# Patent

## Title
Bioerodible endoprosthesis

## Abstract

An endoprosthesis can include a body including an underlying portion and a surface portion overlying the underlying portion. The underlying portion can include a bioerodible metal in the form of a matrix and corrosion enhancing deposits within the matrix. The surface portion including the bioerodible metal of the matrix. The surface portion having a first erosion rate when exposed to a physiological environment and the underlying portion having a second erosion rate when exposed to a physiological environment that is greater than the first erosion rate.

## Background
TECHNICAL FIELD
This invention relates to bioerodible endoprostheses, and more particularly to bioerodible stents.
BACKGROUND
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, covered stents, stent-grafts, and vascular closure pins.
Endoprostheses 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.
The expansion mechanism can 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 The balloon can then be deflated, and the catheter withdrawn.
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.
The endoprosthesis can carry a drug, such as an antiproliferative, to reduce the likelihood of restenosis, i.e., reclosure of the vessel due to immune reactions by the body at the treatment site.
SUMMARY
An endoprosthesis is described that includes a body including an underlying portion and a surface portion overlying the underlying portion. The underlying portion including a bioerodible metal in the form of a matrix and corrosion enhancing deposits within the matrix. The surface portion including the bioerodible metal of the matrix. The surface portion having a first erosion rate when exposed to a physiological environment and the underlying portion having a second erosion rate when exposed to a physiological environment that is greater than the first erosion rate.
The corrosion enhancing deposits can include nano-bubbles of noble gases (e.g., helium, argon, neon, kripton or a combination thereof). The nano-bubbles can have an average diameter of between 1 nm and 600 nm. The corrosion enhancing deposits, in some embodiments, can include silver, manganese, or a combination thereof. In other embodiments, the corrosion enhancing deposits can include the same elements as the bioerodible metal and increase the corrosion rate by increasing the surface tension. In some embodiments, the corrosion enhancing deposits can be more or less noble then the bioerodible metal and form a galvanic couple with the bioerodible metal when the corrosion enhancing deposits are exposed to a physiological environment. In some embodiments, the corrosion enhancing deposits are more noble and act as an anode to accelerate the corrosion rate of the bioerodible metal. In other embodiments, the corrosion enhancing deposits are less noble and erode faster than the bioerodible metal and leave an increased surface area of the matrix material which accelerates the corrosion rate of the bioerodible metal once the corrosion enhancing deposits erode away.
The surface portion can be substantially free of the corrosion enhancing deposits. The surface portion can have a thickness of between 0.2 micrometers and 3 micrometers. In some embodiments, the surface portion can be composed essentially of the bioerodible metal. The surface portion can have a substantially smooth upper surface. The term “substantially smooth” as used herein requires an Ra of 0.5 μm or less.
The bioerodible metal can include iron or an alloy thereof. In other embodiments, the bioerodible metal can include magnesium, zinc, tungsten, and alloys thereof.
The endoprosthesis can be a stent. In other embodiments, the endoprosthesis can be a vascular closure pin.
In another aspect, method of producing an endoprosthesis is described. The method includes implanting ions into a body including a bioerodible metal to create an underlying portion including corrosion enhancing deposits within a matrix of the bioerodible metal and a surface portion overlying the underlying portion comprising the bioerodible metal. The underlying portion has a greater erosion rate when exposed to physiological environment than the surface portion of the bioerodible metal body.
The implanted ions can be noble ions that create the corrosion enhancing deposits of nano-bubbles of noble gases in the matrix of the bioerodible metal and/or ions that react with the bioerodible metal to produce the corrosion enhancing deposits. In some embodiments, the ions are implanted using IBAD or PIII ion implanting processes. In some embodiments, the ions can be implanted at a dose of less than 1×1016 ions/cm2. The ions can be implanted using a minimum energy of at least 10 keV (e.g., within the range of 10 keV and 100 keV). In some embodiments, the temperature range during the ion implanting process is between 100 C. and 500 C. In some embodiments, the temperature is 0.2 times the melting temperature of the bioerodible metal (e.g., between 100 C. and 150 C. for most magnesium based bioerodible alloys and between 200 C. and 350 C. for most iron based bioerodible alloys).
The surface portion can be substantially free of the corrosion enhancing deposits. In some embodiments, the endoprosthesis can include additional surface layers deposited on the surface portion after the implantation of the corrosion enhancing deposits.
The bioerodible metal body can be a stent or a stent precursor. In other embodiments, the bioerodible metal body can be a vascular closure pin or vascular closure pin precursor.
The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims.



DESCRIPTION OF DRAWINGS
FIG. 1 is a perspective view of an example of an expanded stent.
FIGS. 2A-2C depict cross sections of a stent strut having an implanted subcutaneous layer of ions according to different embodiments.
FIG. 3 depicts a stent strut erosion profile.
FIG. 4 illustrates exemplary environments for implanting ions into a stent.



Like reference symbols in the various drawings indicate like elements.
DETAILED DESCRIPTION
Referring to FIG. 1, a stent 20 can have the form of a tubular member defined by a plurality of struts. The struts can include a plurality of bands 22 and a plurality of connectors 24 that extend between and connect adjacent bands. During use, bands 22 can be expanded from an initial, small diameter to a larger diameter to contact the stent 20 against a wall of a vessel, thereby maintaining the patency of the vessel. Connectors 24 can provide stent 20 with flexibility and conformability that allow the stent to adapt to the contours of the vessel.
The stent includes a bioerodible metal. Examples of bioerodible metals include iron, magnesium, tungsten, zinc, and alloys thereof. For example, the bioerodible metal can be a bioerodible iron alloy that includes up to twenty percent manganese, up to 10 percent silver, and up to five percent carbon. The bioerodible metal can also be a bioerodible magnesium alloy that includes up to nine percent aluminum, up to five percent rare earth metals, up to five percent zirconium, up to five percent lithium, up to five percent manganese, up to ten percent silver, up to five percent chromium, up to five percent silicon, up to five percent tin, up to six percent yttrium, and up to ten percent zinc. Suitable magnesium bioerodible alloys include ZK31, which includes three percent zinc and one percent zirconium, ZK61, which includes six percent zinc and one percent zirconium, AZ31, which includes three percent aluminum and one percent zinc, AZ91, which includes nine percent aluminum and one percent zinc, WE43, which includes four percent yttrium and three percent rare earth metals, and WE54, which includes five percent yttrium and four percent rare earth metals. A stent including a bioerodible metal can reopen and/or reinforce a body passageway, yet breakdown overtime so that the stent is no longer present in the body passageway after a healing process is complete. Different bioerodible metals and stent strut structures can have different erosion rates when exposed to a physiological environment. Accordingly, the stent can be designed based on the erosion characteristics of the stent struts to maintain the desired structural properties for a desired period of time.
As shown in FIGS. 2A-2C, a stent strut (e.g., a band 22 and/or a connector 24) includes a surface portion 32 and an underlying portion 34. In some embodiments, as shown in FIG. 2A, the underlying portion 34 can be along the perimeter of the stent strut. In other embodiments, as shown in FIGS. 2B and 2C, the underlying portion 34 can be along select sides of the stent strut, e.g., along the inner diameter and/or outer diameter of the stent. In some embodiments, as shown in FIG. 2C, the stent strut can have an underlying portion 34 along the outer diameter of the stent strut and an additional coating 38 along the inner diameter.
The surface portion 32 overlies the underlying portion 34. The surface portion 32 includes a bioerodible metal and the underlying portion 34 includes corrosion enhancing deposits 28 within a matrix of the bioerodible metal. Upon implantation within a physiological environment, the surface portion 32 erodes at a first rate. Once the surface portion has eroded to expose to the underlying portion to the physiological environment, the underlying portion 34 erodes at a second rate that is faster than the first rate. An example of such an erosion profile is depicted in FIG. 3. As shown, the thickness of the strut decreases over time. During an initial erosion period 42, the surface portion 32 erodes at the first rate. During this initial erosion period 42, the bioerodible stent provides a mechanical support function. Once the surface portion 32 has eroded away to expose the underlying portion 34 to the physiological environment, an accelerated erosion period 44 can be due to the presence of the corrosion enhancing deposits 28 within a matrix of the bioerodible metal. By having a stent with a first erosion rate that is slower than a second erosion rate, the stent strut can be designed to have smaller initial dimensions than a stent having a constant erosion rate because the first erosion rate preserves the structural properties of the stent during an initial healing process during the initial erosion period 42. The accelerated erosion period 44 then reduces the amount of time that a weakened stent strut remains present within a body passageway.
The surface portion 32 can have a thickness of between 0.1 micrometers and 3 micrometers. The surface portion 32 can include a substantially smooth upper surface. The term “substantially smooth” as used herein requires an Ra of 0.5 μm or less. The surface portion 32 can include the same bioerodible metal included in the underlying portion. The surface portion 32 can be essentially free of any corrosion enhancing deposit 28. In some embodiments, the surface portion 32 can be essentially free of other constituents other than the bioerodible metal. In some embodiments, stent 20 can include additional surface layers which can be deposited after the deposition of the corrosion enhancing deposits. For example, the additional surface layers can be formed by the deposition of the bioerodible metal on the surface portion 32 by vapor deposition or pulsed laser deposition techniques. These additional surface layers can have a thickness of 10 micrometers or greater.
The underlying portion 34 includes the corrosion enhancing deposits 28. In some embodiments, the underlying portion can have a thickness of at least 1 micrometer. In some embodiments, the thickness can be between 2 micrometers and 3 micrometers. The corrosion enhancing deposits 28 can be positioned within the underlying portion by implanting ions using energies that implant the ions within the underlying portion while leaving the surface portion substantially free of the corrosion enhancing deposits 28. The energy level of the ions at the time of implantation determines the depth of implantation. For example, the corrosion enhancing deposits 28 can be produced by implanting ions with a minimum energy of 10 keV. In some embodiments, the ions can be implanted within an energy range of between 10 keV and 100 keV. The thicknesses of the surface portion 32 and the underlying portion 34 can be determined by the energy range used to implant the ions. The thickness and depth of the underlying portion are also partially determined by the diffusion of embedded ions within the bioerodible metal. The embedded ions can create a pressure gradient normal to the surface which can force the ions further into the stent strut. This pressure gradient can force ions further into the bioerodible material. The implanting of ions to form the corrosion enhancing deposits can increase the erosion rate of the underlying portion 34 by creating high stress areas and/or compression regions surrounding each corrosion enhancing deposit 28. In some embodiments, the ions can be implanted using Ion Beam Assisted Deposition (“IBAD”) or Plasma Immersion Ion Implantation (“PIII”). In some embodiments, the temperature range during the ion implanting process is between 100 C. and 500 C. In some embodiments, the temperature is about 0.2 times the melting temperature of the bioerodible metal (e.g., between 100 C. and 150 C. for most magnesium based bioerodible alloys and between 200 C. and 350 C. for most iron based bioerodible alloys).
FIG. 4 illustrates an exemplary environment for performing PIII. In order to perform PIII, a precursor of stent 20 is inserted into a chamber 50. The precursor of stent 20 includes a bioerodible metal (e.g., commercially pure iron). Chamber 50 is a vacuum chamber created by a vacuum 54 containing a plasma 56. Plasma 56 contains ions to be implanted into stent 20 to form the corrosion enhancing deposits 28. The precursor of stent 20 is pulsed repeatedly with negative voltages from pulser 58. As a result of the pulses of negative voltages, electrons are repelled away from stent 20 and positive ions 60 are attracted to the negatively charged stent 20. As a result, positive ions will strike all the surfaces of stent 20 and be embedded in and/or deposited onto stent 20.
The corrosion enhancing deposits 28 can include nano-bubbles of noble gases. Nano-bubbles of noble gases can increase the erosion rate of the bioerodible metal by increasing the surface area of the bioerodible metal. Nano-bubbles of noble gases can be formed in the matrix of the bioerodible metal by implanting noble ions. For example, the corrosion enhancing deposits 28 can include nano-bubbles of helium, argon, neon, and/or kripton gas. The nano-bubbles can have an average diameter of between 1 nm and 600 nm. When implanting noble ions to produce nano-bubbles of noble gases within the underlying portion 34, the dose can be controlled to prevent the migration of the nano-bubbles to the surface portion 32. In some embodiments, the dose of noble ions is maintained at less than 1×1016 ions/cm2.
The corrosion enhancing deposits 28 can include solid materials which accelerate the erosion process. For example, ions can be implanted that react with or alloy with the bioerodible metal to form corrosion enhancing deposits 28. For example, the corrosion enhancing deposits can include silver, copper, and/or manganese. In other embodiments, the corrosion enhancing deposits can include the same elements as the bioerodible metal and increase the corrosion rate by increasing the surface tension. In some embodiments, the resulting corrosion enhancing deposits 28 can increase the erosion rate of the underlying portion 34 by separating from the remaining matrix once exposed to the physiological environment. In some embodiments, the corrosion enhancing deposits can be more or less noble then the bioerodible metal and form a galvanic couple with the bioerodible metal when the corrosion enhancing deposits are exposed to a physiological environment. In some embodiments, the corrosion enhancing deposits are more noble and act as an anode to accelerate the corrosion rate of the bioerodible metal. In other embodiments, the corrosion enhancing deposits are less noble and erode faster than the bioerodible metal and leave an increased surface area of the matrix material which accelerates the corrosion rate of the bioerodible metal once the corrosion enhancing deposits erode away. For example, silver and copper would form a galvanic couple that would accelerate the corrosion of iron.
The corrosion enhancing deposits 28, in some embodiments, may not penetrate into a central portion 36 of the stent strut. As shown in FIG. 3, once the underlying portion containing the corrosion enhancing deposits 28 has eroded, the remainder of the stent strut can continue to erode during a bulk erosion period 46. The erosion rate during the bulk erosion period 46 can be slower than the erosion during the accelerated erosion period 44, but faster than the initial erosion period 42, due to an increase in the surface area of the stent strut due to variations in the erosion of the stent.
Stent 20 can be of any desired shape and size (e.g., superficial femoral artery stents, coronary stents, aortic stents, peripheral vascular stents, gastrointestinal stents, urology stents, and neurology stents). Depending on the application, the stent can have a diameter of between, for example, 1 mm to 46 mm. In certain embodiments, a coronary stent can have an expanded diameter of from 2 mm to 6 mm. In some embodiments, a peripheral stent can have an expanded diameter of from 5 mm to 24 mm. In certain embodiments, a gastrointestinal and/or urology stent can have an expanded diameter of from 6 mm to about 30 mm. In some embodiments, a neurology stent can have an expanded diameter of from about 1 mm to about 12 mm. An Abdominal Aortic Aneurysm (AAA) stent and a Thoracic Aortic Aneurysm (TAA) stent can have a diameter from about 20 mm to about 46 mm.
Stent 20 can include one or more struts including the surface portion 32 and the underlying portion 34. In some embodiments, the stent is entirely bioerodible. In other embodiments, the stent can include both bioerodible and non-bioerodible portions. In some embodiments, the stent 20 can include selective treatment of various bands 22 and/or connectors 24 to create a stent that erodes at a faster rate in predetermined areas and in a predetermined pattern to control the overall erosion process of the stent. For example, a preferential erosion of connectors 24 can relieve strain in the bands 22. The preferential erosion areas can be produced either by having different regions with different amounts and/or types of corrosion enhancing deposits 28, by having different regions having different surface portion thicknesses, and/or by having some portions that lack the corrosion enhancing deposits 28.
The stent 20 can, in some embodiments, be adapted to release one or more therapeutic agents. The term “therapeutic agent” includes one or more “therapeutic agents” or “drugs.” The terms “therapeutic agents” and “drugs” are used interchangeably and include pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), viruses (such as adenovirus, adeno-associated virus, retrovirus, lentivirus and a-virus), polymers, antibiotics, hyaluronic acid, gene therapies, proteins, cells, stem cells and the like, or combinations thereof, with or without targeting sequences. The delivery mediated is formulated as needed to maintain cell function and viability. A common example of a therapeutic agent includes Paclitaxel.
The stent 20 can, in some embodiments, also include one or more coatings overlying the surface portion 32. In some embodiments, a surface coating can further delay the erosion of the surface portion 32. In some embodiments, a coating can be a drug-eluting coating that includes a therapeutic agent.
Stent 20 can be used, e.g., delivered and expanded, using a catheter delivery system. Catheter systems are described in, for example, Wang U.S. Pat. No. 5,195,969, Hamlin U.S. Pat. No. 5,270,086, and Raeder-Devens, U.S. Pat. No. 6,726,712. Stents and stent delivery are also exemplified by the Sentinol® system, available from Boston Scientific Scimed, Maple Grove, Minn.
In some embodiments, stents can also be a part of a covered stent or a stent-graft. In other embodiments, a stent 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.
In some embodiments, stents can be formed by fabricating a wire having a surface portion overlying an underlying portion, the underlying portion including the corrosion enhancing deposits, and knitting and/or weaving the wire into a tubular member.
All publications, references, applications, and patents referred to herein are incorporated by reference in their entirety.
Other embodiments are within the claims.

## Claims

1. An endoprosthesis comprising a tubular member defined by a plurality of struts, at least one strut of the tubular member having a central longitudinal axis and including:
(a) a central portion of the at least one strut that extends along the central longitudinal axis, the central portion lacking corrosion enhancing deposits;
(b) an underlying portion comprising a first bioerodible metal including a matrix and corrosion enhancing deposits within the matrix, the underlying portion extending radially outward from the central portion relative to the central longitudinal axis; the underlying portion having a thickness of at least 1 micrometer;
(c) a surface portion having a thickness of between 0.1 micrometers and 3micrometers overlying and extending radially outward from the underlying portion relative to the central longitudinal axis, the surface portion comprising a second bioerodible metal having the composition of the matrix and being substantially free of corrosion enhancing deposits;
the surface portion having a first erosion rate and the underlying portion having a second erosion rate that is greater than the first erosion rate when the surface portion and the underlying portion are exposed to physiological environments.

2. The endoprosthesis of claim 1, wherein the corrosion enhancing deposits of the underlying portion comprise nano-bubbles of noble gases.

3. The endoprosthesis of claim 2, wherein the nano-bubbles comprise helium, argon, neon, krypton, or a combination thereof.

4. The endoprosthesis of claim 2, wherein the nano-bubbles have an average diameter of between 1 nm and 600 nm.

5. The endoprosthesis of claim 1, wherein the corrosion enhancing deposits of the underlying portion comprise silver.

6. The endoprosthesis of claim 1, wherein the corrosion enhancing deposits of the underlying portion comprise manganese.

7. The endoprosthesis of claim 1, wherein the corrosion enhancing deposits in the underlying portion are more noble than the first bioerodible metal and form a galvanic couple with the first bioerodible metal when the corrosion enhancing deposits in the underlying portion are exposed to physiological environments and the corrosion enhancing deposits in the underlying portion act as an anode.

8. The endoprosthesis of claim 1, wherein the corrosion enhancing deposits in the underlying portion are less noble than the first bioerodible metal and form a galvanic couple with the first bioerodible metal when the corrosion enhancing deposits in the underlying portion are exposed to physiological environments and the corrosion enhancing deposits in the underlying portion act as an cathode.

9. The endoprosthesis of claim 1, wherein the surface portion consists essentially of the second bioerodible metal.

10. The endoprosthesis of claim 1, wherein the surface portion has a substantially smooth upper surface.

11. The endoprosthesis of claim 1, wherein the first and second bioerodible metals comprises iron or an alloy thereof.

12. The endoprosthesis of claim 1, wherein the endoprosthesis is a stent.

13. The endoprosthesis of claim 1, wherein the underlying portion has a thickness of between 2 and 3 micrometers.