U.S. patent application number 14/791014 was filed with the patent office on 2015-10-29 for bioabsorbable stent with radiopaque layer and method of fabrication.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to David C. Gale, Yunbing Wang.
Application Number | 20150305827 14/791014 |
Document ID | / |
Family ID | 40336385 |
Filed Date | 2015-10-29 |
United States Patent
Application |
20150305827 |
Kind Code |
A1 |
Wang; Yunbing ; et
al. |
October 29, 2015 |
BIOABSORBABLE STENT WITH RADIOPAQUE LAYER AND METHOD OF
FABRICATION
Abstract
Embodiments of a stent and methods of fabricating the same with
a bioabsorbable radiopaque layer are disclosed.
Inventors: |
Wang; Yunbing; (Sunnyvale,
CA) ; Gale; David C.; (Kennesaw, GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
40336385 |
Appl. No.: |
14/791014 |
Filed: |
July 2, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11951232 |
Dec 5, 2007 |
9101698 |
|
|
14791014 |
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Current U.S.
Class: |
623/1.15 |
Current CPC
Class: |
A61B 2090/3966 20160201;
A61L 31/12 20130101; A61L 31/148 20130101; A61L 31/18 20130101;
A61B 90/39 20160201; A61F 2/915 20130101 |
International
Class: |
A61B 19/00 20060101
A61B019/00; A61F 2/915 20060101 A61F002/915 |
Claims
1. A bioabsorbable stent comprising a stent scaffolding including a
radiopaque layer and a support layer, the radiopaque layer
comprising radiopaque material mixed within a first bioabsorable
polymer, the support layer formed from a second bioabsorbable
polymer.
2. The stent of claim 1, wherein the support layer is adapted to be
primarily responsible for maintaining patency within a vascular
lumen.
3. The stent of claim 1, wherein the second bioabsorbable polymer
has a higher strength and modulus than the first bioabsorbable
polymer.
4. The stent of claim 1, wherein the radiopaque layer is a luminal
or an abluminal layer.
5. The stent of claim 1, wherein the radiopaque layer is an
abluminal layer and the support layer is a luminal layer.
6. The stent of claim 1, wherein the radiopaque layer is a luminal
layer and the support layer is an abluminal layer.
7. The stent of claim 1, further comprising a second support layer
formed from the second bioabsorbable polymer, the radiopaque layer
disposed between the first and second support layers.
8. The stent of claim 1, further comprising a second radiopaque
layer formed from the first bioabsorbable polymer, the support
layer disposed between the first and second radiopaque layers.
9. The stent of claim 1, wherein the radiopaque material comprises
particles.
10. The stent of claim 9, wherein the particles are
nanoparticles.
11. The stent of claim 1, wherein the radiopaque material comprises
a corrodible metal, a biostable metal, metallic salts, or a
combination thereof.
12. The stent of claim 1, wherein the radiopaque material is
selected from the group consisting of iodine, bromine, barium,
tungsten, bismuth, magnesium, iron, zinc, ferrous sulfate, ferrous
gluconate, ferrous carbonate, ferrous chloride, ferrous fumarate,
ferrous iodide, ferrous lactate, ferrous succinate, barium sulfate,
bismuth subcarbonate, bismuth potassium tartrate, bismuth sodium
iodide, bismuth sodium tartrate, bismuth sodium triglycollamate,
bismuth subsalicylate, zinc acetate, zinc carbonate, zinc citrate,
zinc iodate, zinc iodide, zinc lactate, zinc phosphate, zinc
salicylate, zinc stearate, zinc sulfate, and combinations
thereof.
13. The stent of claim 1, wherein the radiopaque material comprises
between 5% and 40% by volume of the radiopaque layer.
14. The stent of claim 1, wherein the support layer is 2 to 10
times thicker than the radiopaque layer.
15. The stent of claim 1, wherein the thickness of the radiopaque
layer is 5-100 .mu.m.
16. The stent of claim 1, further comprising a therapeutic layer
disposed above or below the radiopaque layer.
Description
[0001] This application is a divisional application of U.S. patent
application Ser. No. 11/951,232 filed Dec. 5, 2007, which is
incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to implantable medical devices, such
as stents. In particular, the invention relates to bioabsorbable
polymeric stents with a radiopaque layer.
[0004] 2. Description of the State of the Art
[0005] This invention relates to radially expandable
endoprostheses, which are adapted to be implanted in a bodily
lumen. An "endoprosthesis" corresponds to an artificial device that
is placed inside the body. A "lumen" refers to a cavity of a
tubular organ such as a blood vessel. A stent is an example of such
an endoprosthesis. Stents are generally cylindrically shaped
devices, which function to hold open and sometimes expand a segment
of a blood vessel or other anatomical lumen such as urinary tracts
and bile ducts. Stents are often used in the treatment of
atherosclerotic stenosis in blood vessels. "Stenosis" refers to a
narrowing or constriction of the diameter of a bodily passage or
orifice. In such treatments, stents reinforce body vessels and
prevent restenosis following angioplasty in the vascular system.
"Restenosis" refers to the reoccurrence of stenosis in a blood
vessel or heart valve after it has been treated (as by balloon
angioplasty, stenting, or valvuloplasty) with apparent success.
[0006] The structure of stents is typically composed of scaffolding
that includes a pattern or network of interconnecting structural
elements or struts. The scaffolding can be formed from wires,
tubes, or sheets of material rolled into a cylindrical shape. In
addition, a medicated stent may be fabricated by coating the
surface of either a metallic or polymeric scaffolding with a
polymeric carrier. The polymeric scaffolding may also serve as a
carrier of an active agent or drug.
[0007] The first step in treatment of a diseased site with a stent
is locating a region that may require treatment such as a suspected
lesion in a vessel, typically by obtaining an x-ray image of the
vessel. To obtain an image, a contrast agent, which contains a
radiopaque substance such as iodine is injected into a vessel.
"Radiopacity" refers to the ability of a substance to absorb
x-rays. The x-ray image depicts the lumen of the vessel from which
a physician can identify a potential treatment region. The
treatment then involves both delivery and deployment of the stent.
"Delivery" refers to introducing and transporting the stent through
a bodily lumen to a region in a vessel that requires treatment.
"Deployment" corresponds to the expanding of the stent within the
lumen at the treatment region. Delivery and deployment of a stent
are accomplished by positioning the stent about one end of a
catheter, inserting the end of the catheter through the skin into a
bodily lumen, advancing the catheter in the bodily lumen to a
desired treatment location, expanding the stent at the treatment
location, and removing the catheter from the lumen. In the case of
a balloon expandable stent, the stent is mounted about a balloon
disposed on the catheter. Mounting the stent typically involves
compressing or crimping the stent onto the balloon. The stent is
then expanded by inflating the balloon. The balloon may then be
deflated and the catheter withdrawn. In the case of a
self-expanding stent, the stent may be secured to the catheter via
a retractable sheath or a sock. When the stent is in a desired
bodily location, the sheath may be withdrawn allowing the stent to
self-expand.
[0008] The stent must be able to simultaneously satisfy a number of
mechanical requirements. A stent must be capable of maintaining a
desired degree of patency of a vessel. To accomplish this, the
stent must be capable of withstanding the structural loads, namely
radial compressive forces, imposed on the stent as it supports the
walls of a vessel lumen. In addition to having adequate radial
strength or hoop strength, the stent should be longitudinally
flexible to allow it to be maneuvered through a tortuous vascular
path and to enable it to conform to a deployment site that may not
be linear or may be subject to flexure. The material from which the
stent is constructed must allow the stent to undergo expansion,
which typically requires substantial deformation of localized
portions of the stent's structure. Once expanded, the stent must
maintain its size and shape throughout its service life despite the
various forces that may come to bear thereon, including the cyclic
loading induced by the beating heart. Finally, the stent must be
biocompatible so as not to trigger any adverse vascular
responses.
[0009] In addition to meeting the mechanical requirements described
above, it is desirable for a stent to be sufficiently radiopaque to
be fluoroscopically visible under x-rays. Accurate stent placement
is facilitated by real time visualization of the delivery of a
stent. A cardiologist or interventional radiologist can track the
delivery catheter through the patient's vasculature and precisely
place the stent at the site of a lesion. This is typically
accomplished by fluoroscopy or similar x-ray visualization
procedures. For a stent to be fluoroscopically visible it must be
more absorptive of x-rays than the surrounding tissue. Radiopaque
materials in a stent may allow for its direct visualization.
[0010] It may be desirable for a stent to be biodegradable. In many
treatment applications, the presence of a stent in a body may be
necessary for a limited period of time until its intended function
of, for example, maintaining vascular patency and/or drug delivery
is accomplished. Therefore, stents fabricated from bioerodable
materials such as biodegradable polymers can be configured to
completely erode only after the clinical need for them has
ended.
[0011] However, all commercially available bioabsorbable polymers
are radiolucent and do not possess sufficient radiographic density
to be easily imaged by fluoroscopy. Biodegradable polymers tend to
have x-ray absorption properties similar to body tissue.
SUMMARY OF THE INVENTION
[0012] Various embodiments of the present invention include a
bioabsorbable stent comprising a stent scaffolding including a
radiopaque layer and a support layer, the radiopaque layer
comprising radiopaque material mixed within a first bioabsorable
polymer, the support layer formed from a second bioabsorbable
polymer.
[0013] Further embodiments of the present invention include a
method of fabricating a stent comprising: co-extruding a tube
including a radiopaque layer and a support layer, the radiopaque
layer comprising a radiopaque material mixed within a first
bioabsorable polymer, the support layer formed from a second
bioabsorbable polymer; and cutting a stent pattern in the tube to
form a stent comprising a scaffolding, the stent scaffolding
including a support layer and a radiopaque layer, the scaffolding
support layer formed from the tube support layer and the
scaffolding radiopaque layer formed from the tube radiopaque
layer
[0014] Additional embodiments of the present invention include a
method of fabricating a stent comprising: forming a radiopaque
coating layer over at least a portion of a surface of a tube, the
radiopaque coating layer comprising a radiopaque material mixed
within a first bioabsorable polymer, the tube formed from a second
bioabsorbable polymer; and cutting a stent pattern in the coated
tube to form a stent comprising a scaffolding, the stent
scaffolding including a support layer and a radiopaque layer, the
scaffolding support layer formed from the tube formed from the
first bioabsorbable polymer and the scaffolding radiopaque layer
formed from the radiopaque coating layer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 depicts an exemplary stent.
[0016] FIG. 2A depicts a cross-section of a strut with a radiopaque
layer.
[0017] FIG. 2B depicts an axial cross section of the strut from
FIG. 2A.
[0018] FIG. 2C depicts an expanded portion of the radiopaque layer
of FIGS. 2A-B.
[0019] FIG. 3A depicts a perspective view of a tube with an inner
layer and an outer layer.
[0020] FIG. 3B depicts a radial cross-section of the tube of FIG.
3A.
[0021] FIG. 3C depicts a cross-section of the wall of a tube
parallel to the axis of the tube of FIGS. 3A-B.
[0022] FIG. 4 depicts a radial cross-section of a stent scaffolding
cut from the tube of FIGS. 3A-C.
[0023] FIG. 5 depicts an extrusion die having two circular
orifices, an outer orifice and an inner orifice.
[0024] FIGS. 6A-B depicts a structural element of a stent
scaffolding with an abluminal radiopaque layer and a luminal
radiopaque layer with a support layer disposed between the
radiopaque layers.
[0025] FIGS. 7A-B depict a structural element of a stent
scaffolding with an abluminal support layer and a luminal support
layer with a radiopaque layer disposed between the support
layers.
[0026] FIGS. 8A-B depicts the structural element of FIGS. 2A-B with
a therapeutic layer disposed over the structural element.
[0027] FIGS. 9A-B depicts a structural element with a radiopaque
layer and a support layer with a therapeutic layer disposed
therebetween.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Embodiments of the present invention may be applied to
stents and, more generally, to implantable medical devices such as,
but not limited to, self-expandable stents, balloon-expandable
stents, stent-grafts, vascular grafts, or generally, tubular
implantable medical devices.
[0029] A stent can have virtually any structural pattern that is
compatible with a bodily lumen in which it is implanted. Typically,
a stent is composed of a pattern or network of circumferential and
longitudinally extending interconnecting structural elements or
struts. In general, the struts are arranged in patterns, which are
designed to contact the lumen walls of a vessel and to maintain
vascular patency. A myriad of strut patterns are known in the art
for achieving particular design goals. A few of the more important
design characteristics of stents are radial or hoop strength,
expansion ratio or coverage area, and longitudinal flexibility. The
present invention is applicable to virtually any stent design and
is, therefore, not limited to any particular stent design or
pattern. One embodiment of a stent pattern may include cylindrical
rings composed of struts. The cylindrical rings may be connected by
linking or connecting struts.
[0030] In some embodiments, a stent of the present invention may be
formed from a tube by laser cutting the pattern of struts in the
tube. The stent may also be formed by laser cutting a polymeric
sheet, rolling the pattern into the shape of the cylindrical stent,
and providing a longitudinal weld to form the stent. Other methods
of forming stents are well known and include chemically etching a
polymeric sheet and rolling and then welding it to form the
stent.
[0031] FIG. 1 depicts an exemplary stent 100 with struts 110 that
form cylindrical rings 115 which are connected by linking struts
120. The cross-section of the struts in stent 100 is
rectangular-shaped. The cross-section of struts is not limited to
what has been illustrated, and therefore, other cross-sectional
shapes are applicable with embodiments of the present invention.
The pattern should not be limited to what has been illustrated as
other stent patterns are easily applicable with embodiments of the
present invention.
[0032] A stent can be made of a biostable polymer, bioabsorbable
polymer, or both. In general, polymers can be biostable,
bioabsorbable, biodegradable, bioerodable, dissolvable, or water
soluble. Biostable refers to polymers that are not bioabsorbable.
The terms biodegradable, bioabsorbable, and bioerodable,
biosoluble, as well as degraded, eroded, absorbed, and dissolved
refer to polymers that are capable of being completely eroded or
absorbed when exposed to bodily fluids such as blood and can be
gradually resorbed, absorbed and/or eliminated by the body.
[0033] Some bioabsorbable polymers absorb due to chemical
degradation that occurs in a polymer upon exposure to bodily fluids
as in a vascular environment. Chemical degradation refers to
degradation of a polymer due to chemical reaction of the polymer
with bodily fluids or substances within bodily fluids. The chemical
degradation can result in a decrease in molecular weight,
deterioration of mechanical properties, and decrease in mass due to
erosion. Mechanical properties may correspond to strength and
modulus of the polymer. Deterioration of the mechanical properties
of the polymer decreases the ability of a stent, for example, to
provide mechanical support in a vessel. The chemical degradation
can be the result of hydrolysis, oxidation, enzymolysis, and/or
metabolic processes. Additionally, some bioabsorbable polymers are
water soluble. A water soluble polymer corresponds to a polymer
that is capable of dissolving in water in addition to, or even in
the absence of chemical degradation of the polymer.
[0034] As indicated above, a stent made from a bioabsorbable
polymer is intended to remain in the body for a duration of time
until its intended function of, for example, maintaining vascular
patency and/or drug delivery is accomplished. After the process of
degradation, erosion, absorption, dissolution, and/or resorption
has been completed, no portion of the bioabsorbable stent, or a
bioabsorbable portion of the stent will remain. In some
embodiments, very negligible traces or residue may be left behind.
The duration can be in a range from about a month to a few years.
However, the duration is typically in a range from about one month
to twelve months, or in some embodiments, six to twelve months. It
is important for the stent to provide mechanical support to a
vessel for at least a portion of the duration. Many bioabsorbable
polymers have erosion rates that make them suitable for treatments
that require the presence of a device in a vessel for the
above-mentioned time-frames.
[0035] As indicated above, it is desirable to have the capability
of obtaining images of polymeric stents with x-ray fluoroscopy
during and after implantation. Additionally, during a treatment
period, a biodegradable stent is required to provide adequate
support or maintain patency of the lumen walls for given time
period. Specifically, the stent should maintain sufficient
mechanical properties to oppose the inward radial force imposed by
the lumen walls, including the cyclic loading induced by the
beating heart. The patency should maintain or sustain such patency
in spite of the degradation or erosion of the stent body. An
exemplary desired degree of patency may be greater than 50% of the
deployed diameter of the stent. Thus, the stent should have
sufficient strength, stiffness (modulus), and creep resistance to
keep recoil to an acceptable level during a given period.
Therefore, an erodible stent structure should have the appropriate
combination of mechanical properties and degradation or erosion
properties to allow patency during a specified treatment
period.
[0036] Various embodiments of the present invention include a
bioabsorbable stent having a radiopaque layer that includes
sufficient radiopaque material to allow visualization of the stent
with X-ray imaging for fluoroscopy. In certain embodiments, the
stent includes a stent body or scaffolding having a radiopaque
layer and a support layer. In some embodiments, the radiopaque
layer includes a radiopaque material mixed within a bioabsorable
polymer.
[0037] In certain embodiments, the primary purpose of the
radiopaque layer is to allow fluoroscopic visualization of the
stent during and after implantation. Additionally, the support
layer may be primarily or completely responsible for providing
mechanical support and maintain patency of vessel. In these
embodiments, the support layer is formed from a bioabsorbable
polymer. The polymer of the radiopaque layer can be the same or
different from the polymer of the support layer. In other
embodiments, the radiopaque layer can assist the support layer in
maintaining patency.
[0038] The radiopaque layer can degrade or absorb when it comes
into contact with bodily fluids during delivery and after
deployment of a stent at an implant site. The radiopaque layer can
be configured to be visible a sufficient amount of time for
delivery and implanting the stent.
[0039] Thus, in some embodiments, the functions of visualization
and support are partially or completely delegated to separate
layers of the stent body. Therefore, in such embodiments, the
properties of the radiopaque layer can be selected based primarily
or completely on such factors as degradation rate and degree of
radiopacity of the layer. The properties include the type of
bioabsorbable polymer, type of radiopaque material, and
concentration of radiopaque material. In particular, the
concentration of the radiopaque material in the polymer can be
selected to allow visualization of the stent with fluoroscopy.
[0040] At high enough concentration of some radiopaque materials,
the mechanical properties of the polymer may be adversely affected.
However, since the radiopaque layer is not required to provide
support, in some embodiments, the concentration of the radiopaque
material can be increased with or without regard to this function.
Additionally, the polymer of the radiopaque layer can be selected
so that the radiopaque layer erodes away during a specified time
frame.
[0041] Furthermore, since the polymers in the radiopaque and
support layers are both bioabsorbable, the stent can be designed to
be completely degradable or absorbable. In some embodiments, such a
stent can erode away substantially or completely from an implant
site. In certain embodiments, the radiopaque material can be
absorbable, erodible, or soluble. Additionally, the radiopaque
material can be biostable, but can be carried away upon erosion of
the radiopaque layer with no adverse physiological effects on a
patient. Such biostable radiopaque material that is not
bioabsorbable can be carried away by bodily fluids and eliminated
from the body.
[0042] In certain embodiments, the support layer has a higher
strength, higher modulus, higher toughness or combinations thereof
than the radiopaque layer. In such embodiments, the polymer of the
support layer can have a higher strength, modulus, toughness, or
combinations thereof than the polymer of the radiopaque layer. In
some embodiments, the support layer is formed from a polymer having
strength and stiffness sufficient to maintain patency to a desired
degree and sufficient toughness to resist failure or fracture of
the stent body during use. The bending regions of a typical stent
structure are the most susceptible to failure during use.
[0043] Alternatively, a polymer of the radiopaque layer can be
selected on the basis of degradation rate, rather than the
above-mentioned mechanical properties. In an exemplary embodiments,
the support layer or the radiopaque layer can be formed from
poly(L-lactide) (PLLA), poly(L-lactide-co-glycolide) (PLGA),
poly(DL-lactide) (PDLA), polycaprolactone (PCL), poly(trimethylene
carbonate) (PTMC), and polydioxanone (PDO). In other exemplary
embodiments, the radiopaque layer can be formed from block, random,
or alternating copolymers of two or more of the above-mentioned
polymers. Exemplary copolymers include block copolymers such as
PLLA-b-PCL, PLLA-co-PCL, PLLA-b-PTMC, and PLLA-co-PTMC. In
exemplary embodiments, the support layer is formed form PLLA or
PLGA.
[0044] Various structural embodiments of a stent body with a
radiopaque layer are contemplated and are described and illustrated
herein. In exemplary embodiments, the radiopaque layer is a luminal
or an abluminal layer. In such embodiments, the support layer can
be an abluminal layer or a luminal layer, respectively.
[0045] FIGS. 2A-C illustrate an exemplary embodiment of a strut or
structural element 150 of a stent scaffolding with a radiopaque
layer. FIG. 2A depicts a cross-section orthogonal to a longitudinal
axis 150 of structural element 150 with an abluminal surface 161, a
luminal surface 162, and sidewall surfaces 163. FIG. 2B depicts an
axial cross-section of structural element 150. Structural element
150 has a radiopaque layer 152 disposed over and in contact with a
support layer 154. As shown, radiopaque layer 152 is an abluminal
layer, however, in alternative embodiments, radiopaque layer 152
can be a luminal layer.
[0046] As discussed above, radiopaque layer 152 includes radiopaque
material mixed within a bioabsorable polymer. The radiopaque
material can be in particulate or granular form. FIG. 2C depicts an
expanded portion 156 of radiopaque layer 152. As shown by FIG. 2C,
radiopaque layer 152 includes particles 158 mixed within a polymer
160. Exemplary radiopaque materials can include, but are not
limited to, contrast agents, biostable and erodible metals,
metallic oxides, and biocompatible metallic salts. Contrast agents
that are both soluble and insoluble in bodily fluids may be
used.
[0047] The radiopaque layer can have a sufficient amount of
radiopaque material to make the stent fluoroscopically visible. The
amount of radiopaque material can be adjusted to obtain a desired
degree of radiopacity. In one embodiment, the radiopaque material
may be less than 5%, 5-10%, 10-20%, 20-30%, 30-40%, or greater than
40% by volume of the radiopaque layer.
[0048] As shown in FIGS. 2A-B, radiopaque layer 152 has a radial
thickness Tr and support layer 154 has a radial thickness (Ts). In
some embodiments, the radial thickness of the radiopaque layer can
be adjusted to provide a desired degree of fluoroscopic visibility.
Additionally, the thickness of the support layer can be adjusted so
that the stent maintains a desired degree of patency of a lumen,
such as, less than 50%, 50-60%, 60-80%, 80-95%, or greater than 95%
of the deployed diameter of the stent. In exemplary embodiments,
the thickness of a radiopaque layer can be less than 2 .mu.m, 2-5
.mu.m, 5-15 .mu.m, 15-20 .mu.m, 20-50 .mu.m, 50-80 .mu.m, 80-100
.mu.m, or greater than 100 .mu.m. Also, in exemplary embodiments,
the support layer is less than 2, 2-5, 5-10, or more than 10 times
thicker than the radiopaque layer.
[0049] As indicated above, a stent body or scaffolding can be
formed by cutting a stent pattern into a tube. In certain
embodiments, a stent of the present invention can be fabricated
from a tube having more than one layer of which at least one is a
radiopaque layer and at least one is a support layer. As described
in more detail below, such a tube can be formed by coextrusion. In
such embodiments, a stent pattern is cut into the layered tube to
form a stent scaffolding. The stent scaffolding can include a
scaffolding support layer formed from the tube support layer and a
scaffolding radiopaque layer formed from the tube radiopaque
layer.
[0050] FIG. 3A depicts a perspective view of a tube 180 with an
outer surface 186 and cylindrical axis 185. The wall of tube 180
has two concentric or substantially concentric layers, an outer
layer 182 and an inner layer 184. Outer layer 182 which has an
outer radius, Rr, is a radiopaque layer including radiopaque
material mixed within a bioabsorable polymer. Inner layer 184,
which has an outer radius Rs is formed from a bioabsorable polymer
and with a thickness suitable for a support layer of a stent
scaffolding. FIG. 3B depicts a radial cross-section of tube 180 and
FIG. 3C depicts a cross-section of the wall of tube 180 parallel to
axis 185 of tube 180.
[0051] FIG. 4 depicts a radial cross-section of a stent scaffolding
190 cut from tube 180. Stent scaffolding 190 has structural
elements 191 which have an abluminal radiopaque layer 192 and a
luminal support layer 194. Radiopaque layer 192 is formed from
outer layer 182 of tube 180 and support layer 194 is formed from
inner layer 184 of tube 180. In further embodiments, a stent
scaffolding having more than two layers can be formed from a tube
having more than two radial layers.
[0052] In certain embodiments, a tube with more than one layer with
at least one radiopaque layer can be formed by co-extrusion. In
such embodiments, a tube can be co-extruded to have a radiopaque
layer and a support layer, the radiopaque layer having a radiopaque
material mixed within a bioabsorable polymer and the support layer
formed from the same or different bioabsorbable polymer.
[0053] In general, extrusion refers to the process of conveying a
polymer melt through an extruder and forcing the polymer melt
through a die that imparts a selected shape to the polymer exiting
the extruder. In the case of tubing extrusion, the polymer melt
(extrudate) forced through the die forms a cylindrical film in the
shape of a tube. The film is cooled and drawn axially to form the
final tube product.
[0054] An extruder generally includes a barrel through which a
polymer melt is conveyed from an entrance to an exit port. The
polymer can be fed to the extruder barrel as a melt or in a solid
form below its melting temperature. The solid polymer is melted as
it is conveyed through the barrel. The polymer in the extruder
barrel is heated to temperatures above the melting temperature (Tm)
of the polymer and exposed to pressures above ambient. The polymer
within the barrel is mixed, for example, through the use of
rotating screws. Representative examples of extruders for use with
the present invention may include single screw extruders,
intermeshing co-rotating and counter-rotating twin-screw extruders
and other multiple screw masticating extruders.
[0055] In certain embodiments, the extrudate for forming a
radiopaque layer can include a polymer melt and radiopaque material
in the form of particles. In some embodiments, the
polymer/radiopaque material mixture can be formed first and then
fed to an extruder for forming the layered tubing. In other
embodiments, the polymer and radiopaque polymer can be fed
separately to the extruder and mixed or compounded within the
extruder.
[0056] The polymer melt exits the extruder to a die placed at the
end of the extruder barrel. A die generally refers to a device
having an orifice with a specific shape or design geometry that it
imparts to a polymer melt pumped from an extruder. In the case of
tubing extrusion, the die has a circular shaped orifice that
imparts a cylindrical shape to the polymer melt exiting the die.
The function of the die is to control the shape of the polymer melt
by delivering polymer melt to the orifice. The polymer melt can be
delivered at a constant rate, temperature, and pressure.
[0057] Co-extrusion refers to the process of extruding two or more
materials through a single die with two or more orifices arranged
so that the extrudates from the separate orifices merge and weld
together into a laminar structure before cooling or chilling. Each
material can be fed to the die from a separate extruder, but the
orifices may be arranged so that each extruder supplies two or more
layers of the same material. In the case of tubing co-extrusion,
the die can include concentric circular slits through which the
different materials exit to form a tube with two or more
layers.
[0058] In some embodiments of the present invention, an extrudate
including polymer and radiopaque material is formed in one extruder
and fed to a die with two or more circular orifices for formation
of the layered tube. In an exemplary embodiment, FIG. 5 depicts a
die 200 having two circular orifices, an outer orifice 202 and an
inner orifice 204. An extrudate including a polymer/radiopaque
material can exit through outer orifice 202, as shown by arrows
206, while an extrudate corresponding to a support layer can exit
through inner orifice 204, as shown by arrows 208. The extrudates
are conveyed through die 200, in the direction of an arrow 210. The
exiting extrudates merge and are welded together form a cylindrical
layered film which is cooled to form a tube.
[0059] In some embodiments, a layered tube can be radially expanded
to an expanded state prior to cutting the stent pattern. The
layered tube and also be axially deformed. The radial expansion
increases the radial strength of the tube and a stent formed
therefrom. It has also been observed that radial expansion also
enhances the fracture toughness of formed stents, in particular,
the resistance to the fracture and breaking of struts. In such
embodiments, the tube can be radially expanded by a known method
and the stent pattern can be cut into the tube in its expanded
state.
[0060] In certain embodiments, a layered polymeric tube may be
radially deformed by blow molding. A balloon blowing apparatus may
be adapted to radially deform a polymer tube. In blow molding, a
tube can be deformed radially by conveying a fluid into the tube
which increases the internal pressure in the tube. The polymer tube
may be also be deformed axially by applying a tensile force by a
tension source at one end while holding the other end stationary.
Alternatively, a tensile force may be applied at both ends of the
tube. The tube may be axially extended before, during, and/or after
radial expansion.
[0061] In some embodiments, blow molding may include first
positioning a tube in a cylindrical member or mold. The mold
controls the degree of radial deformation of the tube by limiting
the deformation of the outside diameter or surface of the tube to
the inside diameter of the mold. The inside diameter of the mold
may correspond to a diameter less than or equal to a desired
diameter of the polymer tube.
[0062] The temperature of the tube can be heated to temperatures
above the Tg of the polymer during deformation. The polymer tube
may also be heated prior to, during, and subsequent to the
deformation. In some embodiments, the tube may be heated by
translating a heating source along the cylindrical axis of the
tube. As the heat source translates and heats the tube, the radial
deformation propagates along the axis of the tube. In other
embodiments, in addition to the heat source, the tube may be heated
by the mold or the fluid conveyed into the tube to expand the
tube.
[0063] The polymer tube may be sealed or blocked at a distal end.
The fluid, (conventionally a gas such as air, nitrogen, oxygen,
argon, etc.) may then be conveyed into a proximal end of the
polymer tube to increase the pressure in the tube. The pressure of
the fluid in the tube may radially expand the tube. Cooling the
tube helps insure that the tube maintains the proper shape, size,
and length following its formation. Upon cooling, the deformed tube
retains the length and shape imposed by an inner surface of the
mold.
[0064] In other embodiments, a layered tube including a radiopaque
layer can be fabricated by forming a coating over a surface of a
tube. The coating can be formed over the inner surface, outer
surface, or both. The coating can include radiopaque material mixed
with a bioabsorbable polymer. The tube can be formed from a
bioabsorable polymer and with a thickness suitable for a support
layer of a stent scaffolding. A stent pattern can then be cut into
the coated tube to form a stent scaffolding with a radiopaque layer
and a support layer.
[0065] In such embodiments, a coating material may be applied to
the tube by methods known in the art such as by spraying or
dipping. The coating material can be a solution including a polymer
dissolved in a solvent. The solution can further include radiopaque
particles suspended or dissolved in the solvent. In some
embodiments, the polymer solution can also include a drug dispersed
in the solution to allow the radiopaque layer to serve as a
therapeutic layer. The coating material may be applied to the stent
by immersing the stent in the coating material, by spraying the
material onto the stent, drop coating, or by other methods known in
the art. The solvent in the solution is then removed, for example,
by evaporation, leaving on the stent surfaces a polymer coating
with radiopaque material and in some embodiments, a drug.
[0066] Further embodiments of the stent of the present invention
can include two or more radiopaque layers. Additional embodiments
of the stent can also include two or more support layers.
Embodiments of such stents can be fabricated in by methods
described above. In particular, a tube having the selected number
of layers can be formed through co-extrusion and a stent fabricated
therefrom.
[0067] In an exemplary embodiment, the stent body includes two
radiopaque layers with the support layer disposed between the two
radiopaque layers. FIGS. 6A-B illustrate such an exemplary
embodiment depicting a structural element 220 of a stent
scaffolding with an abluminal radiopaque layer 222 and a luminal
radiopaque layer 225. A support layer 226 is disposed between the
radiopaque layers.
[0068] In another exemplary embodiment, the stent body includes two
support layers with a radiopaque layer disposed between the two
support layers. FIGS. 7A-B illustrate such an exemplary embodiment
depicting a structural element 240 of a stent scaffolding with an
abluminal support layer 242 and a luminal support layer 244. A
radiopaque layer 246 is disposed between the support layers.
[0069] As discussed above, a medicated stent may be fabricated by
coating the surface of either a metallic or polymeric scaffolding
with a polymeric carrier. In further embodiments, a therapeutic
agent can be incorporated within the radiopaque layer, as described
above. In additional embodiments, a therapeutic layer including a
drug can be formed over a stent scaffolding having a radiopaque
layer. In some embodiments, the therapeutic layer can be formed
above the radiopaque layer and the support layer, including the
sidewalls of the stent scaffolding. FIGS. 8A-B depict the
structural element of FIGS. 2A-B with a therapeutic layer 250
disposed over radiopaque layer 152 and support layer 154, including
sidewalls 163. Therapeutic layer 250 is disposed over abluminal
surface 161, luminal surface 162, and sidewalls 163.
[0070] In another embodiment, a therapeutic layer can be formed
between the support layer and the radiopaque layer. FIGS. 9A-B
depict a structural element 260 with a radiopaque layer 262 and a
support layer 264 with a therapeutic layer 266 disposed
therebetween. Such a stent scaffolding can be formed by first
forming a therapeutic layer over a polymer tube and then a
radiopaque layer over the therapeutic layer. Then, a stent pattern
in formed in the tube to form the stent scaffolding.
[0071] Representative iodinated contrast agents may include, but
are not limited to, acetriozate, diatriozate, iodimide, ioglicate,
iothalamate, ioxithalamate, selectan, uroselectan, diodone,
metrizoate, metrizamide, iohexol, ioxaglate, iodixanol, lipidial,
ethiodol, and combinations thereof. Contrast agents also include
biocompatible metallic salts such as barium sulfate.
[0072] As the stent is delivered and implanted, the radiopaque
layer degrades and erodes. The radiopaque layer can erode away in
less than 10 minutes, 10-60 minutes, 1-2 hours, 2-10 hours, 10-24
hours, 1-7 days, 1-2 weeks, 2 weeks to a month, 1-2 months, or
greater than 2 months. As the radiopaque layer erodes, radiopaque
material is lost from the layer, decreasing the radiopacity and
fluoroscopic visibility of the stent. The radiopaque layer can be
fluoroscopically visible for less than 10 minutes, 10-60 minutes,
1-2 hours, 2-10 hours, 10-24 hours, 1-7 days, 1-2 weeks, 2 weeks to
a month, 1-3 months, 3-6 months, 6-12 months, or greater than 12
months. In some embodiments, the radiopaque layer includes a
sufficient amount of radiopaque material to allow the stent to be
visible for a selected period of time after implantation. Although
the implantation procedure may take only a few minutes, it can be
advantageous to have the ability to locate the stent for a longer
period of time after implantation. For example, problems may arise
that may require the need to reintervene.
[0073] The bioabsorbable polymer of the radiopaque layer can be the
same or different from the bioabsorbable polymer of the support
layer. The required degradation time of a stent body and the time
for visualization of a stent are generally different, with the
former typically being longer than the latter. Thus, in some
embodiments, the bioabsorbable polymer in the radiopaque layer can
have a faster absorption rate than the bioabsorbable polymer
body.
[0074] Generally, the life-time of the radiopaque layer can be
controlled through selection of the bioabsorbable polymer in the
radiopaque layer. In particular, the rate at which a layer absorbs
can be tuned based on the selected time period, such as a time
necessary to deliver a stent to an implant site or a longer period,
such as the time needed for reintervention. The content of faster
eroding polymer in the copolymer can be modified to obtain a
desired absorption rate. In exemplary embodiment, the support layer
can be PLLA (degradation time between 2-3 years) and the radiopaque
layer can be formed from PDLA (degradation time 12-18 months), PGA
(degradation time 6-12 months), or PDO (degradation time of 6-12
months). Degradation time is the time for complete absorption or
erosion of a polymer construct.
[0075] In additional embodiments, the bioabsorbable polymer of the
radiopaque layer can be a water soluble polymer. Exemplary water
soluble polymers include poly(vinyl alcohol) (PVA) and
poly(ethylene glycol) (PEG). Water soluble polymers tend to absorb
faster than a non-water soluble hydrolytically degradable polymer.
Thus, for a radiopaque layer of similar thickness, the radiopaque
layer with a water soluble polymer can have a shorter life-time
than a radiopaque layer with a non-water soluble hydrolytically
degradable polymer.
[0076] Representative examples of metals that may be used as
radiopaque agents include, but are not limited to, iron, magnesium,
zinc, platinum, gold, and tungsten. Additionally, oxides of such
metals and other metals may be used as radiopaque agents. In one
embodiment, the metal can be erodible or corrodible. An erodible or
corrodible metal is one that has the propensity for
self-dissolution in an in vivo environment. A metal that undergoes
self-dissolution in an in vivo environment corrodes when subjected
to bodily fluids and breaks down. A self-dissolving metal can be
selected that has little or no ill effect to a patient.
Representative examples of erodible metals include, but are not
limited to, magnesium, zinc, tungsten, and iron.
[0077] A biocompatible metallic salt refers to a salt that may be
safely absorbed by a body. Representative biocompatible metallic
salts that may used in a radiopaque layer include, but are not
limited to, ferrous sulfate, ferrous gluconate, ferrous carbonate,
ferrous chloride, ferrous fumarate, ferrous iodide, ferrous
lactate, ferrous succinate, barium sulfate, bismuth subcarbonate,
bismuth potassium tartrate, bismuth sodium iodide, bismuth sodium
tartrate, bismuth sodium triglycollamate, bismuth subsalicylate,
zinc acetate, zinc carbonate, zinc citrate, zinc iodate, zinc
iodide, zinc lactate, zinc phosphate, zinc salicylate, zinc
stearate, zinc sulfate, and combinations thereof.
[0078] In some embodiments, the size the particles of radiopaque
agent in a radiopaque layer can be small enough to reduce or
eliminate the risk of thrombosis due to release of such particles
from the coating. Reducing the size of bioabsorbable particles
decreases their absorption time. In one embodiment, a dimension of
the particles can be 10-100 .mu.m, 100-200 .mu.m, or greater than
200 .mu.m.
[0079] In certain embodiments, the radiopaque particles can be less
than 10 .mu.m. In particular, the particles can be nanoparticles. A
"nanoparticle" refers to a particle with a dimension in the range
of about 1 nm to about 100 nm. Another significant advantage of
smaller particles such as nanoparticles over larger particles is
that nanoparticles may disperse more uniformly in a polymeric
matrix, which results in more uniform radiopacity.
[0080] Representative examples of polymers that may be used to
fabricate embodiments of layers of stents and coatings on stents of
the present invention include, but are not limited to,
poly(N-acetylglucosamine) (Chitin), Chitosan,
poly(3-hydroxyvalerate), poly(lactide-co-glycolide),
poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyorthoester,
polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic
acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),
poly(L-lactide-co-D,L-lactide), poly(caprolactone),
poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone),
poly(glycolide-co-caprolactone), poly(trimethylene carbonate),
polyester amide, poly(glycolic acid-co-trimethylene carbonate),
co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes,
biomolecules (such as fibrin, fibrinogen, cellulose, starch,
collagen, and hyaluronic acid), polyurethanes, silicones,
polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin
copolymers, acrylic polymers and copolymers, vinyl halide polymers
and copolymers (such as polyvinyl chloride), polyvinyl ethers (such
as polyvinyl methyl ether), polyvinylidene halides (such as
polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones,
polyvinyl aromatics (such as polystyrene), polyvinyl esters (such
as polyvinyl acetate), acrylonitrile-styrene copolymers, ABS
resins, polyamides (such as Nylon 66 and polycaprolactam),
polycarbonates, polyoxymethylenes, polyimides, polyethers,
polyurethanes, rayon, rayon-triacetate, cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers, and
carboxymethyl cellulose. Additional representative examples of
polymers that may be especially well suited for use in fabricating
embodiments of implantable medical devices disclosed herein include
ethylene vinyl alcohol copolymer (commonly known by the generic
name EVOH or by the trade name EVAL), poly(butyl methacrylate),
poly(vinylidene fluoride-co-hexafluoropropene) (e.g., SOLEF 21508,
available from Solvay Solexis PVDF, Thorofare, N.J.),
polyvinylidene fluoride (otherwise known as KYNAR, available from
ATOFINA Chemicals, Philadelphia, Pa.), ethylene-vinyl acetate
copolymers, poly(vinyl acetate), styrene-isobutylene-styrene
triblock copolymers, and polyethylene glycol.
[0081] Active agents or drugs can include anti-inflammatories,
antiproliferatives, and other bioactive agents. An
antiproliferative agent can be a natural proteineous agent such as
a cytotoxin or a synthetic molecule. Exemplary active agents can
include rapamycin, everolimus, structural derivatives and
functional analogues of rapamycin, structural derivatives and
functional analogues of everolimus. An anti-inflammatory drug can
be a steroidal anti-inflammatory agent, a nonsteroidal
anti-inflammatory agent, or a combination thereof.
[0082] The examples set forth below are for illustrative purposes
only and are in no way meant to limit the invention. The following
examples are given to aid in understanding the invention, but it is
to be understood that the invention is not limited to the
particular materials or procedures of examples.
EXAMPLES
Example 1
[0083] 1. A blend of PLLA-co-PCL (90% PLLA and 10% PCL) and
tungsten nanoparticles (polymer/particle--20:1 by volume or 1:1 by
weight) is prepared using a compounder at 200.degree. C.
[0084] 2. A bi-layer tube is formed by the co-extrusion of PLLA as
an inner layer and the PLLA-co-PCL/tungsten nanoparticles as the
radiopaque outer layer. The thickness of the PLLA outer layer and
the radiopaque layer is set to 0.05 inch and 0.02 inch,
respectively. The inside diameter (ID) of the extruded tubing is
set to about 0.021 inch and the outside diameter (OD) is about
0.091 inch.
[0085] 3. The bi-layer tube is radially expanded. A stent pattern
is cut into the expanded tubing. The total thickness of the stent
struts is about 0.008 inch.
Example 2
[0086] 1. A blend of PLLA and barium sulfate (100:30 by weight) is
prepared using a compounder at 200.degree. C.
[0087] 2. A bi-layer tube is formed by the co-extrusion of PLLA as
an inner layer and the PLLA/barium sulfate as the radiopaque outer
layer. The thickness of the PLLA outer layer and the radiopaque
layer is set to 0.05 inch and 0.02 inch, respectively. The inside
diameter (ID) of the extruded tubing is set to about 0.021 inch and
the outside diameter (OD) is about 0.091 inch.
[0088] 3. The bi-layer tube is radially expanded. A stent pattern
is cut into the expanded tubing. The total thickness of the stent
struts is about 0.008 inch.
Example 3
[0089] 1. A blend of PLGA and barium sulfate (100:30 by weight) is
prepared using a compounder at 200.degree. C.
[0090] 2. A bi-layer tube is formed by the co-extrusion of PLGA as
an inner layer and the PLGA/barium sulfate as the radiopaque outer
layer. The thickness of the PLGA outer layer and the radiopaque
layer is set to 0.05 inch and 0.02 inch, respectively. The inside
diameter (ID) of the extruded tubing is set to about 0.021 inch and
the outside diameter (OD) is about 0.091 inch.
[0091] 3. The bi-layer tube is radially expanded. A stent pattern
is cut into the expanded tubing. The total thickness of the stent
struts is about 0.008 inch.
[0092] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *