microns per day, at most about two microns per day, at most about
one micron per day, at most about 0.5 micron per day). In some
embodiments, a medical device that is formed of one or more
biodisintegrable materials can disintegrate over a period of at
least about five days (e.g., at least about one week, at least
about two weeks, at least about three weeks, at least about four
weeks, at least about six weeks, at least about eight weeks, at
least about 12 weeks, at least about 16 weeks, at least about 20
weeks, at least about 24 weeks, at least about 12 months).
[0078] Biodisintegrable materials are described, for example, in
Bolz, U.S. Pat. No. 6,287,332; Heublein, U.S. patent application
Publication No. US 2002/0004060 A1; Kohn et al., U.S. Pat. No.
5,587,507; and Kohn et al., U.S. Pat. No. 6,475,477.
[0079] Referring to FIG. 3, an embodiment of a method 40 of making
stent 20 using a layer-by-layer technique is shown. Method 40
includes providing a starting stent (step 42) and pretreating the
starting stent for layer-by-layer deposition (step 44). Next, a
charged layer 27 containing a polyelectrolyte can be applied on the
starting stent (step 46). A charged layer 30 containing a
polyelectrolyte can then be applied to the previously applied
charged layer 27 (step 48). Steps 46 and 48 can then repeated to
build a multi-layered structure 26 of a desired thickness to form
stent 20. In some embodiments, as described below, multi-layered
structure 26 can further include one or more layers including a
therapeutic agent, one or more layers including a radiopaque
material, and/or one or more layers capable of enhancing the
mechanical properties of structure 26. These additional layers can
be applied between layers 27 and/or layers 30, in any combination.
Layer-by-layer self-assembly is described, for example, in Liu et
al., Journal of Cluster Science, Vol. 14, No. 3, Sep. 2003,
405-419; and Caruso et al., Langmuir 1998, 14, 3462-3465.
[0080] The starting stent that is provided according to step 42 can
be manufactured, or the starting stent can be obtained
commercially. Methods of making stents are described, for example,
in Saunders, U.S. Pat. No. 5,780,807, and Stinson, U.S. application
Publication US 2004/0000046 A1. Stents are also available, for
example, from Boston Scientific Corporation.
[0081] The provided stent can be formed of any biocompatible,
biodisintegrable material, such as the materials described above
with reference to tubular structure 21 of stent 20. The
biocompatible material can be suitable for use in, for example, a
balloon-expandable stent.
[0082] After the stent has been provided, the stent can be
pretreated (step 44). For example, the stent can be cleaned to
remove surface contaminants, such as oil, that can affect the
homogeneity to which multi-layered structure 26 can be formed. The
stent can be cleaned, for example, in a mixture such as acetone,
H.sub.2O.sub.2/HCl, HCl/HNO.sub.3,
H.sub.2SO.sub.4/K.sub.2Cr.sub.2O.sub.7, H.sub.2O.sub.2/NH.sub.3,
and/or NaOH/NaOCl. The stent can also be pretreated with a solution
including 10.sup.-2 M SDS/0.12 N HCl for 15 minutes at 100.degree.
C.
[0083] Next, while certain stent materials may be inherently
charged and thus lend themselves to layer-by-layer assembly, in
certain embodiments (e.g., embodiments in which the stent does not
have an inherent net surface charge), a surface charge may be
provided to the stent. For example, where the stent to be coated is
conductive, a surface charge can be provided by applying an
electrical potential to the stent. Once a first polyelectrolyte
layer is applied in this fashion, a second polyelectrolyte layer
having a second surface charge that is opposite in sign to the
surface charge of the first polyelectrolyte layer can be applied,
and so forth.
[0084] As another example, the stent can be provided with a
positive charge by covalently attaching functional groups having a
positive charge (e.g., amine, imine or other basic groups) to the
stent, or can be provided with a negative charge by covalently
attaching functional groups having a negative charge (e.g.,
carboxylic, phosphonic, phosphoric, sulfuric, sulfonic, or other
acid groups) to the stent.
[0085] As an additional example, a surface charge can be provided
by exposing the stent to a charged amphiphilic substance.
Amphiphilic substances can include any substance having hydrophilic
and hydrophobic groups. In some embodiments, the amphiphilic
substance can include at least one electrically charged group that
can provide the stent surface with a net electrical charge. In such
embodiments, the amphiphilic substances can also be referred to as
ionic amphiphilic substances.
[0086] In certain embodiments, an amphiphilic polyelectrolyte can
be used as an ionic amphiphilic substance. For example, a
polyelectrolyte comprising charged groups (which are hydrophilic)
as well as hydrophobic groups, such as polyethyleneimine (PEI) or
poly(styrene sulfonate) (PSS), can be employed. Cationic and
anionic surfactants can also be used as amphiphilic substances in
some embodiments. Cationic surfactants include quaternary ammonium
salts (R.sub.4N.sup.+X.sup.-), in which R is an organic radical and
X.sup.- is a counter-anion (e.g., a halogenide), for example,
didodecyldimethylammonium bromide (DDDAB), alkyltrimethylammonium
bromides such as hexadecyltrimethylammonium bromide (HDTAB),
dodecyltrimethylammonium bromide (DTMAB), myristyltrimethylammonium
bromide (MTMAB), or palmityl trimethylammonium bromide, or
N-alkylpyridinium salts, or tertiary amines
(R.sub.3NH.sup.+X.sup.-), for example,
cholesteryl-3.beta.-N-(dimethyl-am- inoethyl)-carbamate or mixtures
thereof. Anionic surfactants include alkyl or olefin sulfate
(R--OSO.sub.3M), for example, a dodecyl sulfate such as sodium
dodecyl sulfate (SDS), a lauryl sulfate such as sodium lauryl
sulfate (SLS), or an alkyl or olefin sulfonate (R--SO.sub.3M), for
example, sodium-n-dodecylbenzene sulfonate, or fatty acids
(R--COOM), for example, dodecanoic acid sodium salt, or phosphoric
acids or cholic acids or fluoro-organics, for example,
lithium-3-[2-(perfluoroalkyl)ethylthio]p- ropionate or mixtures
thereof, where R is an organic radical and M is a
counter-cation.
[0087] Thus, a surface charge can be provided on the stent by
adsorbing cations (e.g., protamine sulfate, polyallylamine,
polydiallyldimethylammo- nium species, polyethyleneimine, chitosan,
gelatin, spermidine, and/or albumin) or by adsorbing anions (e.g.,
polyacrylic acid, sodium alginate, polystyrene sulfonate, eudragit,
gelatin (an amphiphilic polymer that fits in both categories
depending how it is being prepared), hyaluronic acid, carrageenan,
chondroitin sulfate, and/or carboxymethylcellulose) to the surface
of the stent as a first charged layer. As an example,
polyethyleneimine (PEI, Aldrich, MW .about.25 kD) can be dissolved
in water in a concentration of about 0.5 g/L to apply a first
coating. In some embodiments, more than one surface charge layer
can be applied to provide complete coverage of the stent.
Application of surface charge layers is described, for example, in
"Multilayer on Solid Planar Substrates", Multi-layer Thin Films,
Sequential Assembly of Nanocomposite Materials, Wiley-VCH ISBN
3-527-30440-1, Chapter 14; and "Surface-Chemistry Technology for
Microfluidics", Hau, Winky L. W. et al., J Micromech. Microeng. 13
(2003) 272-278.
[0088] The species for establishing a surface charge can be applied
to the stent by a variety of techniques. Examples of techniques
include spraying techniques, dipping techniques, roll and brush
coating techniques, techniques involving coating via mechanical
suspension such as air suspension, ink jet techniques, spin coating
techniques, web coating techniques, microstamping techniques, and
combinations of these processes. Microstamping techniques using
polydimethylsiloxane (PDMS) technology are described, for example,
in Lin et al., "Micropatterning proteins and cells on polylactic
acid and poly(lactide-co-glycolide)", Biomaterials 26 (2005),
3655-3662. Dipping and spraying techniques (without masking) can be
employed, for example, to apply the species to an entire stent.
Roll coating, brush coating and ink jet printing can be employed,
for example, to apply the species only to selected portions of the
stent (e.g., in the form of a pattern).
[0089] Once a preselected charge is provided on the stent, the
stent can be coated with a layer of an oppositely charged material.
After each application of a layer, the stent can be washed to
remove excess material. Multi-layer structure 26 can be formed by
repeated treatment with alternating, oppositely charged materials,
for example, by alternating treatment of a positive polyelectrolyte
with treatment with a negative polyelectrolyte to build layers 27
and 30 (steps 46 and 48). Layers 27 and 30 self-assemble by
electrostatic layer-by-layer deposition, thus forming multi-layered
structure 26 over the stent.
[0090] In some embodiments, multi-layered structure 26 can include
nanoparticles. The nanoparticles can, for example, enhance the
mechanical properties (e.g., strength) of the structure. The
nanoparticles can have at least one dimension (e.g., the thickness
for a nanoplate, the diameter for a nanosphere, a nanocylinder and
a nanotube) that is less than 1000 nanometers (e.g., less than 100
nanometers). Nanoplates can have at least one dimension that is
less than 1000 nanometers; nanofibers can have at least two
orthogonal dimensions (e.g., the diameter for a cylindrical
nanofiber) that are less than 1000 nanometers; and other
nanoparticles can have three orthogonal dimensions that are less
than 1000 nanometers (e.g., the diameter for nanospheres).
[0091] Examples of nanoparticles include carbon, ceramic and
metallic nanoparticles including nanoplates, nanotubes, and
nanospheres, and other nanoparticles. Specific examples of
nanoplates include synthetic or natural phyllosilicates including
clays and micas (which may optionally be intercalated and/or
exfoliated) such as montmorillonite, hectorite, hydrotalcite,
vermiculite and laponite. Specific examples of nanotubes and
nanofibers include single-wall and multi-wall carbon nanotubes,
such as fullerene nanotubes, vapor grown carbon fibers, alumina
nanofibers, titanium oxide nanofibers, tungsten oxide nanofibers,
tantalum oxide nanofibers, zirconium oxide nanofibers, and silicate
nanofibers such as aluminum silicate nanofibers. Other examples of
nanoparticles (e.g., nanoparticles having three orthogonal
dimensions that are less than 1000 nm) include fullerenes (e.g.,
bucky balls), silica nanoparticles, aluminum oxide nanoparticles,
titanium oxide nanoparticles, tungsten oxide nanoparticles,
tantalum oxide nanoparticles, zirconium oxide nanoparticles,
dendrimers, and monomeric silicates such as polyhedral oligomeric
silsequioxanes (POSS), including various functionalized POSS and
polymerized POSS. The carbon nanotubes and carbon nanofibers can
have a diameter ranging from 0.5 mn to 200 nm. Still other examples
of nanoparticles include compositions of the Mo--S--I family, such
as Mo.sub.6S.sub.3I.sub.6 and Mo.sub.3S.sub.6I, which are described
in Vrbani et al., Nanotechnology 15 (2004) 635-638; Remkar et al.,
Science 292 (2001) 479; and Mihailovi et al., Phys. Rev. Lett. 90
(2003) 146401-1. Mo.sub.3S.sub.6I, for example when doped, can
exhibit a large paramagnetic susceptibility, which can further
enhance the magnetic shielding capability of the multi-layered
structure.
[0092] In certain embodiments, a polyelectrolyte layer can be used
to encapsulate one or more nanoparticles, such as magnetic
nanoparticles (e.g., CoFe.sub.2O.sub.4) and those described herein.
Polymer/magnetic nanoparticles systems are described, for example,
in Sing et al., Electrochimica Acta 49 (2004) 4605-4612. The
polymer/nanoparticles composite can, for example, enhance the
mechanical properties of the structure and/or enhance a magnetic
shielding effect.
[0093] Various techniques can be used to provide charges on
nanoparticles that are not inherently charged. For example, a
surface charge can be provided by adsorbing or otherwise attaching
species on the nanoparticles that have a net positive or negative
charge, for example, charged amphiphilic substance such as
amphiphilic polyelectrolytes and cationic and anionic surfactants
(see above). Where the nanoparticles are sufficiently stable,
surface charges can sometimes be established by exposure to highly
acidic conditions. For example, carbon nanoparticles, such as
carbon nanotubes, can be partially oxidized by refluxing in strong
acid to form carboxylic acid groups (which ionize to become
negatively charged carboxyl groups) on the nanoparticles.
Establishing a surface charge on nanoparticles can also provide a
relatively stable and uniform suspension of the nanoparticles, due
at least in part to electrostatic stabilization effects.
Layer-by-layer assembly to form alternating layers of SWNT and
polymeric material have also been described, for example, in Arif
A. Mamedov et al., "Molecular Design of Strong Singlewall Carbon
Nanotube/Polyelectrolyte Multilayer Composites", Nature Material,
Vol. 1, No. 3, 2002, pages 191-194. The nanoparticles can be
positively charged or negatively charged, and both types of
nanoparticles can be used in a medical device. A medical device can
include one composition of nanoparticles or different compositions
of nanoparticles.
[0094] As indicated above, in some embodiments, multi-layered
structure 26 can further include one or more layers including a
therapeutic agent, one or more layers including a radiopaque
material, and/or one or more layers capable of enhancing the
mechanical properties of structure 26.
[0095] As an example, in some embodiments, a medical device can
include one or more non-polyelectrolyte layers that include one or
more therapeutic agents. The non-polyelectrolyte layers can be
biodisintegrable or biostable. Examples of non-polyelectrolyte
biodisintegrable materials include polylactides (PLA),
polyglycolides (PGA), poly(lactide-co-glycolides) (PLGA),
polyanhydrides, and polyorthoesters. For example, a stent can
include a tubular structure and a multi-layered structure formed of
polyelectrolytes located on the tubular structure. The stent can
further include one or more non-polyelectrolyte layers, which can
be added to the stent using, for example, spraying techniques. The
non-polyelectrolyte layer(s) may be added on top of the
multi-layered structure, and/or underneath the multi-layered
structure. In some embodiments, a stent can include more than one
multi-layered structure, and/or can include one or more
non-polyelectrolyte layers located between the multi-layered
structures. In some embodiments, the non-polyelectrolyte layer(s)
may be thicker than one or more of the layers in the multi-layered
structure(s). In certain embodiments, a non-polyelectrolyte layer
may exhibit better adhesion to the surface of a tubular structure
of a stent than a polyelectrolyte layer.
[0096] As another example, one or more therapeutic agents can be
disposed on or within multi-layered structure 26 giving the medical
device, for example, a drug releasing function upon implantation.
The therapeutic agent can be charged, for example, because it is
itself a charged molecule or because it is intimately associated
with a charged molecule. Examples of charged therapeutic agents
include small molecule and polymeric therapeutic agents containing
ionically dissociable groups. In some embodiments in which the
therapeutic agent does not possess one or more charged groups, it
can nevertheless be provided with a charge, for example, through
non-covalent association with a charged species. Examples of
non-covalent associations include hydrogen bonding, and
hydrophilic/lipophilic interactions. For instance, the therapeutic
agent can be associated with an ionic amphiphilic substance.
[0097] In certain embodiments in which a charged therapeutic agent
is used, one or more layers of the charged therapeutic agent can be
deposited during the course of assembling multi-layer structure 26.
For example, the therapeutic agent can be a polyelectrolyte (e.g.,
where the therapeutic agent is a polypeptide or a polynucleotide)
and can be used to create one or more polyelectrolyte layers within
multi-layer structure 26. In other embodiments, the charged
therapeutic agent is not a polyelectrolyte (e.g., it may be a
charged small molecule drug), but one or more layers of the charged
therapeutic agent can be substituted for one or more layers of the
same charge (i.e., positive or negative) during the layer-by-layer
assembly process.
[0098] In still other embodiments, the therapeutic agent can
provided within charged nanocapsules, which are formed, for
example, using layer-by-layer techniques such as those described
herein and in commonly assigned U.S. patent application Ser. No.
10/768,388, entitled "Localized Drug Delivery Using Drug-Loaded
Nanocapsules". In these embodiments, one or more layers of the
charged nanocapsules can be deposited during the course of the
layer-by-layer assembly process.
[0099] In still other embodiments, multi-layer structure 26 is
loaded with a therapeutic agent subsequent to its formation. For
example, the porosity, and thus the permeability, of structure 26
can be modified by modifying the pH exposed to the structure, as
described, for example, in Antipov, A. A. et al., "Polyelectrolyte
Multilayer Capsule Permeability Control", Colloids and Surfaces A:
Physicochemical and Engineering Aspects, 198-200 (2002) pp.
535-541.
[0100] Examples of therapeutic agents and methods of incorporated
the agents are described in U.S. patent application Ser. No.
10/849,742, filed on May 20, 2004; and Kunz et al., U.S. Pat. No.
5,733,925. Some examples of therapeutic agents include non-genetic
therapeutic agents, genetic therapeutic agents, vectors for
delivery of genetic therapeutic agents, cells, and therapeutic
agents identified as candidates for vascular treatment regimens,
for example, as agents targeting restenosis.
[0101] To enhance the radiopacity of stent 20, a radiopaque
material, such as gold nanoparticles, can be incorporated into
multi-layered structure 26. As an example, gold nanoparticles can
be made positively charged by applying a outer layer of lysine to
the nanoparticles, as described, for example, in "DNA Mediated
Electrostatic Assembly of Gold Nanoparticles into Linear Arrays by
a Simple Dropcoating Procedure", Murali Sastrya and Ashavani Kumar,
Applied Physics Letters, Vol. 78, No. 19, 7 May 2001. Other
radiopaque materials include, for example, tantalum, platinum,
palladium, tungsten, iridium, and their alloys.
[0102] The layer-by-layer assembly can be conducted by exposing a
selected charged substrate (e.g., a stent) to solutions or
suspensions that contain species of alternating net charge,
including solutions or suspensions that contain charged magnetic
clusters, charged polyelectrolytes, and, optionally, charged
therapeutic agents and/or nanoparticles. The concentration of the
charged species within these solutions and suspensions, which can
be dependent on the types of species being deposited, can range,
for example, from about 0.01 mg/ml to about 30 mg/ml. The pH of
these suspensions and solutions can be such that the magnetic
clusters, polyelectrolytes, and optional therapeutic agents and/or
nanoparticles maintain their charge. Buffer systems can be used to
maintain charge.
[0103] The solutions and suspensions containing the charged species
(e.g., solutions/suspensions of magnetic clusters,
polyelectrolytes, or other optional charged species such as charged
therapeutic agents and/or charged nanoparticles) can be applied to
the charged substrate surface using a variety of techniques.
Examples of techniques include spraying techniques, dipping
techniques, roll and brush coating techniques, techniques involving
coating via mechanical suspension such as air suspension, ink jet
techniques, spin coating techniques, web coating techniques,
microstamping techniques, and combinations of these processes.
Layers can be applied over an underlying substrate by immersing the
entire substrate (e.g., stent) into a solution or suspension
containing the charged species, or by immersing half of the
substrate into the solution or suspension, flipping the same, and
immersing the other half of the substrate into the solution or
suspension to complete the coating. In some embodiments, the
substrate is rinsed after application of each charged species
layer, for example, using a washing solution with a pH that
maintains the charge of the outer layer.
[0104] Using the techniques described herein, multiple layers of
alternating charge can be applied over the underlying substrate,
including the application of one or more charged layers 27 and the
application of one or more charged layers 30. The number of each
layer and/or the total thickness of multi-layered structure 26 can
be determined empirically and can be a function of, for example,
the compositions of the layers and the type of medical device. For
example, for a given medical device, the number of layers, their
sequences and compositions, and/or the total thickness of
multi-layered structure 26 can be varied and the effectiveness of
the multi-layered structure can be tested. After an effective
combination is determined, the same combination can be repeated. In
some embodiments, at least 10 layers (e.g., at least 20 layers, at
least 30 layers, at least 50 layers, at least 100 layers, at least
200 layers) and/or at most 300 layers (e.g., at most 200 layers, at
most 100 layers, at most 50 layers, at most 30 layers, at most 20
layers) can be applied over the substrate. The total thickness of
multi-layered structure 26 can be a function of the materials
(e.g., polyelectrolytes) used. In some embodiments, the total
thickness of multi-layered structure 26 can be at least five
nanometers (e.g., at least 10 nanometers; at least 50 nanometers;
at least 100 nanometers; at least 500 nanometers; at least 1000
nanometers; at least 1500 nanometers; at least 2000 nanometers; at
least 5000 nanometers; at least 10,000 nanometers; at least 20,000
nanometers; at least 30,000 nanometers) and/or at most 40,000
nanometers (e.g., at most 30,000 nanometers; at most 20,000
nanometers; at most 10,000 nanometers; at most 5000 nanometers; at
most 2000 nanometers; at most 1500 nanometers; at most 1000
nanometers, at most 500 nanometers, at most 100 nanometers, at most
50 nanometers, at most 10 nanometers).
[0105] In use, stent 20 can be delivered and expanded using, for
example, a balloon catheter system or other stent delivery systems.
Catheter systems are described in, for example, Wang U.S. Pat. No.
5,195,969, and Hamlin U.S. Pat. No. 5,270,086. Stents and stent
delivery are also exemplified by the Radius.RTM. or Symbiot.RTM.
systems, available from Boston Scientific Scimed, Maple Grove,
Minn.
[0106] Stent 20 can be of any desired shape and size (e.g.,
coronary stents, aortic stents, peripheral vascular stents,
gastrointestinal stents, urology stents, cerebral stents, urethral
stents, ureteral stents, biliary stents, tracheal stents,
esophageal stents, neurology stents). Depending on the application,
stent 20 can have a diameter of between, for example, one
millimeter to 46 millimeters. In certain embodiments, a coronary
stent can have an expanded diameter of from about two millimeters
to about six millimeters. In some embodiments, a peripheral stent
can have an expanded diameter of from about four millimeters to
about 24 millimeters. In certain embodiments, a gastrointestinal
and/or urology stent can have an expanded diameter of from about
six millimeters to about 30 millimeters. In some embodiments, a
neurology stent can have an expanded diameter of from about one
millimeter to about 12 millimeters. An abdominal aortic aneurysm
(AAA) stent and a thoracic aortic aneurysm (TAA) stent can have a
diameter from about 20 millimeters to about 46 millimeters. Stent
20 can be balloon-expandable, self-expandable, or a combination of
both (e.g., Andersen et al., U.S. Pat. No. 5,366,504).
[0107] While a number of embodiments have been described above, the
invention is not so limited.
[0108] As an example, in certain embodiments, one portion of a
medical device can have a different number of layers on it than
another portion of a medical device. For example, FIG. 4 shows a
stent 120 in the form of a biodisintegrable tubular structure 121
defined by a plurality of bands 122 and a plurality of connectors
124 extending between and connecting adjacent bands. As shown in
FIG. 5, one portion of stent 120 (as shown, a portion of a band
122) is coated with a multi-layered structure 126 including a total
of five biodisintegrable layers (three charged layers 127 and two
charged layers 130). As shown in FIG. 6, another portion of stent
120 (as shown, a portion of another band 122) is coated with a
multi-layered structure 150 including a total of 10
biodisintegrable layers (five charged layers 127 and five charged
layers 130). Thus, during use, multi-layered structure 126 will
tend to disintegrate more quickly than multi-layered structure 150.
As a result, the portion of tubular structure 121 that is
underneath multi-layered structure 126 will tend to disintegrate
more quickly than the portion of tubular structure 121 that is
underneath multi-layered structure 150.
[0109] While a medical device including five layers on one portion
and 10 layers on another portion has been shown, other embodiments
are possible. For example, in some embodiments, one portion of a
medical device can include a multi-layered structure with at least
10 layers (e.g., at least 20 layers, at least 30 layers, at least
40 layers), and another portion of a medical device can include a
multi-layered structure with at least 20 layers (e.g., at least 30
layers, at least 40 layers, at least 50 layers). For example, one
portion of a medical device may include a multi-layered structure
with 10 layers and another portion of the medical device may
include a multi-layered structure with 40 layers. In certain
embodiments, a multi-layered structure on one portion of a medical
device can include from five to 50 more layers (e.g., from 10 to 30
more layers) than a multi-layered structure on another portion of
the medical device.
[0110] In some embodiments, one or more portions of a medical
device may not include any polyelectrolyte layers or may not
include any layers at all.
[0111] In some embodiments, stents having portions with different
numbers of layers on them can be formed by dipping one end (e.g.,
2/3) of a stent in one material, turning the stent around, and
dipping the other end (e.g., 2/3) of the stent in another material,
and repeating the process multiple times. The result is that the
middle of the stent (e.g., the middle 1/3 of the stent) receives
more layers than either end of the stent. In certain embodiments,
stents having portions with different numbers of layers on them can
be formed by other techniques, such as ink jet techniques,
microstamping, spraying, roll coating, or brush coating.
[0112] As another example, while a stent including a tubular
structure that is formed entirely of a biodisintegrable material
has been described, in some embodiments, the tubular structure of a
stent can include one or more biostable materials, in addition to
including one or more biodisintegrable materials. For example, the
tubular structure of a stent may include biostable regions and
biodisintegrable regions that are designed to biodisintegrate a
certain period of time after the stent has been delivered to a
target site. In certain embodiments, the disintegration of the
biodisintegrable regions may enhance the MRI-compatibility of the
stent. One or more polyelectrolytes may be used (as described
above) to control the disintegration of one or more of the
biodisintegrable regions of the stent. The polyelectrolytes may be
in the form of layers over the biodisintegrable and/or biostable
regions of the stent. Examples of biostable materials include
Nitinol (e.g., 55% nickel, 45% titanium) and stainless steel.
Specific examples of biocompatible materials are described, for
example, in Weber et al., U.S. patent application Publication No.
US 2004/0230290 A1, published on Nov. 18, 2004; Craig et al., U.S.
patent application Publication No. US 2003/0018380 A1, published on
Jan. 23, 2003; Craig et al., U.S. patent application Publication
No. US 2002/0144757 A1, published on Oct. 10, 2002; and Craig et
al., U.S. patent application Publication No. US 2003/0077200 A1,
published on Apr. 24, 2003. Stents including biostable and
biodisintegrable regions are described, for example, in U.S. patent
application Ser. No. 11/004,009, filed on Dec. 3, 2004, and
entitled "Medical Devices and Methods of Making the Same".
[0113] As an additional example, in some embodiments, a stent can
include a tubular structure that is formed of one or more biostable
materials, such a Nitinol, and no biodisintegrable materials.
[0114] As a further example, in certain embodiments, a
multi-layered structure may include at least two positively charged
layers that are formed of different materials (e.g., different
polyelectrolytes) and/or at least two negatively charged layers
that are formed of different materials (e.g., different
polyelectrolytes).
[0115] As an additional example, in some embodiments, one portion
of a medical device may be coated with a multi-layered structure,
while another portion of the medical device may not have any
coatings on it, or may be coated with just one layer.
[0116] As another example, in some embodiments, a multi-layered
structure such as multi-layered structure 26 can be formed on a
substrate, removed from the substrate, and subsequently applied
(e.g., with an adhesive) to a medical device. The substrate can be
removed by destroying it, for example, by melting, sublimation,
combustion, and/or dissolution, to free multi-layered structure 26.
For example, a removable substrate made of dental waxes (such as
those available from MDL Dental Products, Inc., Seattle, Wash.,
USA) or polyvinyl alcohol (PVOH) can be used. These materials can
melt at moderately elevated temperatures (e.g., 60.degree. C.) and
dissolve in hot water, respectively. Other methods of using a
removable substrate are described in Sukhorukov et al.,
"Comparative Analysis of Hollow and Filled Polyelectrolyte
Microcapsules Templated on Melamine Formaldehyde and Carbonate
Cores, Macromol.", Chem. Phys., 205, 2004, pp.530-535; and U.S.
patent application Ser. No. 10/849,742.
[0117] As an additional example, one or more reinforcement aids can
be provided adjacent to, and/or within, a multi-layered structure
such as multi-layered structure 26 to enhance its mechanical
properties. For example, one or more reinforcement aids can be
applied to a substrate, followed by a series of polyelectrolyte
layers. As another example, a first series of polyelectrolyte
layers can be provided, followed by the application of one or more
reinforcement aids, followed by a second series of polyelectrolyte
layers. Examples of reinforcement aids include fibrous
reinforcement members such as metal fiber meshes, metal fiber
braids, metal fiber windings, intermingled fibers (e.g., metal
fibers, carbon fibers, high density polyethylene fibers, liquid
polymer crystals) and so forth. The reinforcement aids can be
provided with a surface charge to enhance incorporation of the
reinforcement aids onto or into multi-layered structure 26. For
example, layer-by-layer techniques can be used to encapsulate the
reinforcement aids, thereby providing them with a charged outer
layer and enhancing interaction of the reinforcement aids with an
adjacent layer (e.g., a polyelectrolyte layer) of opposite charge.
The loading of the reinforcement aids can be such that they form a
conductive loop or solenoid.
[0118] As another example, in certain embodiments, a stent such as
stent 20 can also be a part of a stent-graft or a covered stent. In
other embodiments, a stent such as stent 20 can include and/or be
attached to a biocompatible, non-porous or semi-porous polymer
matrix made of polytetrafluoroethylene (PTFE), expanded PTFE,
polyethylene, urethane, or polypropylene.
[0119] As a further example, in some embodiments, a multi-layered
structure such as multi-layered structure 26 can be applied to
other types of medical devices. For example, multi-layered
structure 26 can be applied to grafts, filterwires, valves, filters
(e.g., vena cava filters), distal protection devices, guidewires,
and other implantable devices. In some embodiments, a multi-layered
structure such as multi-layered structure 26 can be applied to a
catheter (e.g., a renal or vascular catheter such as a balloon
catheter). In certain embodiments, a multi-layered structure such
as multi-layered structure 26 can be applied to a balloon. In some
embodiments, a multi-layered structure such as multi-layered
structure 26 can be applied to a coil (e.g., an aneurysm coil).
Coils are described, for example, in Twyford, Jr. et al., U.S. Pat.
No. 5,304,195.
[0120] As an additional example, in certain embodiments, a
biodisintegrable layer (e.g., a biodisintegrable
non-polyelectrolyte layer) on a medical device can be coated with
one or more other layers, such as one or more polyelectrolyte
layers and/or one or more biodisintegrable layers.
[0121] All publications, applications, references, and patents
referred to in this application are herein incorporated by
reference in their entirety.
[0122] Other embodiments are within the claims.
* * * * *